[Senate Hearing 109-292]
[From the U.S. Government Publishing Office]



                                                        S. Hrg. 109-292
 
                    HOPE FOR THE FUTURE: DEVELOPING
                          AN HIV/AIDS VACCINE

=======================================================================

                                HEARING



                               BEFORE THE



                     COMMITTEE ON FOREIGN RELATIONS
                          UNITED STATES SENATE



                       ONE HUNDRED NINTH CONGRESS



                             FIRST SESSION



                               __________

                             JUNE 23, 2005

                               __________



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                     COMMITTEE ON FOREIGN RELATIONS

                  RICHARD G. LUGAR, Indiana, Chairman

CHUCK HAGEL, Nebraska                JOSEPH R. BIDEN, Jr., Delaware
LINCOLN CHAFEE, Rhode Island         PAUL S. SARBANES, Maryland
GEORGE ALLEN, Virginia               CHRISTOPHER J. DODD, Connecticut
NORM COLEMAN, Minnesota              JOHN F. KERRY, Massachusetts
GEORGE V. VOINOVICH, Ohio            RUSSELL D. FEINGOLD, Wisconsin
LAMAR ALEXANDER, Tennessee           BARBARA BOXER, California
JOHN E. SUNUNU, New Hampshire        BILL NELSON, Florida
LISA MURKOWSKI, Alaska               BARACK OBAMA, Illinois
MEL MARTINEZ, Florida
                 Kenneth A. Myers, Jr., Staff Director
              Antony J. Blinken, Democratic Staff Director

                                  (ii)




                            C O N T E N T S

                              ----------                              
                                                                   Page

Berkley, Dr. Seth, President and Chief Executive Officer, 
  International AIDS Vaccine Initiative, New York, New York......    39

    Prepared statement...........................................    43

Fauci, Dr. Anthony S., Director, National Institute of Allergy 
  and Infectious Diseases, National Institute of Health, 
  Bethesda, Maryland.............................................    18

    Prepared statement...........................................    20

Gayle, Dr. Helene, Director, HIV/AIDS, Tuberculosis and 
  Reproductive Health, Bill and Melinda Gates Foundation, 
  Seattle, Washington............................................    30

    Prepared statement...........................................    33

Judd, Ms. Ashley, Global Ambassador, YOUTHAIDS, Washington, D.C..     7

    Prepared statement...........................................    12

Lugar, Hon. Richard G., U.S. Senator from Indiana................     1

Visclosky, Hon. Pete, United States House of Representatives, 
  Washington, D.C................................................     4

                                Appendix

Responses to Additional Questions Submitted for the Record by 
  Members of the Committee

    Responses to Additional Questions Submitted for the Record to 
      Dr. Seth Berkley by Senator Dodd...........................    53

Additional Material Submitted for the Record by Dr. Helene Gayle

    Speeding an AIDS Vaccine, by Richard G. Lugar and Patty 
      Stonesifer, Washington Post, ..............................    56

    G-8 Action To Endorse and Establish a Global HIV Vaccine 
      Enterprise.................................................    57

    The Need for a Global HIV Vaccine Enterprise.................    58

    The Global HIV/AIDS Vaccine Enterprise: Scientific Strategic 
      Plan.......................................................    64

                                 (iii)

  


                    HOPE FOR THE FUTURE: DEVELOPING
                          AN HIV/AIDS VACCINE

                              ----------                              


                        Thursday, June 23, 2005

                                       U.S. Senate,
                            Committee on Foreign Relations,
                                                    Washington, DC.

    The committee met, pursuant to notice, at 10:00 a.m. in 
Room SD-419, Dirksen Senate Office Building, Honorable Richard 
G. Lugar, chairman of the committee, presiding.

    Present: Senators Lugar, Kerry, Feingold, Boxer.

          OPENING STATEMENT OF HON. RICHARD G. LUGAR,
                   U.S. SENATOR FROM INDIANA

    The Chairman. This hearing of the Senate Committee on 
Foreign Relations is called to order.

    During the past two and a half years, the Committee on 
Foreign Relations, on multiple occasions, has addressed the 
horrific consequences of the HIV/AIDS pandemic. We've examined 
many subjects related to HIV/AIDS, including the intersection 
of AIDS and hunger, the AIDS orphan crisis, the impact of the 
disease on women and girls in the developing world, and the 
implementation of the President's Emergency Plan for AIDS 
Relief, commonly referred to as PEPFAR.

    This five year, $15 billion initiative is unprecedented in 
its scope and importance. According to Ambassador Randall 
Tobias, the global AIDS coordinator, the United States is 
currently treating 235,000 men, women and children with 
antiretroviral medications, in 15 of the most afflicted 
countries in Africa, Asia and the Caribbean. American agencies 
are also heavily engaged in prevention efforts and caring for 
some of the millions of orphans this disease has created.

    Despite this work to treat those living with HIV/AIDS and 
to prevent new infections and corresponding efforts by 
organizations such as the Global Fund, the Bill and Melinda 
Gates Foundation, and the World Bank, the disease is outpacing 
us. According to the latest figures from the U.N., there are 
approximately 40 million people living with HIV/AIDS around the 
world today. An estimated 4.9 million people were newly 
infected last year. This means that every day around the globe, 
some 14,000 people contract HIV/AIDS.

    Of the 40 million people living with the disease, U.N. AIDS 
estimates that five to six million people, mostly in low and 
middle income countries, need antiretroviral treatment 
immediately. According to the latest statistics in U.N. AIDS, 
only one person in ten who needs the drugs currently is 
receiving them.

    The social, political and economic consequences of this 
pandemic are enormous. HIV/AIDS does far more than weaken the 
immune systems of individuals, it destabilizes families and the 
social and economic infrastructure of communities and nations.

    The AIDS crisis in sub-Saharan Africa has profound 
implications for political stability, development, and human 
welfare that extend far beyond the region. In addition to the 
crises in Africa, public health workers warn of a second wave 
of countries on the verge of a potential AIDS crisis, such as 
China, India, Russia, Nigeria, and Ethiopia. In fact, just two 
days ago, during a hearing on Russia, this committee heard 
testimony about the threat that AIDS poses to that country.

    Getting ahead of this pandemic through prevention and 
treatment programs alone will continue to be a very difficult 
challenge. That's why today we'll be looking toward the future 
to see what hope scientific research can offer for the 
prevention of the spread of the disease, and specifically, we 
will examine the progress in developing an effective HIV 
vaccine.

    Historically, vaccines have led to some of the greatest 
achievements in public health, and are among the most cost 
effective interventions. During the 20th century, global 
immunization efforts have eradicated smallpox, virtually 
eliminated polio from the Western Hemisphere, Europe, and much 
of Asia. Vaccines for diseases such as measles and tetanus have 
dramatically reduced childhood mortality worldwide, and the 
vaccines for diseases such as influenza, pneumonia, and 
hepatitis help prevent sickness and death among young adults.

    An effective HIV vaccine is the world's best chance to stop 
this pandemic, but the search for an HIV vaccine must not come 
at the expense of our immediate life-saving response. Let me 
stress that we are not limited to an either/or choice between 
vaccine research and HIV/AIDS treatment. Rather, we should 
pursue an all-of-the-above approach that includes vaccine 
research, education and prevention programs, and treatment 
efforts as a part of a truly comprehensive response to the 
crisis. It's also important to note that funding is only part 
of the challenge for vaccine researchers. At this stage, we 
must also improve scientific coordination, government 
cooperation and public awareness.

    Because of the promise that an HIV vaccine holds, I've 
introduced a resolution, Senate Resolution 42, supporting 
initiatives to accelerate research on this effort. I've called 
this hearing to raise understanding of the scientific and 
administrative hurdles that must be overcome to make the 
vaccine a reality.

    Last summer, at a meeting of the G-8 at Sea Island, the 
member states endorsed the Global HIV Vaccine Enterprise, which 
is a virtual consortium of the world's leading scientists and 
independent organizations dedicated to an HIV vaccine. Modeled 
after the human genome project, the Enterprise seeks to 
accelerate efforts to develop an effective HIV vaccine by 
enhancing coordination, information sharing, and collaboration 
globally.

    In support of the Enterprise, President Bush established a 
new HIV vaccine research center, known as the Center for HIV/
AIDS Vaccine Immunology. My resolution commends the G-8's and 
the President's actions, and urges the President to work with 
the G-8 countries to support the Enterprise efforts. We want to 
know more about what the scientific community is doing, and we 
welcome input on how Congress can support these efforts. I view 
Senate Resolution 42 and this hearing as just a start. We're 
continuing to work to identify legislative options that might 
help advance vaccine research.

    Today we are honored to be joined by a number of witnesses 
who have brought their estimable talents to bear on addressing 
the global HIV/AIDS crisis. First of all, I would like to 
welcome my special friend, Representative Peter Visclosky of 
Indiana to the Senate Committee on Foreign Relations. The 
Congressman is the author of the companion resolution to Senate 
Resolution 42, which he has introduced in the House of 
Representatives. He's taking a lead in promoting legislative 
awareness of HIV vaccine issues in the House.

    I've had the pleasure of working with Pete on many 
initiatives over the years, I'm excited to have him as a 
partner in advancing the Lugar-Visclosky Resolution. I also 
want to thank Representative Peter Kind, the lead House 
Republican co-sponsor, who could not be with us today.

    Next, we will welcome actress Ashley Judd, who joins us in 
her capacity as Global Ambassador for YouthAIDS, an 
organization dedicated to educating and protecting young people 
from HIV/AIDS. Ms. Judd has traveled extensively in Africa and 
Asia, where she has raised awareness of HIV prevention, and has 
been a source of comfort and strength to individuals stricken 
with the disease. She also has been a committed advocated in 
this country for AIDS education and philanthropy. We look 
forward to her presentation, and thank her for sharing her 
important work with us today, which will underscore the urgency 
of achieving an AIDS vaccine.

    We will also hear from three distinguished experts in the 
field of HIV vaccine research. Dr. Anthony Fauci, is Director 
of the National Institute of Allergy and Infectious Diseases at 
the National Institute of Health. Dr. Helene Gayle is Director 
of HIV/AIDS/Tuberculosis and Reproductive Health with the Bill 
and Melinda Gates Foundation. Dr. Seth Berkley is President and 
CEO of the International AIDS Vaccine Initiative. The 
enterprise of these three individuals is extraordinary, and 
we're grateful for the benefit of their counsel today. I look 
forward to hearing from our witnesses about the progress of the 
enterprise, and other efforts in developing an effective HIV 
vaccine.

    May 18th is HIV Vaccine Awareness Day, and this year's 
theme was ``Hope for the Future.'' Given the potential 
lifesaving benefits of an HIV vaccine, this was an appropriate 
theme, and one we have adopted for today's hearing. I am 
confident that this hearing will help us better understand what 
the public and private sectors can do to accelerate efforts in 
developing an HIV vaccine. I note the presence of two of my 
distinguished colleagues, Senator Kerry and Senator Boxer, and 
I ask their permission to proceed with the witnesses, unless 
you have an opening statement, Senator Boxer. I thank the 
Senator.

    It's a pleasure to call now upon Pete Visclosky of Indiana.

STATEMENT OF THE HONORABLE PETE VISCLOSKY, UNITED STATES HOUSE 
              OF REPRESENTATIVES, WASHINGTON, D.C.

    Representative Visclosky. I want to thank Senator Boxer for 
allowing me to testify today, to highlight the need for a 
coordinated effort in developing an HIV vaccine. Mr. Chairman, 
in particular, your leadership on this issue throughout the 
years is laudable, and it is an honor to work with you now on 
this initiative.

    This is a time of great opportunity in the fight against 
HIV, and the United States has a chance to assume a leadership 
role in developing an HIV vaccine. I'm proud to work with you 
by introducing the Lugar Resolution in the House, as House 
Resolution 286. This resolution is significant because it 
represents a bicameral, bipartisan effort to combat HIV.

    I'm particularly happy to represent Representative King, as 
well--he could not be here today, he is chairing a hearing--my 
fellow Notre Dame alumnus who has joined with me in introducing 
this important legislation reaching across the aisle to do what 
is right.

    Working between the parties and between the chambers of 
Congress, we can make considerable progress on the issue. Your 
initiative to coordinate research is important if we are ever 
going to get ahead of the disease. The magnitude of the crisis 
is unfathomable.

    Most disturbing, last year alone roughly 600,000 of the 
cases worldwide afflicted children. In fact, 50 percent of the 
new HIV cases reported in 2003 were in young people between the 
ages of 15 to 24. The worse area of the world, of course, is 
Africa. Sub-Saharan Africa has only 10 percent of the world's 
population, yet it has 60 percent of the world's HIV/AIDS 
cases. Over 7 percent of the adult population is living with 
the disease, orphaning a whole generation of children. HIV is 
ravaging the continent. But this is a disease that knows no 
boundaries, political or cultural. Eastern Europe and the 
former Soviet Union have experienced a nine-fold increase in 
the number of HIV cases over the last decade alone.

    HIV is affecting every facet of life in the hardest hit 
areas of the world. In addition to the human toll of the AIDS 
pandemic, this disease threatens the political and economic 
stability of those countries and regions. AIDS cases in key 
government officials have gone undisclosed for years in some 
countries. AIDS threatens to destabilize governments in Africa, 
Southeast Asia, and Eastern European nations, and could have 
serious repercussions for global stability.

    The country of Zambia offers a good example. Between 1984 
and 2003, there were 102 special elections, due to vacant 
public offices. Of this number, 29 elections were due to the 
deaths of the incumbent. Similar figures can be cited in 
numerous sub-Saharan African nations. Often times these deaths 
or resignations are reported as due to prolonged illness, 
instead of AIDS, masking the true extent of the problem.

    While this epidemic is worse in other parts of the world 
than it is here at home, we cannot ignore the ravaging effect 
of HIV and what it is doing to our nation. Today, AIDS is one 
of the top three causes of death for African American men and 
women, for example. There are close to 1 million people living 
with HIV in the United States today. This is an epidemic that 
is affecting the security and public health of our nation, and 
we should act.

    In order to fight this epidemic, we must have a coordinated 
global effort, and the tools of the public health community 
must be expanded to include more prevention technology, such as 
the vaccine. Given the scientific complexity of developing an 
HIV vaccine, only a large-scale coordinated effort can 
effectively accomplish this goal.

    Yet, in 2004, only 1 percent of the spending on HIV-related 
programs worldwide went toward vaccine research. We cannot 
sacrifice current efforts to combat HIV and AIDS, instead, we 
need to expand the scope of the fight against it. The global 
community must come together and share research, resources, and 
technology if the goal of creating an HIV vaccine is to be 
achieved.

    Without increased resources and coordination, the 
development of the vaccine remains unlikely. Senate Resolution 
42 and House Resolution 286 are important first steps in 
coordinating the efforts on vaccine research. Last year at the 
G-8 summit at Sea Island, the United States took the lead on 
this issue, and encouraged the G-8 members to endorse the 
Global HIV Vaccine Enterprise. This virtual consortium, if you 
will, of scientists, researchers, and other stakeholders 
committed to developing an effective vaccine will be critical 
to accelerating efforts to develop it. We must continue to 
build on the G-8's efforts to develop an HIV vaccine through 
global cooperation and coordination.

    Senate Resolution 42 and House Resolution 286 will show the 
world that the United States is committed to the Global HIV 
Vaccine Enterprise, and that we are committed to the 
development of the vaccine. Mr. King and I will continue to 
work hard in the House for the passage of H.R. 286. Mr. 
Chairman, I know you and others in the Senate will be similarly 
occupied, and I do urge the committee to support Senate 
Resolution 42.

    The Chairman. Thank you very much, Congressman; we really 
appreciate your personal witness and your leadership on this 
effort.

    Let me ask my colleagues if they have questions or comments 
for the Congressman?

    Senator Kerry. Mr. Chairman, I do not have a question for 
the Congressman. I want to thank the Congressman for taking 
time to come over here and for his concern and involvement in 
this issue.

    I would like to make just a couple of comments, and I ask 
the indulgence of the Chair because the Iraqi Prime Minister is 
here, and I have to go over and meet with him quickly, but Mr. 
Chairman, I really commend you for holding today's hearing. As 
we both know, there's a lot of attention that's been given to 
treating victims of HIV/AIDS, as it ought to be, and we've done 
a fair amount of good work on this committee, but I really want 
to express a very deep frustration. And I think the Congress 
itself ought to be--I don't know, I mean, the words just sort 
of leave you gasping for where the reality is, because we've 
been at this for five years, six years in the committee--
Senator Frist and I co-chaired in 2001, a national effort, and 
we passed legislation right here in this committee, and we put 
together the Vaccines for the New Millennium Act of 2001. We 
put in incentives for pharmaceutical companies to develop 
vaccines. It passed this committee, passed the Senate, and it 
was stripped out in conference by the Finance Committee.

    So, the Congress of the United States is culpable. It 
stripped it out. We had an opportunity to do something on this 
in 2001, we talked a lot about it; we have big hearings, you 
know, big moments, but I think it's critical that we really get 
this right this time, Mr. Chairman. Now, it wasn't in committee 
that we did it--the tax credits were done on the floor--so I 
want to make that clear. But, Mr. Chairman, you've been 
committed to this; you're deeply committed to it; this 
committee has been deeply committed to it; we've tried to do 
what's right; we even got Senator Helms on board, and we had a 
unanimous effort out of this committee; and yet, a few people 
are able to strip something, and the result is, you know, 
millions more people get infected, and millions more people are 
going to die. And we are looking at something that we know is a 
national security issue, as well as a moral and compelling 
human condition issue, because countries that have this kind of 
devastation with respect to their human infrastructure, are 
countries that are going to wind up as failed states, and we 
all understand the consequences of that.

    So, Mr. Chairman, I hope that you and I and others can 
really work together and convince our colleagues of the 
importance of getting it right this time, and I really look 
forward to doing that with you. I hope you'll join again in 
supporting that effort within the Millennium Act Bill for those 
credits.

    The Chairman. Senator Kerry, I deeply appreciate your 
recitation of the history. I think it's very appropriate that 
the committee, and all who are witnessing, hear and understand 
the struggle. This is a situation in which resiliency by the 
committee, as well as those who are involved, is of the essence 
because there has been disagreement about the priority, about 
the money, about the program. But, here we are again, and this 
is an important initiative, and I welcome your enthusiasm, as 
always, and your resiliency.

    Senator Boxer, do you have a comment?

    Senator Boxer. Just one question, I wanted to thank you, 
Mr. Chairman, very much for holding this hearing, and thank 
Senator Kerry for his strong leadership on this. I do have a 
question. When President Bush announced his plan, the 
President's Emergency Plan for AIDS Relief, it was very well 
received by, I think, everyone in the Congress and in the 
country and around the world, and he announced plans to spend 
$15 billion to combat HIV/AIDS. He announced that in his State 
of the Union speech, that was January of 2002, and as of March 
'05, only a very small percentage of the program's funds have 
been spent, now my understanding is it's just a couple 
billion--I'm asking, Congressman, if you're aware of that--but 
the other issue that concerns me is that China, India and 
Russia are not on that list of countries. And my good staff 
tells me that if India, China and Russia were to reach even 
half the prevalence rate of sub-Saharan Africa, or 3.7 percent, 
more than 92 million people would fall ill. Ninety two million 
people. So, I guess my question of the Congressman is, what's 
your sense about how the spend out is going, and does it 
concern you that these countries are left out? Is it realistic 
to just shut our eyes to the potential catastrophe here?

    Representative Visclosky. Well, we shouldn't close our 
eyes. The trend is very disturbing, and I think the position 
you have enumerated here, really suggests why we should make 
sure that the Senate and House resolutions are passed, and that 
we do everything possible on a daily basis, and continue to 
focus attention on this problem. Because the situation, from my 
perspective, continues to deteriorate, and again, you state the 
problem very well.

    Senator Boxer. Thank you.

    The Chairman. Thank you very much, Senator Boxer. Clearly 
the spending issues have been before the committee, as well as 
the issue of Russia, specifically, which you have commented on. 
In our hearing just two days ago, we had testimony that as many 
as 100 cases of HIV/AIDS are actually in Russia now, although 
the status of denial exists on the part of the government, but 
that won't cure the realities. So, I appreciate your 
illuminating that. Thank you very much, Representative 
Visclosky; thank you for coming over today.

    The Chair would like to call now our second panel of the 
morning, a very distinguished guest, Ms. Ashley Judd, Global 
Ambassador of YouthAIDS. Would you please come forward, Ms. 
Judd? We welcome you to the committee, and we look forward to 
your testimony.

    Let me mention to you and to all of our other witnesses, 
that the written testimony that you have submitted to the 
committee will be included in the record in full. So, you need 
not ask permission, that will occur, and then we will ask that 
you make your presentation or summaries in ways that you find 
most acceptable, and then we will proceed with questions. 
Please proceed.

  STATEMENT OF MS. ASHLEY JUDD, GLOBAL AMBASSADOR, YOUTHAIDS, 
                        WASHINGTON, D.C.

    Ms. Judd. Good morning, honorable members of the committee, 
it's a genuine honor, thrill, and pleasure to be here before 
you today, and I'm most grateful to have been invited.

    As you have stated, my name is Ashley Judd. I am the Global 
Ambassador for YouthAIDS and a member of the Board of Directors 
of Population Services International (PSI), which is the parent 
company of YouthAIDS.

    YouthAIDS, a global initiative, is working in more than 60 
countries to educate and protect young people from HIV/AIDS. 
YouthAIDS generates funding to develop worldwide education and 
awareness programs to prevent the spread of HIV amongst the 
most at-risk population: youth.

    Before I begin my testimony, I'm actually going to give you 
a sneak preview of a VH1 program--I doubt VH1 has ever been 
played in this chamber before.

    It is a documentary that was made of my trip to Madagascar 
to see our programs which are funded by the global fund. The 
documentary is entitled, ``Tracking the Monster,'' and will air 
August 23rd, it also features India Arie, the unabashedly 
spiritual singer of terrific integrity. The contrast will be of 
the decimation in Kenya and the hope in Madagascar. This clip 
highlights the way we reach out to youth.

    AV stuff is always so tricky, is that department feeling a 
little pressure right about now?

    [The transcript of the video clip played for the committee 
follows:]

           Transcript of Ms. Ashley Judd's Film Presentation

 [A portion of the presented video is spoken in French. The translated 
                  French is indicated by italic text.]

          Text: Roughly 60 percent of teenagers in Madagascar are 
        sexually active.

          Man: We are going to be going to a school today, and the 
        youth are an important target of our HIV activities because in 
        Madagascar they actually have a greater rate of HIV than any 
        other group.

          Ms. Judd: Is there very limited understanding of how the 
        virus is spread?

          Woman: Oh yes.

          Ms. Judd: Sweet.

          Man: These are all your friends from the [name of school not 
        translated].

          Ms. Judd: One of the things I really love about the YouthAIDS 
        Global Ambassadors is that I'm always working with kids. We 
        educate them about risky behavior before they have a chance to 
        engage in it. And so many kids here in Madagascar, and so 
        little time, we needed to get the word out in a big way.

          Ms. Judd: So I'm scheduled to shoot a TV spot with some 
        students. Do you know what we're going to do together? It will 
        play on Madagascar television. Has someone already explained 
        it? No? You're going to shoot a commercial with me! We have 30 
        seconds to present information that can save lives. The topic: 
        abstinence.

          Man: For the moment you must abstain yourselves. You can 
        prove your love without having sex.

          Ms. Judd: So roses, chocolates, love letters, my personal 
        favorite.

          Teacher: Have you ever written a love letter?

          Student: No, not yet.

          Ms. Judd: Maybe you can practice on me. I can be your first. 
        And I can tell you, I was too young, and I still have my 
        regrets. Now, I wish I would have had a conversation like this, 
        adults and young people talking with me--encouraging me to 
        wait.

          Ms. Judd: Tim's co-worker, Lantu, wrote the script for the 
        spot. A.J. that's me. I speak to the camera. Ok, so it's like 
        this. The basketball is between the couple. I throw the ball 
        and I say: Over 150,000 people are already infected with HIV in 
        Madagascar. Sex can wait. Play like a winner. Sex isn't the 
        only proof of love. The ball is in your court. What do you 
        think of the dialogue?

          Student: It's cool.

          Ms. Judd: They do think it's important to get the word 
        ``cool'' in there, somehow.

          Teacher: So, I'm cool because I practice abstinence.

          Ms. Judd: That would be good?

          Student: But one must not say that. Slang isn't allowed in 
        school.

          Ms. Judd: Especially because it is slang and is forbidden in 
        school; it gives the feeling that it's between young people, 
        and not an adult telling you all this. Cool.

    Ms. Judd. So, in addition to showing how we dialogue with 
youth to hear what it is they would like to see in their 
education and dialogue about abstinence, I get to show off my 
fancy education from the University of Kentucky.

    As an actor, I know the importance of setting the stage, 
but never in my career have I had to set the stage for a drama 
as devastating, and of such historic proportion and 
consequence, as the HIV/AIDS emergency that we now battle.

    There are currently 39 million people living with HIV, the 
virus that causes AIDS. Twenty million have already died. 
Roughly half of the infected adults are women, and tragically, 
2 million children carry the virus--all preventable. In 2004 
alone, the last year for which we have reliable statistics, 
there were 3 million deaths related to AIDS-related cases and 
nearly 5 million new infections.

    To what in recent memory can we compare this new 
catastrophe? Approximately 50 million lives were lost during 
the infamous darkness of World War II. That number will be 
surpassed by deaths due to AIDS when those now infected 
inevitably, and most in shameful fashion, are laid to rest. 
Stalin's totalitarian regime in the Soviet Union took a toll of 
20 million lives, roughly equal to the number that have already 
died of AIDS-related causes globally. These numbers are 
staggering. They are truly without precedent, and our words and 
actions in the face of this crisis will certainly be studied 
for generations to come. How will history judge us?

    With the hope of doing more to save lives, this committee 
has convened to hear testimony, principally about AIDS vaccine, 
an eagerly awaited strategy for prevention. Dr. Fauci, Dr. 
Gayle, and Dr. Berkley, all of whom are leaders in the public 
health community, will address this important topic. I would 
like to focus my testimony on another critical aspect of AIDS 
prevention, and that is the imperative need to do more for 
girls and women around the world.

    In Africa young women are up to six times more likely to 
become infected with HIV than their male peers. And little, if 
anything, is being done to address the problems that put young 
women at such high risk, and more must be done if we honestly 
hope to stop the HIV/AIDS emergency.

    To give you an idea of how bad things are, let me tell you 
about a group of young women in Zambia. These young girls, aged 
15 to 19, met with PSI staff last year, to talk about 
abstinence, and their experiences growing up, generally. I was 
going to give you more detail to try to conjure them right in 
this room, but then I remembered that all of our conversations 
are confidential and anonymous. So I'm going to call one of 
them by the name of a friend I made in Madagascar, Sahule.

    Sahule lived with her sister and brother-in-law, and 
Sahule's sister and her husband had a fight one night, and her 
sister left the house in a fit. At about 1:30 in the morning, 
Sahule awoke in pain, and discovered her brother-in-law on top 
of her, raping her. Family elders, after learning of the 
incident, decided this was something the family should take 
care of on its own. It was never reported to the police, and 
ultimately nothing was done.

    Immediately after Sahule told this story, another young 
girl told how she was locked in a room and raped by her 
boyfriend. She kept the matter a secret for fear of being 
mocked. After hearing these two stories, two other girls in the 
group of 10 described how they had also been raped, one by an 
uncle who pushed a cloth in her mouth and tied her hands, and 
the other by the 19-year-old friend of her brother. One of the 
girls reported the case to the police, but the other did not 
because she was ashamed of herself.

    Five others in this small group also reported how they were 
accosted, or barely managed to escape or avoid sexual violence. 
All of this had happened before these young women were 19 years 
of age. And in this testimony, I am not even touching on the 
outrage of sexualization and sexual violence toward pre-
pubescent girls, which is shockingly pervasive.

    What can we conclude from this group of young women who 
shared their stories of abuse? I think we can conclude that 
most of us in this room really have no idea of how difficult 
life is for women in Africa, and elsewhere in the developing 
world. Even though sexual violence happens everywhere on our 
planet, women in developing countries are at extremely high 
risk of abuse; social norms and economic pressure are often at 
the root of the problem.

    Recent research confirms that these young women's stories 
are not isolated cases. A report published in 2002 concluded 
that nearly one out of three women surveyed in South Africa, a 
country I have visited, had their sexual initiation through 
rape. Is there a more sordid and cynical rite of passage to 
adulthood?

    The abuse of girls and women stretches beyond sexual 
violence. I will now tell you about a degrading and utterly 
common phenomenon known as ``cross-generational sex.'' The 
social norms in many developing countries that determine what 
is tolerable, or at least not punishable, for a man to do to a 
girl or woman, have also created an environment in which girls 
as young as 15 are encouraged to seek financial or material 
gain by entering into empty sexual relationships with men a 
generation, or more, older than they. These cross-generational 
relationships are common across the continent of Africa, and 
result in young women exchanging their bodies for modest 
financial support--lunch, perhaps a cell phone, a pair of 
plastic shoes, or maybe half a liter of fuel to heat the shack 
in which she is raising her younger siblings.

    And while these relationships are fundamentally 
transactional, this is not commercial sex. These are young 
women in both urban and rural settings who have been persuaded 
by both peers and adults that have an older sexual partner, a 
``sponsor,'' as they're called--quite a perversion on a 
relatively happy word--is an acceptable and common way to 
acquire fashionable items, or meet basic needs that they need 
for their very survival. Rarely do these young women consider 
the possibility of becoming infected with HIV. But the risks 
are very real.

    Already at an increased biological risk because of our 
anatomy, such cross-generational relationships are fueling the 
HIV/AIDS epidemic among young women. Two recent academic 
journal articles document how a young girl's risk of HIV 
infection increases significantly as a result of having an 
older partner. Both papers were clear that this practice of 
cross-generational sex was an important factor which explained 
why young women are six times more likely to be HIV positive 
then young men in Africa.

    And here I pause to ask you, honorable members of this 
distinguished committee, are we really doing everything that we 
can to protect young girls and women from HIV/AIDS?

    We want them to abstain, or at the bare minimum, delay 
their sexual debut, but it will be difficult, if not 
impossible, for them to do so if they are not protected from 
sexual abuse, exploitation, economic disempowerment, poverty--
the norms that encourage sex with older men for support and 
survival.

    I am confident that this problem of cross-generational sex 
slices across the politics that color the current, and highly 
polarized, debate on how best to combat HIV/AIDS in Africa. 
People of all political and spiritual persuasions are deeply 
distressed and disturbed by the abuse of girls and young women.

    But if that is, in fact, the case, why is so little being 
done to address these problems? With all the research that has 
been conducted, it's certainly not because we don't know that 
it's happening. I would like to think it's not because we don't 
care. I believe it is because the problem is so pervasive, so 
deeply rooted and so long standing, that we simply don't know 
where or how to start. The journey to decrease the 
vulnerability of girls and women in the developing world must 
begin, like all journeys, with the first steps. I'm getting a 
little ``George Washington crossing the river,'' very moved by 
all of our beautiful monuments in Washington, D.C.

