Influenza Pandemic: Efforts Under Way to Address Constraints on  
Using Antivirals and Vaccines to Forestall a Pandemic (21-DEC-07,
GAO-08-92).							 
                                                                 
Pandemic influenza poses a threat to public health at a time when
the United Nations' World Health Organization (WHO) has said that
infectious diseases are spreading faster than at any time in	 
history. The last major influenza pandemic occurred from 1918 to 
1919. Estimates of deaths worldwide if a similar pandemic were to
occur have ranged between 30 million and 384 million people.	 
Individual countries and international organizations have	 
developed and begun to implement a strategy for forestalling	 
(that is, containing, delaying, or minimizing the impact of) the 
onset of a pandemic. Antivirals and vaccines may help forestall a
pandemic. GAO was asked to examine (1) constraints upon the use  
of antivirals and vaccines to forestall a pandemic and (2)	 
efforts under way to overcome these constraints. GAO reviewed	 
documents and consulted with officials of the Departments of	 
State and Health and Human Services (HHS), international	 
organizations, and pharmaceutical manufacturers. WHO commented	 
that the report was comprehensive and useful. HHS stressed that  
vaccines and antivirals must be viewed in a larger context. State
and HHS commented that the term "forestall" is ambiguous and	 
misleading. However, GAO has used the word in a way that is	 
consistent with WHO's use of the term.				 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-08-92						        
    ACCNO:   A79148						        
  TITLE:     Influenza Pandemic: Efforts Under Way to Address	      
Constraints on Using Antivirals and Vaccines to Forestall a	 
Pandemic							 
     DATE:   12/21/2007 
  SUBJECT:   Avian influenza					 
	     Disease control					 
	     Disease detection or diagnosis			 
	     Disease surveillance				 
	     Emergency preparedness				 
	     Emergency response plans				 
	     Emerging infectious diseases			 
	     Infectious diseases				 
	     Influenza						 
	     Pandemic						 
	     Program management 				 
	     Public health					 
	     Research and development				 
	     Risk management					 
	     Vaccination					 

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GAO-08-92

This is the accessible text file for GAO report number GAO-08-92 
entitled 'Influenza Pandemic: Efforts Under Way to Address Constraints 
on Using Antivirals and Vaccines to Forestall a Pandemic' which was 
released on January 22, 2008. 

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Report to Congressional Requesters:

United States Government Accountability Office: 
GAO:

December 2007:

Influenza Pandemic:

Efforts Under Way to Address Constraints on Using Antivirals and 
Vaccines to Forestall a Pandemic:

GAO-08-92: 

GAO Highlights:

Highlights of GAO-08-92, a report to congressional requesters. 

Why GAO Did This Study:

Pandemic influenza poses a threat to public health at a time when the 
United Nationsï¿½ World Health Organization (WHO) has said that 
infectious diseases are spreading faster than at any time in history. 
The last major influenza pandemic occurred from 1918 to 1919. Estimates 
of deaths worldwide if a similar pandemic were to occur have ranged 
between 30 million and 384 million people. Individual countries and 
international organizations have developed and begun to implement a 
strategy for forestalling (that is, containing, delaying, or minimizing 
the impact of) the onset of a pandemic. Antivirals and vaccines may 
help forestall a pandemic. 

GAO was asked to examine 
(1) constraints upon the use of antivirals and vaccines to forestall a 
pandemic and (2) efforts under way to overcome these constraints. GAO 
reviewed documents and consulted with officials of the Departments of 
State and Health and Human Services (HHS), international organizations, 
and pharmaceutical manufacturers.

WHO commented that the report was comprehensive and useful. HHS 
stressed that vaccines and antivirals must be viewed in a larger 
context. State and HHS commented that the term ï¿½forestallï¿½ is ambiguous 
and misleading. However, GAO has used the word in a way that is 
consistent with WHOï¿½s use of the term. 

What GAO Found:

The use of antivirals and vaccines, two elements of the international 
strategy to forestall a pandemic, could be constrained by their 
uncertain effectiveness and limited availability. To use antivirals 
effectively, health authorities must be able to detect a pandemic 
influenza strain quickly through surveillance and diagnostic efforts 
and use this information to administer antivirals. The effectiveness of 
antivirals could be limited if they are used more than 48 hours after 
the onset of symptoms or by the emergence of strains resistant to 
antivirals. Unlike antivirals, vaccines are formulated to target a 
specific influenza strain in advance of infection. The effectiveness of 
vaccines in forestalling a pandemic could be limited because such a 
targeted pandemic vaccine cannot be developed until that strain has 
been identified. Due to the time required to identify the virus and 
develop and manufacture a pandemic vaccineï¿½20 to 23 weeks according to 
HHSï¿½such vaccines are likely to play little or no role in efforts to 
forestall a pandemic in its initial phases. The availability of 
antivirals and vaccines in a pandemic could be inadequate due to 
limited production, distribution, and administration capacity. WHO has 
stated that it is unlikely that sufficient quantities of antivirals 
will be available in any country at the onset of a pandemic. The 
distribution and administration capacity for antivirals and vaccines is 
limited in some countries by poor or nonexistent delivery plans and 
networks, a lack of facilities for administering the drugs, and small 
numbers of personnel trained to administer them. 