    Here's how we can start: First we must acknowledge that 
preventing HIV/AIDS amongst young women will entail reversing 
social norms and practices which support their abuse. Societies 
must reject violence against girls and women, as well as social 
norms which encourage young women to exchange sex for financial 
and material support. The Global Fund, thanks to its unique 
country-level structures, could play an important role in 
coordinating local partners, and I've seen personally what 
their good work in Madagascar can do, and for further detail 
and information about the programs they have there, and the 
vulnerable population it serves, I refer you to my diaries at 
www.youthAIDS.org.

    Second, acknowledge that the transformation of these 
unhealthy social norms must come from within. This does not 
mean that we stand by idly waiting for something to happen; it 
means that international organizations and donors must work 
hand in hand with indigenous groups that are prepared to fight 
for change in their own communities. The African Union will be 
a key partner in this struggle, and they are eager to begin 
their work. I have a lot of hope.

    Third, honorable committee members, you could insist on 
legislation that would tie future foreign aid to a country's 
demonstrated commitment to enforcing laws that protect women 
from all forms of sexual violence, genital mutilation, 
including statutory rape, and reaching all the way to 
strengthening our anti-human trafficking laws.

    And fourth, national campaigns promoting healthier gender 
norms and role models for men should be launched throughout 
Africa and in many, many other places in the developing world.

    Having an HIV/AIDS vaccine would be of great benefit to 
women of all ages because it could reduce their chances of 
becoming infected. As there is no vaccine to prevent the abuse 
of girls and women, however, there is nothing more important in 
this struggle against this virus and its diseases, than 
reversing destructive social norms, cultural practices, 
traditions, myths, beliefs, superstitions, religious ideas, and 
the flat out ignorance that perpetuates our economic 
disempowerment, lack of status in society, and general gender 
inequality.

    I thank you so much for letting me be here today, and my 
last remark is that we're a very special, unique country, and 
we have accomplished unprecedented things in our history. I do 
believe that our greatest export is our ideas, gender equality 
being the most important one. Thank you so much for your time 
today.

    [The prepared statement of Ms. Ashley Judd follows:]

                   Prepared Statement of Ashley Judd

    My name is Ashley Judd. I am YouthAIDS' Global Ambassador, and a 
member of the Board of Directors of Population Services International 
(PSI). YouthAIDS, a global initiative of PSI, is working in more than 
60 countries to educate and protect young people from HIV/AIDS. 
YouthAIDS generates funding to develop worldwide education and 
awareness programs to prevent the spread of HIV among the most at-risk 
population--youth. Distinguished members of the Senate Foreign 
Relations Committee, thank you for giving me the honor of testifying 
here today.

    As an actress, I know the importance of setting the stage. Never in 
my career, however, have I had to set the stage for a drama as 
devastating and of such historic proportions as the AIDS epidemic that 
we now battle. There are currently 39 million people living with HIV, 
the virus that causes AIDS. Twenty million have already died. Roughly 
half of the infected adults are women, and over two million children 
carry the virus. In 2004 alone, the last year for which we have 
reliable statistics, there were three million deaths due to AIDS, and 
nearly five million new infections.

    To what in recent memory can we compare this catastrophe? 
Approximately 50 million lives were lost during the darkness of World 
War II; that number will be surpassed by deaths due to AIDS when those 
now infected are laid to rest. Stalin's totalitarian regime in the 
Soviet Union took a toll of 20 million lives--roughly equal to the 
number that have already died of AIDS globally. The numbers are 
staggering. They are truly without precedent, and our words and actions 
in the face of this crisis will certainly be studied for generations to 
come.

    With the hope of doing more to save lives, this committee has 
convened to hear testimony principally about AIDS vaccines as a 
strategy for prevention. Dr. Fauci, Dr. Gayle, and Dr. Berkley, all of 
whom are leaders in the public health community, will address this 
important topic. I would like to focus my testimony on another critical 
aspect of AIDS prevention, and that is the urgent need to do more for 
young women around the world.

    In Africa, young women are up to six times more likely to become 
infected with HIV than their male peers. Little, if anything, is being 
done to address the problems that put young women at such high risk, 
and more must be done now if we honestly hope to stop the AIDS 
epidemic.

    To give you an idea how bad things are, let me tell you about a 
group of young women in Zambia. These young girls, age 15-19, met with 
PSI staff last year to talk about abstinence and their experiences 
growing up generally. I'll start with someone who I'll call Jane.

    Jane lived with her sister and brother-in-law. Jane's sister and 
her husband had a fight one night, and her sister left the house for 
the evening. At about 1:30 in the morning, Jane awoke in pain, and 
found her brother-in-law on top of her. Raping her. Family elders, 
after learning of the incident, decided this was something the family 
should take care of on its own. It was never reported to the police.

    Immediately after Jane finished telling this story, another young 
girl told how she was locked in a room and raped by her boyfriend. She 
kept the matter a secret for ``fear of being mocked.''
    After hearing these two stories, two other girls in the group of 
ten described how they had also been raped--one by her uncle, who 
pushed a cloth in her mouth and tied her hands; and the other by the 19 
year old friend of her brother. One of the girls reported the case to 
the police, but the other did not because she was ``ashamed'' of 
herself.

    Five others in this small group reported how they were accosted, or 
barely managed to escape sexual violence. All this had happened well 
before any of the girls had reached the age of 19.

    What can we conclude from this group of young women who shared 
their stories of abuse? We can conclude that most of us in this room 
have no idea how difficult life is for young women in Africa and 
elsewhere in the developing world. Even though sexual violence happens 
in all corners of our planet, women in developing countries are at 
extremely high risk of abuse. Social norms and economic pressure are 
often at the root of the problem.

    Recent research confirms that these young women's stories are not 
isolated cases. A report published in 2002 concluded that nearly one 
out of three young women surveyed in South Africa had their initial 
sexual experience through rape.\1\ What more sordid and cynical rite of 
passage to adulthood could we imagine for a young woman?
---------------------------------------------------------------------------
    \1\ Jewkes R, Abrams N; The Epidemiology of Rape and Sexual 
Coercion in South Africa: An Overview. Social Science and Medicine. 
October, 2002; 55 (7): 123 1-44.

    The abuse of women stretches beyond the sexual violence that I just 
described; I will now tell you about a degrading and common phenomenon 
called ``cross generational sex.'' \2\ The social norms in many 
developing countries that determine what is ``tolerable'' (or at least 
not punishable) for a man to do to a woman have also created an 
environment in which girls as young as 15 are encouraged to seek 
financial or material gain by entering empty sexual relationships with 
men a generation or more older than them. These ``cross generational'' 
relationships are common across the continent of Africa, and result in 
young women exchanging their bodies for modest financial support--such 
as lunch, a cell phone, plastic shoes, or half a liter of fuel.
---------------------------------------------------------------------------
    \2\ Luke N, Kurz K; Cross Generational and Transactional Sexual 
Relations in Sub-Saharan Africa: Prevalence of Behavior and 
Implications for Negotiating Safer Sexual Practices. AIDSMark. 2002.

    And while these relationships are fundamentally transactional, this 
is not commercial sex. These are young women--in both urban and rural 
settings--who have been persuaded by both peers and adults that having 
an older ``sponsor,'' and sexual partner, is an acceptable and common 
way to acquire fashionable items or meet basic needs. Rarely do these 
young women seriously consider the possibility of becoming infected 
with HIV.\3\
---------------------------------------------------------------------------
    \3\ Longfield K, Glick A, Waithaka M, Berman J; Relationships 
Between Older Men and Younger Women: Implications for STIs/HIV in 
Kenya. Studies in Family Planning. Volume 35, no. 2, June 2004. pp. 
125-134.

    But the risks are very real. Already at increased biological risk, 
such ``cross generational relationships'' are fueling the AIDS epidemic 
among young women. Two recent academic journal articles document how a 
young girl's risk of HIV infection increases significantly as a result 
of having an older partner. Both papers were clear that this practice 
of cross generational sex was an important factor which explained why 
young women are six times more likely to be HIV positive than young men 
in Africa.\4\ \5\
---------------------------------------------------------------------------
    \4\ Gregson S; Sexual Mixing Patterns and Sex Differentials in 
Teenage Exposure to HIV Infection in Rural Zimbabwe. The Lancet. June, 
2002. Volume 359. pp 1896-903.
    \5\ Kelly, R; Age Differences in Sexual Partners and Risk of HIV-1 
Infection in Rural Uganda. Journal of Acquired Immune Deficiency 
Syndromes. Volume 32, no. 4. April, 2003. pp. 446-451.

    And here I pause and ask you, honorable members of this 
distinguished committee, if we are really doing everything we can to 
protect these young girls from AIDS? We want them to abstain, or delay 
their sexual debut, but it will be difficult for them to do so if they 
are not protected from both sexual abuse, and from social norms that 
---------------------------------------------------------------------------
encourage sex with older men in return for financial support.

    I am sure this problem of cross-generational sex cuts across the 
politics that color the current and highly polarized debate on how best 
to combat AIDS in Africa. People of all political and religious 
persuasions are deeply disturbed by the abuse of young women.

    But if that is the case, why is so little being done to address 
these problems? With all the research that has been conducted, it is 
certainly not because we don't know this is happening. And I would like 
to think it is not because we don't care that these young women are 
being violated or contracting AIDS. I believe it is because the problem 
is so pervasive, so deeply rooted, and so long standing that we simply 
don't know where or how to start. The long journey to decrease the 
vulnerability of women in the developing world to AIDS and sexual 
violence must begin, like all journeys, with first steps. Here is how 
we can start.

    First, we must acknowledge that preventing AIDS among young women 
will entail reversing the social norms which support their abuse. 
Societies must reject violence against women, as well as social norms 
which encourage young women to exchange sex for financial or material 
support. The Global Fund, thanks to its unique country level 
structures, could play an important role coordinating local partners.

    Second, acknowledge that the transformation of these unhealthy 
social norms must come from within. This does not mean that we should 
stand by idly waiting for something to happen. It means that 
international organizations and donors must work hand in hand with 
indigenous groups that are prepared to fight for change in their own 
communities. The African Union will be a key partner in this struggle, 
and they are eager to begin work.

    Third, honorable committee members, you could insist on legislation 
that would tie future foreign aid to a country's demonstrated 
commitment to enforcing laws that protect women from all forms of 
sexual violence, including statutory rape.

    And fourth, national campaigns promoting healthier gender norms and 
role models for men should be launched throughout Africa and in many 
other places in the developing world.

    Having an AIDS vaccine would be of great benefit to women of all 
ages because it could reduce their chances of becoming infected. As 
there can be no vaccine to prevent the abuse of women, however, there 
is nothing more important in the struggle against this disease than 
reversing destructive social norms that endanger women across Africa 
and in other developing countries.

    I thank you again, honorable members, for allowing me to contribute 
today.

    The Chairman. Thank you very much, Ms. Judd. Let me just 
pursue for a moment the very important point you made about 
cross-generational sex and its impact on girls in Africa. What 
type of interventions does your organization, YouthAIDS have? 
What sort of programs? Are they effective? At how broad a scale 
have you been able to approach the situation?

    Ms. Judd. So that I don't waste your time, may I consult 
with my colleague?

    In general, I can say that peer education is a very 
powerful tool, I've seen it around the world, and that entails 
like talking to like, so you get a young woman, one who is a 
little more empowered and a little more educated about 
medically accurate sex education and her reproductive health, 
talking to a vulnerable at-risk girl about the different ways 
she can protect herself.

    In Kenya, we have a fantastic mass media campaign that's 
called ``NEmA Chill,'' it's a combination of Swahili and 
English slang as you saw from our campaign from Madagascar, 
slang being extremely popular with young people. The NEmA Chill 
Campaign is on televisions, radios, billboards, it's painted on 
the sides of buildings, so it's able to transcend literacy 
issues, and what it encourages kids to do is ``chill'' which is 
a euphemism for being abstinent, and I can tell you that kids 
are embracing this message heartily. I was in the bathroom at 
the Nairobi airport talking with the janitor, she wanted my 
necklace, which I was reluctant to give her because it was 
special--my husband had given it to me. When I asked her if 
she'd been tested for HIV (HIV status is a whole other very 
important issue), she said, ``Oh, I've been tested, and I 
chill.'' Which is the slogan, so I gave her my earrings. It was 
obviously saturating the population.

    The role model campaign we have in Uganda is fantastic for 
girls who already have a little bit of a leg up; they're in 
University, and the exact name of the program is ``Go 
Getters.'' We get older women to come in and talk to the girls 
about the importance of setting long-term goals and getting 
past instant gratification. The older women mentor them, and we 
use faith-based organizations and businesses to help provide 
internships for the girls who enroll in the Go-Getters Club.

    The Chairman. Let me just proceed to the Madagascar 
situation which was illustrated so well on the film. I 
congratulate you on your linguistic ability as you communicate 
with those in the film. What is your general view of abstinence 
programs? You responded to that a bit, but obviously you've 
addressed that in Madagascar, is this effective?

    Ms. Judd. I will be completely blunt with you--I was not a 
fan of abstinence programs until I saw, first hand, that there 
are kids that are really hungry for an abstinence message. I 
was doing a peer education session in a classroom where we were 
talking about the ABC's--abstaining, delaying sexual debut, 
being faithful to one partner, correct and consistent condom 
use. We reach out to dynamic, poised, compelling young people 
to be the peer educators. I was assisting in this. And when the 
peer educator was finished, this one kid raised his hand, he 
wanted to go back and talk about abstinence again. So that was 
a one-on-one experience that I had that made me say, ``You know 
what? This is really valuable, and valid.'' And then, of 
course, our ``Chill'' campaign as I mentioned in Kenya, is 
wildly popular.

    We actually have been doing abstinence in Kenya since 1988, 
and in fact have just launched one that is considered to be the 
largest abstinence campaign in the world. However, I would like 
to say that one is not effective without the other, and there 
must be a balanced and targeted approach. Married women need 
condoms. Married women are at risk for HIV, married women in 
Cambodia are the highest new infection group--it is common 
around the world for men to have extra-marital sexual 
relations, and they bring HIV home to their wives, who then 
pass it on to their children. Married women need to know how to 
successfully insist upon and negotiate a condom with their 
husbands.

    The Chairman. Let me just follow through with one more 
question because you mentioned the African Union in your 
comments. Describe more extensively what role the African Union 
might play in the things that you have talked about today?

    Ms. Judd. The African Union has such an excellent mandate 
to look after its population across Africa, not just in sub-
Saharan Africa, and their leadership has the potential to be 
extremely dynamic. And again, it's that ``like helping like,'' 
so it's not a bunch of us blowing in there saying, ``This is 
really how you should do it.'' And again, with your permission, 
I'll get a little more detail from my colleague.

    We need a continent-wide advocacy campaign--getting heads 
of state to all agree on the same principles of education. An 
example is that we work with Muslims in Eastern Africa, and we 
have helped to develop standardized information about medically 
accurate sex education and HIV prevention, and the Imams can 
use these standardized texts in mosques. They don't have to 
second guess themselves, or wonder if they're getting it right. 
It's very factual, this is the information, and people don't 
have to be nervous or editorialize. Also, of course, I had the 
great privilege of working with the All-Africa Conference of 
Churches in Nairobi, they sang ``We Shall Overcome.'' I felt 
very at home. In this way we will collaborate to challenge the 
African governments to implement laws against female genital 
mutilation, statutory rape--there's tremendous potential there.

    The Chairman. I think the point you make about the heads of 
state of the governments, plus the religious leadership, is 
very important. As you have found in some countries, without 
describing any one scene, the official leadership has been in 
denial that there's a national problem. That has made it very 
difficult for others within the government, or NGO's, or other 
persons, really, to take an active part.

    Ms. Judd. There's a lot of superstition; there's a lot of 
ignorance, and there are a lot of myths. In Kibera, which is 
the second largest slum in the world, in Nairobi, I saw peer 
educators have a fantastic impact on a very poor, an extremely 
poor and disempowered population. And during the question and 
answer periods, a lot of those myths come to the surface: Can 
you get HIV from a mosquito bite? Can you get HIV from shaking 
hands? You know, if someone is HIV-positive, many people 
believe they should be ostracized and outcast--and the 
leadership, when they break the silence and start breaking down 
the cultural taboos, are going to have a massive positive 
impact on their population's health and well-being.

    The Chairman. I thank you. Senator Boxer, do you have 
questions of our witness?

    Senator Boxer. Thank you again, Mr. Chairman. Ashley Judd, 
I just want to thank you so much. We have discussed your work 
before, and I'm just so proud of you and seeing you actually 
bring such an important message as an American leader in this 
area, it's just, it's tremendous. I just don't want to lose 
this opportunity to publicly thank you, as I did privately. If 
everyone did just a fraction of what you've done, it would just 
change the world.

    I'm very proud that Chairman Lugar and I have been working 
together on providing assistance for orphans and other 
vulnerable children in the developing world. We had a bill last 
year, we're working on a new version of it this year, and among 
other things, our bill would authorize the President to provide 
assistance to orphans by eliminating school fees, increasing 
pediatric health care, increasing psychological support for 
orphans and victims of the disease. And what we're learning is 
that you also have to protect the inheritance of these orphans, 
widows and sick children when something happens to the father, 
when the father dies of AIDS, and they're just left, and 
they're so vulnerable, and people will take away their 
inheritance, and they find themselves in desperate straits.

    So, I was just wondering, and I know this--I didn't tell 
you about this question, so you may want to consult with your 
colleagues--but you've got a golden opportunity, with both of 
us here--is there anything we're missing in our approach to 
this bill that you think we could do to make part of this bill? 
And if you don't have the answer today, we'll be happy to take 
it in writing over the next few days because I think on the 
heels of this hearing, maybe we will have some momentum to get 
our bill through. Anything come to mind, when the breadwinner 
dies of AIDS?

    Ms. Judd. The situation of orphans is so utterly 
devastating. An specific example I can give you is that of an 
exquisitely beautiful young Kenyan woman named Scola whom I met 
in a brothel, she's 19 and was actually nursing her second 
child while she was forced to work in commercial sex. Her 
parents died of HIV/AIDS-related causes, her older brother 
vanished and she did not have any inheritance rights to the 
small bit of land that her parents had owned. Her boyfriend 
left her when she became pregnant with their second child. 
She'd had no sex education whatsoever. She didn't know anything 
about abstaining, or how to delay her debut, or how to protect 
herself from both pregnancy and STD and HIV. This has forced 
her to feed herself and her two children, as her first baby--a 
10-month old--had increased dietary needs, and she literally 
couldn't satisfy him on a daily basis, she ended up on the 
streets, and this isn't always the right answer universally, 
but we just stuffed money in her pockets and sent her home. 
There was no way that we could tolerate this woman finishing 
her work in the brothel that night, she had to go home and 
breastfeed her second child. It was disgusting what had 
happened to her.

    What I've learned from both YouthAIDS and Equality Now--
which does such fine work--is that we have to press the local 
leaders in the African countries to lobby their governments to 
put that legislation into place to legally empower mothers and 
their children.

    We would love to take more time to consider what you said, 
and appreciate your inviting our input. Education, of course, 
is the most critical and fundamental tool, and that can be done 
through schools as well as peer education.

    Senator Boxer. One last question I have, Mr. Chairman.

    You suggest that future U.S. foreign aid be tied to a 
country's demonstrated effort to reduce statutory rape. What is 
your assessment and the assessment of your colleagues on 
African countries willing to prosecute individuals for the 
crime of rape?

    Ms. Judd. It's sketchy, it's sketchy. You will get a judge 
who is all for it, and then somebody from his tribe comes in, 
and he's like, ``No,'' he wants to revert and do it the 
traditional way with his people, and it just takes education, 
ongoing education. And how do you say that word? Sensitization, 
of the issue.

    Senator Boxer. Well, thank you very much, and Mr. Chairman, 
I do hope that we can work with YouthAIDS as we put this 
together. It's a perfect opportunity for us, and I think with 
the bipartisanship you bring to this issue, maybe we can 
actually make a difference in the lives of some of these young 
people, which would be a contribution.

    The Chairman. The Senator makes an excellent point, and 
this hearing may be able to spur that legislation. And we do 
invite the testimony, as the Senator has indicated, the record 
will remain open so that further comments by your organization, 
YouthAIDS or others are welcome.

    Well, Ashley Judd, we thank you very much for appearing 
today and for your very compelling testimony, and being 
forthcoming in your responses to our questions. We wish you 
every good fortune in your good work. Thank you.

    Ms. Judd. Yes, sir, thank you, Mr. Chairman.

    The Chairman. The Chair would like to call now in our next 
panel, Dr. Anthony Fauci, Director of the National Institute of 
Allergy and Infectious Diseases at the National Institutes of 
Health in Bethesda, Maryland.

    Dr. Fauci, we welcome you again to the committee. We 
appreciate especially your testimony on this occasion this 
morning, and ask you to proceed.

STATEMENT OF DR. ANTHONY S. FAUCI, DIRECTOR, NATIONAL INSTITUTE 
   OF ALLERGY AND INFECTIOUS DISEASES, NATIONAL INSTITUTE OF 
                   HEALTH, BETHESDA, MARYLAND

    Dr. Fauci. Thank you very much, Mr. Chairman, and thank you 
for giving me the opportunity this morning to discuss with you 
the role of the National Institutes of Health in the research 
endeavor to develop a safe and effective HIV vaccine.

    You've just heard in the statements, as well as from Ms. 
Judd, about the compelling reason why we do need an HIV 
vaccine, and that is the extraordinary problem that does not 
have an end in sight, with approximately 40 million people 
worldwide living with HIV, the vast majority of them living in 
developing countries, two-thirds of whom are in sub-Saharan 
Africa.

    There are, as you know, 5 million new infections each year, 
with 3 million deaths this past year. One of the things we need 
to do is as important as anything else--the prevention of HIV 
infection. As is shown on this poster, there are multifaceted 
ways that we can prevent HIV infection, ranging from 
interruption of transmission from mother to child, to topical 
microbicides, which are a woman-based way to take into her own 
power the ability to protect herself, just like the use of 
condoms, as Ms. Judd has mentioned.

    But importantly, there's the issue of a vaccine, without 
which most of us feel we will not have a totally effective 
prevention campaign. But there are particular issues related to 
vaccines that provide a very unique and rather compelling 
challenge, very unique when you compare it to the other 
successful vaccines that you mentioned in your opening 
statement.

    And these relate to the fact that the natural immune 
response to HIV is inadequate--I'll get back to that in just a 
moment. HIV hides itself from the immune system, it actually 
targets and destroys the very immune system that's programmed 
to protect the body against an infection. And then, finally, it 
replicates rapidly, and mutates, so it's constantly evading and 
eluding our ability to control it.

    With regard to the first one--namely that the immune 
response is inadequate--this is really quite unique. If you 
look at all the killers that we've had to face--smallpox, 
polio, measles and others--although there's considerable 
morbidity and mortality, the vast majority of people who get 
infected with those infections ultimately completely eradicate 
the microbe, in these cases, viruses from the body. So, when we 
develop a vaccine, we try to mimic the natural infection itself 
with our vaccine. The problem with HIV is that HIV doesn't do 
that--the body is not able to completely eradicate the virus by 
itself, so we in the field of developing vaccines have to do 
even better than the natural infection itself, and that is a 
formidable scientific problem that we're all putting our 
efforts toward.

    If you look at the vaccine research resources, this is the 
NIH HIV vaccine research funding. Dr. Berkley will shortly give 
you an idea of what the global effort is, but as you can see, 
this is actually very dramatically increased over the past 
several years, to the point now--we at the NIH are scheduled to 
spend in fiscal 2006 over $600 million for research alone on 
HIV vaccine.

    Now, importantly, the vaccine endeavor does not include 
only the development of products. There is a list of products 
that are in clinical trial, those that are in different phases, 
and those that are in the pipeline. But what we've done over 
the years is develop an international network of clinical trial 
sites. I know it's difficult to see from that distance, but 
this is a map of the world with a number of our sites, 
including the NIH's vaccine trial network, as well as the 
Department of Defense and the CDC. This is an interdigitated 
network that is ready and already functioning in a manner of 
being able to do the kinds of vaccine trials internationally, 
in which information will be readily shared.

    You mentioned in your own statement, and in Resolution 42, 
the issue of the Global HIV Vaccine Enterprise. Just a word 
about that--this is a concept that was developed a couple of 
years ago, and in fact myself and others including Dr. Berkley, 
Dr. Gayle and others, were involved in putting together a piece 
in the scientific journal, Science, in which we called for, and 
spoke of, the need for an enterprise. As you correctly said, 
it's a virtual consortium of stakeholders, of funders, of 
scientists, who are dedicated to the common goal of developing 
an HIV vaccine. The reason why it's important is because it has 
become clear to us that the scientific obstacles were so 
imposing that we needed to have a commonality and a 
coordination in our effort. The basis and the fundamental 
infrastructure of this is a strategic plan which we've worked 
on for well over a year, and is now publicly available on a 
website for all to see. For any countries or other funders who 
want to get involved in HIV vaccine research, there is an 
agreed upon, strategic plan.

    One of the things that was in that plan was the question of 
developing centers that could do vaccine research. This was 
modeled after the highly successful NIH Vaccine Research Center 
on our campus in Bethesda, which goes from the fundamental 
basic research, up through and including the conduct of 
clinical trials. And when the President gave the endorsement of 
the G-8 in Sea Island in the spring of 2004, one of the things 
he put on the table is that we would get the ball rolling by 
initiating yet another extramural center that was mentioned in 
Resolution 42, and that is the Center for HIV/AIDS Vaccine 
Immunology, which we refer to as CHAVI. The review of the 
applications for these have been finished, and the winner of 
the award, which is a seven year award, will be announced 
within a reasonable amount of time this summer. We do hope that 
this will serve as an example for other nations and other 
funders to abide by that spirit of the Enterprise and of the 
strategic plan.

    Finally, let me just close with a comment that when one 
looks at how we might successfully confront AIDS in the 21st 
century, it is based very heavily on basic and clinical 
research that would call for treatment, care and importantly, 
the concept of prevention. And integral to the concept of 
prevention is the development of a safe and effective vaccine.

    Thank you, Mr. Chairman, and I'd be happy to answer any 
questions you have.

    [The prepared statement of Dr. Fauci follows:]

              Prepared Statement of Anthony S. Fauci, M.D.

    Mr. Chairman and members of the committee, thank you for giving me 
the opportunity to discuss the ongoing efforts of the National 
Institutes of Health (NIH) to develop a safe and effective vaccine for 
the prevention of human immunodeficiency virus (HIV) transmission. 
Today I will first briefly outline the daunting scientific barriers 
that must be overcome to develop such a vaccine, and then describe some 
of our domestic and global HIV vaccine research and development 
programs, including a major new international initiative to foster 
global collaboration and cooperation in research leading to the 
development of an HIV vaccine.

    Approximately 40 million people worldwide are now living with HIV/
AIDS. Sub-Saharan Africa is the hardest hit, with more than 25.4 
million people infected. South and South-East Asia together account for 
more than 7.1 million infected people, with 1.4 million more in Eastern 
Europe and Central Asia, 2.1 million in Latin America and the 
Caribbean, 1.1 million in East Asia, 1 million in North America, 
610,000 in Western and Central Europe, and 35,000 in Oceania. 
Approximately 14,000 people worldwide are newly infected with HIV every 
day.

    The first line of defense against any disease, and particularly an 
infectious disease pandemic, is prevention. Fortunately, we have proven 
ways to prevent HIV transmission. For example, in addition to the role 
that certain antiretroviral drugs play in the treatment of HIV-infected 
individuals, drug regimens have also been shown to dramatically reduce 
the risk of HIV transmission from mother to child in both developed and 
developing countries. Moreover, the risk factors associated with HIV 
transmission have been well defined, and prevention programs are 
operating to some extent in most nations of the world. In virtually all 
developed nations and in certain developing countries such as Uganda, 
Brazil, and Thailand, these prevention programs have proven effective 
in slowing the spread of the virus. Interventions that have been 
employed successfully include mass media campaigns; voluntary HIV 
testing and counseling; screening of donated blood; education and 
outreach to at-risk populations; behavioral modification programs, such 
as the promotion of abstinence and fidelity; abbreviated courses of 
antiretroviral drugs to prevent mother-to-child transmission of HIV; 
treatment for drug abuse, which could include measures to reduce the 
sharing of contaminated injecting equipment by injection drug users; 
and condom distribution. Missing from this arsenal of preventive tools, 
however, is an effective vaccine.

    Historically, vaccines have led to some of our greatest successes 
in the fight against infectious diseases, including the eradication of 
smallpox, the near eradication of polio, and enormous reductions in the 
disease burden imposed by measles, mumps, hepatitis, influenza, 
diphtheria, and many other infections. For virtually all infections, 
particularly viral infections, if the patient does not die, the immune 
system ultimately clears the infection and the person is immune to 
subsequent exposure to the infectious agent, sometimes for life. An 
effective vaccine preparation only needs to mimic the effect of natural 
infection on the immune system to prevent infection and/or disease upon 
exposure to the infectious agent in question.

    Smallpox, for example, was a terrible disease, but most patients 
survived and were protected thereafter by lifelong immunity. In 1796, 
Edward Jenner demonstrated in England that smallpox could be prevented 
by inoculation of a person with material from a cowpox lesion. This 
finding led to the development of a modern smallpox vaccine which was 
deployed globally in a massive campaign in the 1960s to eradicate 
smallpox from the human population, a goal that was achieved in 1979. 
Jenner's smallpox vaccine, like the modern equivalent, was based on a 
live virus that was closely related to the virus that causes smallpox 
but that did not cause illness. Vaccination primed the immune system to 
fend off infection if the person subsequently was exposed to the 
virulent smallpox virus. The Salk vaccine against polio, which became 
available in 1955, was based on a killed polio virus. Injection of the 
inactivated virus alone was sufficient to provoke an immune response 
that mimicked natural immunity and was capable of blocking infection 
upon exposure to the live, virulent virus.

    The scientific challenges that must be solved to develop an 
effective vaccine against HIV have proven more daunting than those 
challenges that scientists had faced previously. Perhaps the biggest 
obstacle is that immune-mediated eradication of HIV from the body, with 
subsequent naturally induced immunity, simply does not occur. Even 
after more than 60 million cumulative HIV infections since the 
beginning of the pandemic, there never has been a documented case in 
which a person with established HIV infection has completely eliminated 
the virus from his or her body. The fact that the immune system is 
apparently never able to defeat HIV on its own makes it more difficult 
for scientists to develop a way to induce a protective immune response. 
In other words, a vaccine that mimics natural infection will likely not 
be good enough. It must do better than natural infection in inducing 
what should ultimately be a protective immune response.

    We have gained a solid, if incomplete, understanding of how HIV 
evades and ultimately defeats the immune response. First, because the 
primary target of its devastation is the immune system itself, HIV 
disables the very cells that are responsible for fighting it. Second, 
HIV is a retrovirus, which means that it can integrate its viral 
sequence into the chromosomes of infected cells. Thus, the virus can 
shield itself from immune attack for many years, only to emerge when 
the infected cell is activated by the immune system to fight another 
infection. Third, HIV conceals the protein components that can induce a 
protective immune response, and therefore presents itself to the body 
in a way that makes it difficult for the immune system to respond 
effectively. Fourth, HIV is genetically diverse and rapidly changing, 
especially in its outer coat proteins; its mutability allows HIV to 
evade the modest protective responses the immune system is naturally 
able to make.

    All of these factors combine to create a scientific challenge as 
difficult as any we have ever confronted in infectious disease 
research. I do not believe it is an insurmountable problem, however, 
and we are doing everything in our power to meet this daunting 
challenge. Our activities include a strong program of basic research on 
HIV and the immune system, multiple initiatives to create and test new 
vaccine candidates, and development of a large, international network 
of clinical research sites through which vaccine candidates are 
evaluated. NIH leads the Federal effort for the development and 
evaluation of HIV vaccine candidates; the U.S. Centers for Disease 
Control and Prevention, the Department of Defense, and other Federal 
agencies collaborate in this effort. In budgetary terms, the 
President's Budget request for fiscal year (FY) 2006 for HIV/AIDS 
research at NIH is $2.9 billion. Of this, $607 million is for vaccine 
research and development; this figure represents a nearly six-fold 
funding increase for vaccine research over the past ten years and 
accounts for the majority of global HIV vaccine development spending 
worldwide. In fact, the NIH HIV vaccine program represents the largest 
public investment in HIV vaccines in the world.

    Development of a successful HIV vaccine candidate rests upon a 
foundation of basic research on the virus itself, including how it 
attacks the human immune system, and how the immune system responds to 
HIV infection. Since the earliest days of the pandemic, researchers 
have applied what they had learned about the virus to create vaccine 
candidates, which then were tested in both animals and human 
volunteers. In the 21 years since HIV was first identified as the cause 
of AIDS, we have made considerable progress not only on these basic HIV 
research questions, but also in our overall understanding of the 
structure and function of the immune system.

    These advances are now allowing us to pursue new vaccine 
strategies, and create new vaccine candidates that would have been 
impossible even a few years ago. In the early years of the pandemic, 
vaccine development efforts focused primarily on humoral immunity, that 
is, on the induction of specific antibodies that could neutralize the 
virus. From these studies, scientists discovered that it is 
extraordinarily difficult to raise antibodies that neutralize the many 
strains of the virus that circulate in the world. Because of this 
difficulty, development efforts have focused more recently on cell-
mediated immunity, which, in general, does not protect against initial 
infection but can stop progression of disease in animal models. The 
leading candidates that induce primarily cell-mediated immunity are now 
or will soon be in clinical trials that will determine whether this 
approach may have an impact on infection or disease progression. 
Researchers are now turning their attention to the identification of 
new vaccine candidates based on strategies that induce both humoral and 
cell-mediated immunity.

    Clinical testing of candidate vaccines is a key component of 
vaccine development. Once a candidate vaccine has been developed in a 
pre-clinical setting, the process by which the vaccine is tested in 
humans requires three distinct phases of evaluation. Phase I trials are 
the first human tests of a candidate vaccine, generally conducted on 
small numbers (10-30) of healthy adult volunteers. The main goal of a 
Phase I trial is to evaluate safety and, to a lesser extent, to 
evaluate the immune responses evoked by the vaccine. In addition, 
different vaccine doses and immunization schedules are compared. Phase 
II testing involves a larger number of volunteers (50-500) and is 
designed to generate additional safety data as well as information to 
refine the dosage and immunization schedule. Occasionally, preliminary 
efficacy data are gathered from Phase II studies. Phase III trials are 
the definitive test of whether a vaccine is safe and effective in 
preventing disease; these trials involve thousands of volunteers. 
Successful demonstration of efficacy in a Phase III trial can lead to 
an application for licensure of the vaccine. These three phases take 
several years to complete.

    Because most HIV infections occur in developing nations, HIV 
vaccine testing must in large part be carried out internationally. Many 
of the countries most affected by the HIV pandemic, however, have few 
resources and, in many cases, have virtually no public health or 
medical care delivery infrastructure. NIH has therefore developed an 
extensive network of clinical research sites in partnership with 
thirteen countries worldwide that are capable of conducting rigorous 
and ethically sound clinical trials of candidate vaccines. Since the 
1980s, NIH has conducted a total of 85 clinical trials of candidate HIV 
vaccines in the United States and worldwide, involving more than 18,000 
human volunteers. The majority of these trials have been Phase I 
immunogenicity and safety trials; nine such trials are currently 
underway. Others are larger Phase II studies designed to gather further 
safety data while beginning to shed light on possible efficacy. One 
large Phase III trial currently underway is testing a two-pronged 
``prime-boost'' strategy of two candidate vaccines that in combination 
induce immune responses quantitatively and qualitatively different from 
those induced by either component alone. Only one other candidate HIV 
vaccine, AIDSVAX, has undergone a Phase III trial, and it unfortunately 
did not prevent HIV infection.

    A few years ago, it became apparent that although the scientific 
research base was expanding rapidly and substantial resources were 
being devoted to HIV vaccine research by the U.S. government, 
international coordination of and support for HIV vaccine development 
efforts could be improved. In 2003, a group of scientists, of which I 
was a member, proposed the creation of a ``Global HIV Vaccine 
Enterprise'' to foster collaboration, cooperation and transparency in 
the conduct of HIV vaccine research on a global scale. The proposal, 
published in the journal Science, called for the creation of a 
``virtual consortium'' of independent government and non-government 
organizations committed to accelerating the development of a preventive 
HIV vaccine. President Bush proposed this concept of a Global HIV 
Vaccine Enterprise to the G-8 meeting of industrialized countries in 
June 2004, which endorsed it unanimously.

    Since then, the Global HIV Vaccine Enterprise has continued to grow 
and mature. It is important to note that the Enterprise is not a 
distinct organization with a hierarchical structure and formal 
leadership, nor is it a multi-national fund that centrally administers 
pooled resources. Instead, Enterprise partners will advance HIV vaccine 
research and development through the shared implementation of a 
globally developed strategic plan, mobilization of increased resources 
for vaccine development, and greater collaboration among researchers 
from participating organizations. The overarching purpose is to 
efficiently bring resources to bear on the gaps in HIV vaccine 
research, while at the same time allowing for flexibility in how 
research is carried out by the various participants.

    The strategic plan that will guide the Enterprise was published 
online in January 2005 in the journal Public Library of Science 
Medicine. Importantly, the plan concludes that the major difficulties 
encountered in the development of an HIV vaccine are scientific. The 
plan proposes five major activities to address the scientific 
priorities: (1) creation of HIV vaccine development centers or 
consortia to address the key scientific obstacles; (2) creation of a 
network of individuals and companies with vaccine manufacturing 
expertise to facilitate advancement of improved candidates; (3) 
development of a global system of laboratories that will standardize 
laboratory evaluation parameters; (4) sharing of common reagents; and 
(5) development of a network of clinical research training centers, all 
with the full engagement of scientists from developing countries.

    At the same time the President sought and obtained G-8 endorsement 
of the Enterprise, he announced that NIH would fund a major new 
research initiative, called the Center for HIV/AIDS Vaccine Immunology, 
or CHAVI. This initiative builds on existing Federal HIV vaccine 
research efforts, such as the Dale and Betty Bumpers Vaccine Research 
Center (VRC) located on the NIH campus in Bethesda, MD. Five years ago, 
NIH inaugurated the VRC, a single state-of-the-art facility that brings 
together scientists with different areas of expertise critical for 
rapid development of vaccines against HIV and other infectious 
diseases. The research scope of the VRC encompasses all stages of 
vaccine development, including basic research; design and development 
of vaccine candidates; preclinical testing; production of vaccine 
candidates; and conduct of human clinical trials to determine vaccine 
safety and efficacy. To date, the VRC has conducted or supported twelve 
Phase I HIV vaccine clinical trials. A VRC vaccine candidate designed 
to protect against the three major classes of the virus in the world 
will advance to Phase II clinical testing in the United States, Africa, 
South America, and the Caribbean in the coming year.

    CHAVI is based on the VRC model, but with two key differences: 
CHAVI will be dedicated entirely to HIV vaccine research, and unlike 
the ``bricks and mortar'' VRC, CHAVI will be a ``virtual center'' that 
will link scientists at multiple sites into a single functional unit. 
The mission of CHAVI will be to support intensive, coordinated, and 
multi-faceted approaches to address key immunological roadblocks to the 
discovery and development of a safe and effective HIV vaccine, as 
defined by NIH and as identified by the strategic plan of the Global 
HIV Vaccine Enterprise. We are now evaluating several very strong 
applications from groups of leading HIV researchers, and we expect to 
make an award this fiscal year. Funding for CHAVI will be provided for 
seven years; the award will be approximately $14 million in FY 2005 for 
start-up costs; funding for FY 2006 is estimated to be as much as $49 
million.

    In closing, Mr. Chairman, I look to the future of the HIV pandemic 
with both deep concern and great hope. Concern, because as bad as the 
situation is now, unless we can change the trajectory of the pandemic 
it will certainly become much worse. Hope, because I am optimistic that 
a successful vaccine candidate will eventually emerge, even though the 
scientific barriers to success are such that I cannot say when that day 
will come. In fact, success is likely to be only incomplete at first, 
and a partially effective vaccine will have to be studied and refined. 
Meanwhile, we at NIH will do everything in our power to successfully 
address as rapidly as possible the complex scientific obstacles to the 
development of an HIV vaccine.

    Thank you for this opportunity to testify before you today, and I 
would be happy to answer any questions that you may have.

    The Chairman. Well, thank you very much, Dr. Fauci. Let me 
just ask, how well can we anticipate the global community will 
keep up with providing treatments for HIV/AIDS? As we discussed 
broadly today--and we really can not get it down to a country 
by country analysis, but I made the assumption in my initial 
statement that treatment is occurring, but at the same time, 
the numbers of cases are outstripping the treatments, very 
rapidly--if this were thought of, some think about a war, maybe 
that's not the appropriate terminology, but it's like the war 
is not being won, the numbers are overwhelming us. How does 
treatment fit in to the process, including as you say, 
prevention, we have care and then hopefully, the vaccine, and 
why is a vaccine important? I think it is, and you do, too, but 
explain in the course of this tripartite approach, where all 
this fits?

    Dr. Fauci. Well, in fact, you just said it yourself, it's a 
tripartite approach, you can't do one without the other. We 
cannot abandon people who are already infected, so it's our 
responsibility to get treatment to them as well as care, and 
that includes care for orphans of the epidemic, children whose 
parents have passed away because of HIV.

    Prevention is paramount, because if you just look at the 
numbers, simple math will tell you that we have 5 million new 
infections each year, and we aren't even beginning to see the 
end of it, because we still haven't emphasized the potential 
new epicenters in Asian countries, such as China and India and 
other countries where you have over a billion people, and just 
a small percentage increase in infections spells out in tens 
and tens of millions of new infections.

    Now, just to answer specifically the question of treatment, 
over the past couple of years, there have been considerable 
strides made with the President's Emergency Plan for AIDS 
Relief, the $15 billion program over five years, the Global 
Fund, as well as bilateral agreements. The difficulty is that 
even though we're going in the right direction, the gap between 
people who need treatment, predominantly in developing nations, 
and those who are getting them, is still enormous. It's much, 
much better today then it was two years ago, but we can't be 
complacent and say, because we're making progress we don't have 
an awful lot to do. With regard to vaccine--as in any disease 
that's a communicable disease--it's an integral part of the 
prevention process.

    The Chairman. I appreciate that explanation. You will 
recall, I suspect, as we became involved as a Congress in this 
area, and began to think about appropriating money, there were 
divisions in our body, as well as at the White House, and what 
have you--when it came to prevention and treatment, there were 
some persons who devoutly felt that abstinence was the only 
course, and that prevention included that, but was a little bit 
broader, but the President, I can recall, in a very dramatic 
meeting in the East Room, when he asked me to be on the 
platform with him as a sponsor of this legislation, talked to 
the faith-based community and to others, about the fact that we 
needed to do both.

    We're extending that today to say both, plus vaccine. This 
has been perceived then, hopefully not now, as really a bridge 
too far. Something that's not a pie in the sky, but on the 
other hand, sort of off the charts in terms of reality. People 
say, get real, we have to deal with people here and now, which 
we're saying today, we do. It's not one or the other of these, 
but all three of the above.

    The importance of understanding that is tremendously 
valuable in the political context. Senator Boxer has asked, 
Senator Kerry, likewise, about various bills and initiatives 
we've offered, and some do better than others, some have had 
more enthusiasm and some find appropriations after we've 
authorized money, as you have found in your institution, but 
this is one of the purposes of our hearing today, to try to 
give more of a global approach, really, to our own legislative 
efforts.

    Now, let me just ask your own view about what has been 
called being a popular wave, a second wave of potential crises 
in various countries are often mentioned or omitted from that, 
but the thought is that quite apart from our concentration of 
attention on African states--Russia, China, various other very 
large, and India is mentioned from time to time--are turning 
into potential crises which may or may not being acknowledged 
completely by their governments, but the reality is in a world 
as small as ours, it's going to have enormous impact, whether 
people recognize it or not, but what is your own view about the 
second wave business?

    Dr. Fauci. Well, history has proven that that is indeed 
what is going to happen when people deny the realities of what 
HIV is and how it spreads in their societies, and I would even 
go beyond that, Mr. Chairman, and say not second wave, it's 
probably third or fourth wave. Because when the reality and the 
awareness in this country--mainly because of our health care 
delivery system and our ability to recognize infections--when 
it occurred in the early 80's there was this big wave in the 
developed world, and in the developing world, it was felt, 
``Well, there's not much of a problem there,'' when in fact it 
was smoldering and getting ready to explode, which is what 
happened in sub-Saharan Africa and the Caribbean. Absolutely, 
you can predict, as surely as we're talking to each other now, 
that the explosions are going to occur in countries, and we 
already have the indications, if you look in Eastern Europe, in 
Russia over the past year and a half, that has been the fastest 
growing caseload of HIV in the world. If you look at the slope 
of the increase in the number of cases. If you look at China 
and India, that's a disaster waiting to happen, particularly 
because of what we've seen in some quarters of people of those 
countries, they don't really admit that they have a problem. 
And if you don't admit you have a problem, you're not going to 
do the appropriate things to prevent that problem from 
exploding. So, I'm very concerned about the fact that there are 
people, and even leaders throughout the world who think as 
people have thought a decade or two decades ago, ``That's 
somebody else's problem, it's not going to happen to us.'' It 
is going to happen.

    The Chairman. I had an experience, just anecdotally, at the 
ultra pure laboratory in St. Petersburg, Russia, I was visiting 
the laboratory under a different set of circumstances, the Non-
legal Cooperative Threat Reduction Program during the few years 
that chemical or biological substances were involved in 
research there and were trying to persuade the employees to 
take up other courses, which they have been doing, with half of 
the employees doing some pharmaceuticals used in St. Petersburg 
hospitals. But, during the course of that visit, members came 
from Moscow to talk about AIDS in Russia. They said, 
essentially, what we heard in testimony here in this room a 
couple of days ago, that they felt that the cases were 
approaching a million in Russia, which was a sizable number of 
cases, largely unacknowledged by many parts of their 
government. They have administrative/legislative situations in 
Russia as we do here--people having different views.

    But we heard, disturbingly, two days ago from experts on 
Russia, that the population of the country might decline very, 
very substantially in the course of the next quarter century 
due to HIV/AIDS. We've already heard that due to the birth rate 
being lower, great problems of alcoholism and tuberculosis, 
that already there was an unusual demographic feature of 
Russia--a declining population of a major European state. But 
the suggestion was the decline might be all the way from the 
range of a 140 million persons, more or less, to something in 
the hundred tens, or a hundred twenty millions in the course of 
a quarter century of time, which is astonishing and has, of 
course, an enormous impact on a major country in the world 
today.

    So, this is a situation that could be compounded if China 
or India were not to take preventative measures as has been 
suggested by Ms. Judd earlier. The United States cannot intrude 
into the affairs of all of the countries, we can't surround 
their leadership, and say ``Do this and that,'' and so forth. 
The question is how, through our diplomacy, how people in your 
business, as you deal with professionals, can have an 
influence? In the same way as a local sailor has influence with 
these DUMA members, all of us in our various ways, perhaps, may 
have this kind of interest, and I appreciate your own specific 
leadership.

    Let me ask one more question and then I'm going to be 
recognizing my colleague--you've commented in testimony before 
other committees about the NIH budget and the problems that you 
have in conducting the vaccine research in the years ahead. You 
mentioned a little bit today about the new Center for HIV/AIDS 
and Immunology at NIH. Describe as best you can, what the 
budgetary problems are as you perceive that institution that 
you have founded, and its growth, give some dimensions, maybe, 
for the intermediate future.

    Dr. Fauci. Well, first, thank you for that question, Mr. 
Chairman. The budget for the NIH is a substantial budget, as 
you know, it's $28.6 billion. We have devoted greater than 10 
percent of our budget to HIV/AIDS, which is a substantial 
amount, it's about 11 plus percent of the budget, $2.93 billion 
for HIV, of which $607 million will be for vaccines.

    The issue that we're facing at the NIH is no secret, as you 
know, due to generosity of the Congress, we've been able--from 
1999 to 2003--to have a doubling of the NIH budget. But what we 
have now, this year and in previous years is a situation where 
the increase is, because of the constraints of budget 
throughout the government, is about a .5 percent increase. When 
you're dealing with a .5 percent increase in budget, a lot of 
the momentum that you may have built up during the doubling 
period, you have to re-look at it, and re-prioritize, so if we 
have opportunities, for example, for vaccine trials, we have to 
take a very careful look. We'll do it as best as we can, we'll 
spend the money we have, which is substantial, as best as we 
can, but when you have that kind of constraint, it may, in 
fact, cause a delay in certain projects that you would like to 
complete.

    The Chairman. I understand.

    I welcome now Senator Feingold to the hearing. Let me just 
mention to the witnesses and those who are in our audience, 
even as we are involved in this important hearing, the Senate 
is in the final stretches of debate on the energy legislation, 
which is important to the country, and likewise in the last 
hour we've had a visit from the Prime Minister of Iraq, with 
some of his Cabinet officials, which has occupied the Committee 
on Foreign Relations, understandably, some of our members. But 
we appreciate the appearances of members, it's duly noted, and 
we appreciate, especially, Senator Feingold coming over to 
raise some questions now.

    Senator Feingold. I thank you, Mr. Chairman, for that and 
for holding the hearing, and I thank you, Doctor, and all of 
the witnesses for your testimony and for your dedication to 
this issue that we all feel so properly compelled to focus on 
as often as we can, and the Chairman has been very helpful in 
that regard.

    Let me ask you just a few questions. My understanding is 
that the coordinating committee of the Global HIV Vaccine 
Enterprise has noted that the acute shortage of qualified 
personnel is a major bottleneck to conducting clinical trials 
in the developing world, and this seems to echo serious 
concerns about the overall state of health care infrastructure 
in many AIDS-affected countries, especially the problem of 
training and retaining qualified personnel. Doctor, what steps 
are being taken by the United States to improve the human 
resource capacity in the developing world, both in terms of 
clinical researchers, and more broadly in terms of health care 
professionals?

    Dr. Fauci. Well, with regard to what we at the NIH do, 
which is part of the broader issue that you mentioned, Senator, 
is that in our programs in our vaccine trial networks, our 
prevention trial networks and our AIDS clinical trial groups 
for therapy, we have a substantial training component to train 
people in-country. We've learned from our own experiences, from 
the experiences of the European countries, that when you go 
into a developing nation and just do your thing--noble as it 
may be--and get out, without leaving an intellectual capital 
infrastructure, as well as some physical infrastructure, then 
after a relatively short period of time what you've done, 
essentially, goes to attrition. So, we've made it an important 
part of the networks that we've created internationally, to 
train people who, in fact, would maintain and continue that 
intellectual capital in those countries, specifically in the 
area that we're responsible for. There are other areas, and 
namely the delivery of health care, of trying to train 
physicians, that in fact we need to do much better on. People--
not just physicians--physicians, health care providers, nurses 
and technicians.

    Senator Feingold. How do you keep people there under this 
technique that you've talked about, because I've heard this 
complaint in African countries from the Presidents of 
countries, concerning personnel, health care personnel, and 
health care workers. It's basically a complaint about donors 
and developed countries poaching some of the key health care 
people. Are there incentives being used to keep them there? How 
do you do that?

    Dr. Fauci. Not good enough, Senator, in that what we often 
see is that we will train people who will become really quite 
qualified, and within their own native country, after a while 
if they don't get the firm, long-term, committed support from 
their own nation, then they either move to something else or 
leave the country, because since they are trained, they know 
they can get a job someplace else.

    Senator Feingold. That's what I'm getting at, the concern 
about people going to Europe or the U.S. or elsewhere after 
they become quite proficient and enormously helpful in their 
own country.

    Dr. Fauci. So what we really do need, and we've not been 
successful, we need to put pressure on the nations that are the 
host countries to provide for the sustained support of those 
individuals, and that is not an easy thing to do, because 
you're essentially requesting another country to do something 
that they may not have the resources to do, or might not want 
to do. But it certainly is an appropriate thing to do, or we'll 
lose the people that we've trained.

    Senator Feingold: Maybe that's a targeted thing we could 
help with. To the best of your knowledge, does the U.S. intend 
to make any new proposals on the health care infrastructure 
issue of the G-8 meeting in Gleneagles?

    Dr. Fauci. To my knowledge, no, but I don't have the full 
knowledge of exactly what's going to be put--I know there are 
certain initiatives that will go on, but I do not know if that 
is one of them.

    Senator Feingold. Maybe we'll try to follow on that. Let me 
ask you another question--where does the effort to find 
microbicides that can halt the spread of HIV stand, and how 
much is being spent on this effort internationally? How soon 
might we expect to find something that can make a substantial 
prevention difference in this regard, and how much of the 
international funding is the United States providing for this 
effort?

    Dr. Fauci. Good question, and thank you for that question. 
In fact, microbicides, particularly over the past several 
years, has become one of the major initiatives that we have 
been pushing. We started off with something like $25 million, 
we now total up to about $70 million. Of particular note is a 
trial that was just started recently, an international trial 
testing two candidate microbicides in the United States and in 
sub-Saharan Africa--the site in the United States is in 
Philadelphia, there are three or four sites in sub-Saharan 
Africa to test two products, as you know, because the 
rationale, the need for a topical microbicide is quite 
important, particularly if you're dealing with societies or a 
societal infrastructure or philosophy where women really don't 
have any option to be able to protect themselves. You heard Ms. 
Judd mention the idea about allowing, for example, married 
women to use condoms, sometimes they can't negotiate the use of 
a condom, even within their own marriage, and end up being a 
battered wife. But if you had a good, successful microbicide, 
you could use it without even the knowledge of your sexual 
partner. So we are moving on this, I feel cautiously optimistic 
and confident that within a reasonable period of time, we will 
have a safe and effective topical microbicide. We certainly 
have made strides over the last year that are much better than 
they have been in the previous several years.

    Senator Feingold. What portion did you say was the American 
funding of the overall budget?

    Dr. Fauci. Our institute, it's about forty something; for 
the total NIH, it's about $70 million.

    Senator Feingold. Thank you, Doctor.

    Efforts to address public health crises in the developing 
world from polio to AIDS, as you know, are often hampered by 
some suspicions regarding the donor intentions. And there have 
been instances of improperly conducted research in the 
developing world that have sometimes lent some credence to 
these suspicions.

    What can you tell the committee about the ethics of vaccine 
trials and clinical research in the developing world?

    Dr. Fauci. That is something that we have paid considerable 
amount of attention to, because years ago, there wasn't that 
much attention. There may not have been flagrant violations, 
but there wasn't explicit attention paid to the ethics of a 
clinical trial, particularly of a vaccine.

    One of the things that we've initiated is that you don't go 
into a trial unless you have a clear cut plan that if the 
vaccine is successful that that vaccine will be made available 
to the country in which you have done the testing. So you can't 
use a country as a testing vehicle, without providing the 
benefit that if you're successful, you in fact would make that 
vaccine available to them. That's also very important.

    Also, we have a considerable number of training exercises 
now, particularly in the arena of informed consent, so that you 
get informed consent and education of the parties involved in a 
language and a venue that relates to them, not in a Washington, 
D.C., Boston, New York, discussion, but in a Kampala, Nairobi 
discussion. That's also something that I think has not been 
fully appreciated in the past, but is fully appreciated now.

    Senator Feingold. Finally, to what degree are governments 
in developing countries and local officials consulted about 
ethical standards and briefed on the procedures in place?

    Dr. Fauci. Intensively, in fact, you really can not, and 
should not, but you can not get a trial going in--for example--
the rural area of sub-Saharan Africa without the elders and the 
leaders, the cultural leaders of the tribes involved and of the 
populous involved to buy in fully to a trial. In fact, that's 
an important dilemma that we sometimes face, because when 
you're trying to get informed consent, not infrequently if you 
go into a community, the elders make informed consent for 
everybody--we've got to do both--we've got to get the buy in of 
the leaders, but you've got to make sure that individuals who 
participate are not swayed because their elders have consented 
for them, so you have to have both a broader, generic consent, 
as well as individual consent.

    Senator Feingold. Thank you, Doctor, for all the answers, 
thank you, Mr. Chairman.

    The Chairman. Thank you very much, Senator Feingold. I join 
the Senator in our thanks to you, Dr. Fauci, for your 
remarkable leadership every day at the Institute, and for your 
specific testimony which is most helpful this morning. Thank 
you very much, sir, we appreciate it.

    The Chair would like to call now a panel composed of Dr. 
Helene Gayle, Director, HIV/AIDS, Tuberculosis and Reproductive 
Health at the Bill and Melinda Gates Foundation, Seattle, 
Washington, and Dr. Seth Berkley, President and Chief Executive 
Officer of the International AIDS Vaccine Initiative in New 
York. We welcome the panelists, Dr. Gayle, I appreciate your 
coming this morning from a remarkable philanthropy effort by 
Bill and Melinda Gates and the foundation they have founded, 
and for your remarkable advocacy. I would like to thank also 
Patty Stonesifer, co-chair and President of the foundation with 
whom I had the privilege of collaborating on an article in the 
Washington Post this year, on January the 19th, entitled, 
``Speeding an AIDS Vaccine,'' at that time our office 
collaborated, I know with you, personally, to make certain that 
we had the facts straight, and that we knew what a remarkable 
initiative you have given.

    And Dr. Berkley, we appreciate especially your coming today 
and the remarkable work of you, personally, and your 
organization. We look forward to hearing from both of you, and 
I'll call first, I'll call upon you, Dr. Gayle, for your 
testimony.

STATEMENT OF DR. HELENE GAYLE, DIRECTOR, HIV/AIDS, TUBERCULOSIS 
  AND REPRODUCTIVE HEALTH, BILL AND MELINDA GATES FOUNDATION, 
                      SEATTLE, WASHINGTON

    Dr. Gayle. Thank you, I really want to thank you, as others 
have, for your committee and the leadership particularly as 
Chair to learn about the progress for developing a safe and 
effective HIV vaccine, and we really very much appreciated the 
Op Ed that you mentioned working along with our President, who 
is an Indiana native, as you know.

    We also know that in addition to your tremendous leadership 
in this area, all of the members, virtually all of the members 
of your committee have traveled and have taken on the issue of 
HIV/AIDS seriously, and have traveled to Africa and other parts 
of the world where HIV has really had a toll, and I think they 
all--as yourself--have returned even more committed to this 
issue. So, we really thank not only you, Chair, but also the 
committee for its leadership.

    As you mentioned, I direct the Gates Foundation efforts in 
HIV, TB and reproductive health, but I also am the co-Chair of 
the Global HIV Vaccine Enterprise. In the time that I have I 
want to briefly touch on our Foundation's work, but also 
highlight some of the issues related to the HIV vaccine 
Enterprise, and we have submitted a more detailed version of my 
testimony to be included in the record.

    I'm not going to reiterate the statistics that many people 
have already gone into here, I think we know them well, but 
suffice it to say, that HIV/AIDS represents the greatest global 
health challenge of our era. The epidemic has not, in fact, 
peaked as we talked about before, but instead, is relentlessly 
expanding throughout the world. And we talked about the issue 
of next wave countries that are going to have a huge impact on 
the global epidemic.

    Ultimately, we do need a preventive vaccine to end the 
spread of HIV worldwide, and the work in this area must be seen 
as one of our highest priorities. However, as several people 
have also mentioned, it's important that at the same time we 
recognize that this cannot be allowed to compete with the 
equally important need to expand existing HIV prevention and 
treatment services, so they must go hand in hand.

    Important progress has been made in the search for a 
vaccine, and developing an HIV vaccine is one of our 
Foundation's highest health priorities. To date, our Foundation 
has granted more than $126 million for HIV vaccine research, 
much of it, in fact, to the International AIDS Vaccine 
Initiative, NIAVI, and you're going to hear more from Dr. 
Berkley in a few moments.

    Thanks to the effort of institutions like the NIH, and 
NIAVI, and many, many others, we really do know a lot about 
HIV, much more than we did at the beginning of this epidemic, 
but despite all of this tremendous work, progress in finding a 
vaccine has been far too slow.

    So, let me just describe for a moment, Dr. Fauci alluded to 
it in some of his comments, the Global HIV Vaccine Enterprise. 
As he mentioned in 2003, the Foundation joined with more than 
20 leading international researchers in vaccine efforts, 
including Drs. Fauci and Berkley, called for a new global 
effort to address the roadblocks to accelerating the progress 
to vaccine research, and the Enterprise was launched and the 
Enterprise was born.

    This Enterprise is premised on the belief that finding a 
preventative HIV vaccine could be accelerated by a different 
kind of approach than the traditional research paradigm that 
has been used for much of the biomedical research in this 
country. That paradigm generally relies on more individual and 
a more independent approach, and it's been critical for 
stimulating new ideas, advancing our understanding of HIV and 
our body's response to HIV, but it's also created research 
silos, and a much less coordinated effort than we need for 
this, for developing this vaccine. This way of doing business 
is still going to be important, but by itself is not 
sufficiently targeted to most efficiently reach our target of 
an effective and safe HIV vaccine.

    The Global HIV Vaccine Enterprise is an international 
alliance of researchers as has been mentioned, and it also 
includes advocates, donor organizations, and others who are 
united in their commitment to work together to accelerate HIV 
vaccine research.

    Let me emphasize that the HIV vaccine Enterprise is not a 
new bureaucratic organization, and the Enterprise itself is not 
going to conduct biomedical research. Instead it is an alliance 
dedicated to increased focus, resources, and importantly, the 
collaboration and coordination of HIV vaccine research. It's 
guided by the strategic--the scientific strategic plan that Dr. 
Fauci mentioned in his comments, and I think importantly it 
included more then 120 people from 15 countries around the 
world to put that plan together and really look at what were 
the major scientific roadblocks, and propose a series of large-
scale, collaborative HIV vaccine research centers to address 
them and focus on accelerating progress in these areas. The 
plan also calls for increasing the capacity to conduct clinical 
trials, something that Senator Feingold alluded to in 
developing countries and also addressing some of the key 
challenges like intellectual property, manufacturing and 
regulatory issues in order to expedite vaccine research and 
eventually to expedite the delivery and the access of a safe 
and effective vaccine.