The United States, its international partners, and the pharmaceutical 
industry are investing substantial resources to address constraints on 
the availability and effectiveness of antivirals and vaccines. Efforts 
are under way to improve influenza surveillance, including diagnostic 
capabilities, so that outbreaks can be quickly detected. Increased 
demand and government support has led manufacturers to increase 
research into more effective antivirals and vaccines. Manufacturers are 
developing new antivirals to combat influenza. New methods for 
developing vaccines are being studied in order to reduce the amount of 
vaccine that is needed and to increase the number of strains against 
which it is effective. Pre-pandemic vaccines, which are formulated to 
target influenza strains that have the potential to cause a pandemic, 
are being developed. However, these vaccines may or may not be 
effective against the pandemic strain that ultimately emerges. To 
overcome limitations on the availability of antivirals and vaccines, 
manufacturers are working to increase production at existing facilities 
and build new facilities. To address constraints on the distribution 
and administration of antivirals, stockpiles are being established to 
allow faster delivery of antivirals to countries experiencing 
outbreaks. WHO is also working to establish stockpiles of pre-pandemic 
vaccines. Additionally, other efforts also face limitations. For 
example, increasing production capacity of vaccines and antivirals will 
take several years as new facilities are built and necessary materials 
acquired.

To view the full product, including the scope and methodology, click on 
[hyperlink, http://www.gao.gov/cgi-bin/getrpt?gao-08-92]. For more information, contact Marcia 
Crosse at (202) 512-7114 or [email protected], or David Gootnick at (202) 
512-3149 or [email protected].

[End of section] 

Contents:

Letter:

Results in Brief:

Background:

Uncertain Effectiveness and Limited Availability Would Likely Constrain 
the Use of Antivirals and Vaccines to Forestall the Onset of a Pandemic:

U.S. Government and International Partners' Efforts Are Under Way to 
Address Constraints on Use of Antivirals and Vaccines, but Certain 
Efforts Face Limitations:

Agency Comments and Our Evaluation:

Appendix I: Comments from the Department of Health and Human Services:

Appendix II: Comments from the Department of State:

Appendix III: GAO Contacts and Staff Acknowledgments:

Related GAO Products:

Tables:

Table 1: Influenza Vaccine Types:

Table 2: Antiviral Drugs Available for the Prevention and Treatment of 
Influenza:

Table 3: HHS Contracts Awarded to Companies in December 2006 to Develop 
Rapid Diagnostic Tests for Influenza:

Table 4: HHS Contracts Awarded in May 2006 to Develop Cell-Based 
Vaccines:

Table 5: HHS Contracts Awarded in January 2007 to Develop Influenza 
Vaccines Containing an Adjuvant:

Figure:

Figure 1: Pandemic Vaccine Production Timeline:

Abbreviations:

CDC: Centers for Disease Control and Prevention: 

FAO: Food and Agriculture Organization of the United Nations: 

FDA: Food and Drug Administration: 

GLEWS: Global Early Warning and Response System for Major Animal 
Diseases, including Zoonoses: 

HHS: Department of Health and Human Services: 

IFPMA: International Federation of Pharmaceutical Manufacturers & 
Associations: 

NIH: National Institutes of Health: 

OFFLU: OIE/FAO Network of Expertise on Avian Influenza: 

OIE: World Organisation for Animal Health (Office International des 
Epizooties): 

WHO: United Nations' World Health Organization:

United States Government Accountability Office: 
Washington, DC 20548:

December 21, 2007:

The Honorable Edward M. Kennedy: 
Chairman: 
Committee on Health, Education, Labor and Pensions: 
United States Senate:

The Honorable Daniel K. Akaka: 
Chairman: 
Subcommittee on Oversight of Government Management, the Federal 
Workforce, and the District of Columbia: 
Committee on Homeland Security and Governmental Affairs: 
United States Senate:

The Honorable Bennie G. Thompson: 
Chairman: 
Committee on Homeland Security: 
House of Representatives:

The Honorable Judd Gregg: 
United States Senate:

An influenza pandemic--caused by a novel strain of influenza virus that 
is virulent and highly transmissible among humans--would be of global 
significance. While some scientists and public health experts believe 
that the next influenza pandemic could be caused by a strain of the 
H5N1 avian influenza virus (also known as "bird flu") that is currently 
circulating in parts of Asia, Europe, and Africa, it is unknown when an 
influenza pandemic will occur, where it will begin, or whether an H5N1 
strain or another strain would be the cause. Pandemic influenza poses a 
grave threat to global public health at a time when the United Nations' 
World Health Organization (WHO) has said that infectious diseases are 
spreading faster than at any time in history. Of the three pandemics of 
the twentieth century, the most deadly was the pandemic of 1918-1919 in 
which scientists estimate that there were 50-100 million deaths 
worldwide, including at least 675,000 in the United States, making it 
among the most deadly events in human history. The U.S. government has 
estimated that as many as 2 million U.S. citizens could die in the next 
pandemic. If an influenza pandemic were to occur on the same scale as 
the 1918-1919 pandemic, estimates of deaths worldwide have ranged 
between 30 million and 384 million people.

The concern regarding an influenza pandemic has prompted the United 
States, other governments, and international organizations such as WHO 
to develop and begin to implement an international strategy to respond 
to the threat of an influenza pandemic.[Footnote 1] The international 
strategy comprises local, national, regional, and global strategies, 
which include a variety of countermeasures designed to contain or delay 
a pandemic or to minimize its impact once it emerges. Included among 
the elements of these strategies aimed at forestalling a pandemic (that 
is, containing, delaying, or minimizing the impact of) are antivirals 
and vaccines. Both could potentially be used to prevent infection and, 
in the case of antivirals, to also treat infected individuals.[Footnote 
2]

The important role that antivirals and vaccines could play in 
containing or limiting the spread of a pandemic has led to questions 
regarding their use. For example, antivirals and vaccines could be 
needed in greater quantities than ever before. As agreed with your 
offices, we are reporting on (1) the constraints upon the use of 
antivirals and vaccines to forestall the onset of a pandemic and (2) 
the efforts under way to overcome these constraints.