    One of the examples, the first example of support to the 
Enterprise was the vaccine center, the Center for HIV/AIDS 
Vaccine Immunology, which Dr. Fauci talked about. Another 
example in support of the Enterprise is the meeting of 
interested donors that the Welcome Trust, one of our major 
partners in the Enterprise will host on behalf of the 
Enterprise in October--as an effort to educate donors and help 
mobilize additional resources needed to implement the 
scientific plan. We hope that others will continue to follow 
the lead of NIH and Wellcome Trust and others in really 
focusing efforts around the strategic plan of the Enterprise.

    Several have already mentioned the U.S. Government's role 
in launching the Enterprise, and the birth of the Enterprise, 
you yourself mentioned that last year's Sea Island summit of G-
8 nations was really important in giving the political 
endorsement and also announcing the first financial 
contribution to support the Enterprise strategic plan, the 
Center that Dr. Fauci talked about. In two weeks G-8 leaders 
will again gather in the United Kingdom, and we hope that the 
upcoming summit meeting will generate a further and more 
specific affirmation of the G-8's commitment to the Enterprise, 
and we would appreciate and assistance that the members of this 
committee could provide in encouraging the Administration to 
advocate strongly for continued G-8 support for a robust, 
global HIV vaccine research effort.

    The challenge of creating this HIV vaccine will be a 
marathon, it's not a sprint. In working to strengthen the 
vaccine research effort, it's going to be important to 
understand that while a vaccine may not be achieved overnight, 
staying the course over the long haul is really what's key.

    Now let me suggest a few other ways that you and the 
committee could help. First of all, to arrive more quickly to 
the day when we will have an HIV vaccine, substantially more 
funding is needed for HIV vaccine research, and I think Dr. 
Berkley is going to discuss some of the funding issues, but we 
know that there's a tremendous unmet need.

    When our foundation recently announced the availability of 
up to $360 million new dollars to begin certain aspects of the 
Enterprise scientific plan, we received proposals equal to 
three times that amount. So clearly there is good science 
waiting to be funded. So that's first, more resources.

    Second, to engage--to increase the engagement of private 
industry in the search for an HIV vaccine, we recommend that 
the U.S. government significantly increase it's support for 
programs that provide incentives for private companies to 
conduct research on HIV vaccines and other global health 
technologies. With incentives, industry is in fact a willing 
partner. A good example of this is the Bio-ventures for Global 
Health, an initiative of biotechnology industries and 
foundations including ours to help small biotech firms conduct 
critical research into solutions like an HIV vaccine, we're 
very proud of this bio-venture, we just announced funding in 
support for this, and we think those kind of public/private 
partnerships are going to be the key in working on developing 
an HIV vaccine, and giving incentives for this is important.

    And third, as has already been mentioned by several people 
today, the need to support a comprehensive approach for HIV. 
This means making maximal use of all the prevention tools we 
have available. You yourself mentioned, Mr. Chair, we need a 
comprehensive approach that includes all the strategies that we 
know--to encourage abstinence, faithfulness, condom use, 
treatment of other sexually transmitted diseases, providing 
anti-retroviral treatment to HIV infected pregnant women, 
encouraging people to get tested--all of these things are going 
to be necessary to make a difference, if we really use these to 
reach the people who need them most. We know that we can reduce 
what is a preventable infection in large measure, just by using 
the things we already know exist and work if we use those 
fully.

    But we know that existing methods of prevention don't serve 
the needs of all populations and all life circumstances, and I 
think Ashley Judd talked about that in great detail. This is 
especially true for women who are now roughly represent one 
half of all new infections worldwide, and about 30 percent of 
new infections even here in this country. It is critical to 
invest in research on microbicides and other potential methods 
for women to protect themselves from HIV while we continue our 
search for a new vaccine.

    So, let me conclude with just a few words about the overall 
importance of prevention. Others have also hit on this issue, 
but prevention--reducing the spread of HIV is not only vital in 
its own right, but is also critical to the success of HIV 
treatment initiatives. Last year while the world scaled up 
treatment programs to deliver antiretrovirals to an estimated 
700,000 people, there were five million new infections. Unless 
the number of new infections is sharply reduced through 
prevention, treatment programs will quickly become 
unsustainable. In short, prevention helps preserve the promise 
of treatment for those who need it.

    Although the quest for a vaccine and other new prevention 
tools is daunting, I have no doubt that we can succeed. To do 
that, we need not only the world's best scientific talent, but 
also sustained political support, significant new funding and 
stronger collaboration within the field between developed, and 
developing countries.

    I'll close, but again, thank you for hosting this hearing 
and for your continued efforts to expand U.S. leadership in the 
fight to bring an end to AIDS, and I look forward to your 
questions.

    The Chairman. Well, thank you very much to Dr. Gayle for 
your very comprehensive and compelling testimony.

    [The prepared statement of Dr. Gayle follows:]

                 Prepared Statement of Dr. Helene Gayle

    Let me express my thanks to the Chair and this committee for 
holding this hearing to learn more about progress in HIV vaccine 
research. It is an honor to appear before you and with Dr. Anthony 
Fauci of the National Institutes of Health (NIH) and Dr. Seth Berkley 
of the International AIDS Vaccine Initiative (IAVI). Thank you also to 
Ashley Judd for your very informative remarks.

    I am Dr. Helene Gayle and serve as the director of HIV, 
Tuberculosis, and Reproductive Health at the Bill & Melinda Gates 
Foundation. I am also co-chair of the Global HIV Vaccine Enterprise, 
serving with Dr. Michel Kazatchkine, who is France's Ambassador on HIV/
AIDS and Transmissible Diseases. In addition, I serve as president of 
the International AIDS Society and co-chair of the Global HIV 
Prevention Working Group.

    In my testimony today, I will discuss the importance of an HIV 
vaccine in the fight against AIDS, the work of our foundation in 
supporting HIV vaccine research, the establishment of the Global HIV 
Vaccine Enterprise, and finally a few thoughts on the role of an HIV 
vaccine within the broader picture of HIV prevention and treatment.

    Last year, more people were infected with HIV than in any previous 
year. The nearly 5 million children, women, and men who were newly 
infected in 2004 brought the total number of people living with HIV 
worldwide to nearly 40 million. A few weeks ago, the Centers for 
Disease Control and Prevention (CDC) announced that here in the United 
States the number of people living with HIV topped 1 million. You are 
all aware of the human and financial cost that lies behind these 
numbers so I won't elaborate further, other than to say that the 
epidemic continues to outpace our efforts to contain it, and the road 
ahead is indeed long. More, much more, must be done now if we are to 
have a chance of beating this deadly virus.

    Ultimately, a safe and effective preventive vaccine offers the best 
long-term hope for stopping the spread of HIV. Put another way, there 
is no conceivable way to end this epidemic without a vaccine. Thus, 
global efforts in the vaccine field must be seen as of the highest 
priority, but should not have to compete with the equally important 
need to expand current HIV prevention and treatment services, or with 
other aspects of our efforts to fight poverty and eradicate disease.

    Much good research has been done, and important progress has been 
made toward a vaccine. Scientists across the globe have been working on 
finding a vaccine for about as long as we have known about HIV. The 
United States has been a leader in the global search for a vaccine, 
largely through the efforts of NIH, and also through the Army Medical 
Research program, the CDC, and countless laboratories in academic 
research institutions and pharmaceutical and biotechnology companies 
throughout the country. Our nation leads the world in biomedical 
research capacity, and so we have led the world in HIV vaccine 
research.

    These efforts have taught us a great deal about the virus: how it 
enters the body, establishes itself, multiplies, and evades and 
undermines the immune system. Though far from a cure, drugs have been 
developed that can, for many, substantially slow the impact of the 
virus. These antiretrovirals--ARVs--give hope to millions who are 
living with HIV infection.

    Yet despite all of this tremendous work, progress in finding an HIV 
vaccine has been too slow. If we measure the end of the pipeline for 
vaccine candidates, we see only a few drips. While a number of 
candidate vaccines have been tested in human trials over the last 18 
years, only one approach has completed the Phase III trials that 
ultimately are needed to establish whether something that worked in a 
test tube is effective in humans. Sadly, no candidate vaccine has yet 
emerged with demonstrated capacity to prevent HIV infection. Additional 
research progress is urgently needed to develop a new generation of 
candidate vaccines with a better chance of success than those currently 
being evaluated.

    All of us are disappointed that we currently lack a safe and 
effective preventive vaccine. Those of us who are participating in this 
hearing are united in our desire to make the search for an HIV vaccine 
as short as possible. An understanding of the history of vaccine 
research, though, helps us put into proper context the global effort 
that is currently underway. This year we commemorate the 50th 
anniversary of the vaccine against polio--the one developed by Jonas 
Salk. Few people remember that it took many years for Dr. Salk and his 
colleagues to travel from concept to an approved product. Indeed, the 
first two trials for the Salk vaccine occurred in the mid 1930s. 
Moreover, the vaccine that was successfully tested 50 years ago was 
subsequently improved by additional research.

    In the case of HIV, certain basic scientific questions remain 
unanswered, and critical areas of research merit substantially greater 
attention. In 2003, the Bill & Melinda Gates Foundation joined with a 
group of international researchers and vaccine experts, including Dr. 
Fauci from the NIH and other U.S. government officials, and Dr. Berkley 
from IAVI, to author an article in Science magazine that described 
these challenges in more detail and proposed a new global effort to 
address them. (I have attached a copy of this article and ask that it 
be incorporated into the record.) We called for creation of a global 
alliance, modeled in many ways on the Human Genome Project, to 
concentrate and accelerate the world's HIV vaccine research efforts.

    [The documents to which Dr. Gayle refers throughout her prepared 
statement can be found in the appendix to this hearing.]

    This was the start of the Global HIV Vaccine Enterprise, which is 
an alliance of researchers, advocates, donor agencies, and others 
united in their commitment to work together to accelerate HIV vaccine 
research. Soon thereafter, six working groups were established, 
bringing together some of the best scientists and advocates, to design 
a blueprint for action. Early this year, the results of their work were 
presented with the publication of the Enterprise's Scientific Strategic 
Plan. It identified six areas for concentrated work and collaboration:

          Vaccine Discovery: While vaccines for some other diseases 
        have succeeded by triggering an antibody response, there is now 
        a strong consensus that an effective vaccine for HIV will need 
        both to generate a broad-based antibody response that can 
        neutralize the virus and recruit and influence the immune cells 
        that suppress the virus's ability to replicate and evade the 
        immune system.
          The Strategic Plan proposes a two-pronged approach to broaden 
        the candidate pipeline. First, we should expedite rigorous 
        testing and comparative evaluation of candidates currently in 
        the pipeline, although none of these is believed to induce the 
        full range of immune responses that scientists believe will be 
        required. Second, new and better candidates must be developed 
        to widen the product pipeline. Simply put, we must speed up 
        clinical research on what we have, and push more vaccine 
        candidates into the pipeline.

          Laboratory Standardization: Improving collaboration and 
        strategic prioritization in the vaccine field requires that we 
        have a common way of understanding trial results and comparing 
        different candidates. We need to build tools and systems that 
        enable scientists working across the globe to compare their 
        work from one laboratory to another, and from one clinical 
        trial to another.

          Product Development and Manufacturing: Processes will be 
        needed for producing consistent, active vaccine batches on a 
        sufficient scale to meet the needs of large clinical trials and 
        eventually worldwide demand. Typically, manufacturing processes 
        are built slowly over time, as each vaccine candidate advances 
        from early clinical testing to late-stage evaluation and 
        licensure. Worldwide capacity for manufacturing new products is 
        limited and exists almost exclusively in the private sector, 
        which usually gears its capacity in the early years of a 
        product to address demand in high-income countries.
          The historic reliance on private industry for manufacturing 
        capacity may not meet the world's needs in the case of an HIV 
        vaccine. Few private companies are presently engaged in any 
        form of vaccine research, and many fewer still are involved in 
        HIV vaccine research. To address the manufacturing needs 
        associated with vaccine research, the number of private sector 
        organizations working on HIV vaccines should significantly 
        increase, and product development and manufacturing capacity 
        should be built in the non-profit and governmental sectors.

          Building Clinical Trial Capacity: Demonstrating that a 
        candidate vaccine works in humans is difficult, time consuming, 
        and expensive. Global capacity to conduct this research is 
        limited, especially the large Phase III studies that involve 
        tens of thousands of healthy human volunteers. Research on 
        vaccines and other new prevention technologies is best 
        conducted in parts of the world where HIV is hitting hardest 
        because this is where we most urgently need to know if a 
        vaccine is safe and effective. Yet these areas are already 
        reeling from the effects of the epidemic, and as we have seen 
        in the struggle to expand access to current prevention and 
        treatment services, there are simply not enough trained people 
        and adequate facilities to do this work at an accelerated pace.

          Building Regulatory Capacity: In this country, we all benefit 
        from the oversight provided by the Food and Drug 
        Administration, which helps ensure that medical products on the 
        market are safe and effective. This capacity does not exist or 
        is very weak in many of the countries hit hardest by AIDS, so 
        their ability to regulate HIV vaccine clinical research and to 
        ensure that clinical research is conducted safely and ethically 
        is quite limited. Weak national regulatory structures can 
        significantly delay the initiation of clinical trials and the 
        approval of new products.

          Intellectual Property Issues: Intellectual property issues 
        often inhibit the flow of information and dialogue among 
        researchers. To permit and encourage the active, real-time 
        collaboration needed to accelerate HIV vaccine research, a 
        framework is needed that allows organizations working on novel 
        vaccine candidates to share information openly without 
        compromising protection of their intellectual property. (I have 
        attached a copy of the full Strategic Scientific Plan and ask 
        that it be incorporated into the record.)

    Having identified these six core focus areas, the Enterprise aims 
to create new groups and mechanisms to the monitor the Plan and to make 
appropriate revisions as necessary.

    The Enterprise is not a new institution that will make grants or 
conduct biomedical research on its own, and the Enterprise's Scientific 
Strategic Plan is not intended to describe the entirety of HIV vaccine 
research. Rather, the Enterprise is an alliance for strategic planning, 
collaboration and information-sharing, and its Plan focuses on the key 
challenges that will most benefit from global collaboration. The 
Enterprise is premised on the belief that finding a preventive HIV 
vaccine could be accelerated by an approach that augments the 
traditional paradigm for biomedical research. The usual research 
approach relies principally on individual research teams, working 
independently from others, generating incremental progress. This way of 
doing business is still important but by itself may not be sufficiently 
targeted to most efficiently reach the goal of an effective HIV 
vaccine.

    To have a meaningful impact on the global search for a vaccine, the 
Scientific Strategic Plan must be shared with, and embraced by, others 
that have important roles to play. We hope that funders of HIV vaccine 
research will use the Plan to guide their allocation of new resources--
both to direct resources toward key challenges and to ensure that 
recipients of such funds adhere to the spirit of collaboration and 
transparency represented by the Enterprise. This doesn't mean that we 
want to stifle innovation. Just the opposite. We strongly believe that 
greater communication and collaboration are essential to speeding up 
our progress. One example of support for the priorities identified in 
the Enterprise Strategic Plan is the resources that NIH will make 
available for a new Center for HIV/AIDS Vaccine Immunology.

    In October, the Enterprise will convene a Funders Forum, hosted by 
the Wellcome Trust in London, to bring together those currently funding 
HIV vaccine research with those that could potentially provide 
additional resources. The Funders Forum will help current and future 
donors better understand the Enterprise and its Scientific Strategic 
Plan, and our hope is that it will also persuade them to use the Plan 
as a guiding tool in their funding processes. We are also hopeful that 
other donor countries and private foundations and businesses will soon 
be in a position to commit new resources towards the Enterprise plan.

    The Enterprise also intends to engage policy makers, advocates, 
clinical trial hosts and volunteers, regulatory and host government 
officials, and others. The first meeting of stakeholders was held in 
May of this year, also in London, and was co-hosted by the Enterprise 
and the United Kingdom's Department for International Development 
(DfID). We are also working to establish a permanent secretariat for 
the Enterprise and have launched an international search for its first 
executive director.

    The U.S. government has played a very important role in the birth 
and development of the Enterprise. At last year's Sea Island summit of 
G-8 nations, the U.S. shepherded through a strong statement of 
political support for the Enterprise and announced the first financial 
contribution to implement the Enterprise's strategic vision. (I have 
attached a copy of the G-8's endorsement to this statement and ask that 
it be incorporated into the record.)

    I was also very pleased that the goals of the Enterprise were 
highlighted in an op-ed in January, 2005 in The Washington Post by 
Chairman Lugar and by Patty Stonesifer, President and Co-chair of the 
Gates Foundation. (The op-ed is attached, and I ask that it be 
incorporated into the record.)

    Let me now briefly describe the work of our foundation in 
supporting HIV vaccine research. It is a critical part of our broader 
global health agenda, which focuses on a fundamental commitment by Bill 
and Melinda Gates to global health equity. It is both a philosophical 
premise that people shouldn't suffer from illness and disease simply 
because they were born into poverty, and an understanding that 
improving health is fundamental to fighting poverty and giving every 
child an equal chance at a safe and productive life.

    Our commitment to HIV vaccine research has been longstanding, 
initially reflected through our support for the International AIDS 
Vaccine Initiative, to which we have made grants totaling $126.5 
million. IAVI, which is based in New York City, is a not-for-profit 
organization that conducts HIV vaccine research through partnerships 
with private industry and developing world scientists and also 
advocates for a greater global response in this area. IAVI is a partner 
in developing the HIV Vaccine Enterprise. We also support the work of 
the AIDS Vaccine Advocacy Coalition, also based in New York and an 
Enterprise partner, which is a small organization with a big, informed 
voice that helps to monitor global progress on HIV vaccine research.

    More recently, we have helped to launch the Enterprise and are 
currently serving as its interim secretariat. The foundation announced 
in February a commitment of up to $360 million over five years to fund 
work on scientific priorities identified by the Enterprise Plan, 
including development of novel candidate vaccines and laboratory 
standardization. I should tell you that the response was overwhelming. 
We received more than $1.4 billion in requests for support, many of 
which were for serious, innovative research. We are now in the process 
of identifying those that best match the goals of our request for 
proposals, but there clearly is great, unmet demand by researchers.

    We are also committed to doing more over time. We work closely with 
our colleagues at the NIH, the Wellcome Trust, and other government and 
research agencies across the world to leverage our resources with those 
from others. We hope that more resources are forthcoming, because a 
significant gap exists between resources currently available for 
vaccine research and amounts needed to finance a robust research 
effort. IAVI has estimated that $700 million was spent worldwide on HIV 
vaccine research last year, including in the public and private 
sectors, and that as much as $1.2 billion per year may be needed to 
develop a more robust and comprehensive approach. That gap of $500 
million is about equal to what the NIH is currently investing in this 
area, so we need others to step up to the plate.

    Finally, let me describe how HIV vaccines fit into the broader 
context of the global effort on HIV/AIDS. Vaccines are part of the 
long-term strategy to prevent expansion of the epidemic. In all 
probability, we will not have a safe, effective preventive HIV vaccine 
for more than a decade. I would be delighted were my projection to 
prove too pessimistic, but this timeframe represents the best estimate 
among leaders in the field. Moreover, developing the kind of preventive 
vaccine that can halt the epidemic will likely happen in stages, with 
the first generation of vaccines protecting only some people some of 
the time, and then improving over time to protect more people all of 
the time. Because an estimated 95% of all new HIV infections occur in 
developing countries, we would also hope to see vaccines that require 
one shot instead of three, that would not need refrigeration, and that 
could be easily administered. This will take time.

    Even a very good vaccine will not be a silver bullet. It will take 
time to get the vaccine to those at risk. We see even today that 
vaccines that are cheap and effective sit on shelves while millions of 
children suffer and die needlessly. Our track record for getting 
vaccines to those who need them is poor. Even after a safe and 
effective vaccine emerges, we will also need to continue and possibly 
even expand our other prevention efforts.

    For the medium term, we see the importance of developing other new 
tools to expand options for slowing the spread of HIV. We know that our 
current strategies aimed at abstinence, faithfulness, condom use, 
treatment of other sexually transmitted disease, and encouraging people 
to be tested for HIV can make a difference if they reach the people who 
need these the most. HIV infection remains 100% preventable, but today 
fewer than one in five adults at high risk for HIV have access to 
existing prevention information or services. We also know that existing 
methods of prevention don't serve the needs of all populations and all 
life circumstances. This is especially true for women, who now 
represent roughly one-half of all new HIV infections worldwide and 
about 30% of new infections in this country. Many women are at risk for 
HIV not because of their own behaviors but because of the behavior of 
their male partners. It is critical to invest in research on 
microbicides, vaginal ointments or gels, female barriers like 
diaphragms or female condoms, and use of anti-HIV medications for 
prevention--these are all potential methods for women to protect 
themselves from HIV without requiring their partner's knowledge or 
permission. These will be our best hope for reducing the spread of HIV 
in the short to medium term.

    Providing life-preserving therapies, such as antiretroviral drugs, 
is a pressing global priority. At the current rate, however, another 
50-60 million people will have contracted HIV during the 10 years it 
might take to find an HIV vaccine. Unless the rate of new infections is 
sharply reduced through prevention, demand for antiretrovirals will 
rapidly outstrip the world's financial and technical means to deliver 
them. Effective prevention helps preserve the promise of HIV treatment.

    Let me conclude by suggesting what you can do to help:

          1. More funding is needed. We know that this is a familiar 
        refrain, and the American people have been extremely generous 
        in the global fight against AIDS. We need to continue to expand 
        our efforts and to do so at a faster pace. We will find an HIV 
        vaccine to help bring an end to this global nightmare, and that 
        day will come much sooner if researchers have the funding to do 
        their work.
          I mentioned earlier that the G-8 endorsed the Enterprise at 
        its summit last year. In two weeks, G-8 leaders will gather 
        again in the United Kingdom. We hope that the upcoming summit 
        meeting will generate a reaffirmation of the G-8's commitment 
        to the Enterprise, and we would appreciate any assistance that 
        members of this committee could provide in encouraging the 
        Administration to advocate for continued G-8 support for a 
        robust global vaccine research effort.

          2. We need to engage the private sector. There is a wealth of 
        talent and knowledge and experience in the private sector that 
        we must have to be successful, although too few companies have 
        joined this effort. The reasons aren't complicated: vaccine 
        research is risky, expensive, and the financial payouts are 
        small in comparison to more lucrative pharmaceuticals. 
        Moreover, we don't yet have enough candidate vaccines with 
        demonstrated efficacy in the test tube to excite private sector 
        investments. You can help by supporting the purchase and use of 
        vaccines that are currently available--there's no better 
        inducement to private investment than knowing that there's a 
        market ready, willing, and able to purchase their products. If 
        they see the vaccines we have now gathering dust on the shelf, 
        why should they believe that an HIV vaccine will be treated any 
        differently?
          We also need to increase support for programs that provide 
        incentives for private companies to conduct global health 
        research. With incentives, industry is a willing partner. A 
        good example is BIO Ventures for Global Health (BVGH), an 
        initiative of the biotechnology industry and charitable 
        foundations to overcome the market barriers, funding barriers, 
        and information barriers that have long restricted biotech 
        firms from conducting research into diseases that primarily 
        affect developing countries. BVGH is working with companies and 
        foundations to build new partnerships and is preparing a series 
        of business cases that describe market and funding 
        opportunities for biotech firms to increase their involvement 
        in global health research. In addition, BVGH has represented 
        the biotech industry in negotiations with finance ministers 
        over the role that advance purchase agreements can play in 
        spurring research into critical solutions like HIV and malaria 
        vaccines.

          3. We need to support a comprehensive approach to HIV. All 
        that you are doing now to support the expansion of prevention 
        and treatment services for HIV is extremely helpful in our HIV 
        vaccine research work. As an example, in the course of clinical 
        research on vaccine candidates, thousands of volunteers are 
        screened and tested. For this research to be ethical, they need 
        to be provided access to the best prevention and treatment 
        services available regardless of whether they are enrolled in 
        the trial. If the responsibility for providing these prevention 
        and treatment services falls onto the research project itself, 
        the financial burden is so substantial that the research itself 
        is inhibited. On the other hand, if other programs like the 
        Global Fund to Fight AIDS, Tuberculosis, and Malaria or the 
        President's Emergency Plan for AIDS Relief (PEPFAR) are able to 
        step in to fund those services, the research can move forward 
        without carrying the load for an entire community.

          4. We need your patience. This will be a long, tough road, 
        and there will be more failures than successes. That is the 
        nature of scientific research, and we need to know that you 
        will persevere with political commitment and resources until 
        we've accomplished our goal.

    I thank all of you, and particularly Chairman Lugar, for your 
interest in this area, your commitment to U.S. leadership in the fight 
against this terrible epidemic, and your special interest in supporting 
the global effort to find a safe and effective preventive HIV vaccine.

    Let me also acknowledge the tremendous leader we all have in Dr. 
Fauci. He has been a stalwart supporter of the Global HIV Vaccine 
Enterprise, and a real partner to our foundation in this and so many 
other areas of biomedical research.

    Thank you again for allowing me to share my thoughts with you. I 
look forward to your questions.

    The Chairman. I call now upon Dr. Berkley to continue this 
panel's discussion. Dr. Berkley?

 STATEMENT OF DR. SETH BERKLEY, PRESIDENT AND CHIEF EXECUTIVE 
 OFFICER, INTERNATIONAL AIDS VACCINE INITIATIVE, NEW YORK, NEW 
                              YORK

    Dr. Berkley. Thank you very much, Mr. Chairman, for the 
opportunity to appear before you to discuss the state of 
vaccines and also to talk about IAVI. We appreciate your 
interest in this critical matter because obviously we need to 
continue to work on this over the future and we'd also like to 
commend what the United States has done in responding to this 
terrible epidemic. The U.S. really has been the leader, we 
applaud what President Bush and the Congress has done to try to 
get out these treatments and push prevention and the important 
research that Dr. Fauci talks about.

    The focus on the short-term emergency, which is what most 
of it is about, is critical and appropriate, but without these 
better tools, we're not going to be able to end the epidemic, 
as you've heard from the other speakers. Just to emphasize, and 
I think you brought this up in your question, the goal must be 
to the end this terrible epidemic, and if we lose sight of that 
goal we can get caught up in the day to day needs of both the 
existing prevention technologies today, as well as treatment as 
a critical issue. As a result, we were really happy with the 
U.S. leadership at the G-8, and hopefully, as Dr. Gayle has 
said, that that will continue for this year, your resolution 
that just has been submitted is quite important, as is the 
other work of the members of the committee.

    On behalf of my organization, IAVI, I also would like to 
express appreciation for the financial and political support 
that this country has provided to our organization. Our mission 
is to ensure the development of a safe and effective, 
accessible, preventive HIV vaccine for use throughout the 
world, and our particular focus is developing countries. We 
represent true collaborations in our science and policy 
programs, and I think what's important is that we bring with 
us, not only the U.S. government, but seven other governments 
who support the important work going on, the European Union, 
which has been slow to support these activities, is an active 
supporter now, the World Bank, a range of corporations, a range 
of private foundations, Dr. Gayle has already talked about the 
Bill and Melinda Gates Foundation, but also Rockefeller, Sloan, 
Starr, AIDS charities, et cetera.
    Your funding has really created a unique model of an 
efficient and global non-profit public/private partnership, and 
we're committed to work with the best in the world, not in any 
one country. So, whether that be in London, whether it be in 
Nairobi, or New Delhi, whether it be in Ohio, or Washington 
State, whether it's a small company, privately traded, a larger 
bio-tech, publicly traded, or frankly, a large vaccine 
manufacturer, individual researchers, or the outstanding team 
of scientists that Dr. Fauci has working at the NIH, we can 
demonstrate partnership and efficiency. In fact, we're very 
happy that the NIH has recently decided to test one of their 
candidates at two of the sites IAVI has developed in Africa. 
This is a tribute to the types of partnerships we've created on 
the ground in the developing world with the key stakeholders 
and the political support that's associated with this. And this 
is really the type of collaborative work that IAVI and other 
groups represented today recognize as important in creating the 
Global HIV Vaccine Enterprise. We're a founding member of this, 
and we really welcome the opportunity to share our global 
experience, expertise and model of innovation with many others.

    You've already heard today, without a vaccine, we are not 
going to be able to get rid of this epidemic, and the virus is 
always on the move, we didn't talk about that, but drug 
resistance is spreading and the virus is constantly changing. 
As a physician, I believe that every life is sacred and 
providing treatment is absolutely critical, and of course we 
must do everything to prevent every new infection we can, for 
the reasons Dr. Gayle has said, however, the current prevention 
and treatment strategies, which is the question on the table, 
are only partially effective. So therefore, we absolutely have 
to go ahead and push forward on a vaccine, and one of the 
important points is that lifetime treatment is the only option 
for those infected. And the drug toxicity and viral resistance 
spreading--this does not bode well for a global, sustainable 
response. And as this committee was responsible for thinking 
about overseas development aid, this is something that is going 
to continue to expand unless we do something to stop it.

    So, we need to think of the work on vaccines, not only as 
pushing the science forward, but really as a way to avert these 
future treatment costs, which are going to be an enormous cost 
for public treasuries around the world, and not only developed 
countries, but in developing countries. These costs will 
bankrupt their ability to do the broad range of issues, whether 
it be women's education, other vaccine work, water and 
sanitation, because the focus on AIDS is taking up so much 
money. So we really have to go ahead and get a vaccine.

    Why don't we have one after 20 years? Science does remain 
the greatest challenge, but we really have good reason to think 
the science is solvable. From the effort today, we know that 
monkeys can be protected by certain types of vaccines, but that 
people get immune responses and hold the virus in check for a 
long time and suppress it. We also have now found individuals 
who make the right type of antibody response. So, building on 
these, we have to take the best in academic science, and we 
have to connect that to the best in industry. This is a 
critical important point.

    This epidemic, the worst infectious disease epidemic since 
the 14th century, compels us to work as quickly and efficiently 
as possible, and our paradigm as an organization is premised on 
a focused business model to enable us to do that.

    Ten years ago, and people asked about this, the total 
global spending on AIDS vaccine research and development was 
less than $160 million--that's public, private sector, 
philanthropic, all of it. And obviously that was clearly 
inadequate, particularly given how complex it is to make a 
vaccine, as Dr. Fauci explained. At that time a lot of basic 
research was done, but with little emphasis on product 
development, and whatever product development work was being 
done was focused on countries where the markets were best, and 
not where the epidemic was spreading quickly.

    The private sector where most of the expertise resides, 
stayed on the sidelines because of the scientific challenge, 
because of the political controversies, because of the unclear 
market and resultant financial risks. As a result, we were 
established in 1996 to fill that gap between the public and 
private sectors, and to establish a new model.