To report on these issues, we reviewed documents and consulted 
officials from the Departments of Health and Human Services (HHS) and 
State, WHO, the Asian Development Bank, and pharmaceutical 
manufacturers.[Footnote 3] Within HHS, we examined documents and 
consulted officials from the Office of the Secretary, the Centers for 
Disease Control and Prevention (CDC), the Food and Drug Administration 
(FDA), and the National Institutes of Health (NIH). We obtained 
information from the International Federation of Pharmaceutical 
Manufacturers & Associations (IFPMA), including information about 
influenza vaccine development projects initiated by members of its 
Influenza Vaccine Supply International Task Force.[Footnote 4] We 
reviewed reports published by the Institute of Medicine focusing on 
pandemic influenza. In addition, we interviewed experts and attended 
academic symposia on pandemic influenza and the challenges to 
addressing its threat. We determined the data on the funding of 
antiviral and vaccine research as well as the data on the 
manufacturing, use, and availability of antivirals and vaccines were 
sufficiently reliable for the purposes of this report. Our goal in 
collecting the information in this report was to provide a picture of 
ongoing efforts by the U.S. government, other national governments, 
international organizations like WHO, and industry to prepare for a 
pandemic. This often involved reporting technical information on the 
research and development on antivirals and vaccines. In some cases, 
rapid scientific advances may have outpaced the timing of this report 
such as, for example, the initiation of a new area of research not 
specifically identified in the report. In other cases, there is no 
consensus on the appropriate use and likely results of various medical 
countermeasures, including different types of antivirals and vaccines. 
This report was not intended to provide the most complete, current, or 
definitive discussion of scientific developments and knowledge 
concerning the use of antivirals and vaccines. We have, instead, sought 
to report information that is necessary to understand the challenges 
faced by the U.S. government and others in their efforts to develop 
measures involving antivirals and vaccines in efforts to forestall a 
pandemic. We conducted our work from January 2006 through December 2007 
in accordance with generally accepted government auditing standards.

In recent related work, we examined the extent to which U.S. agencies 
and their international partners have assessed pandemic risk by country 
and prioritized countries for international assistance. In addition, we 
examined the steps that U.S. agencies and their international partners 
have taken to improve global preparedness to forestall a pandemic. 
[Footnote 5] This work was also conducted in accordance with generally 
accepted government auditing standards.

Results in Brief:

The use of antivirals and vaccines to forestall the onset of a pandemic 
would likely be constrained by their uncertain effectiveness and 
limited availability. Health authorities must be able to detect the 
virus strain quickly through surveillance and diagnostic efforts and 
use this information to test and administer effective antivirals. The 
effectiveness of antivirals could be limited if they are used more than 
48 hours after the onset of symptoms and by the emergence of influenza 
strains that are resistant to antivirals. Due to the time required to 
detect the virus and develop and manufacture a targeted vaccine for a 
pandemic--about 20 to 23 weeks according to HHS--pandemic vaccines are 
likely to play little or no role in efforts to stop or contain a 
pandemic, at least in its initial phases. Furthermore, weaknesses in 
the global influenza surveillance system, including weaknesses in 
diagnostic capability, could limit the effectiveness of antivirals and 
vaccines in treating and preventing cases of infection because of 
limitations in many countries that impede the detection of influenza 
strains. In addition, the supply of antivirals and vaccines available 
in the event of a pandemic would probably be inadequate due to limited 
production, distribution, and administration capacity. WHO has stated 
that it is unlikely that sufficient quantities of antivirals will be 
available in any country at the onset of a pandemic. The supply of 
pandemic vaccine would likely not be able to meet demand without 
additional production capacity, achieved either by current 
manufacturers scaling up production or by increasing the number of 
manufacturers. The distribution and administration capacity for 
antivirals and vaccines is limited in some countries by poor or 
nonexistent delivery plans and networks, a lack of facilities suitable 
for administering the drugs, and small numbers of personnel trained to 
administer them.

The United States, its international partners, and the pharmaceutical 
industry are investing substantial resources to address constraints on 
the availability and effectiveness of antivirals and vaccines, but some 
of these efforts face limitations and are not expected to produce 
results for several years. To better ensure the effectiveness of 
antivirals and vaccines by being able to quickly identify a pandemic 
strain, the United States and its international partners are involved 
in efforts to improve influenza surveillance, including diagnostic 
capability. WHO's revised International Health Regulations seek to 
minimize the international spread of disease, in part by improving 
disease surveillance in humans. International surveillance networks for 
influenza in animals have been established and efforts are under way to 
improve data sharing among scientists. However, WHO and HHS officials 
have raised concerns regarding Indonesia's refusal to share influenza 
samples and how this could harm global public health. Indonesia has 
refused to consistently share influenza samples because of concerns 
that the resulting vaccines would not be available to developing 
countries and from a desire for royalties from any invention derived 
from an influenza sample isolated within its borders. Increased demand 
and government support have encouraged manufacturers to increase their 
research and development into more effective antivirals and vaccines. 
For example, the U.S. government awarded a $103 million contract to one 
company to develop a new antiviral. The United States also has awarded 
approximately $1.1 billion to companies to develop a new influenza 
vaccine production technology that would expand vaccine manufacturing 
capacity in the United States. Alternative methods for developing 
vaccines are also being studied in order to reduce the amount of 
vaccine that is needed to provide protection and to increase the number 
of strains against which a vaccine is effective. Pre-pandemic vaccines, 
which are formulated to target influenza strains that have the 
potential to cause a pandemic, are being developed. However, these 
vaccines may or may not be effective against the pandemic strain that 
ultimately emerges. To overcome limitations on the availability of 
effective antivirals and vaccines, national governments and 
international organizations are working with pharmaceutical 
manufacturers to expand global production capacity to increase 
production at facilities and build new production facilities. To 
address constraints on the distribution and administration of 
antivirals, international organizations and pharmaceutical 
manufacturers have established global and regional antiviral stockpiles 
to deliver these drugs more quickly to countries experiencing 
outbreaks. WHO has recently begun to establish a pre-pandemic vaccine 
stockpile for use in countries without influenza production capacity or 
the ability to purchase vaccines. Several industrialized countries, 
including the United States, have established pre-pandemic influenza 
vaccine stockpiles to vaccinate critical workforce and primary health 
care workers at the onset of a pandemic. However, some of these efforts 
face limitations. For example, increasing global production capacity of 
vaccines and antivirals will take several years as new production 
facilities are built, materials necessary for production are acquired, 
and the necessary approval is received to market these medical products 
in various countries.