    IAVI is now working in 23 countries, and has raised almost 
$400 million in new funds, and I'm very proud of the work that 
the team has done on the ground, not only here in the U.S., but 
in Africa, in India we've talked about a number of times, and 
in Europe in such a short time. In nine years since we've been 
founded, we've brought six different candidates from the 
laboratory to the clinic for testing on human volunteers in 
nine countries. And those countries now have a high quality 
infrastructure to conduct clinical trials and analyze results, 
and obviously this quality is critical, Senator Feingold asked, 
because safety of participants is absolutely critical to being 
able to do this.

    We are now the largest funder of vaccine research in 
Europe. That's a disgrace, and one of the things we need to do 
is figure out how to increase European investments. We also 
brought the first vaccines forward in India, and in many of the 
African countries that are now engaged.

    So, we're now working on new ways to take this innovative 
model, using industry-like paradigms to bear on trying to solve 
some of these scientific questions that Dr. Gayle has talked 
about, and then to design immediately new candidates and test 
these--that fast process is critical. We have an example of 
this in the Neutralizing Antibody Consortium, which brings 
together the government, academia and researchers, and together 
they are trying to solve this problem.

    The other critical point is that developing countries are 
critical to being involved in here, because the incidence of 
HIV infections is highest. They need to be full partners, 
because they can not only ensure that the trials go well, but 
that they have manufacturing systems, they have scientific 
groups that can help, and that communities are ultimately 
prepared for the distribution and use of vaccines, which is a 
critical issue we're going to have to do at the end.

    Countries like India have a science and technology field, 
they've got vaccine manufacturers, in fact, most of the 
vaccines for UNICEF now are made in India, so getting them 
engaged is critical. And this is not only important for the 
vaccine effort, but also provides a meaningful, sustained 
development effort that will build on their scientific 
capability, and that's going to have long-term benefits for the 
communities, including for the distribution of the other 
preventions and the treatments we've talked about. We also have 
to make sure that we do think about accessibility now, because 
that has been the way other vaccines have not been able to be 
used, and we need to work with religious leaders, political 
leaders, community leaders, in doing that.

    The private sector is something that hasn't been mentioned 
enough here, because we need their expertise. They are the only 
people who have made vaccines in the last 50 years, and 
yesterday we announced a new partnership with Glaxo-Smith 
Kline, one of the world's largest manufacturers, to move 
forward a vaccine for Africa, and this is really important 
because they are committed to bringing all of their 
technologies to bear, along with our technologies, and to try 
to accelerate them forward. And, of course, like all our 
partnerships, there exists an agreement that this will be made 
available at a low price in adequate quantities for the poor 
living in the developing world, so a new paradigm working, 
that's important.

    So, my asks for this committee are obviously to sustain and 
continue the leadership and commitment that's here. This does 
need more funding, you've heard that from Dr. Gayle and Dr. 
Fauci. The world is now spending a little less than $700 
million, this is hundreds of millions short of what we believe 
is needed, and what does that mean? We believe that there ought 
to be a program that is absolutely optimized for success in the 
shortest period of time. The cost of the epidemic now is $25-
$30 billion a year, so optimizing that program and getting 
every single vaccine that's out there tested and all the ideas 
jumped on is absolutely critical. Ninety percent of the 
expenses are coming out of the United States, most of this is 
from the public sector, so these are things we need to change. 
We think the world ought to be spending about $1.2 billion 
globally to do this.

    The other issue is that new incentives for industries Dr. 
Gayle has talked about are critical, an advanced purchase 
commitment, a legally binding agreement to pay a decent price 
to companies that successfully make an AIDS vaccine for use in 
the developing world, would help overcome the substantial 
scientific and commercial risk that industry currently faces, 
and industry has really come out for this, and as you know, 
this is on the G-8 agenda in Gleneagles, and we hope that the 
U.S. government will support the leadership of the U.K. 
Treasury in this, and we were with Chancellor Brown two days 
ago discussing this.

    Other important incentives include liability protection and 
tax credits as Senator Kerry talked about, and we're also 
delighted the new bio-defense legislation, under consideration 
by the Senate will also include now major diseases of poverty, 
AIDS, malaria and TB, and so we're very optimistic that 
Congress will continue to set this example for all countries, 
rich and poor, to make sure that these technologies are 
included.

    The other issue that the Committee on Foreign Relations 
could do is to encourage the PEPFAR, Global Fund and the World 
Bank to ensure that communities where critical prevention 
research is being conducted are prioritized for voluntary 
counseling and testing services and antiviral treatment. This 
collaboration of synergy would appropriately reward those 
communities engaged in this absolutely critical research, and 
make U.S. efforts more successful in building capacity for 
research in these countries. So, I thank you for very much for 
the opportunity to speak to you and tell you what IAVI is 
doing.

    [The prepared statement of Dr. Berkley follows:]

                 Prepared Statement of Dr. Seth Berkley

    Mr. Chairman, thank you for this opportunity to appear before you 
and other members of this Committee to discuss the state of vaccine 
development globally and to describe the work of the International AIDS 
Vaccine Initiative, IAVI. We appreciate your interest in this critical 
matter and we look forward to working with you and other Senators in 
the future. Your role is crucial to ensuring adequate resources and 
incentives to accelerate vaccine development.

    The United States has been a leader in the global response to this 
terrible epidemic, and it must continue to lead. We applaud President 
Bush and the Congress's work to significantly expand AIDS treatment and 
prevention in the countries hit hardest by this disease. This focus on 
the short term emergency is critical and appropriate, but without 
better tools, we will not be able to end this terrible epidemic. And 
that must be our goal; to have an effective end game strategy. As a 
result, we were also gratified by the outcome of last year's Group of 
Eight summit, chaired by the United States, which called for increased 
resources and coordination to accelerate the development of a 
preventive vaccine. Senator Lugar, we welcomed your leadership in 
introducing a resolution on AIDS vaccines in the wake of last year's G-
8. We hope that this year's G-8 summit will agree to fulfill its 
earlier commitments and undertake creative and concrete new incentives 
to spur research and development. We also applaud the important work on 
global AIDS undertaken by other members of this Committee.

    On behalf of the International AIDS Vaccine Initiative, I want to 
express appreciation for the financial and political support provided 
by the United States to our organization, whose mission is to ensure 
the development and delivery of safe, effective, accessible vaccines to 
prevent HIV infection around the world, with a particular focus on 
developing countries hit the hardest by HIV/AIDS. IAVI's scientific and 
policy programs represent true collaboration and have also attracted 
funding from seven other governments, the European Union, the World 
Bank, corporations, and private foundations such as the Bill and 
Melinda Gates Foundation and the Rockefeller, Sloan, and Starr 
Foundations. Your funding has helped create a unique model of an 
efficient and global non-profit public-private partnership, committed 
to collaborating with the best scientists around the world, whether in 
London, Nairobi or New Delhi; in Ohio and Washington State; whether 
with a small biotech company, a large vaccine manufacturer, a leading 
academic researcher, or the outstanding scientists of our own 
government, including Dr. Fauci's team. Indeed, we are delighted that 
NIH has decided to conduct a test of one of their AIDS vaccine 
candidates at two of the sites IAVI developed in Africa--a tribute to 
the partnership we have fostered with developing country researchers 
and other key stakeholders in the field. This is exactly the type of 
collaboration that IAVI and other groups represented today recognize as 
critical, and the basis for our joint establishment of the Global 
Vaccine Enterprise. IAVI, as a founding member of that Enterprise, has 
welcomed the opportunity to share our global experience, expertise and 
model of innovation.

    As you know, Mr. Chairman, the devastation caused by HIV/AIDS is 
almost unprecedented in modern times. The facts are staggering: five 
million people worldwide are infected with HIV each year, including 
over 40,000 Americans. More than 20 million people have died of AIDS 
and it is likely that more than 100 million will have been infected or 
died of this disease before we have a vaccine. For the first time since 
the height of the epidemic in the US in the 1980s, more than 1 million 
Americans are infected and living with the virus that causes AIDS.

    As you have already heard today, without a vaccine, the infection 
will always be with us and always on the move. As a physician, I 
believe that every life is sacred, and so providing treatment is 
vitally important. We must also focus on doing our best to prevent each 
and every new infection. However, current prevention strategies are 
only partially effective, and with lifetime treatment as today's only 
option for those infected, and with drug toxicity and viral resistance 
spreading, this does not bode well for a sustainable global solution. A 
preventive vaccine is the best long-term solution to blunting and 
ultimately ending the epidemic. Without one, the epidemic will continue 
to spread personal tragedy and economic hardship as well as political 
instability. Funding vaccine research is also an important investment 
in averting future treatment costs--an enormous future burden for 
public treasuries around the world. Like all other viral infectious 
diseases, ultimately the most medically and economically effective 
prevention will be through a vaccine.

    So why don't we have an AIDS vaccine after 20 years? Science 
remains the greatest challenge, but we have good reasons to believe 
that we can solve the scientific challenges that currently stand in our 
way. From our efforts to date, we have learned many useful things. 
Monkeys can be protected by certain types of vaccines; most people 
develop immune system responses that suppress the viral infection for 
years; and we are beginning to uncover individuals who make some 
promising antibody responses. We can build on these, but to do so, we 
need to match the best in academic scientific research to the best in 
industry. The magnitude of this epidemic, the worst infectious disease 
epidemic since the 14th century, compels us to work as quickly and as 
efficiently as possible. The IAVI paradigm is premised on this focused 
business model and has enabled us to do exactly that.

    Ten years ago, total global spending on AIDS vaccine research and 
development was less than $160 million. That may sound like a lot of 
money, but given the high cost of biomedical research and product 
development, especially against a foe as dreadful and complex as HIV, 
it was woefully inadequate. Basic scientific research was conducted, 
but very little emphasis was placed on actually developing a product, 
and what little product work was being done, was not designed to ensure 
its applicability for use in the countries that have the worst 
epidemics. The private sector, where most vaccine product development 
expertise resides, generally stayed on the sidelines, because of the 
scientific challenges, political controversies, unclear market and 
resultant financial risks. To address this situation, IAVI was founded 
in 1996 to fill the gap between the public and private sectors and to 
establish an innovative new way of tackling global health crises.

    Mr. Chairman, IAVI is now working in 23 countries and has raised 
almost $400 million in new funds. I am very proud of the progress my 
team in the U.S., Africa, India and Europe has made in so short a time. 
In the nine years since we were founded, IAVI and its international 
partners have brought six vaccine candidates from the laboratory to the 
clinic, for testing in human volunteers in nine countries--countries 
that now have high quality infrastructure to conduct clinical trials 
and analyze results. Quality is critical, as the safety of all our 
participants is of paramount importance to us and to the global effort 
we are attempting to create. We are also now working in innovative ways 
to bring the industrial model to bear by harnessing recent scientific 
advancements to answer critical scientific questions, and to use that 
information to design and test new candidates. New models of applied 
research and collaboration--such as the neutralizing antibody 
consortium of government, academic and industrial researchers--are 
critical if we are to solve these enormously difficult scientific 
challenges.

    It is critical that developing countries conduct AIDS vaccine 
trials because the incidence of new HIV infections is among the highest 
in these areas. We welcome them as full partners in these efforts so 
that they ensure that trials go well, their manufacturing systems are 
available to help with product development, and that communities are 
prepared for the ultimate distribution and use of vaccines. Some of the 
emerging technological innovators such as India have enormous 
scientific talent to bring to the effort. Our activities in these 
countries will not only advance vaccine development, but provide very 
meaningful and sustainable development assistance that will provide 
long-lasting benefit these communities, including for current 
prevention and treatment efforts. We will also continue to engage with 
political, religious and community leaders in developing countries to 
ensure that once a vaccine is available, the vaccination effort 
succeeds at the grassroots level. We have been pleased by the enormous 
level of political will that many countries have now demonstrated in 
support of vaccine development.

    We are also committed to engaging the private sector, because we 
need their unique expertise to accelerate the development of a vaccine. 
To that end, IAVI recently entered into our first product development 
agreement with a major global vaccine manufacturer to focus on vaccines 
designed to elicit immune responses against variants of HIV that 
circulate predominantly in Africa, although of course the ultimate goal 
of the collaboration is to develop vaccines that would be applicable 
worldwide. Like all of our partnerships, our agreement contains 
provisions to ensure that any AIDS vaccine that emerges will be made in 
adequate quantities and will be accessible to the poor living in 
developing countries.

    I ask for your sustained and increased leadership and commitment. 
Research into designing and testing AIDS vaccines needs more funding. 
Today, total global spending including basic research, product 
development and clinical trials to develop a vaccine still is less than 
$700 million, hundreds of million short of what we believe is needed 
and a very small percentage of total spending on AIDS. IAVI and its 
partners in the Global Vaccine Enterprise estimate that approximately 
$1.2 billion needs to be spent annually in the coming years to speed 
the discovery and licensing of an AIDS vaccine. More incentives are 
needed to harness the expertise of the biopharmaceutical sector. An 
advance purchase commitment--a legally binding agreement to pay a 
decent price to companies that successfully make an AIDS vaccine for 
use in the developing world--would help overcome the substantial 
scientific and commercial risks they currently face. Other important 
incentives include liability protection and tax credits. We are 
delighted that new biodefense legislation under consideration by the 
Senate will also include the major diseases of poverty--AIDS, malaria 
and tuberculosis. We are optimistic that the United States Congress 
will continue to set an example for other all countries--rich and 
poor--in making vaccine development a priority and ensuring that it is 
included as part of the comprehensive HIV/AIDS agenda.

    The Foreign Relations Committee could also encourage the PEPFAR, 
the Global Fund, and the World Bank to ensure that communities where 
critical prevention research is being conducted are prioritized for 
voluntary counseling and testing services and antiretroviral treatment. 
This collaboration and synergy would advance prevention, treatment and 
research, would appropriately reward communities engaged in important 
global research, and make U.S.-funded efforts more successful and 
sustainable by building long term research capacity in these developing 
countries.

    I thank you for this opportunity to highlight the need for a 
preventive AIDS vaccine and IAVI's efforts to develop a vaccine, and I 
look forward to answering any questions you may have.

    The Chairman. Well thank you very much, Dr. Berkley. I want 
to ask both of you to comment further because you have already 
highlighted some specific ways in which the pubic/private 
partnership is operating, and by that I am include foundations 
with governments and with private enterprise--is the Enterprise 
idea one that's, since this coordination, how does it fit? I'm 
trying to get some scope of who's in charge of this? And no one 
can be completely, we're dealing with several different nation 
states, we've got the G-8 meeting to try to coordinate at least 
eight of those states successfully, foundations that are 
prominent in this country, hopefully some are elsewhere 
likewise, and of course, you have mentioned, Dr. Berkley, 
ideally that private firms obtain an order or a commitment for 
a substantial amount of business in the event that they make 
commitments up front now, they're helpful. And so you might 
want to elaborate further, because that would be an important 
incentive, perhaps, but discuss if you can again, more broadly, 
given this invitation, first of all Dr. Gayle, this partnership 
among these various classifications of entities in the large 
world, so that we are the most effective in coordinating what 
we are doing, have some metrics to determine how much progress 
is occurring.

    Dr. Gayle. Right, thank you for that question, because I 
think sometimes this concept of the Enterprise, because it's 
not directly funding, or conducting research, is sometimes 
difficult to get a grasp of, but I think in some ways it's the 
most analogous to the human genome project, it was not an 
entity, but really a collaboration between the major partners 
that united around a blueprint, so that's the same as our 
scientific strategic plan, united around the highest priority 
areas that we think can make the biggest difference towards 
developing an HIV vaccine. So we have a plan that we hope that 
additional funders will fund against, and that's a critical 
part of it. But we also have an international steering 
committee, the coordinating committee, that is 19 people from 
multiple different countries including India, two countries in 
Africa, several European countries as well as the United 
States, and that coordinating committee is the body that 
convenes to make sure that the Enterprise is moving forward.

    The Chairman. How often do they meet so I have an idea of 
the governance situation?

    Dr. Gayle. Well, so far we have met three times over the 
last 15 months. Since this is still in the launch phase in many 
ways, I think we still have to see how often we'll meet, but at 
least twice a year, and then there's sub-committees of this 
coordinating committee that have met to look at development, 
overall development, to look at something as straight forward 
as the selection of the executive director, because we still 
are in the search for an executive director. The interim 
secretariat of the Enterprise is right now with the Gates 
Foundation, so we have agreed to provide the initial support to 
get this launched, but we don't want it or don't think that it 
should stay within the Gates Foundation, and it will become its 
own entity with an executive director, a steering committee, 
forums where donors can meet, forums where other stakeholders 
can meet, and importantly, forums that bring together the 
scientific community that is collaborating around the 
scientific plan.

    The Chairman. So, you have Enterprise as sort of the 
overall plan?

    Dr. Gayle. Right, exactly.

    The Chairman. And then the coordinating committee, the 19 
members as you've mentioned, plus sub-committees undergirding 
their activity, and a search for an executive director, but 
meanwhile, the Gates Foundation's serving that purpose, 
although as you've indicated, you would prefer to pass that 
along to someone who's identified by the 19, but I think that 
gives a good idea, at least to the general public, as well as 
the members of this committee that there is some plan there. So 
all of these efforts that we're mentioning may be parts of that 
plan, people may come into this in some way, but the 
coordinating committee hopefully is overlooking the whole thing 
to make sure there are not some elements of the plan that are 
forgotten all together, or are not addressed, is that correct?

    Dr. Gayle. Exactly, and part of the role of the 
coordinating committee is to be the guardians, if you will, of 
the strategic plan, and to make sure that all elements are 
fully developed and that they are kept up to date as our 
science advances, and as we keep evolving the search for an HIV 
vaccine.

    The Chairman. Dr. Berkley, you mentioned this company, 
Glaxo Smith Kline collaboration the last day or two they were 
involved, but let me ask you from your perspective--clearly 
there's been an ongoing dialogue as to why companies that 
gifted in pharmaceutical products and not simply tackling this 
head-on and sort of solve the problem, and the spirit of 
enterprise that we often get with this. Now, granted it's a 
very difficult problem, or set of problems that are involved, 
and the scope of the capital, and the risk that is involved in 
this is very substantial, and so you double back by pointing 
out one way that you offer some incentives, is that at the end 
of this there are orders for pharmaceutical products, or 
whatever the product is that's going to work in this thing, 
with the idea that it needs to be at least relatively 
inexpensive, given the numbers of cases all over the world that 
need to be treated.

    And, sort of give some idea, sort of at the end of the 
rainbow of this. How is, whatever is going to be produced, 
physically, who may do that? In this country or around the 
world, how much it may cost, how are we likely to have 
something that has the expense elements that lead to high 
distribution, as well as a distribution channel that often is a 
part of marketing in this situation.

    This has always been the delicate part of this, because you 
say, this is not exactly a commercial enterprise, this is a 
real live search for a humanitarian concern, but so, at the end 
of the day we know that somebody somewhere has to produce 
whatever it is, and manufacture, continue on, distribute, sell, 
handle the money--so give some idea how what you are doing fits 
into this and what we can anticipate?

    Dr. Berkley. Thank you very much, and let me add on to Dr. 
Helene's comment about how this works.

    So, if you think about the Enterprise as the coordinator, 
we're about 10 percent of the vaccine effort, and Dr. Fauci is 
about another 80 percent, so together we're now most of the 
world's effort. What's interesting about the way we're working, 
is we are a partnership that sits outside of government, but 
working with governments, and for the governments that give us 
money, they do not target that money to their own national 
programs, that's very important, because the tension now is 
between national research and global research, and we want the 
best products in the world to rise up, and that's what we see 
our job to be.

    The Chairman. We kind of have a trade war here.

    Dr. Berkley. Absolutely.

    The Chairman. The need for a WTO adjudication, or someone 
needs to rise above this, hopefully.

    Dr. Berkley. So each of the governments is supporting its 
own work, but then, what we do is take a small amount of money, 
and try to do it globally. Now, what's important about trying 
to get industry engaged, why are they not engaged? Well, to the 
big companies, it is the scientific difficulty, but also the 
market is mostly in the developing world, and it is politically 
controversial. You know, the day a vaccine comes out, it might 
not be a required vaccine because of all of the social 
controversies, religious controversies and others, and lastly, 
because of that, their own business has been under attack in 
terms of patents and other issues, so they're quite nervous in 
this area, and it's not a good place for them to invest 
capital.

    Small companies which are critical, you know, the bio-tech 
is where innovation occurs, their lead comes from the big 
companies, because that's who buys the products in the end and 
that's who their venture capitals look at for direction, so 
there really has been almost a failure of the ability to do 
that. And the role we're playing in that is by both directly 
financing those groups where it makes sense, but that the 
important part of that is that we're fast, efficient. Seventy-
five percent of the people in IAVI are out of industry, we 
speak their language, we operate like a business, we hold them 
to milestones, and they understand that and trust that, and so, 
the more we can get these groups engaged. The other thing that 
would help, though, are these long-term incentives--why? Well, 
because when they sit there and they compare this to other 
products, the opportunity costs--even if we pay for the 
research--the opportunity costs are huge, and so if we can say, 
``Look, there is going to be a market, look, you'll be able to 
sell it,'' and most importantly, it will get to the poor, so 
that we will not be dragged across the PR of the world and say, 
``Why didn't you provide it?'' You know, because they'll now 
believe it really will get to the poor people, then we can tip 
those companies into bringing their expertise.

    Another big issue, though, not to forget is distribution, 
because for current vaccines, the six of them costs a dollar, 
the distribution system costs $35. And an AIDS vaccine would be 
going to adolescents, commercial sex workers, IV drug users, 
and other groups that we don't know how to reach, and so 
there's going to need to be a real global effort to do that, 
but obviously, given the cost-effectiveness of a vaccine here I 
think we can get groups to step up. For industry, knowing the 
quantity of the vaccine is critical for manufacturing. And, you 
know, we can bring in manufacturers from developing countries, 
we can bring generic manufacturers in, but only if we know how 
many vaccines over that time, because huge investments need to 
go into the facilities to produce these types of products.

    The Chairman. Well, you make a very important point, the 
last, as well as all the other important points you made before 
that--we've had a problem in this country, this past year, with 
just a regular flu vaccine. I guess the situation, it's no 
longer rocket science, but at the same time it almost seems to 
be as you come along and fall comes and suddenly an 
announcement is made to the public, ``Not everybody is going to 
be able to get it.'' You start with high priority groups, 
people at risk--old people and people in bad health and so 
forth, and then they run out, you even begin go get some 
tremors that that might occur in this year, if we're not very 
thoughtful.

    Dr. Berkley. That was a market-related issue, and it 
related to the fact that the old technology, which is the egg-
based vaccine, there isn't enough money to drive and to move 
innovative technologies, and one of the problems with that is 
that every year you have to make it, so they didn't make a lot 
of money, so now, as part of the bio-shield work and other 
work, there's beginning to be an effort from the government to 
figure out if we can create, now, a way to help those companies 
make that technological leap which is going to be critical to 
supplying these type of products.

    The Chairman. Well that is very good news and I hope that 
both of you can offer some leadership on that in addition. But, 
you've made the point which is important--that it's really not 
clear to companies as they start this how they're going to 
finance it, quite apart from the scientific questions about 
solving the problem, and how distribution might occur. Many 
governments involved--some in denial as we've talked about 
today, or semi-denial--so that even if we're in a consensus 
today, around this table, this is a crisis, this is 
tremendously important, trying to save lives, but then you come 
up against the political realities, or religious doctrine, 
realities, what have you around the world, it's a large world, 
many different viewpoints, and not everybody sees it that way. 
So, as you say, some companies in some countries are 
discouraged, really, from becoming too aggressive in this area, 
or talking about it too much, which is extremely frustrating.

    Dr. Gayle. Just to add, Chairman, I think this issue for 
being able to show support for buying vaccines is critical, and 
so for instance, continued U.S. Government support for programs 
like GAVI are instrumental in demonstrating that if vaccines 
are made, and if there's a commitment to purchasing them and 
then making them available, in fact, you can give industry 
incentive, so I think on the donor side, showing that 
commitment to purchasing vaccines is critical in kind of 
breaking this logjam in the long run.

    The Chairman. I agree, and I appreciate very much that 
there is such entities as GAVI, as you do, Dr. Gayle. But, I 
appreciate, likewise the Foundation, Bill and Melinda Gates 
tackling this issue. Now, I suspect often, the thought has 
been--well, why haven't commercial institutions been involved? 
Well, in part, because of the controversy we're talking about, 
and certainly markets, distribution and all of the rest of 
this, and the fact that it involves very poor people in remote 
parts of the world on occasion, quite apart from cases in the 
United States in which is not very clear how, commercially, you 
support that situation, as opposed to other objectives of firms 
who are busy saving lives in various other ways.

    Now, thank goodness someone in the Foundation Community, in 
this case, a very large foundation, stepped forward and have 
said that this is where we can play a very important role, not 
only in transition, but in leadership. That's the genius of the 
American scene, that we have philanthropists who have this kind 
of vision, and it's very important.

    But I stress the commercial side of this because as both of 
you, eventually you finally have to get back to the nitty-
gritty of how it is to be done--physically, the product 
produced, distributed, what the cost will be, how many people 
can imbibe, and therefore we need to think about the vaccine as 
well as prevention, and knowing that the treatments, no matter 
how many treatments you have, this is always going to be one 
part of the picture, and hopefully a transition phase.

    Now, let me just ask sort of a, we call it the $64 
question: Are you optimistic that a vaccine can be found, or 
maybe vaccine is wrong--vaccines or whatever, maybe, finally 
the protocol in this--why? Why do you think that's the case, 
this has not been obvious to the world for awhile, and as a 
matter of fact, even as persons who are citizen amateurs myself 
are advocating this, people are saying, ``Oh, come off of it, 
that's all well and good, pie in the sky, but as a matter of 
fact, life is going in earnest, and this is going to be a 
situation of people dying perpetually, and none of us find that 
acceptable, but why should we have optimism that the vaccine 
will happen?''
    Dr. Berkley. May I, Mr. Chairman?

    The Chairman. Yes.

    Dr. Berkley. If I could take two points here, first of all, 
to date, one AIDS vaccine in the world has been fully tested to 
see if it works, that's 24 years into the epidemic. Now, 
science is tough, but a lot of that represents the lack of 
focused attention, finance, et cetera, so, when people say, 
``Well, this hasn't worked,'' that's the fact.

    Well, why do we think it could work? Well, there are two 
arms to the immune system, one is the cell mediated arm, and 
one is the antibody arm. We would like a vaccine that does 
both. We now have pretty good vaccines that do the cell 
mediated arm, the Merck Company has an exciting vaccine, which 
unfortunately may have some issues working in the developing 
world, but that's in testing now, and a number of other 
vaccines, we have some, the NIH have one that are now striking 
that----
    The Chairman. When you say several out there? Several 
possibilities?

    Dr. Berkley. Well, why is that important? Well, every 
person who gets infected with the virus it goes ahead and 
circulates in them and then it gets driven way down by their 
immune system, and that's why they stay 10 years, 15 years, 
without getting the disease. So, we know that that part of the 
immune system can have a dramatic effect, and we think we can 
reproduce that. But that's not good enough. What we need to do 
is solve this other problem, and it's an extremely difficult 
problem. Yet, we now have found some people who make the right 
type of antibody. We don't know why they do it--in other words, 
we have a lock, but we don't know what the key is----
    The Chairman. So, human beings on earth could produce these 
antibodies?

    Dr. Berkley. And recently our consortium crystallized the 
different antibodies and showed what they look like, and 
figured out how they work, and the way they work is they've got 
these funny shapes that kind of reach in behind the coating of 
the virus that is very wise to kind of keep the immune system 
from seeing it, so the challenge for us is can we produce 
something that will make those type of antibodies? And that's 
the search that's underway, but that needs to be focused, it 
needs industry, it needs science, and it needs to be done as a 
product of an initiative, that's not an individual researcher 
thing, like Dr. Gayle said, that's coming together to try to 
solve that type of problem, and I believe it will be solved, 
but of course we can't definitively say that, so one of the 
things is to move this forward with the existing antibodies, 
but also now to search all the people elsewhere in the world, 
and let's do it on an industrial scale, let's not do it in this 
lab or that lab, but let's bring the tools of industry, high 
through-put screening and combinational work to try to 
accelerate this, and that I think is the challenge. But, we can 
protect monkeys, we certainly know that people can suppress the 
virus for a long time, so I am absolutely convinced protection 
is possible, the question is when, and is it practical and is 
it going to be cost effective.

    Dr. Gayle. Just to add to that, I think as Dr. Berkley 
said, the approach has to be a different approach. We can't 
continue to go down blind alleys and everybody going down that 
same approach without more systematically looking at whether or 
not we're looking at each part of the immune system, looking at 
how to optimize responses, and doing that in a much more 
coordinated, across the board way and at the scale that is 
necessary to do that so we can look at all of the ways you can 
investigate these, but do it in a much more coordinated 
fashion. We have not given ourselves the opportunity to do that 
kind of research, and that's what the Enterprise, and the work 
of IAVI, NIH, and all the other partners are doing, is to 
really look at this in a coordinated way, and giving ourselves 
the opportunity to do the kind of industrial-strength, 
coordinated more strategic research than we've done thus far, 
kind of taking one lead at a time. And I agree and we all feel 
the same sort of optimism, there's enough information now to 
suggest that it is possible.

    But also, as I made, said in my comments earlier, this is 
not a sprint. We do think that it will take at least another 
decade to be able to get to the point where we have a safe and 
effective HIV vaccine, so we know that we need to be in it for 
the long haul, and we know that it has to be a combination of 
different approached. Microbicides, which may be able to be 
available sooner than a vaccine--critically important--other 
prevention tools that might be able to be available, barrier 
methods for women, other prevention strategies, so we really 
need to do all of these and they really can't compete with each 
other. Even when we have a vaccine, it's unlikely to be 100 
percent effective, so it will still need to be mixed and 
matched until we keep having new, successive evolutions in our 
vaccines, so we have more and more effective vaccine. The first 
one may not be 100 percent effective, it's likely that it will 
not be, so we have to make sure that we're maintaining the 
research on all fronts, as well as putting in place the things 
that we already know can make a difference, and we believe that 
we can get there.

    The Chairman. As you said, Dr. Berkley, as opposed to one 
attempt, sort of on the industrial scale, this means, I 
suppose, hundreds, thousands of persons, cases, in other words, 
just a myriad of possibilities as well as many trials, and you 
need, I suppose for statistical validation a lot of people, a 
lot of cases, a lot of trying, maybe, to watch the evolution of 
hat it will be doing, how it works. And as Dr. Gayle speaks 
about, I suppose even with intensive operation, both of you 
testifying to make certain you've got something that is as 
close to being right as opposed to being perfect, and human 
lives are at stake, you have to have this period of time for 
validation, I would guess, although that would be disturbing 
for anyone listening to this hearing, a decade is a long period 
of time, we've discussed this, both of you have the statistics 
of the number of developing cases day by day, how that number 
is racing ahead of however many treatments are occurring as the 
world becomes more efficient in actually getting to persons as 
we have to in a humane way.