In commenting on a draft of this report, WHO provided comments via e- 
mail and stated that the report was comprehensive and useful. HHS 
stressed that vaccines and antivirals should be viewed in the context 
of a broader pandemic strategy. The Departments of State and HHS 
commented that the term "forestall" is ambiguous and misleading. 
However, we have defined the term in a way that is consistent with how 
WHO has used the word in describing its efforts to respond to a 
pandemic. We defined the term to mean contain, delay, or minimize the 
impact of a pandemic.

Background:

WHO, in conjunction with the United States and other governments, has 
developed an international strategy for forestalling the onset of an 
influenza pandemic. Elements of this strategy include restricting the 
movement of people in and out of the affected area, isolation of ill 
persons, and school closures. Antivirals are also an important element 
of this strategy. Studies suggest that using antiviral drugs, along 
with other interventions, to treat infections and prevent illness might 
contain a pandemic at the site of the outbreak or at least slow its 
international spread, thus gaining time to put emergency measures in 
place and begin producing matched vaccines that would be effective in 
preventing individuals from being infected with the strain of influenza 
causing the pandemic.

Influenza:

Influenza, also called "the flu," is caused by a virus that primarily 
attacks the upper respiratory tract--the nose and throat--and sometimes 
the lungs. Influenza is characterized by cough, fever, headache, and 
other symptoms and is more severe than some viral respiratory 
infections, such as the common cold. In almost every year a seasonal 
influenza virus causes acute respiratory disease in epidemic 
proportions somewhere in the world.[Footnote 6] Most people who 
contract seasonal influenza recover completely in 1 to 2 weeks, but 
some develop serious and potentially life-threatening medical 
complications, such as pneumonia.[Footnote 7] Most healthy adults may 
infect others 1 day before getting symptoms and up to 5 days after they 
first develop symptoms. Some young children and people with weakened 
immune systems may be contagious for more than a week. WHO estimates 
that seasonal influenza affects about 5 to 15 percent of the world's 
population each year, causing 3 to 5 million cases of severe illness 
worldwide including 250,000 to 500,000 deaths.

There are three types of influenza viruses: A, B, and C. However, only 
influenza A viruses cause pandemics.[Footnote 8] Influenza A viruses 
are further categorized into subtypes according to differences in the 
"HA" and "NA" proteins that are on the outer surface of the 
virus.[Footnote 9] These influenza A subtypes are further characterized 
into strains. Influenza strains mutate, or genetically change, over 
time. As strains mutate, new strains of influenza viruses appear and 
may replace older, circulating strains. When a new strain of human 
influenza virus emerges, immunity that may have developed after a 
previous infection or vaccination may not provide protection against 
the new strain. Small mutations in the influenza virus are the reason 
why someone who has previously been infected with influenza can still 
be susceptible to seasonal or common influenza. More substantial 
changes in the influenza virus can result in the emergence of a 
pandemic influenza subtype.[Footnote 10]

Pandemic human influenza is a virulent influenza that causes a global 
outbreak, or pandemic, of serious illness. It occurs when an existing 
strain of the influenza virus is replaced by a new influenza A strain 
to which humans have no immunity, resulting in widespread morbidity and 
mortality.[Footnote 11] According to WHO, pandemic influenza can spread 
to all parts of the world very quickly, usually in less than a year, 
and can sicken more than a quarter of the global population.[Footnote 
12] Three conditions must be met before an influenza pandemic begins: 
(1) a new influenza virus subtype that has not previously, or at least 
recently, circulated in humans must emerge, (2) the virus must be 
capable of causing disease in humans, and (3) the virus must be capable 
of sustained human-to-human transmission. The H5N1 virus currently 
meets the first two of these three conditions but not the 
third.[Footnote 13]

The current H5N1 pandemic influenza threat stems from an unprecedented 
outbreak of H5N1 influenza that first appeared in birds in southeastern 
China and Hong Kong in 1996 and 1997 and was first detected in humans 
in Hong Kong in 1997. The virus reappeared in late 2003 and early 2004 
and has since spread in bird populations across parts of Asia, Europe, 
and Africa, with limited infections in humans.[Footnote 14] From 
December 1, 2003, to December 11, 2007, H5N1 was detected in animals in 
60 countries. According to WHO, the geographical spread of H5N1 in 
animals in 2006 was the fastest and most extensive of any pathogenic 
avian influenza virus recorded to date. From January 1, 2003, through 
December 12, 2007, WHO reported 338 confirmed human cases, including 
208 human deaths from the H5N1 virus in a total of 12 countries--a case 
fatality rate of 62 percent.[Footnote 15] Scientists and public health 
officials agree that the spread of the H5N1 virus in birds and the 
occurrence of infections in humans have increased the risk that this 
disease may change through adaptive mutation or reassortment into a 
form that is easily transmissible among humans, resulting in an 
influenza pandemic.[Footnote 16]

HHS stated that little is known about how to control a pandemic and 
that it is important to distinguish between seasonal influenza and 
pandemic influenza. Current knowledge about how antiviral drugs and 
influenza vaccines perform is largely drawn from experience with 
seasonal influenza. HHS stated that how antivirals and vaccines will 
perform against a pandemic influenza virus cannot be predicted, but as 
there are currently no better options, the agency has made plans for 
their use in response to a pandemic.

Vaccines:

Vaccines are considered the first line of defense against influenza to 
prevent infection and control the spread of the disease. Vaccines 
stimulate immune responses which include causing the body to produce 
neutralizing antibodies to provide protective immunity to a particular 
virus strain.[Footnote 17] After vaccination, the body takes about 2 
weeks to produce protective antibodies for that strain. For the one FDA-
licensed H5N1 vaccine, two doses administered about 4 weeks apart would 
be required to provide what is believed to be an adequate immune 
response based on past experience with seasonal influenza vaccines. 
When a vaccinated person is exposed to the specific virus proteins in 
the vaccine, antibodies develop in response that will help either to 
prevent infection or reduce the severity of the illness caused by 
infection.[Footnote 18] To be most effective, an influenza vaccine 
needs to closely match the circulating influenza strain. However, 
because influenza viruses undergo minor but continuous genetic changes 
from year to year, a matched vaccine cannot be developed until the 
circulating strain has been identified. Generally, the purpose of 
vaccination is to prevent infection; however, in the event of a 
pandemic, the purpose could be broadened to include decreasing 
mortality or morbidity. The impact of such a change could be to 
increase vaccine availability since a vaccine that is not fully matched 
to the virus might be available more quickly and still help reduce 
mortality and morbidity.

In the case of vaccines for seasonal influenza, WHO, CDC, FDA, health 
officials around the world, and vaccine manufacturers participate in a 
system that develops and produces vaccines targeted to the influenza 
strains most likely to be in circulation during the next influenza 
season. This system collects and analyzes circulating influenza 
viruses, uses the information to determine the three human strains most 
likely to circulate in the upcoming year, and formulates and 
distributes virus reference strains to vaccine manufacturers, who 
produce seed viruses to manufacture influenza vaccines.[Footnote 19] 
Influenza vaccine is produced in a complex process that involves 
growing viruses in millions of fertilized chicken eggs. Seasonal 
vaccine production generally takes 6 or more months after virus strains 
have been selected.[Footnote 20] The same general system would be used 
in the event of a pandemic to manufacture a vaccine targeted to the 
influenza strain causing it.

Influenza vaccines can be categorized into three types: seasonal, pre- 
pandemic, and pandemic. As discussed in table 1, seasonal vaccines 
protect against annual (i.e., seasonal) influenza strains. Pre-pandemic 
vaccines are formulated to match strains of influenza viruses that have 
had limited circulation in humans but have pandemic potential. However, 
they are not matched or targeted to the specific pandemic strain that 
may eventually emerge.[Footnote 21] Pandemic vaccines are formulated to 
match a pandemic strain that has already emerged. Influenza vaccines 
are made either from inactivated (i.e., killed) viruses or from live 
viruses that have been attenuated (i.e., weakened).[Footnote 22] 
Generally, inactivated influenza vaccines are made from parts of the 
influenza virus rather than the whole virus.

Table 1: Influenza Vaccine Types:

Type: Seasonal; 
Definition: A vaccine produced annually that protects against that 
year's strains of seasonal influenza. Current seasonal vaccines are 
trivalent, meaning they contain three different strains of influenza 
viruses. 

Type: Pre-Pandemic; 
Definition: A vaccine against strains of influenza virus in animals 
that have caused isolated infections in humans and have pandemic 
potential. This vaccine is prepared prior to the emergence of a 
pandemic strain and may be a good or poor match (and hence of greater 
or lesser protection) for the pandemic strain that ultimately emerges. 

Type: Pandemic; 
Definition: A vaccine targeted to a specific novel influenza virus 
strain that has the capacity for sustained and efficient human-to-human 
transmission. This vaccine can only be developed once the pandemic 
strain emerges. 

Sources: European Commission and U.S. Homeland Security Council.

[End of table] 

Globally, influenza vaccine production is largely a private-sector 
activity and vaccine manufacturing is concentrated in Europe and North 
America, with approximately 90 percent of worldwide production capacity 
located in these areas. However, there are manufacturers throughout the 
world, including in Australia, China, and Japan. Some manufacturers 
have production facilities in more than one country. In some cases, 
more than one manufacturer may be producing vaccine for distribution in 
a particular country. For example, there were four manufacturers 
producing five vaccines for the 2006-2007 influenza season in the 
United States.[Footnote 23] In the event of a pandemic, manufacturers 
would switch production from seasonal to pandemic vaccine, and would 
use the same facilities to produce the pandemic vaccine as they had 
used to produce seasonal vaccine.[Footnote 24] Pre-pandemic vaccines 
are currently produced only during the 3-to 4-month period when 
manufacturers are not producing seasonal vaccine.

Antivirals:

Antiviral drugs are also used against seasonal influenza in humans to 
reduce symptoms and complications and could be used in the event of a 
pandemic. Antivirals can be used to both prevent illness and treat 
those who are already infected by killing or suppressing the 
replication of the influenza virus. Antivirals are not reformulated to 
match a specific influenza strain and could be used from the early 
phase of an influenza pandemic.