    So, our optimists would hope that the decade idea is 
realistic, but too pessimistic, as often happens. In the 
meanwhile, on the other hand, the purpose of this hearing is 
really to try to illuminate, so that this is not something that 
we guess, but people will know from your testimony that there 
are hundreds of scientists, doctors, researchers, maybe 
thousands of persons, individual persons in this world looking 
for the antibodies, for example, or how there can be an 
arresting of the situation, if not total prevention.

    Dr. Gayle. Mr. Chair, if I may, I'd just like to add a 
couple of points. I think you emphasized why this must b e a 
global effort, because we will need to do--once we get suitable 
candidates--we will have to do trials that will include tens of 
thousands of people, so we need to have a global collaboration, 
we need to work with the countries where HIV is having the 
biggest impact, because that's where the trials need to be 
done, and we need to make sure that we're working hand in hand 
with those, and again that's why an umbrella like the Global 
HIV Vaccine Enterprise is so critical. And I think, while a 
decade seems a long period of time, if we don't put the 
resources and the effort in today, then you'll be talking about 
even further out than that, so whenever we start, we've got to 
put the effort in--we've already started obviously, but I think 
if we put in an even more intensive effort, a more coordinated 
effort than we really will be able to get there, but any delay 
will continue to push that finish line even further out and 
that's what we want to avoid.

    The Chairman. We thank both of you, but this committee does 
not have complete jurisdiction over the situation, and we will 
work with the other important committees who have equal 
interests. But, at the same time, as Dr. Gayle has pointed out, 
the global aspects of this are undeniable. In situations that 
are really serious, although not at the gravity we're talking 
this morning, the world is deeply worried about soybean rust, 
for example, which may have a tremendous impact on soybean 
farmers, but likewise on agricultural America, and we really 
don't know nearly as much about that as we need to know as we 
approach this particular year. We're worried about Avian flu--
no one knows precisely how many cases are occurring somewhere 
in Asia now, and whether particular drugs are used by certain 
people, maybe Chinese farmers have surrendered whatever they 
were doing and in fact, with regard to fighting the disease 
involving human beings, but there is clearly concern about that 
and it happens because it's a small world, and that is why the 
global perspective is important. And as small as the world may 
be, the political divisions, the different views, politically, 
religiously and so forth that people take of this are very 
diverse, and therefore the coming together of people of 
goodwill is not easy. But we thank both of you for your 
leadership in making that more possible, and those who have 
sponsored you.

    And so saying, we thank all of the witnesses, and the 
hearing is adjourned.

    [Whereupon, the hearing was adjourned.]


                            A P P E N D I X

                              ----------                              


 Responses to Additional Questions Submitted for the Record by Members 
                            of the Committee

                               __________

       Responses to Additional Questions Submitted for the Record
                  to Dr. Seth Berkley by Senator Dodd

             THE NEED FOR PEDIATRIC TESTING OF HIV VACCINES

    Some of the populations hardest hit by the pandemic--infants and 
youth--are at risk of being left behind in the search for an effective 
vaccine against HIV/AIDS. To date, the vast majority of HIV vaccine 
trials have not included children. Because we cannot assume that a 
vaccine tested in adults will also be safe and effective when used in 
pediatric populations, it will be important to ensure that promising 
vaccines are tested in infants and youth as early as is medically and 
ethically appropriate. Failure to begin planning for the inclusion of 
these groups in clinical trials could mean significant delays in the 
availability of a pediatric HIV vaccine, at the cost of countless 
thousands of lives.


    Question. Where are we in testing possible vaccine candidates in 
children?

    Answer. Children's risk of HIV infection, and hence their need for 
vaccination, varies enormously with age.

    Infants of HIV-infected mothers are at great risk if their mother 
is not treated with antiviral medications, during gestation, birth and 
breastfeeding. Vaccination at birth, added to temporary antiviral 
therapy such as nevirapine, could reduce this risk if the vaccine were 
safe and efficacious, and if the vaccine could induce a protective 
response within weeks after birth. For infants, the ``bar'' must be 
particularly high for both safety of the vaccine and for the 
possibility that the infant will benefit from the vaccination.

    Investigation of HIV vaccines in infants has been carried out in 
the United States under the auspices of the NIH-supported Pediatric 
AIDS Clinical Trial Group. The vaccination of these infants raised no 
safety concerns, but in the U.S., where infants are protected from HIV 
infection by treatment of mothers with highly active antiretroviral 
therapy, it is not feasible to assess whether the vaccine protects 
infants. One of the three vaccines tested in the infants subsequently 
failed to protect adults against HIV and another is currently being 
studied for efficacy in adults.

    After infancy, most children are at relatively low risk from HIV 
infection until they reach the age of sexual debut (here called 
``adolescence,'' but in fact quite variable). The level of adolescent 
risk varies enormously by age, by gender, and by region.

    Adolescents are vulnerable to infection through blood transmission; 
sex, including incest, other sexual abuse, and commercial exploitation; 
and injection drug use. Adolescent girls, in particular, are often at 
high risk of infection. One of the most effective strategies for 
controlling the spread of the epidemic will be to vaccinate pre-
adolescents before the onset of behavior that puts them at risk.

    IAVI is committed to working with others in the field to ensure 
timely access for adolescents to a safe and efficacious preventive HIV 
vaccine. This will, however, require a clear understanding of the 
requirements of national regulatory and licensing authorities for 
testing and data on adolescents. Given the special vulnerability of 
adolescents as described below in question two, it probably makes sense 
to do most early screening of vaccines in adults and then assure that 
promising vaccines are further developed for children and adolescents.

    To meet these requirements it may be necessary to include a subset 
of adolescents in efficacy trials, while weighing the risks and 
benefits for individual adolescents when planning such trials. Phase I 
(safety) trials are conducted in lower risk communities, while efficacy 
trials, by necessity, occur in populations at risk for the disease. In 
regions where adolescents are not at high risk of infection, it would 
not be useful or likely ethical to enroll them in efficacy trials.

    There is an underlying assumption in the field that a vaccine that 
is effective in adults will also work in adolescents and pre-
adolescents. It may not be necessary to enroll large numbers of 
adolescents in efficacy trials. Instead it seems likely that 
``bridging'' data showing safety and immunogenicity in adolescents and 
pre-adolescents, generated simultaneously with efficacy data in adult 
populations, may be adequate for licensure.


    Question. What are the logistical, regulatory, medical and ethical 
issues that must be overcome in pediatric testing of HIV vaccines? How 
do we address them?

    Answer. Before enrolling infants or adolescents into clinical 
trials, it is critical to weigh the risks and benefits to them, just as 
we do with adults. Children are vulnerable, both biologically and 
socially; therefore, it is essential that any research study in 
children incorporate safeguards. The evidence for vaccine safety and 
tolerability should be strong and most feel that there should be a 
relatively high probability of success--infants and adolescents should 
not be the first group used to test most vaccines. For trials in 
infants or adolescents, the trial design should incorporate ethical and 
procedural safeguards to protect these vulnerable research subjects.

    In a research study enrolling pregnant women prior to or at the 
time of delivery, one overriding consideration is that the study be 
clearly explained to the child's mother so that she can freely consent, 
and that all reasonable measures be taken to care for the mother and to 
prevent mother-to-child transmission (the experimental vaccination 
cannot be assumed to be effective for this purpose). Designing such a 
study will not be simple.

    With adolescents, we must consider the social and psychological 
risks of trial participation. There are two significant risks from 
trial participation. One is stigmatization; participants in a trial may 
be thought to have HIV or to partake in ``immoral'' behavior, and this 
may lead to social discrimination, expulsion from the family, or 
violence. It is important that adolescents volunteering for the trials, 
and their parents or guardians, understand these risks. AIDS vaccine 
trials in adolescents must avoid and prevent any social harm that may 
result from their trial participation, whether this social harm be 
directed from his/her family, friends or community against the 
adolescent or from the community against the adolescent's family.

    The second significant risk is that trial participants may be 
tempted to think of themselves as protected and to increase their risk-
taking behavior. While this has not been documented as a significant 
risk in the HIV vaccine trials undertaken to date among adults, 
adolescents may lack maturity and judgment. On the positive side, the 
education and counselling involved in a trial may be of great benefit 
to an adolescent at risk, if s/he has the power to alter that risk, by 
altering behavior.

    Laws regarding the age of consent vary in the United States from 
state to state, and elsewhere between countries. Some countries make 
the distinction between the legal age of consent and the age of 
participation in biomedical research. For example, young women who have 
already given birth may be considered ``emancipated'' and be legally 
allowed to consent for themselves but may not be authorized to enroll 
in trials. This may vary on a country-by-country basis. The major 
difficulty in some countries is that the law may not specifically 
address the age of consent for clinical research involving an 
investigational agent. Vaccine research conducted in developing 
countries typically involves infants and children, with parental 
consent. In some developing countries where adolescents are at high 
risk of acquiring HIV, regulators may therefore be tempted to take a 
more conservative approach, precluding adolescents' participation in 
AIDS vaccine trials.

    Some countries typically register only vaccines or drugs that have 
been licensed in Europe, the U.S., or other countries, a practice that 
could cost many years.

    The U.S. Code of Federal Regulations takes a more conservative 
approach on preventive-based research, such as for vaccines and 
microbicides, which involve healthy HIV-negative participants, compared 
to therapeutic-based research where a direct, immediate benefit for 
trial participants could be anticipated.

    Prior to enrollment in any trial, potential participants are 
informed regarding the trial and must demonstrate a clear understanding 
of the potential risks and benefits of participation. This assessment 
is difficult for well-educated adults, and may be much more difficult 
for adolescents, most of whom are not well educated. Further, it may be 
difficult for researchers to ascertain the level of understanding and 
maturity of adolescent trial candidates. A traditional approach has 
been to require both assent of a minor child and informed consent of 
the parent(s) on behalf of the child. Where sexually transmitted 
diseases are involved, even asking a parent for consent may put a child 
at significant risk of expulsion from the family or violence. Hence, it 
is important to arrive at a proper legal and ethical definition of 
``emancipation,'' so that it is clear whether adolescents can be 
counselled and possibly enrolled without parental consent. In any 
trial, and certainly later in the deployment of a vaccine in the 
general population, it will be critical to avoid the tendency for 
vaccinated individuals to conclude that they are safe from HIV and can 
increase their risk behavior. This disinhibition factor is of greater 
concern with adolescents than adults. Research on the best way to 
inform, educate, obtain informed consent from and assess understanding 
in adolescents should be supported.

    Liability concerns have been raised frequently as a possible 
obstacle to HIV vaccine trials in children. In the U.S., for licensed 
and recommended childhood vaccines, the Vaccine Injury Compensation Act 
provides liability protection for vaccine manufacturers and 
compensation for children who may have suffered harm from vaccination. 
There is no comparable system for investigational vaccines, and most 
large pharmaceutical companies ``self-insure,'' an approach, which may 
prove difficult for small biotech companies and non-governmental 
organizations involved in the search for an HIV vaccine. The 
indemnification clause of the Homeland Security Act may provide a path 
forward to remove this potential barrier.

    IAVI is committed to working with others in the field to clarify 
the practical, legal and ethical challenges for enrolling adolescents 
and pre-adolescents in HIV vaccine trials.


    Question. Do you have specific recommendations--legislative or 
others that we could implement to ensure that children are not an 
afterthought when it comes to preventing HIV infection?

    Answer. In addition to the recommendations already mentioned, we 
believe that participation of adolescents in vaccine trials must occur 
in the context of strong HIV prevention programs, adolescent-friendly 
services, and community support of their participation. It is important 
that a comprehensive and widely accepted package of preventive 
interventions be made available for adolescents. Everyone engaged in 
vaccine research should work to establish a receptive and supportive 
environment for a future HIV preventive vaccine among families, 
communities, and governments.

    The utility of a vaccine, however, will depend not only on its 
efficacy, but also on the duration of protection. This duration of 
protection will have tremendous public health implications. For 
example, if a vaccine is only active for a period of five years, it 
would be inefficient to vaccinate young children in a population where 
the average age of sexual debut is 16. Determining a vaccine's duration 
of protection will take years of follow-up and monitoring of trial 
participants after the initial efficacy trial is completed. Everyone 
involved in vaccine studies should commit to doing this, allowing us to 
extend the lowest age of vaccination to a time before risk activities 
begin.

    Specifically, relevant government agencies should commit to 
supporting long-term follow-up studies once a vaccine is proven 
efficacious, to determine the duration of protection.

    Regulatory agencies should clarify requirements for approval so 
that adolescents' access to the vaccine will happen without delay.

    IAVI plans to gather data on safety, immunogenicity, and, if 
required, efficacy responses of adolescents, prior to licensure or 
registration, so that young people's access will be timely. IAVI's 
current plans commit to long-term follow-up of immunogenicity and 
efficacy for promising vaccine candidate(s), so as to best gauge the 
earliest time at which a vaccine would be useful. We encourage others 
in the field to do so as well.

                               __________

              Additional Material Submitted for the Record
                          by Dr. Helene Gayle

                        Speeding an AIDS Vaccine

                by richard g. lugar and patty stonesifer

         Washington Post, Wednesday, January 19, 2005; Page A19

    Picture two scientists in adjacent labs. They're working on the 
same problem--how to stop a disease that kills 3 million people every 
year--but although they compare notes and share findings, they need a 
better plan to coordinate their research. They labor for years at the 
same task, but as individuals rather than as a community of scientists.

    Although they make important progress, after two decades just one 
vaccine makes it into large-scale clinical trials--and it doesn't work.

    With a few exceptions, this has been the story of the search for an 
HIV vaccine. While dedicated scientists around the world have 
collaborated on significant discoveries, they've had no shared strategy 
for finding a preventive vaccine, no standardized tools to compare 
results, no forum to identify priorities and share information. 
Meanwhile, HIV-AIDS is spreading at an alarming pace, with a record 4.8 
million new infections in 2003. At the current rate, there will be 45 
million new infections by 2010 and nearly 70 million more deaths by 
2020.

    Preventing the transmission of HIV-AIDS by discovering and making 
accessible an effective vaccine must be a priority for our government, 
for the private sector and academia, and for other countries, including 
the Group of Eight industrial nations. While promising results are 
coming from new approaches to changing behavior, such as the Ugandan 
"ABC" model--which promotes abstinence, being faithful and condoms--
that is clearly not enough.

    Fortunately, a group of the world's leading scientists is 
mobilizing to coordinate and improve vaccine efforts. This alliance of 
independent organizations, called the Global HIV Vaccine Enterprise, is 
committed to accelerating the development of a preventive HIV vaccine 
by working more collaboratively, more strategically and more 
aggressively.

    But such a risky and expensive venture can succeed only if 
government leaders, donors and researchers around the world work 
together to make it happen. And while the progress so far has been 
promising, there's much more to do. This year will present three 
concrete opportunities to achieve real progress for the Global HIV 
Vaccine Enterprise.

    First, Congress must continue to make the fight against AIDS a 
priority in U.S. foreign policy and in future spending. Besides causing 
massive human suffering and loss of life, the disease is undermining 
the stability of nations, creating labor shortages and making orphans 
of an entire generation of children. President Bush, through his 
Emergency Plan for AIDS Relief, has provided new leadership and 
resources for the worldwide campaign to fight the disease. The federal 
government, through the National Institutes of Health, already has one 
Vaccine Research Center and, in support of the Global HIV Vaccine 
Enterprise, has unveiled plans for a second one. The NIH's continued 
leadership and support are critical.

    Congress, businesses, foundations and others must fund the Global 
HIV Vaccine Enterprise and its components, including vaccine research 
centers. The investment we make now in finding a vaccine will not only 
save millions of lives but could save billions of dollars in future 
treatment costs. We also need to determine whether tax or other 
incentives will be necessary to get the most talented private-sector 
scientists to contribute to this enterprise, and whether we need to 
help developing countries improve their pharmaceutical regulations to 
break down barriers that discourage collaboration.

    Second, governments, scientists, donors, the private sector and 
community leaders must act on a set of priorities to help accelerate 
the search for a vaccine. The Global HIV Vaccine Enterprise brought 
many of the world's leading researchers together to develop just such a 
blueprint, which for the first time identifies key research priorities. 
The blueprint, which was published yesterday, calls for new approaches 
to crack the major scientific barriers to an HIV vaccine, for affected 
countries to host more clinical trials and train more researchers, for 
more private-sector investment in research and development, and for 
local leaders to encourage volunteers to participate in studies. It is 
a global summons to action.

    Finally, other developed countries must make this project a 
priority by focusing their resources on it. The G-8 industrial nations 
endorsed the Global HIV Vaccine Enterprise at their 2004 summit, and 
AIDS-ravaged Africa will be at the top of their agenda when they meet 
in July in Scotland. Now is the moment for these countries--Japan, 
Germany, France, Britain, Canada, Italy and Russia--to make real 
commitments to support the Enterprise, for instance by creating their 
own vaccine research centers and linking them in a global effort.

    This year we can make genuine headway in the fight against AIDS--a 
pandemic that threatens mankind in a way no other disease has. In the 
1960s we launched the Apollo program to put a man on the moon. In the 
1990s we came together to map the human genome. In the decade ahead why 
shouldn't we demand a similarly urgent effort--this time an 
international one--to stop this scourge?

    Richard G. Lugar is a Republican senator from Indiana and chairman 
of the Senate Foreign Relations Committee. Patty Stonesifer is co-chair 
and president of the Bill & Melinda Gates Foundation.

                               __________

  G-8 Action To Endorse and Establish a Global HIV Vaccine Enterprise

    1.  We reaffirm our commitment to combating the global HIV/AIDS 
pandemic. Both individually and collectively, we have increased our 
efforts aimed at HIV treatment, care, and prevention. We acknowledge 
the important role of the Global Fund to Fight AIDS, Tuberculosis, and 
Malaria, UNAIDS, and WHO in fighting this pandemic. But the human and 
economic toll of the AIDS pandemic demands that these activities be 
complemented by accelerated efforts to develop an HIV vaccine. In 2001 
and 2002, only seven vaccine candidates entered clinical trials, and 
only one entered advanced human testing, but proved to be ineffective. 
Vaccine development efforts have proceeded slowly, due largely to the 
enormous scientific challenges. The best way to meet these challenges 
is for scientists around the world to work together in a complementary 
manner.

    2.  We believe the time is right for the major scientific and other 
stakeholders--both public and private sector, in developed and 
developing countries--to come together in a more organized fashion. 
This concept has been proposed by an international group of scientists. 
Published as a ``Policy Forum'' in Science magazine. Klausner, RD, 
Fauci AS, et al: ``The need for a global HIV vaccine enterprise.'' 
Science 300:2036, 2003. We endorse this concept and call for the 
establishment of a Global HIV Vaccine Enterprise--a virtual consortium 
to accelerate HIV vaccine development by enhancing coordination, 
information sharing, and collaboration globally.

    3.  The Enterprise should establish a strategic plan that would 
prioritize the scientific challenges to be addressed, coordinate 
research and product development efforts, and encourage greater use of 
information sharing networks and technologies. This plan should serve 
as a blueprint for helping to align better existing resources and to 
channel more efficiently to the needs at hand new resources as they 
become available. Specifically, the strategic plan should seek to:

          3.1.  Encourage the development of a number of coordinated 
        global HIV Vaccine Development Centers: Each center should have 
        the critical mass and scientific expertise to advance the 
        development of a particular HIV vaccine approach. These centers 
        could be self-contained, as is the National Institute of 
        Allergy and Infectious Diseases (NIAID) Vaccine Research Center 
        at the U.S. National Institutes of Health, the European 
        Research Institutes or could be virtual centers, such as those 
        funded by the public-private partnerships of the International 
        AIDS Vaccine Initiative (IAVI), the European Developing 
        Countries Clinical Trials Program (EDCTP), the Gates 
        Foundation, and others.

          3.2.  Stimulate the development of increased dedicated HIV 
        vaccine manufacturing capacity: There is inadequate existing 
        capacity to produce HIV vaccines for advanced clinical testing. 
        Therefore, the resources and facilities involved in 
        manufacturing potential HIV vaccines must be increased, 
        particularly for testing of vaccine candidates that are 
        currently in or will soon be in the developmental pipeline, 
        like in the EDCTP.

        3.3.  Establish standardized preclinical and clinical 
        laboratory assessment: Data gathered from clinical trials on a 
        given vaccine candidate should be available and applicable to 
        trials being conducted on other vaccine candidates. Therefore, 
        standardized protocols and measures of effectiveness need to be 
        adopted at the preclinical and clinical stages of vaccine 
        development. In turn, laboratories need to be better linked to 
        clinical trials, which will require wider use of novel 
        confidentiality agreements and information-sharing 
        technologies.

          3.4.  Expand an integrated international clinical trials 
        system: Large, clinical programs capable of conducting phase I, 
        II, and III trials of potential HIV vaccines have been 
        established by the U.S. NIAID, France's Agence Nationale de 
        Recherches sur le SIDA, Italy 's National AIDS Program, IAVI, 
        and the EU. This global clinical trials system should be 
        expanded and coordinated. It should facilitate a 
        multidisciplinary approach which draws in inputs from social 
        and behavioral scientists, alongside biomedical teams.

          3.5.  Optimize interactions among regulatory authorities: 
        Increased cooperation, communication and sharing of information 
        among regulatory authorities in various countries and regions 
        involved in licensing HIV vaccines are essential. This can be 
        accomplished without reducing safety or manufacturing 
        standards.

          3.6.  Encourage greater engagement by scientists from 
        developing countries: Since most phase III trials will need to 
        be conducted in the developing countries hardest hit by the 
        disease, the international clinical trials system must involve 
        local scientists, ethical review committees comprised of local 
        and international representatives, and regulatory bodies.

    4.  We call on all stakeholders in the Global HIV Vaccine 
Enterprise to complete the development of this strategic plan by our 
next Summit.

    5.  The United States, in its role as president of the G-8, will 
convene later this year a meeting of all interested stakeholders in the 
Enterprise to encourage their collaborative efforts in HIV vaccine 
development. This meeting should clarify how the strategic plan is to 
be implemented. We support this conference becoming an annual event and 
we look forward to a report on the follow-up of the Initiative at the 
next G-8 Summit.

    From the U.S. State Department web site at: http://
usinfo.state.gov/ei/Archive/2004/Jun/10-92350.html

                               __________

            The Need for a Global HIV Vaccine Enterprise \1\
---------------------------------------------------------------------------

    \1\ ``The Need for a Global HIV Vaccine Enterprise,'' Richard D. 
Klausner, Anthony S. Fauci, Lawrence Corey, et al., Science Magazine, 
Vol. 300, June 27, 2003. Enhanced online at: www.sciencemag.org/cgi/
content/full/300/5628/2036.

    Since the discovery of HIV 20 years ago and the demonstration that 
HIV is the cause of AIDS, the world has awaited the development of an 
effective preventive vaccine. Recent projections from the World Health 
Organization (WHO) and the Joint United Nations Programme on HIV/AIDS 
(UNAIDS) indicate that if the pandemic proceeds at its current rate, 
there will be 45 million new infections by 2010 and nearly 70 million 
deaths by 2020. \2\ Although the scientific establishment has made 
extensive progress on extending survival of people with HIV and 
reducing maternal-fetal HIV transmission by antiretroviral therapy, 
transferring concepts for HIV-1 vaccines into clinical application has 
lagged.
---------------------------------------------------------------------------
    \2\ J. Stover, et al., Lancet 360, 73 (2002)
---------------------------------------------------------------------------
    Almost everyone involved in HIV vaccine development agrees that 
there is an urgent need to create and to evaluate systematically more 
candidate vaccines. Despite the wide variety of conceptual approaches 
to HIV vaccine design, the pace of development of new HIV vaccine 
candidates needs to be accelerated. In 2001 and 2002, only seven 
immunogens entered clinical trials. Only one candidate vaccine, aimed 
at eliciting neutralizing antibodies to a soluble HIV envelope protein, 
entered human phase III testing. Unfortunately, the recently released 
results from this trial did not demonstrate vaccine efficacy in the 
overall trial cohort. \3\ Although many approaches to producing 
immunogens have been discussed and initiated, systematic evaluation and 
optimization have proceeded slowly, in part because of factors such as 
the expense and complexities in advancing new candidate vaccines into 
phase I trials and scientific challenges.
---------------------------------------------------------------------------
    \3\ D.P. Francis, personal communication.

    These challenges include (i) the inability of current vaccine 
designs to elicit effective neutralizing antibodies against the 
circulating strains of HIV, (ii) the inability of current designs to 
prevent HIV from establishing persistent infection, (iii) the extensive 
global variability of HIV, (iv) the lack of understanding regarding the 
mechanisms of protection in the most effective HIV vaccine animal model 
system--the live attenuated approach, and (v) the lack of understanding 
of which HIV antigens induce protective immunity and which immune 
effector mechanisms are responsible for protection. The best engine for 
solving these major scientific challenges is the creativity of 
individual scientists working together in multidisciplinary problem-
solving consortia, adequately resourced and linked to vaccine 
development capabilities. Two decades after the discovery of HIV, even 
with a variety of advanced cell and molecular technologies, the need 
remains for improved vaccine designs that will deal with the genetic 
and phenotypic variation of HIV-1 and effectively prevent the 
establishment of lifelong infection. The ``enterprise'' of HIV vaccine 
development must be designed as a high-quality collaborative research 
system that goes well beyond the high-quality but separate research 
---------------------------------------------------------------------------
projects that we have today.

    We propose a model that could achieve the goals of a more efficient 
and integrated HIV vaccine research enterprise. We hope this Policy 
Forum helps open an international dialogue about options to achieve the 
goal of developing a safe and effective HIV vaccine in the shortest 
time possible.
Basic Principles for the Enterprise
    Vaccine development has historically been empiric and iterative, 
building on sequential successes to define correlates of immune 
protection that guide product development. Preclinical and clinical 
experiments and evaluation systems with objective measurements and 
analysis have been critical. Perhaps one of the most successful 
examples of such a concerted, empiric approach in medicine generally is 
the improvement in the treatment of childhood acute lymphocytic 
leukemia (ALL). Cure rates for children with ALL have improved from 10% 
in the 1950s to more than 80% (and for some subtypes, 100%) in 2002. 
This increase has been produced almost entirely by a coordinated and 
iterative series of preclinical drug evaluations and subsequent 
clinical trials, in which partially effective drug regimens have been 
systematically altered (through studies of the effects of combination 
and sequence), to produce steady and significant improvement in 
survival as well as reduced toxicity.

    HIV vaccine development has several similarities with developing 
treatment for ALL: (i) Although animal model data provide major 
conceptual insights, human clinical trials are ultimately required to 
define vaccine or drug effectiveness; (ii) the number of possible 
variables in reagent de-sign and clinical outcome are large but 
definable; (iii) combinations of reagents (vaccines for HIV, drugs for 
ALL) are likely needed to maximize benefit; (iv) no single regimen is 
likely, at least initially, to provide the optimal balance of efficacy, 
safety, and cost for all regions of the world; (v) a centralized, 
coordinated clinical trial and laboratory evaluation system facilitates 
progress in the field; and (vi) the program has substantial support 
from medical and political communities.

    There are also features that are unique to developing an HIV 
vaccine. The pace of progression of the HIV epidemic, as well as the 
international, political, and economic toll, require a more rapid 
iterative process than the multi-decade process described above. A 
well-coordinated global enterprise necessary to drive this scientific 
effort does not exist and must be created. The cost and process of 
developing new vaccine candidates, especially protein-based immunogens 
or noninfectious particles is typically substantially higher than those 
of new or modified drugs. Also, as the scientific risk of failure and 
the cost of vaccine development are high, reliance on industry to carry 
the major load for discovery and development for HIV vaccines is 
unrealistic. Thus, creative new public and public-private partnerships 
are necessary to drive the vaccine discovery effort, with industry's 
development expertise a key element that must be marshaled effectively.
HIV Vaccine Development Centers
    Even with the current paucity of prototype antigens in clinical 
trials, the portfolio of vaccine candidates contains significant 
overlap in approach (see ``the pipeline project''). \4\ Increasing the 
diversity of approaches and coordinating the types of vaccines entering 
clinical trials are fundamental to speeding global HIV vaccine 
development. We believe that this requires the creation of a series of 
coordinated global HIV vaccine centers, each of which has the critical 
mass, focus, and scientific expertise, especially in vaccine 
development, to advance the rational development of a particular HIV 
vaccine approach rapidly and systematically. Features we believe vital 
to the success of such centers are as follows: (i) a critical mass of 
re-searchers with experience in basic and clinical research and an 
appreciation for the empiric aspects of vaccine development, (ii) 
concentrated dedication to the single goal of a global preventive 
vaccine, (iii) long-term commitment free of the strict requirements of 
the classical short-term measures of success used by academic 
institutions, (iv) sufficient resources to conduct costly preclinical 
development activities, and (v) collaborative arrangements with the 
private sector.
---------------------------------------------------------------------------
    \4\ See www.hvtn.org and www.iavi.org

    Each of these centers would have the funding, structure, and 
resources to devote itself to a specific vaccine development need and 
product. The sole focus would be to test systematically and to improve 
incrementally the immunogenicity and safety of the immunogens that they 
develop. The core of an integrated enterprise approach to HIV vaccine 
development would begin by conceiving of the world of potential vaccine 
concepts as a grid, with each cell representing a particular approach 
to immunogen construction, composition and delivery. We propose the 
development of as many HIV vaccine development centers (VDCs) as are 
needed to fully cover the agreed-on ``cells'' of the vaccine product 
pipeline grid; they would be supported by a variety of international 
funding agencies. The structure, scope, and scale of each VDC would be 
organized to explore fully design, development, and testing in 
preclinical and early-phase human trials of a particular approach with 
the capacity to examine an adequate range of variables of dose, 
delivery, adjuvants, and combinations. The goal would be to learn 
whether their approach is immunogenic, with what characteristics 
(nature of the immune response, breadth of response, intensity and 
persistence of the response) and whether any of the variables modify 
the response in a way that indicates whether and how to produce second- 
---------------------------------------------------------------------------
and third-generation candidates.

    The structure of the VDCs could vary. These centers may be self-
contained, as in the National Institutes of Health (NIH) Vaccine 
Research Center, or may be virtual centers such as those funded by the 
public-private partnerships of the International AIDS Vaccine 
Initiative (IAVI) and NIH. These VDCs may be developed within 
commercial or academic and/or research institutes, or through novel 
collaborations between different types of institutions, but would be 
unified by a central concept or theme. For example, multiple 
investigators and laboratories interested in the evaluation of a 
particular approach (e.g., specific viral vectors or protein antigens) 
would work together to systematically ``cover the grid'' of vaccine 
immunogenicity and toxicity for this specific vaccine vector or 
concept. Each center would be expected to work in collaboration with 
the larger global enterprise.

    Areas of potential emphasis might be the development of novel 
adjuvants including recently discovered cytokines and chemokines, 
systematic modification of the envelope protein to maximize 
immunogenicity, bacterial vector design and delivery, optimized DNA and 
viral vector delivery, construction of immunogenic particles or 
structures, practical nonparenteral delivery systems and systematic 
approaches to define enhanced antigen presentation. Each center would 
systematically create reagents and conduct preclinical experiments that 
would provide vaccine prototypes for human clinical trials. We estimate 
that between 6 and 10 new VDCs are needed to comprehensively cover the 
various approaches. As the most significant problem relates to 
developing vaccines that achieve rapid and broad viral neutralization, 
priority should be given to developing VDCs with this focus.