As shown in table 2, two classes of antiviral drugs are currently 
available for the prevention and treatment of influenza, and two types 
of drugs within each class have been approved. Amantadine and 
rimantadine belong to the older class, adamantanes.[Footnote 25] 
Tamiflu and Relenza belong to the newer class, neuraminidase 
inhibitors.[Footnote 26] Amantadine is given as a capsule, syrup, or 
tablet, while rimantadine is administered as a syrup or tablet. Tamiflu 
can be administered as either a capsule or liquid. Relenza is a powder 
that must be inhaled using a special device. According to CDC, 
antivirals are about 70 to 90 percent effective for preventing illness 
in healthy adults; that is, they are about as effective as vaccines, 
when the vaccine and circulating virus strains are well matched, in 
preventing illness among healthy adults. For maximal effectiveness in 
preventing infection, the antiviral must be taken throughout the entire 
period of a community outbreak. According to current research involving 
seasonal influenza, if taken within 2 days of the onset of symptoms, 
these drugs can shorten the duration of the illness by 1 or 2 days, 
alleviate symptoms, reduce complications and serious illness, and may 
make someone with influenza less contagious to others. However, it is 
unknown if antivirals will perform the same for pandemic influenza as 
they do for seasonal influenza. In addition, influenza virus strains 
can become resistant to one or more of these drugs, and so they may not 
always be effective for prevention or treatment.[Footnote 27]

Table 2: Antiviral Drugs Available for the Prevention and Treatment of 
Influenza:

Class: Adamantanes (M2-ion channel inhibitors); 
Scientific name[A]: Amantadine; 
Drug name(s)[B]: Symmetrel, Amantadine Hydrochloride; 
Route of administration: Oral (capsule, syrup, tablet).

Class: Adamantanes (M2-ion channel inhibitors); 
Scientific name[A]: Rimantadine; 
Drug name(s)[B]: Flumadine, Rimantadine Hydrochloride; 
Route of administration: Oral (syrup, tablet).

Class: Neuraminidase inhibitors; 
Scientific name[A]: Oseltamivir; 
Drug name(s)[B]: Tamiflu; 
Route of administration: Oral (capsule, suspension)[C].

Class: Neuraminidase inhibitors; 
Scientific name[A]: Zanamivir; 
Drug name(s)[B]: Relenza; 
Route of administration: Inhalation (powder).

Sources: HHS and WHO.

[A] The scientific name of a drug is also referred to as the generic 
name.

[B] These are the names under which the drug is currently marketed in 
the United States.

[C] Suspension is a liquid dosage form that contains solid particles 
dispersed in a liquid.

[End of table]

WHO has stated that the neuraminidase inhibitors are preferred for 
prevention and treatment of influenza because there is lower risk for 
adverse events (compared historically to adamantanes), less evidence of 
drug resistance, and greater therapeutic value associated with these 
particular antivirals.[Footnote 28] Of the two currently available 
neuraminidase inhibitors, WHO strongly recommends the use of Tamiflu. 
Tamiflu is generally less expensive and easier to ship than Relenza 
and, because it is given as a capsule or liquid, it is easier to 
administer.

Pharmaceutical manufacturers are currently producing both brand name 
and generic versions of antivirals approved for preventing and treating 
influenza. Tamiflu is produced by Roche, a health care company that 
sells products throughout the world. Relenza is manufactured by 
GlaxoSmithKline, another health care company that sells products 
worldwide.[Footnote 29] Neither drug is patent protected in all 
countries, so generic drug manufacturers may produce these drugs where 
they are not under patent protection.[Footnote 30] Both amantadine and 
rimantadine are no longer under patent protection and, consequently, 
the number of manufacturers that can produce the drug worldwide is not 
limited by patent restrictions.

U.S. Government Entities Engaged in International Pandemic Influenza 
Preparedness:

HHS, along with the Departments of Agriculture, Defense, and State and 
the U.S. Agency for International Development, carries out U.S. 
international animal and pandemic influenza assistance programs. The 
Department of State leads the federal government's international 
engagement on influenza and coordinates U.S. international assistance 
activities through an interagency working group.[Footnote 31] The 
Homeland Security Council is monitoring the U.S. efforts to improve 
domestic and international preparedness.

HHS provides technical assistance and financing to improve human 
disease detection and response capacity. HHS received total 
appropriations specifically available for pandemic-influenza-related 
purposes in fiscal year 2006 of $5.683 billion.[Footnote 32] Of this 
amount, HHS allocated approximately $3.2 billion to vaccines, $1.1 
billion to antivirals, and $179 million to international collaboration 
with the remainder going to such areas as state and local preparedness 
and risk communications.

The U.S. Agency for International Development provides technical 
assistance, equipment, and financing for both animal and human health- 
related activities. In addition, the Department of Agriculture provides 
technical assistance and conducts training and research programs and 
the Department of Defense stockpiles protective equipment.

International Strategy to Contain a Pandemic:

WHO, in conjunction with the United States and other governments, has 
developed an international strategy on how to contain an emerging 
pandemic virus at the site of the outbreak, whether it is H5N1 or 
another influenza virus with pandemic potential.[Footnote 33] 
Containment is a key element of the broad U.S. National Strategy for 
Pandemic Influenza.[Footnote 34] The public health community has 
generally not attempted to contain an initial outbreak of a pandemic- 
potential strain or to eradicate it while it is still confined to a 
limited area.[Footnote 35] WHO has noted that the success of the 
strategy in halting a pandemic or delaying its spread cannot be 
assured. However, WHO has stated that given the potential health, 
economic, and social damage a pandemic can produce, forestalling a 
pandemic must be tried. Further, WHO notes that should early 
containment fail, once a certain level of spread of the pandemic virus 
is reached, no interventions are expected to halt international spread, 
and the public health response will need to shift to the reduction of 
morbidity and mortality.

The international containment strategy is based on studies suggesting 
that efforts, centered on using antiviral drugs to prevent infection as 
well as treat cases, might contain a pandemic at the site of the 
outbreak or at least slow its international spread, thus gaining time 
to put emergency measures in place and develop vaccines.[Footnote 36] 
Such a strategy includes the creation of a geographically defined 
containment zone. According to WHO, the containment zone would be 
created around the cases where widespread antiviral and 
nonpharmaceutical countermeasures should be used. The containment zone 
should be large enough so that all known persons infected by the 
pandemic virus are located within the zone as well as many of the 
people in frequent contact with them. Rapid detection and reliable 
reporting of outbreaks, immediate availability of necessary antivirals 
for large numbers of people, and the restriction of the movement of 
people in and out of the affected area (or containment zone) are 
components of the strategy. Other elements of the strategy include 
isolation of ill persons, voluntary quarantine of people in contact 
with these persons, school closures, and cancellation of mass 
gatherings. These measures are meant to reduce the opportunities for 
additional human-to-human transmission to occur.

Disease surveillance in animals and humans has a critical role in the 
success of the international strategy to forestall the onset of a 
pandemic. The Director of CDC has stated that for optimal response, an 
emerging influenza pandemic outbreak anywhere in the world must be 
recognized within 1 to 2 weeks and then be investigated and confirmed 
within days. Infectious disease surveillance activities include 
detecting and reporting cases of disease, analyzing and confirming this 
information to identify possible outbreaks or longer-term trends, 
exchanging information related to cases of infectious disease, and 
applying the information to inform public health decision-making. HHS 
officials have noted that as outbreaks of animal influenza viruses 
spread and affect people, collaboration between animal and human 
influenza surveillance systems is needed. Additionally, WHO has stated 
early detection of animal diseases, which might be transmissible to 
humans, leads to quicker actions to reduce threats to humans. Alerts of 
animal outbreaks can provide early warning so that human surveillance 
can be enhanced and preventive action taken. When effective, 
surveillance can facilitate (1) timely action to control disease 
outbreaks, (2) informed allocation of resources to meet changing 
disease conditions and other public health programs, and (3) adjustment 
of disease control programs to make them more effective.

Diagnostic tests are an important component of identifying pandemic 
influenza and putting measures in place to forestall its spread. 
Diagnostic tests for a range of viruses help assess patients for the 
presence of H5N1, other emerging influenza viruses, and seasonal 
influenza. Quick and accurate diagnosis of influenza is essential to 
early treatment. In addition, accurate, rapid diagnosis enables timely 
implementation of containment and treatment procedures, and will be 
critical in identifying the beginning of a pandemic and possibly 
slowing the spread of the disease. Rapid diagnosis allows more time for 
equipment and personnel to be mobilized to aid in pandemic response.

As part of the WHO Global Influenza Surveillance Network, individual 
countries, including the United States, collect and analyze influenza 
virus samples and submit selected samples to WHO Collaborating Centres 
for further analysis.[Footnote 37] These samples allow WHO to perform a 
number of influenza-related public health activities, including:

* determining if the virus has acquired human genes or made other 
significant changes,

* tracking the evolution of the virus and its geographic spread,

* updating diagnostic tests and reagents,[Footnote 38]

* identifying potential vaccine strains, and:

* testing to determine if the virus remains susceptible to antivirals.

The success of this network is dependent upon the participation of its 
members. According to HHS, the network has functioned efficiently in 
the past for the detection and characterization of newly emergent 
influenza viruses of epidemic potential.

Uncertain Effectiveness and Limited Availability Would Likely Constrain 
the Use of Antivirals and Vaccines to Forestall the Onset of a Pandemic:

The use of antivirals and vaccines to forestall the onset of a pandemic 
would likely be constrained by their uncertain effectiveness and 
limited availability. Weaknesses within the international influenza 
surveillance system impede the detection of strains, which could limit 
the ability to promptly administer or develop effective antivirals and 
vaccines to treat and prevent cases of infection to prevent its spread. 
The delayed use of antivirals and the emergence of antiviral resistance 
in influenza strains could limit their effectiveness. A targeted 
vaccine cannot be manufactured until the pandemic strain has emerged 
and been identified. The availability of antivirals and vaccines is 
constrained by existing limitations in their production, distribution, 
and administration. Current antiviral production capacity is inadequate 
to reach the number of antivirals WHO estimates will be needed to 
contain a pandemic. Vaccines targeted to match a pandemic strain are 
unlikely to be available for prevention of disease at the onset of a 
pandemic as, according to HHS officials, they would not become 
available until 20 to 23 weeks following detection of a pandemic. 
Moreover, most countries do not possess the capacity to distribute and 
administer these antivirals and vaccines quickly enough to forestall a 
pandemic.

The Effectiveness of Antivirals and Vaccines in Containing Initial 
Outbreaks Could Be Constrained by the Limited Capacity to Monitor the 
Virus and Successfully Treat and Prevent Cases:

Antiviral and vaccine effectiveness depends upon their timely 
application. To achieve timely application, health authorities must be 
able to detect the virus strain quickly through surveillance efforts 
and use this information to administer or develop effective antivirals 
and vaccines. However, weaknesses within the global influenza 
surveillance system could limit the effectiveness of antivirals and 
vaccines in treating and preventing cases of infection. In addition, 
limited support for clinical trials could hinder their ability to 
improve understanding of the use of antivirals and vaccines against a 
pandemic strain.

The Effectiveness of Antivirals and Vaccines to Forestall a Pandemic 
Depends on Influenza Surveillance:

An influenza surveillance system that can promptly detect outbreaks 
would facilitate the timely use of antivirals. The effectiveness of 
antivirals in containing an initial influenza outbreak of a new strain 
depends in part on the timely use of the appropriate drug. Experience 
with seasonal influenza indicates that antivirals are most effective 
for treatment if started within 48 hours of the onset of symptoms; 
therefore, rapid detection of human outbreaks of potential pandemic 
strains is necessary. If an individual is diagnosed too late, 
antivirals may not be effective. WHO has noted that a critical problem 
is the tendency of human H5N1 cases to be detected late in the course 
of the illness. Antivirals used for prevention should be started either 
before exposure or as soon as possible after initial exposure.