    This system of collaborating vaccine developers would allow centers 
that work on cross-cutting technologies, such as novel adjuvant 
development or mucosal delivery, to work with the most promising 
antigens so that each component of a candidate vaccine would be 
optimized. This is currently lacking in HIV vaccine development. The 
purpose of this approach is to create a systematic and coordinated 
pipeline of vaccine constructs that can be tested, evaluated, and 
redesigned. It is especially important that combination vaccine 
regimens are developed and tested early and that there is a systematic 
evaluation of the strains and antigens used. Ways must be found to 
address how proprietary issues, such as exclusive licensing deals, can 
be reconciled with open communication and vaccine development paths 
that combine materials and technology platforms owned by different 
entities. Creative solutions to this problem will be required if the 
critically important role of industry in this enterprise is to be 
realized.

    Organizations like NIH, IAVI, Agence Nationale de Recherches sur le 
SIDE (ANRS), and the European Union (EU) as well as pharmaceutical 
companies have funded vaccine development programs that are directed at 
many of these issues. Their work could form the foundation for this 
collaborative enterprise. Our concept could facilitate increased scale 
as well as greater communication and cooperation. This is particularly 
important among groups working on similar vaccine concepts. We expect 
that the infusion of funds, intellectual focus, and collaborations 
brought by such centers will result in increased participation of 
industry in HIV vaccine development. As product development and process 
engineering have largely resided in the biotechnology and/or 
pharmaceutical industry, incorporation of these skills should be an 
integral part of each VDC.
Vaccine Science Consortia
    Many of the fundamental scientific questions impeding AIDS vaccine 
development have remained unchanged and unsolved since the 
identification of HIV as the etiologic agent responsible for AIDS. 
Answering these questions would provide crucial support to the VDCs and 
would be aided by the creation of a series of coordinated HIV vaccine 
scientific consortia. As with the vaccine research centers, we do not 
propose a specific structure for a given consortium, but the goal is to 
focus a range of researchers from many disciplines on a specific 
applied vaccine problem. The ultimate goal is to create effective, 
novel antigens for the pipeline. Commercial, academic, and research 
institutes must work together to solve the scientific challenge. 
Features we believe critical to the success of such consortia are (i) 
clearly defined goals and effective project management, (ii) dynamic 
scientific leadership and commitment of consortium members to the 
mission, (iii) a critical mass of researchers and the resources and 
infrastructure to rapidly translate preclinical leads toward clinical 
development, (iv) creative intellectual property agreements to provide 
incentives for data sharing and cooperative research, (v) long-term 
commitment free of the strict requirements of the classical short-term 
measures of success used by academic institutions, (vi) sufficient 
resources for each element of the consortium and flexibility to move 
resources between elements of the consortium, and (vii) collaborative 
arrangements with the private sector and/or the VDCs. Some of the 
possible scientific challenges are noted above, although these will 
undoubtedly change over time.
Development of Dedicated HIV-1 Vaccine Manufacturing Capacity
    At present, there is inadequate capacity to produce vaccines to the 
standards needed for human clinical testing and insufficient resources 
devoted to the process of taking a research construct through the 
rigors of vaccine production. Therefore, the resources and facilities 
involved in manufacturing candidate HIV vaccines must be increased 
markedly. This entails the development of dedicated personnel and 
manufacturing facilities devoted to the process development, scale-up, 
formulation, stability, safety, toxicology, and production (in accord 
with ``good manufacturing practice'' or GMP) of experimental HIV 
vaccines, disciplines that are largely found in the private sector. A 
critical feature of this is the need for assay development to control 
the manufacturing process, something that is required for each 
technology and is often responsible for slowing product development. 
The importance of building manufacturing infrastructure has become even 
more acute as the major focus of HIV vaccine development has shifted 
from large pharmaceutical corporations to small biotechnology 
companies, or nonprofit or academic organizations, all of which have 
little or no vaccine manufacturing capabilities and experience. This 
lack of manufacturing capacity and expertise for vaccines and 
uniformity in production facilities has accounted for repeated delays 
in the HIV vaccine clinical trials programs. A system must be devised 
in which experienced industrial colleagues and facilities are devoted 
to the development and manufacturing of candidate HIV vaccines for 
human clinical trials. Expansion of this program must be coordinated 
with expansion of the product pipeline from the HIV VDCs.
Establishment of Standardized Preclinical and Clinical Laboratory 
        Assessment
    Although regulators and clinical trial specialists have recognized 
the need to standardize laboratory measurement in human clinical 
trials, preclinical assessments of candidate immunogens are still based 
largely on experiments in single research laboratories. As such, access 
to the primary data, standardization of the laboratory assays utilized, 
and interpretations of such data within the context of the field are 
generally not available. A more transparent and standardized 
preclinical evaluation system for candidate immunogens is essential for 
defining and developing successful vaccine regimens. For example, 
despite a wide variety of prototype vectors, only one standardized 
preclinical evaluation of their comparative immunogenicity has been 
initiated, and comparative human trials have not been performed. This 
issue has been recognized and begun to be addressed by NIH and IAVI, 
but should be considerably expanded.

    Standardized protocols and immunogenicity measurements need to be 
broadly implemented at the preclinical and clinical stages of vaccine 
development to measure humoral and cell-mediated immunity and to 
provide a test bed for reproducibly assessing the immune response to 
HIV antigens and adjuvants. The preclinical discovery system provides a 
foundation on which choices for manufacturing and testing of 
formulations for human clinical trials can be made. Laboratories should 
be established to develop and deploy robust, reproducible, and 
interpretable assays of immune response; to standardize reagents for 
such assays; and to incorporate quality-control measures for 
consistency. This paradigm might prove challenging to academic-based 
laboratories; therefore, linking these laboratories with clinical 
trials requires wider use of novel confidentiality agreements, working 
relationships, and information-sharing technologies. Such a preclinical 
laboratory program will also improve the pace of developing immunologic 
assessments in human clinical trials and will increase the likelihood 
of defining important correlates of immune protection.
Expansion of an Integrated, International Clinical Trials System
    Large, comprehensive, coordinated, international clinical trials 
programs to conduct phase I, II, and III trials of candidate HIV 
vaccines have been established by the National Institute of Allergy and 
Infectious Diseases (NIAID), ANRS, IAVI, and the European Union. A 
rapid, iterative HIV vaccine trials enterprise will require expanded 
clinical trials capacity with emphasis on speed of accrual and 
retention of participants, high ethical standards, and enrollment of 
participating populations appropriate to the antigens being tested. 
Phase I/II clinical trials to define safety and immunogenicity are an 
integral part of vaccine development because, to date, animal models 
have been used with limited success in predicting human immune 
responses to HIV vaccines, especially to vector-based immunogens. The 
expanded global clinical trials system must therefore be considered 
part of vaccine product development and design. The clinical trials 
themselves must use standardized protocols and immunogenicity 
measurements. After an initial and rapid safety assessment in phase I 
trials, phase II trials must be adequately powered to define 
immunogenicity of new constructs as preclinical discovery and phase I/
II clinical trials systems provide the foundation for choosing sets of 
large-scale phase IIb/III efficacy trials. Initial phase IIb/III 
clinical trials must assess laboratory and clinical efficacy and also 
attempt to define correlates of protection with validated assays.

    Phase I safety and immunogenicity assessment of candidate HIV 
vaccine trials average 100 persons per protocol and phase II 
evaluations to define optimal dose and schedules, between 300 and 600 
persons. The number of enrollees into phase III vaccine trials varies, 
depending on their goals, the nature of the population, and the 
transmission rate--but in general have averaged from 2500 to 10,000 
persons per trial. To keep pace with the expanded pipeline, eventually 
the vaccine development enterprise would need to support a clinical 
trials program that enrolls about 5000 individuals in phase I/II and 
30,000 persons into the phase III efficacy trials yearly. Multiple 
phase III trials will be needed to assess the protective efficacy of 
different vaccine concepts against different HIV-1 clades and in 
populations that may differ on the route of HIV-1 transmission or 
genetic background. In addition, gender, diversity in viral strains, 
duration, and magnitude of the ongoing epidemic are likely to influence 
vaccine efficacy. Most of these phase III trials will need to be 
conducted in developing countries, where most infections are occurring, 
and where a vaccine will have the most benefit. Assuring that true 
partnerships are developed with the research, medical, public health 
policy, and civic communities in those countries is essential and must 
begin early in the design of this enterprise. The international 
clinical trials system must engage local investigators, communities, 
ethical review committees, and regulatory bodies and must be 
coordinated with other national efforts to control the HIV/AIDS 
epidemic.
Optimizing Interactions Among Regulatory Authorities
    Cooperation, communication, and sharing of information among 
regulatory authorities in various countries involved in licensing HIV 
vaccines are essential. We are not implying reduced standards in safety 
or manufacturing. In fact, the proposed system, with its more 
centralized manufacturing and immunogenicity programs, may be viewed as 
advantageous by regulatory bodies. This iterative process requires that 
regulatory bodies in a large number of regions or countries share 
access to preclinical and clinical information. Risk-benefit analyses 
for regulatory decisions should recognize regional variations in the 
social, economic, and health burdens of HIV and decisions by local 
regulatory authorities. Participation in the Enterprise requires 
transparency and equality for all countries and regions involved. 
Vaccines that are partially effective should be made available for 
regions of the world that might benefit from their use at their 
explicit request while new trials and improved vaccines are being 
developed and evaluated.
Coordinating International HIV Vaccine Development
    The Human Genome Project provides an interesting model for 
international coordination as many funders agreed on a scientific road 
map, voluntarily divided the work, and agreed to an evolving set of 
production standards. The frequent sharing of progress and problems 
allowed coordination, cooperation, and internal competition. The 
``governance'' was driven by an open agreement of the scientists and 
the funders about the blueprint of the project, which allowed 
coordination without unnecessary duplication. No one entity actually 
ran the international genome project, although the leadership was 
assumed by the major funders and implementers. We believe that the time 
is right for the major scientific and product-development leaders and 
the stakeholders involved in the global HIV vaccine development 
enterprise to come together in an analogous way.

    We propose the development of a road map for the Global Vaccine 
Enterprise that (i) would prioritize the scientific challenges to be 
addressed as well as product development efforts, (ii) would rapidly 
develop an implementation plan for all the components of the system, 
and (iii) would develop a plan that identifies the resources needed. 
The Enterprise, however, should have multiple models for structures to 
accomplish these goals and must find solutions that engage the public 
and private sectors.

    For this system to work, it must address several challenges. 
Funders and major stakeholders of HIV vaccine development must agree to 
a common vision so that they can coordinate their activities with other 
components of the Enterprise. There must be considerable sharing of 
information among vaccine developers regarding preclinical 
investigation and trial results, with the ultimate goal of advancing to 
clinical trials. Solving problems of access to reagents, platforms, and 
technologies of potential commercial interest will be required. 
Finally, this must be a global effort. The research and development 
enterprise described here must build and include full participation of 
the developing world where this pandemic is raging. Tens of millions of 
lives are dependent on the development of a safe and effective HIV 
vaccine. It is essential that we aggressively explore all mechanisms 
that might expedite this process. While comparable vaccine access 
initiatives will also be required to ensure that HIV vaccines are made 
available to populations in need throughout the world, the expanded 
global AIDS vaccine effort proposed here hopefully would be a major 
step towards accelerating successful HIV vaccine development.

                               __________

   The Global HIV/AIDS Vaccine Enterprise: Scientific Strategic Plan

  coordinating committee of the global hiv/aids vaccine enterprise\1\
---------------------------------------------------------------------------
    \1\ Citation: Coordinating Committee of the Global HIV/ AIDS 
Vaccine Enterprise (2005) The Global HIV/AIDS Vaccine Enterprise: 
Scientific strategic plan. PLoS Med 2(2): e25. This is an open-access 
article distributed under the terms of the Creative Commons Public 
Domain Declaration, which stipulates that, once placed in the public 
domain, this work may be freely reproduced, distributed, transmitted, 
modified, built upon, or otherwise used by anyone for any lawful 
purpose.
    Abbreviations: BMGF, Bill & Melinda Gates Foundation; GLP, Good 
Laboratory Practices; IP, intellectual property; NIH, United States 
National Institutes of Health; R&D, research and development; SIV, 
simian immunodeficiency virus; UNAIDS, Joint United Nations Programme 
on HIV/AIDS; WHO, World Health Organization.
    Members of the Coordinating Committee: M. K. Bhan (Department of 
Biotechnology, New Delhi, India), S. Berkley (International AIDS 
Vaccine Initiative, New York, United States of America), M. DeWilde 
(Aventis Pasteur, Swiftwater, United States of America), J. Esparza 
(Bill & Melinda Gates Foundation, Seattle, United States of America; 
Interim Secretariat), A. S. Fauci (National Institutes of Health, 
Bethesda, United States of America), H. Gayle (Bill & Melinda Gates 
Foundation, Seattle, United States of America), M. I. Johnston 
(National Institutes of Health, Bethesda, United States of America), P. 
Kaleebu (Uganda Virus Research Institute, Entebbe, Uganda), M. D. 
Kazatchkine (Agence Nationale de Recherches sur le SIDA, Paris, 
France), R. D. Klausner (Bill & Melinda Gates Foundation, Seattle, 
United States of America), E. S. Lander (Massachusetts Institute of 
Technology, Cambridge, United States of America), M. W. Makgoba 
(University of KwaZulu-Natal, Durban, South Africa), P. Mocumbi 
(European and Developing Countries Clinical Trials Partnership, the 
Hague, the Netherlands), P. Piot (United Nations Programme on HIV/AIDS, 
Geneva, Switzerland), O. Quintana-Trias (European Commission, Brussels, 
Belgium), W. Snow (AIDS Vaccines Advocacy Coalition, New York, United 
States of America), M. J. Walport (The Wellcome Trust, London, United 
Kingdom), and H. Wigzell (Karolinska Institute, Stockholm, Sweden).
    Competing Interests: The authors have declared that no competing 
interest exist. Most of the authors hold directive or managerial 
positions in agencies and organizations conducting or supporting HIV 
vaccine research and development.
---------------------------------------------------------------------------
Introduction
    In June 2003, an international group of scientists proposed the 
creation of a Global HIV Vaccine Enterprise. \2\ The authors invited 
discussion of this proposal, and challenged scientists to identify new 
strategies and mechanisms to accelerate the global effort to develop a 
safe and effective HIV vaccine. This paper describes the processes that 
led to agreement on the major roadblocks in HIV vaccine development, 
summarizes current scientific priorities, and describes an initial 
strategic approach to address those priorities. Specific research is 
not prescribed. Rather, the intent is to stimulate both researchers and 
funders to explore new, more collaborative, cooperative, and 
transparent approaches to address the major obstacles in HIV vaccine 
development identified in the plan, in addition to continuing the 
productive, high-quality programs already underway.
---------------------------------------------------------------------------
    \2\ Klausner RD, Fauci AS, Corey L, Nabel GJ, Gayle H, et al. 
(2003), The need for a global HIV/AIDS vaccine enterprise. Science 300: 
2036-2039.

    The motivation behind the proposal for a Global HIV/AIDS Vaccine 
Enterprise was the recognition that development of an HIV vaccine 
remains one of the most difficult challenges confronting biomedical 
research today.\3\ \4\ Fortunately, scientific progress has created new 
opportunities that could be harnessed more effectively through global 
coordination and collaboration. These new opportunities include an 
expanded HIV vaccine candidate pipeline, improvements in animal models, 
a growing database from clinical trials, and the availability of new 
quantitative laboratory tools that make comparisons among vaccine 
studies feasible. Confronting major roadblocks and harnessing these new 
opportunities requires an effort of a magnitude, intensity, and design 
without precedent in biomedical research, with the Human Genome Project 
as a potentially useful model.\5\ More specifically, the critical 
scientific insights generated by the creativity of individual 
investigators, as well as small groups and individual networks, could 
be significantly augmented by a properly organized, managed, and 
systematized international effort targeted on the design and clinical 
evaluation of novel HIV immunogens. An international collaborative 
effort that addresses a shared scientific plan, provides information 
exchange among groups, links clinical trials with standardized 
laboratory assays and evaluation in animal models, applies new 
knowledge to improvements in vaccine design in an iterative manner, and 
supports a transparent process for decision making in all aspects of 
vaccine discovery, design, development, and clinical testing will prove 
critical to success.
---------------------------------------------------------------------------
    \3\ Fauci AS (2003), HIV and AIDS: 20 years of science. Nat Med 9: 
839-843.
    \4\ Desrosiers RC (2004), Prospects for an AIDS vaccine. Nat Med 
10: 221-223.
    \5\ Waterston RH, Lander ES, Sulston JE (2002), On the sequencing 
of the human genome. Proc Natl Acad Sci USA 99: 3712-3716.

    The Global HIV/AIDS Vaccine Enterprise represents a novel paradigm 
to seek and identify international agreement on the critical roadblocks 
for developing an HIV vaccine and on creating a shared scientific plan 
that addresses those roadblocks (see Box 1). The Enterprise proposes to 
coordinate efforts at a global level, facilitate use of common tools 
and technologies, and help ensure access to optimized resources. 
Furthermore, the Enterprise approach is a way of behaving as a global 
community of problem solvers, more openly sharing information, ensuring 
that the shared scientific plan is implemented, and basing decisions on 
---------------------------------------------------------------------------
evidence rather than advocacy.

    It must be emphasized, however, that the major difficulties 
encountered in the development of an HIV vaccine are scientific, not 
organizational, and arise directly from the complexities of HIV and 
AIDS. ``Small science'' should not be replaced with ``big science.'' 
Both approaches must be undertaken. Creation of research environments 
that support the creativity both of individual investigators and of 
larger, collaborative efforts will accelerate the scientific 
breakthroughs needed to successfully develop a safe and effective HIV 
vaccine.
Scientific Priorities
    Prioritization Process. In August 2003, the authors of the 
Enterprise proposal invited a group of leading scientists, public 
health experts, and policy makers to meet at the Airlie House in 
Warrenton, Virginia, United States, to refine the vision for the 
Enterprise. The Airlie group agreed that the Global HIV/AIDS Vaccine 
Enterprise should be developed as an alliance of independent 
organizations committed to accelerating the development of a preventive 
vaccine for HIV/AIDS through implementation of a shared scientific 
strategic plan, mobilization of additional resources, and greater 
collaboration among HIV vaccine researchers worldwide.\6\
---------------------------------------------------------------------------
    \6\ Klausner RD, Fauci AS, Corey L, Nabel GJ, Gayle H, et al. 
(2004), The challenges of an HIV vaccine enterprise: Response. Science 
303: 1293.

    The subsequent initial planning phase of the Enterprise involved 
leading government research agencies, private industry, non-
governmental organizations, and funders involved in HIV vaccine 
research and development (R&D) activities, including the Bill & Melinda 
Gates Foundation (BMGF), the International AIDS Vaccine Initiative 
(IAVI), the National Agency for Research on AIDS of France (ANRS), the 
United States National Institutes of Health (NIH), the United Nations 
Joint Programme on HIV/AIDS (UNAIDS), the World Health Organization 
(WHO), and the Wellcome Trust. The Enterprise is expected to grow with 
time and include additional organizations and research groups willing 
to contribute to the implementation of its scientific strategic plan. A 
Steering Committee composed of representatives from several of the 
founding organizations provided guidance and coordination, with the 
---------------------------------------------------------------------------
BMGF serving as interim Secretariat.

    Six Working Groups involving more than 120 participants from 15 
countries, the WHO, and UNAIDS were formed to develop the scientific 
plan of the Enterprise. These Working Groups met from January to April 
2004, identified critical unanswered questions, and proposed actions to 
address them. In May 2004, the Steering Committee of the Enterprise 
analyzed the recommendations from the Working Groups and identified the 
scientific priorities for initial action.

    Several common themes emerged from the Working Groups. There was 
clear agreement on the key scientific challenges, as well as strong 
consensus that the HIV vaccine field has progressed to a point where it 
should be possible to answer some of the persistent questions more 
definitively. To meet these challenges, the Working Groups called for 
enhanced access to reagents and technologies, adequate resources, and 
strengthened human capacity in several key areas, especially in 
developing countries, where clinical trials need to be conducted. There 
was also agreement that the present way of doing business, which 
centers primarily on individually led research groups or networks, 
needs to be supplemented by establishing focused, collaborative 
structures and providing access to common standards and technologies, 
which would enable comparison of data and candidate vaccines. This 
would, in turn, support a rational process for decision making to 
advance candidate vaccines through the different phases of evaluation.


                                                     Box 1.
----------------------------------------------------------------------------------------------------------------
                                   Key Points in the Scientific Strategic Plan
-----------------------------------------------------------------------------------------------------------------
More new HIV infections and AIDS deaths occurred in 2004 than in any prior year. A vaccine is critical for the
 control of the pandemic.
 
Development of an HIV vaccine is one of the world's most difficult and important biomedical challenges.
 
Harnessing new scientific opportunities for HIV vaccine development will require an effort of a magnitude,
 intensity, and design without precedent in biomedical research.
 
The Global HIV Vaccine Enterprise is an alliance of independent organizations committed to accelerating the
 development of a preventive HIV/AIDS vaccine based on a shared scientific plan.
 
The scientific strategic plan was developed with the collaboration of over 140 scientists and other participants
 from 17 countries and several international organizations.
 
The plan identifies critical unanswered scientific questions along the critical path for vaccine discovery, from
 antigen design to the conduct of clinical trials.
 
Novel vaccine candidates need to be designed to induce high levels of broadly reactive and persistent immune
 responses against HIV strains circulating in different parts of the world.
 
Standardization and validation of high-throughput laboratory assays conducted under GLP will allow comparison of
 results from different vaccines, which is a linchpin of rational decision making in vaccine development.
 
The Enterprise will encourage decision makers to establish clear and transparent processes to identify and
 prioritize the most promising vaccine candidates.
 
The Enterprise will seek to engage the best researchers who are willing to work in a highly collaborative manner
 and to dedicate the majority of their efforts to solve the fundamental roadblocks in HIV vaccine development.
 
To mount an accelerated global search for a safe and effective HIV/AIDS vaccine, annual funding for such
 research should double--to US$1.2 billion per year.
 
Several founding partners of the Enterprise have already committed, or are planning to commit, new funding to
 support the proposed Enterprise activities, and to create a culture of mutual accountability for the effective
 implementation of the scientific strategic plan.
 
Enterprise activities are guided by an international Coordinating Committee, supported by different technical
 expert groups, including representatives from funders and implementers of HIV vaccine R&D.
----------------------------------------------------------------------------------------------------------------

      
    Vaccine Discovery. One immediate goal is to design HIV candidate 
vaccines that consistently induce potent, broadly reactive, persistent 
neutralizing antibodies, as well as memory T cells that suppress viral 
replication and prevent escape of virus from immune control.\7\ \8\ 
Additional research is also needed to identify how mucosal \9\ and 
innate\10\ \11\ immunity could be harnessed to develop effective HIV 
vaccines. The ability to develop effective vaccines would be greatly 
enhanced by an understanding of what specific immune response or 
responses correlate with vaccine-induced protection. \12\
---------------------------------------------------------------------------
    \7\ Wei X, Decker JM, Wang S, Hui H, Kappes JC, et al. (2003), 
Antibody neutralization and escape by HIV-1. Nature 422: 307-312.
    \8\ Barouch DH, Letvin NL (2004), HIV escape from cytotoxic T 
lymphocytes: A potential hurdle for vaccines? Lancet 364: 10-11.
    \9\ Veazey R, Lackner A (2003), The mucosal immune system and HIV-1 
infection. AIDS Rev 5: 245-252.
    \10\ Kottilil S, Chun TW, Moir S, Liu S, McLaughlin M, et al. 
(2003), Innate immunity in human immunodeficiency virus infection: 
Effect of viremia on natural killer cell function. J Infect Dis 187: 
1038-1045.
    \11\ Pulendran B (2004), Modulating vaccine responses with 
dendritic cells and Toll-like receptors. Immunol Rev 199: 227-250.
    \12\ Pantaleo G, Koup RA (2004), Correlates of immune protection in 
HIV-1 infection: What we know, what we don't know, what we should know. 
Nat Med 10: 806-810.

    The current state of the art suggests a two-pronged strategy to 
accelerate the development of a safe and effective HIV vaccine. One 
component should center on candidate vaccines already in the pipeline, 
nearly all of which are designed primarily to induce T cell responses. 
In some animal models these T-cell-inducing candidate vaccines suppress 
post-infection viremia and prevent or delay HIV disease, rather than 
prevent infection.\13\ \14\ In studies of individuals infected with 
HIV, viral load correlates with efficiency of transmission,\15\ 
suggesting that a vaccine capable of suppressing viral load might 
reduce HIV transmission.
---------------------------------------------------------------------------
    \13\ Shiver JW, Fu TM, Chen L, Casimiro DR, Davies ME, et al. 
(2002), Replication-incompetent adenoviral vaccine vector elicits 
effective anti-immunodeficiency-virus immunity. Nature 415: 331-335.
    \14\ Tang Y, Villinger F, Staprans SI, Amara RR, Smith JM, et al. 
(2002), Slowly declining levels of viral RNA and DNA in DNA/recombinant 
modified vaccinia virus Ankara-vaccinated macaques with controlled 
simian-human immunodeficiency virus SHIV-89.6P challenges. J Virol 76: 
10147-10154.
    \15\ Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, et 
al. (2001), Probability of HIV-1 transmission per coital act in 
monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. 
Lancet 357: 1149-1153.

    The second component should address critical gaps in scientific 
knowledge through carefully designed, focused, coordinated, and well-
supported approaches. The fruits of this work will be a clearer 
understanding of what properties are needed for a successful vaccine 
---------------------------------------------------------------------------
and how to design candidates that incorporate those properties.

    Scientific areas in which a more collaborative and organized 
Enterprise approach will be beneficial include the following: vaccine 
design based on the characteristics of recently transmitted viruses, 
evaluation of immune correlates of protection in animal models, and 
design of novel candidates vaccines that induce neutralizing antibodies 
and T cell immune responses.

    Vaccine Design. Strategically, vaccines that are designed based on 
recently transmitted viruses hold the best hope of inducing relevant 
immune responses against currently circulating strains. Recent data 
suggest that the subset of viral strains that are sexually transmitted 
has unique genetic and anti-genic properties, including greater 
susceptibility to neutralization than the bulk of circulating 
virus.\16\ While such observations require confirmation, newly 
transmitted viruses are nonetheless the crucial targets of vaccine-
induced immunity. Therefore, virological and immunological 
characterization of acute/early HIV infection should inform the design 
of vaccines and also guide the design of trials capable of determining 
whether immunization impacts virus levels and the course of HIV 
infection.
---------------------------------------------------------------------------
    \16\ Derdeyn CA, Decker JM, Bibollet-Ruche F, Mokili JL, Muldoon M, 
et al. (2004), Envelope-constrained neutralization-sensitive HIV-1 
after heterosexual transmission. Science 303: 2019-2022.

    To address these issues, a representative number of virus strains 
derived from recently infected individuals representing those 
populations who will participate in vaccine efficacy trials, including 
populations in developing countries, should be obtained. These virus 
isolates should be subjected to a comprehensive genetic and biologic 
characterization, together with an analysis of host immune responses 
and the genetic background of those populations participating in the 
---------------------------------------------------------------------------
clinical trials.

    This continuous and ongoing effort will require a multidisciplinary 
global approach, linking investigators who are conducting 
epidemiological and cohort studies (to allow for detection of acute/
early infections), laboratory scientists working on the virology and 
immunology of acute/early infection and on the genetic characterization 
of affected human populations, vaccine designers and manufacturers, and 
clinical trialists. In addition, systems for data management and 
analysis that will facilitate the rapid translation of new information 
into improved vaccine designs need to be developed.

    Immune Correlates. Nonhuman primate models of AIDS offer 
opportunities to evaluate potential correlates of immune protection. 
While a particular immunization strategy that works in animal models 
may or may not predict protection in humans, important insights into 
potential immunologic mediators of protection would result from such 
studies. Several experimental vaccines induce varying degrees of 
protection against simian immunodeficiency virus (SIV) or chimeric 
simian/human immunodeficiency virus in rhesus macaques. In particular, 
studies using models in which a very high level of protection from 
acquisition of infection was achieved are needed, i.e., immunization 
with live attenuated SIV and attenuation of SIV infection by short-term 
antiretroviral treatment administered immediately after SIV 
inoculation.\17\ \18\
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    \17\ Mills J, Desrosiers R, Rud E, Almond N (2000), Live attenuated 
HIV vaccines: A proposal for further research and development. AIDS Res 
Hum Retroviruses 16: 1453-1461.
    \18\ Lifson JD, Piatak M Jr, Cline AN, Rossio JL, Purcell J, et al. 
(2003), Transient early post-inoculation anti-retroviral treatment 
facilitates controlled infection with sparing of CD4+ T cells in gut-
associated lymphoid tissues in SIVmac239-infected rhesus macaques, but 
not resistance to rechallenge. J Med Primatol 32: 201-210.

    To facilitate this process, assays for many different immune 
responses to SIV and chimeric simian/human immunodeficiency virus need 
to be standardized, validated, and made available to different research 
groups. Likewise, agreements need to be reached on those monkey 
challenge models that most closely resemble HIV transmission and 
infection in humans. Large numbers of animals will be needed to achieve 
statistical significance for experimental findings,\19\ which in turn 
will require expanded primate breeding and housing capability. A 
multidisciplinary approach that links virologists, immunologists, 
vaccine developers, primatologists, data and project managers, and 
others will be needed.
---------------------------------------------------------------------------
    \19\ Warren J (2002), Preclinical AIDS vaccine research: Survey of 
SIV, SHIV, and HIV challenge studies in vaccinated nonhuman primates. J 
Med Primatol 31: 237-256.

    Neutralizing Antibodies. There is increasing agreement that a 
successful vaccine needs to induce both humoral and cell-mediated 
immunity. Development of immunogens capable of inducing antibodies that 
neutralize primary HIV isolates from all genetic subtypes and regions 
of the world remains the most difficult challenge in the field of HIV 
vaccinology.\20\ \21\ Success will likely require a deeper 
understanding of the structural motifs of the HIV envelope protein that 
interact with cellular receptors and/or that are recognized by broadly 
neutralizing antibodies. This strategy will require numerous well-
characterized, broadly neutralizing monoclonal antibodies, the 
application of peptide and carbohydrate chemistry, structural biology, 
and genetic engineering approaches to immunogen design, and the use of 
iterative approaches guided by the immunogenicity of new designs.
---------------------------------------------------------------------------
    \20\ Burton DR, Desrosiers RC, Doms RW, Koff WC, Kwong PD, et al. 
(2004), HIV vaccine design and the neutralization antibody problem. Nat 
Immunol 5: 233-235.
    \21\ Mascola JR (2003), Defining the protective antibody response 
for HIV-1. Curr Mol Med 3: 209-216.

    Given the importance of these endeavors and the uncertainty as to 
what path will lead to success, multiple intersecting approaches need 
to be explored, including, for example, the design, production, and 
evaluation of (1) envelope proteins that stably reveal neutralization 
epitopes that may be only transiently exposed during viral entry into 
target cells, (2) immunogens that contain rigid, stable epitopes that 
mimic the portion or portions of envelope recognized by broadly 
neutralizing monoclonal antibodies, (3) modified envelope proteins that 
better expose existing relevant epitopes, and (4) molecules that 
resemble a stabilized version of the mature envelope trimer on the 
virion surface. These are examples of current approaches being 
explored, some or all of which may prove ineffective. Additional novel 
---------------------------------------------------------------------------
ideas need to be proposed and explored.

    To achieve the above objectives, new tools and technologies such as 
those able to detect rare, broadly neutralizing monoclonal antibodies 
through large-scale screening of human sera will have to be developed. 
In addition, the very limited existing capacity to translate structural 
information into stable immunogen products needs to be expanded.

    T Cell Vaccines. Nearly all current vaccine candidates in the 
clinical pipeline are T-cell-inducing vaccines, e.g., poxvirus 
recombinant vectors, adenoviral vectors, DNA constructs with or without 
adjuvants, and lipopeptides. The ongoing effort to evaluate these 
products and to develop new ones is considerable.\22\ Identifying which 
T cell candidate vaccine or vaccines are most promising has become an 
urgent priority. However, these evaluations are being conducted within 
separate preclinical research groups and, to a lesser extent, separate 
clinical trial networks, with the result that candidate vaccines may 
not be optimally compared preclinically or clinically. This approach 
may result in delays in identifying the most promising candidates, and 
it risks devoting time and resources to inferior products, although it 
is recognized that the specific immune responses needed for a 
successful vaccine remain unknown. The identification and optimization 
of promising candidates will require (1) defining clear, transparent 
processes for decision making, (2) establishing agreement on vaccine 
characteristics upon which decisions should be based, (3) developing 
and using validated assays to assess those parameters, to allow for 
preclinical and clinical comparison among candidates, and (4) 
establishing closer coordination and data-sharing among product 
developers, which will accelerate the availability of critical 
information needed to identify and further develop the most promising 
candidates.
---------------------------------------------------------------------------
    \22\ Graham BS (2002), Clinical trials of HIV vaccines. Annu Rev 
Med 53: 207-221.
---------------------------------------------------------------------------
    Research is also needed to develop improved novel T-cell-inducing 
candidate vaccines, especially those that avoid or otherwise circumvent 
anti-vector immune responses,\23\ and those that induce persisting high 
levels of immunity, especially mucosal immunity. In addition, a 
thorough, systematic exploration of adjuvants that markedly enhance the 
quantity, quality, and durability of immune responses to HIV vaccines 
is needed.
---------------------------------------------------------------------------
    \23\ Barouch DH, Pau MG, Custers JH, Koudstaal W, Kostense S, et 
al. (2004), Immunogenicity of recombinant adenovirus serotype 35 
vaccine in the presence of pre-existing anti-Ad5 immunity. J Immunol 
172: 6290-6297.

    Laboratory Standardization. Comparison of results from preclinical 
and clinical studies is the linchpin of rational decision making 
regarding further development of vaccine candidates. Therefore, the 
---------------------------------------------------------------------------
initiation of approaches that will permit valid comparisons is crucial.

    Progress to standardize and validate a limited number of T cell 
assays has been made within the laboratories of vaccine developers and 
within some partnering research networks. This approach now needs to be 
more broadly applied and extended to the analysis of neutralizing 
antibody responses. A robust infrastructure that develops, expands, and 
ensures broad access to quality assay technologies will allow valid 
comparison of data across trials and networks worldwide.

    In order to achieve this goal, the following are required: (1) a 
decision-making process to select a set of robust assays, standardized 
and validated across laboratories, for measuring vaccine-induced immune 
responses in humans and animals; (2) wide availability of common 
reagents (such as peptides, control sera, and virus panels); (3) 
capacity for developing novel assays and reagents of potential value 
and for their translation to preclinical and clinical settings; (4) 
``core'' laboratories that run selected assays and serve as a reference 
laboratory for satellite laboratories (clinical and preclinical work 
would take place in separate facilities, and clinical studies would 
require Good Laboratory Practices [GLP] conditions); (5) satellite 
laboratories located at or very near clinical trial sites to carry out 
a range of activities such as processing blood, storing and shipping 
specimens, and conducting basic immunological evaluation, and to 
participate in other Enterprise-organized activities such as acute/
early infection studies; (6) an ongoing global quality assurance 
function encompassing all participating core and satellite laboratories 
and covering both routine safety as well as immunologic and virologic 
assessments; and (7) transfer of research assays and, when and where 
feasible, validated endpoint assays to satellite labs, including the 
necessary training activities.

    In addition, new assay development has failed to keep pace with 
current understanding of the biology of the immune system and recent 
advances in technology. A more active program of applied research and 
assay development is needed to explore new concepts that would advance 
technical abilities and provide a better understanding of the immune 
responses generated by HIV vaccines.

    Cellular Immunity. Two assays are currently used for the primary 
evaluation and enumeration of antigen-specific T cells: Interferon-l 
ELISPOT and multiparameter flow cytometry. The ELISPOT assay was 
initially developed to measure CD8+ T cell responses. Several 
observations in both mice and humans have indicated that protective 
immune responses will likely require stimulation of both CD4+ and CD8+ 
T cell effector and memory functions; it is unlikely that induction of 
Interferon-l-secreting T cells alone correlates with protective 
immunity. Therefore, additional laboratory assays measuring multiple 
HIV-specific cell types as well as functional capabilities will be 
needed to thoroughly evaluate vaccine-induced immune responses. These 
assays should also permit rapid assessment of the magnitude and breadth 
of immune responses, and enumerate the specific epitopes that are 
recognized.

    Humoral Immunity. Different laboratories use different assays to 
measure antibodies that neutralize HIV and related viruses, SIV and 
chimeric simian/human immunodeficiency virus. These assays vary 
technically, but the most widely accepted assays measure reduction in 
virus infectivity in cells that express the receptors necessary for 
virus entry. Assays that offer the greatest value are those that are 
validated, amenable to high throughput, low in cost, readily 
transferable, and that can be performed according to GLP guidelines.

    The ability to measure the magnitude and breadth of neutralization 
against diverse HIV strains is essential to evaluating responses 
generated by candidate HIV vaccines. Only with multiple strains of 
virus can neutralization breadth be ascertained in a meaningful way. 
Standard panels of HIV strains are in early stages of development. 
Expansion or extension of current standardization and validation 
activities, production and provision of necessary reagents, and access 
to quality assurance programs are needed to ensure worldwide 
comparability of assay results.\24\ The strains of virus incorporated 
into a worldwide panel need to be carefully selected to reflect the 
current epidemic and should include early isolates from individuals at 
potential vaccine trial sites.\25\ Molecular epidemiological studies 
and elucidation of the role of genetic factors and immune responses of 
the host in the transmission of HIV at the population level will also 
help guide vaccine design and evaluation.\26\ \27\ Another specific 
priority is an assessment of the neutralizing antibody response 
generated in the recently completed Phase III trials of HIV envelope 
glycoprotein 120 candidate vaccines using a global virus panel. The 
results would establish a baseline level of neutralization potency and 
breadth that is nonprotective, which would be extremely valuable in 
reaching informed decisions about advancing future antibody-based 
candidate vaccines.
---------------------------------------------------------------------------
    \24\ Moore JP, Burton DR (2004), Urgently needed: A filter for the 
HIV-1 vaccine pipeline. Nat Med 10: 769-771.
    \25\ Osmanov S, Pattou C, Walker N, Schwardlander B, EsparzaJ, et 
al. (2002), Estimated global distribution and regional spread of HIV-1 
genetic subtypes in the year 2000. J Acquir Immune Defic Syndr 29: 184-
190.
    \26\ Allen TM, Altfeld M, Yu XG, O'Sullivan KM, Lichterfeld M, et 
al. (2004), Selection, transmission, and reversion of an antigen-
processing cytotoxic T-lymphocyte escape mutation in human 
immunodeficiency virus type 1 infection. J Virol 78: 7069-7078.
    \27\ Moore CB,John M,James IR, Christiansen FT, Witt CS, et al. 
(2002), Evidence of HIV-1 adaptation to HLA-restricted immune responses 
at a population level. Science 296: 1439-1443.

    A major obstacle to designing a suitable global virus panel is the 
paucity of information on neutralization serotypes. There is general 
agreement that if a reasonably small number of neutralization serotypes 
exist, their identification would guide the creation of an optimal 
panel of isolates for neutralizing antibody assays and the design of 
polyvalent immunogens. Although there is some controversy as to whether 
HIV-1 neutralization serotypes exist, the magnitude of benefit that 
would result if serotypes were identified warrants establishment of a 
neutralization serotype discovery program that employs the latest 
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technologies.

    Product Development and Manufacturing. Manufacture of vaccine 
candidates for large clinical trials and to meet eventual worldwide 
demand requires the development of processes for producing consistent, 
active vaccine batches on a large scale. Development of these 
bioprocesses must be integrated with analytical work (e.g., toxicity 
and stability testing), incorporate validated assays, and be applicable 
to the manufacture of sufficient vaccine to meet global needs after 
licensure. These processes are typically individually developed as a 
candidate vaccine advances from early clinical testing to late-stage 
evaluation and licensure. Worldwide expertise and capacity for this 
bioprocess development work is already limiting and exists almost 
exclusively in the private sector. As more HIV candidate vaccines enter 
the pipeline, current capacity will be rapidly exhausted.

    The initial priority is to identify or establish one or more 
dedicated HIV vaccine bioprocess and analytical development groups that 
bring together the skill set and capacity to manufacture different 
promising candidates for clinical trials. The bioprocess development 
groups would also help train people and transfer manufacturing skills 
in whole or in part to manufacturing sites around the world. This 
training program would address the acute shortage of bioprocess 
experts.

    At a later stage, building, acquiring, or contracting facilities to 
carry out bioprocess and analytical work and to produce several 
different types of candidate vaccines should be considered. Such 
facilities would further assist in transferring manufacturing 
technology to other production facilities, preferably in one or more 
developing countries. Decisions about which candidates a facility 
undertakes would be made through a well-defined, comprehensive 
evaluation process. The facilities could eventually be expanded to 
provide production capacity to launch a vaccine for public health use, 
should no manufacturer be available to produce the vaccine quickly upon 
licensure.

    Clinical Trials Capacity. As a growing number of HIV candidate 
vaccines begin to move through the clinical trials pipeline, the gap 
between existing global capacity and future requirements for conducting 
large efficacy trials has grown in magnitude and urgency, especially in 
developing countries. This gap in developing countries must be 
addressed through (1) increasing the quantity and quality of research 
staff, (2) establishing sustainable research facilities to support 
trials, and (3) expanding access to large, well-defined populations of 
uninfected people at high risk of HIV infection.

    The recommended solutions take a long-term view and are aimed at 
building site capacity rather than preparing for specific trials. Sites 
should not be confined to conducting HIV vaccine trials but should be 
positioned to contribute to other research of public health importance 
to the community and the country, including, for example, other areas 
of HIV research (e.g., microbicides and treatment) and/or other 
diseases. Additional field trial sites must be developed to be able to 
conduct planned and anticipated efficacy trials. Sites should be 
selected in a strategic, data-driven manner, and should demonstrate the 
ability to recruit and retain large numbers of HIV-negative volunteers 
from populations with substantial HIV incidence. New efficacy trial 
sites should be developed in regions with emerging epidemics rather 
than only in areas with already-established disease. ``Early-warning 
systems'' must be available to identify these newly emerging sub-
epidemics. Defining optimal methods for collection of HIV incidence 
data from populations at potential efficacy trial sites is essential. 
Whenever possible, efficacy trial sites should be linked to (1) 
academic medical centers to enhance research capacity and help train 
clinical researchers, (2) accredited local and regional laboratory 
facilities to provide infection endpoint and safety assessments, and 
(3) centers that can provide appropriate care and treatment to trial 
participants.

    The acute shortage of qualified personnel is a major bottleneck to 
the conduct of clinical trials in developing countries with severe or 
rapidly emerging HIV epidemics. Development of intellectual capacity at 
these sites should emphasize (1) expanding research training 
opportunities for personnel in the broad range of topics required to 
conduct high-quality clinical research, (2) establishing and adequately 
supporting long-term career paths for such individuals, and (3) 
fostering political and social environments locally and nationally that 
support the conduct of clinical research. Building HIV scientific and 
operational expertise at clinical trial sites should be linked to other 
HIV/AIDS research activities (e.g., identifying and characterizing 
incident/early HIV infections, collecting newly transmitted strains, 
and measuring incidence in high-risk populations).

    Site development must include strategies to develop or enhance 
existing capacity to deliver health care, including HIV prevention, 
care, and treatment, to the local community participating in clinical 
trials. Provision of, or referral to, basic clinical services such as 
voluntary counseling and testing and diagnosis and treatment of 
sexually transmitted infections will be essential.

    In addition, site development should include building skills that 
are ancillary but critical to the actual conduct of clinical trials, 
such as educating communities, building community partnerships, 
managing site finances, and piloting applications through regulatory 
decision-making processes.

    Regulatory Considerations. The Enterprise must address a number of 
problems that currently impact the review of HIV vaccine trial 
protocols and that could delay future decisions regarding product 
licensure in developing countries. Most regulatory challenges arise 
from the fact that regulatory approvals are granted at the national 
level, but many developing countries lack the expertise, well-defined 
processes, clear delineation of authority, and/or other system 
components needed to make regulatory decisions expeditiously. As a 
result, new products are often licensed in these regions based on prior 
approval in the U.S. or Europe and/or endorsement by the WHO. Under 
these circumstances, data specific to developing country populations 
(e.g., disease burden or childhood vaccination schedules) often do not 
enter into the decision making. The absence of defined pathways to 
approve products targeting a country's needs when a product is not also 
submitted to regulators in the U.S. or Europe remains another obstacle. 
The Enterprise process has identified these action-item priorities: (1) 
harmonize and exchange information needed by regulatory bodies within 
the differing legal frameworks of different countries, (2) facilitate 
regulatory decision making, possibly using regional approaches for 
conducting reviews and making recommendations, (3) build regulatory 
capacity, (4) perform risk/benefit evaluations in the context of 
differing epidemic dynamics and country needs and resources, (5) 
identify and remove potential scientific impediments to rapid 
regulatory decision making, and (6) address ethical issues that 
interface with regulatory decision making, such as ensuring informed 
consent and defining the degree to which trial participants should 
receive a standard of care that is higher than others in their 
community.

    Intellectual Property Issues. Given the Enterprise focus on 
stronger collaboration, data sharing, and use of common materials and 
reagents, an intellectual property (IP) framework that facilitates this 
``enabling environment'' is crucial for success. While IP issues may 
arise throughout the vaccine development process, at present the top 
priority is to stimulate early stage research and vaccine design by 
increasing scientific freedom to operate and sharing of data and 
biological materials.

    Specific areas for further consideration include: (1) minimizing 
restrictions on freedom of operation, perhaps by early stage covenants 
not to litigate and followed by later stage agreements based on true 
valuations of IP; (2) sharing of information (including clinical trial 
data), materials, expertise, trade secrets, and platform technologies 
in a protected and secure manner while also remaining in compliance 
with national laws devised to prevent monopolies and insider trading; 
(3) recognizing the contribution of different countries to HIV vaccine 
development through approaches that assure affordable access to 
successful vaccines; and (4) maximizing access to essential 
technologies and inventions.
Scientific Plan
    Scientific Activities. On October 21, 2004, a group of participants 
from 16 countries, the European Commission, UNAIDS, and the WHO met to 
finalize the scientific plan and to discuss how to formulate specific 
actions.

    Participants noted that the structure of an activity should depend 
on several factors, including, for example, the degree to which the 
activity can be predefined, the degree to which the creativity of 
academic researchers needs to be harnessed, and the mechanisms 
available to the funding organization.

    A number of options were discussed, with consensus as to those that 
would fit various scientific priorities.

    First, networks of focused consortia and real or virtual centers 
are well suited to systematically address many of the major scientific 
roadblocks identified in this plan. These consortia or centers would 
link to each other to ensure a comprehensive, systematic approach, 
sharing information so that each can be as productive as possible, and 
also to share reagents and procedures so that data among groups can be 
compared and, where possible, merged for analysis. The specific 
scientific areas that could be supported by consortia or centers 
include (1) addressing fundamental scientific problems, such as the 
definition of correlates of immune protection in selected animal models 
and the characterization of acute/early infection in potential vaccine 
trial sites; (2) designing and evaluating novel vaccines, such as 
immunogens that neutralize primary isolates, and improved T cell 
vaccines that avoid immunological escape and/or that induce persisting 
mucosal or persisting systemic responses; and (3) providing for a 
systematic evaluation of potential adjuvants. The success of consortia 
or virtual centers will depend on engaging the best researchers, 
getting them to work collaboratively and dedicate the majority of their 
effort to HIV vaccine research, resolving IP issues, obtaining support 
for researchers from their institutions, and keeping the group focused 
on specific, well-defined questions. More than one consortium may be 
needed for systematic coverage of vaccine design research (e.g., 
monoclonal-antibody-identified epitopes, native envelope, and modified 
envelope).

    Second, a global system of central laboratories linked to satellite 
laboratories that work together (using GLP) would provide a range of 
standardized functions, help ensure the quality of clinical research, 
and enable comparison of data from different trials. Together this 
system could (1) conduct preclinical or clinical assays, particularly 
critical endpoint assays that require standardization and/or 
validation; (2) develop, optimize, and validate new assays and 
platforms; (3) transfer assays from central labs to satellite labs; (4) 
develop and implement a global quality control/quality assurance 
program and proficiency testing for assays performed at central and 
satellite laboratories; (5) implement vaccine-related research that 
requires validated assays and close cooperation and collaboration among 
labs globally, such as a Virus Neutralization Serotype Discovery 
Program, and the characterization of recently transmitted HIV isolates; 
and (6) contribute to the development of technological infrastructure 
in developing countries.

    Third, a number of contract laboratories capable of developing, 
acquiring, storing, and distributing common reagents will prove 
critical to the success of collaborative research and development 
projects, and to ensuring reagent quality. These reagents could include 
(1) peptides, antisera/antibodies, and viral isolates for immune 
assays, including a standard panel of virus strains and sera 
representative of the global genetic and immunologic variability of 
HIV, and (2) additional broadly neutralizing monoclonal antibodies, 
especially from non-clade B viruses, to facilitate elucidation of the 
motif or motifs they recognize. These contract laboratories would be 
expected to work very closely with and enable the work of Enterprise 
consortia, centers, immune assessment laboratories, and clinical sites.

    Fourth, a network of Clinical Research Training Centers in 
developing countries could work collaboratively to ensure development 
of quality trial sites. These centers would (1) conduct or facilitate 
training of trial site personnel in activities that are generic to the 
conduct of clinical trials, as well as those specific for HIV vaccine 
trials, for example, an HIV vaccine fellowship program for developing 
country scientists; (2) coordinate and work together with other 
Enterprise consortia or centers, such as those established to 
characterize acute/early infection in developing country settings or to 
prepare a standard panel of HIV strains representative of currently 
circulating viruses; and (3) share standard operating procedures, 
vaccine development plans, and strategies for engaging and ensuring 
community and political support.

    Fifth, a network of individuals and companies with manufacturing 
experience, particularly process development expertise, could link to 
consortia, centers, and others involved in vaccine development to 
provide development and manufacturing expertise to facilitate the 
advancement of improved HIV vaccine candidates. The above structures 
are proposed to address the initial Enterprise scientific priorities. 
Additional consultative groups, reference and centralized facilities, 
and other mechanisms may be needed to facilitate collaborative work and 
strengthen the global capacity for the conduct of HIV vaccine research 
and development as the field progresses.

    Different implementing and funding agencies will need to work in 
close collaboration to ensure harmonious implementation of the 
scientific plan. Initial actions should focus on the areas of vaccine 
discovery and standardization of laboratory assays, which are 
considered critical for the success of the Enterprise and the eventual 
development of a safe and effective HIV vaccine. Activities to address 
recommendations in the areas of product development and manufacturing, 
clinical trials capacity, regulatory considerations, and IP issues 
should be launched after these initial components of the plan are under 
way.

    Regardless of timing, each scientific endeavor needs to outline 
specific strategies to ensure information exchange and capacity 
building among the collaborating partners and institutions. The funding 
mechanisms employed (i.e., contracts, grants, interagency agreements, 
etc.) will depend on the task to be accomplished and the needs and 
capabilities of each funding organization. In the spirit of 
coordination, collaboration, and transparency promoted by the 
Enterprise, two or more partners may jointly support one or more 
activities, taking care to avoid duplication in the use of their 
respective resources. When a research area is jointly funded, all 
communication regarding goals, research plans, progress, obstacles, 
etc., should be openly and transparently shared among all 
stakeholders--funders, project managers, and researchers.

    Guiding Principles. As an alliance of independent entities, the 
Global HIV/AIDS Vaccine Enterprise will be challenged to carry out 
three essential functions. One is to continue regular scientific 
assessments. The scientific priorities outlined in this paper will need 
to be monitored, reevaluated, and updated. An evolving scientific plan 
must reflect lessons learned, new opportunities, and the influence of 
new scientific findings and new technologies. Revised versions of the 
scientific plan must be made fully and publicly available. The second 
essential function is to establish global processes. To optimize 
progress across a large and complex set of activities at the global 
level, standards, performance criteria, and processes for data sharing, 
communication, and convening must be established. The Enterprise will 
convene fora to address policy issues such IP, clinical trials, site 
development, and regulatory hurdles. And the third essential function 
is shared accountability. The partners in this alliance will need to 
create a culture of mutual accountability for the effective 
implementation of the scientific strategic plan. Since the Enterprise 
is not a single organization, a shared ``way of doing business'' is one 
of its most important defining traits. Articulating an explicit set of 
``working principles'' is therefore crucial to the identity and smooth 
functioning of the Enterprise.

    For the Enterprise as a whole the following conditions apply: (1) 
the central task is to develop and implement an ambitious scientific 
plan with the necessary scale, balance and sequence of activities, and 
structure to carry it out; (2) the plan must focus on critical 
roadblocks that would benefit substantially from global collaboration 
while fostering continued R&D by individuals, small groups, and 
individual networks; (3) the incentives holding the alliance together 
will include collaborative arrangements and structures that give people 
the resources, necessary critical mass, centralized facilities, common 
reagents, assays and technologies, and data they need to effectively 
remove critical roadblocks; (4) all activities will reflect the 
commitment to create an environment that maximizes the ability of 
participants to share data and biological materials, e.g., through the 
use of common standards for measurements and appropriate IP 
arrangements; and (5) the Enterprise also commits to working for rapid 
global access to a successful vaccine.

    For participating investigators and organizations, key principles 
include (1) the willingness and desire to work in an open, 
collaborative fashion, sharing data and reagents in a collegial 
fashion, with the appropriate balance between productive competition 
and effective collaboration, and (2) the willingness and ability to 
devote the majority of their time to tackling these problems within a 
focused environment, completely committing to solve the problems at 
hand.

    Organizational Structure of the Enterprise. The Coordinating 
Committee will facilitate all aspects of the Enterprise's activities. 
This committee consists of representatives of the Enterprise founders 
as well as additional scientific leaders selected from inside and 
outside the field of HIV vaccine research and development. The 
committee will develop procedures for term rotation and inclusion of 
new members, to ensure appropriate representation of all relevant 
partners, and will engage external stakeholders for advice, expertise, 
and assistance, appointing technical expert groups as needed. A 
Secretariat will provide logistical and administrative support to the 
Coordinating Committee and Enterprise partners. The BMGF will serve as 
Interim Secretariat until a permanent Secretariat is established.

    The Funders Forum will be an open forum of sovereign, independent 
funding organizations, starting with a nucleus of those who already 
embrace the principles of the Enterprise and who are actively 
supporting or intend to support and fund HIV vaccine research and 
development. Members of the Funders Forum will be high-level decision 
makers within the ranks of funding organizations and governments, as 
close as possible to the source of resources. Since the Enterprise is 
not a discrete organization with a pool of money, funders will support 
specific areas using their own mechanisms, according to their own 
practices and policies, and following Enterprise principles. The road 
to success will be a bumpy one. The scientific plan will provide 
guidance that may help funders better align existing resources but, 
more importantly, will facilitate the efficient and focused application 
of new resources as they become available. Multiple funders who wish to 
support a single Enterprise-defined project could form collaborative 
agreements, memoranda of understanding, or other forms of written 
agreement among themselves to outline their respective roles and 
responsibilities; address IP, program management, oversight, and other 
issues; and establish mechanisms for communication and conflict 
resolution.

    The funders with greatest flexibility could provide incentives for 
sharing reagents and data, and linking projects together, e.g., by 
supporting the additional work that nationally or regionally funded 
laboratories would need to undertake in order to participate in a 
global network, or by supporting a program to develop and share 
reagents.

    In some cases, funders may wish to support an implementing 
organization that will take responsibility for managing the project and 
reporting back to the funder and other stakeholders. In other cases, 
funders may have the capability and capacity to play a substantial role 
in facilitating the project. In still other cases, funders may have the 
capability to assume a leadership role in overseeing the conduct of the 
activity, particularly in cases where the activity is well defined in 
advance.

    In addition, an Annual Stakeholders Forum will be organized to 
bring together the broader community of scientists, policy makers, 
public health officials, and community representatives involved in the 
search for an HIV/ AIDS vaccine. This meeting will serve as a forum to 
(1) update the broader community on Enterprise activities and progress, 
and (2) provide the community with a mechanism for feedback and dialog.

    Funding Issues. Global expenditures on HIV vaccine research and 
development in 2002 were tentatively estimated to be on the order of 
US$624-670 million, the large majority (67.3%) provided by the public 
sector, followed by the philanthropic sector (17.4%) and industry 
(15.3%). An analysis of how those funds have been invested revealed 
that the large majority (43.1%) is being used in preclinical research 
activities, followed by clinical trials (28.2%), basic research 
(20.7%), cohort development and clinical trial infrastructure (6.5%), 
and vaccine education, advocacy, and policy development (1.4%). \28\
---------------------------------------------------------------------------
    \28\ Bing A, Gold D, Lamourelle G, Rowley J, Sadoff S (2004), 
Quantifying global expenditures on AIDS vaccines R&D [abstract]. XV 
International AIDS Conference; 2004 July 11-16 Bangkok, Thailand. 
Abstract number Tu-PeE5325. Available: http://www.iasociety.org/ ejias/
show.asp?abstract--id=2170619. Accessed 8 December 2004.

    The largest funder of HIV vaccine research and development 
activities has been the NIH, with almost US$350 million in 2002. The 
NIH budget for HIV vaccine research has grown from less than US$50 
million in 1996, to an estimated US$514.6 million for 2005, 
corresponding to 17.6% of the NIH total HIV-related research budget for 
---------------------------------------------------------------------------
2005.

    The Enterprise Coordinating Committee will analyze the additional 
financial requirements to fully implement the scientific plan of the 
Enterprise, and the Enterprise Secretariat will explore options to 
leverage these funds from the public and private sector. Initial 
estimates by Enterprise partners suggest that US$1.2 billion per year, 
or double the current expenditures on HIV vaccine research and 
development, will be needed. Although this amount may appear 
unrealistic at present, it would represent only a fraction of the total 
global expenditures in response to the AIDS pandemic and a very 
reasonable investment in view of the enormous social, political, and 
economic consequences of the pandemic. However, it is essential that 
the proposed increase in funding for HIV vaccine R&D be additional to 
existing AIDS expenditures, and not at the expense of current 
prevention, treatment, and care efforts.

    The founding partners of the Enterprise, including the NIH, the 
BMGF, and the Wellcome Trust have already committed, or are considering 
committing, resources towards new initiatives that will begin to enact 
portions of the Enterprise scientific plan over the next six to nine 
months. Each funder will utilize their own funding processes and will 
align the design, scope, and scale of programs to those laid out in 
this plan. For example, the NIH National Institute of Allergy and 
Infectious Diseases will establish the Center for HIV Vaccine 
Immunology, which will target several scientific priorities identified 
here.

    Political Support. As a sign of global recognition of the 
importance of better, more strategic coordination in the search for an 
HIV vaccine, the ``Group of Eight'' leading industrialized nations in 
June 2004 endorsed the goals of the Enterprise and agreed to review 
progress in implementation at its 2005 summit meeting in the United 
Kingdom.\29\ Likewise, on October 19, 2004, Ministers of Health from 
seven European countries (France, Germany, Italy, the Netherlands, 
Spain, Sweden, and the United Kingdom) adopted a statement of intent to 
coordinate efforts to accelerate research for an HIV vaccine within the 
context of the global effort.
---------------------------------------------------------------------------
    \29\ Vogel G (2004), AIDS vaccines. G-8 leaders endorse global 
effort. Science 304: 1728.
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Next Steps
    With almost 5 million new HIV infections and 3 million AIDS deaths 
occurring every year worldwide, the development of a safe, effective, 
and accessible HIV vaccine represents one of the most urgent global 
public health needs. This global emergency led to the proposal to 
harness the power of science to find a definitive solution to one of 
the most catastrophic health problems of our time. The Global HIV/AIDS 
Vaccine Enterprise has evolved over the past 18 months from a concept 
proposed in a scientific journal by a cadre of researchers to a global 
consensus concerning the major scientific roadblocks facing HIV vaccine 
development, a strategic approach to address those roadblocks, and 
guiding principles for the plan's implementation in a manner and degree 
commensurate with the challenges at hand. Several organizations have 
already embraced the Enterprise concept and are moving to tackle 
portions of the scientific plan. Still, much more remains to be done. 
The road to success will be a bumpy one requiring the energy, 
commitment, and action of a wide number of government and 
nongovernmental organizations globally. Recognizing the enormity of the 
roadblocks as well as the potential benefits of a safe and effective 
HIV vaccine, it is essential that many more organizations and agencies 
contribute additional expertise and resources and work together as a 
global community in a cooperative, collaborative, and transparent 
manner to fully implement the Enterprise scientific plan.
Acknowledgments
    The scientific strategic plan of the Global HIV/AIDS Vaccine 
Enterprise was developed though a complex process of consultation that 
involved more than 140 participants from 17 countries, the European 
Commission, the WHO, and UNAIDS. Special thanks are given to the Co-
Chairs of the different Working Groups of the Enterprise that provided 
invaluable insights and recommendations for the development of this 
document (L. Corey, G. Douglas, E. Emini, N. Ketter, A. McMichael, G. 
Monroy, D. Montefiori, G. Nabel, G. Pantaleo, H. Rees, G. Sadoff, and 
J. Wasserheit). Thanks are also given to C. Hankins and J. Whitworth 
for their valuable comments and suggestions.

                                 
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