International surveillance is also required to monitor strain evolution 
for the development of vaccines targeted to a potential pandemic strain 
or the actual pandemic strain. A well-matched vaccine cannot be ensured 
until the pandemic virus strain has been identified. According to HHS 
officials, 20 to 23 weeks are currently required from the detection of 
a pandemic before a well-matched vaccine can be developed.[Footnote 39] 
Consequently, well-matched vaccines are likely to play little or no 
role in efforts to stop or contain a pandemic, at least in its initial 
phases. However, an effective surveillance system is necessary to 
develop a safe and effective pandemic vaccine as soon as possible so 
that a vaccine is available for later stages of the pandemic.

Another concern is that influenza strains can be resistant to 
antivirals, rendering them ineffective in treating or preventing 
infection. Monitoring strain evolution to determine susceptibility or 
emergence of antiviral resistance is one element of assessing the 
likelihood that a particular antiviral will be effective. The 
effectiveness of an antiviral against one strain of seasonal influenza 
does not mean that it will be effective against an H5N1 strain or 
another potential pandemic strain. While both classes of antivirals, 
adamantanes and neuraminidase inhibitors, could potentially be used 
against a pandemic strain, experts caution against the use of 
adamantanes without prior indication that the emerging strain is 
susceptible to them. For example, CDC recommends against the use of 
adamantanes to treat or prevent currently circulating influenza because 
strains resistant to adamantanes have emerged. Similarly, WHO 
recommends only neuraminidase inhibitors be used to respond to H5N1 
outbreaks unless neuraminidase inhibitors are not available or local 
surveillance data show that the H5N1 virus is known or likely to be 
susceptible to the adamantanes. A high proportion of H5N1 strains 
circulating in Indonesia, Thailand, and Vietnam have been resistant to 
adamantanes. Like adamantanes, the effectiveness of neuraminidase 
inhibitors against potential pandemic strains could also be constrained 
by the emergence of antiviral-resistant strains of the virus. In 
Vietnam, a study identified H5N1 strains resistant to Tamiflu, a 
neuraminidase inhibitor, and a few seasonal influenza viruses--less 
than .5 percent--have been resistant to Tamiflu. Another study examined 
the effectiveness of Tamiflu and Relenza, another neuraminidase 
inhibitor, against H5N1 viruses. The researchers found that there was 
little variation in the effectiveness of Relenza against all H5N1 
viruses studied but that there was variation in the effectiveness of 
Tamiflu. For example, they reported that one group of H5N1 viruses was 
15-to 30-fold less sensitive to Tamiflu than was another group of H5N1 
viruses.

Weaknesses in International Influenza Surveillance:

According to the U.S. National Strategy for Pandemic Influenza 
Implementation Plan, international capacity for influenza surveillance 
still has many weaknesses, including limited influenza sample 
collection and sharing. Surveillance requires the collection and 
sharing of virus samples and the genetic sequencing of these samples 
from both infected humans and animals to monitor if and how a strain is 
mutating.[Footnote 40] According to WHO, global influenza surveillance 
in humans is weak in some parts of the world, particularly in 
developing countries. Surveillance systems in many of the countries 
where H5N1 influenza is of greatest concern are inadequate, 
particularly in rural areas where many cases have occurred. WHO has 
noted that to increase the likelihood of successfully forestalling the 
onset of a pandemic, surveillance in affected countries needs to 
improve, particularly concerning the capacity to detect clusters of 
cases closely related in time and place. Such clusters could provide 
the first signal that the virus has begun to spread more easily among 
humans. If early signals are not identified, the opportunity for 
preemptive action will be missed. In addition, some countries 
experiencing H5N1 influenza outbreaks (e.g., Indonesia) have at times 
not promptly shared human virus samples with the international 
community, thus further weakening international surveillance efforts.

Similarly, a surveillance network to monitor influenza in animals faces 
weaknesses. Global animal influenza surveillance can help provide early 
recognition of viruses with the potential for causing human influenza. 
Surveillance in animals may indicate how an influenza virus is 
spreading and evolving. WHO has recommended combining the detection of 
new outbreaks in animals with active searches for human cases. However, 
influenza surveillance in animals has weaknesses. For example, 
definitions of what constitutes an outbreak vary between countries and 
may be reported as a single infected farm, an affected village, or an 
affected province. In addition, only the number of outbreaks may be 
reported rather than more specific information. Moreover, animal 
disease surveillance is completely lacking in some countries. For 
example, Djibouti and Uganda have no capacity to collect, transport, 
and diagnose animal influenza samples. Just as with human influenza 
samples, there are concerns that animal samples have also not always 
been shared promptly, or for every outbreak.

According to WHO, few countries have the necessary expertise and 
facilities to diagnose H5N1. This leads to the need for countries 
lacking laboratories these facilities to wait until collected samples 
of a strain are tested by labs outside the country, possibly delaying 
both timely diagnosis and antiviral administration. Therefore, 
laboratories must have the necessary information, guidance, and 
materials to allow them to recognize, store, and safely transport H5N1 
samples to more specialized laboratories in other countries. In a 
previous report, we reported, for example, that Indonesia and Nigeria 
both had limited capacity to collect, diagnose, or transport influenza 
in human samples.[Footnote 41]

Currently, there is not a good way to quickly and easily determine 
whether a patient has H5N1 or a more common type of influenza. The 
accuracy of clinical diagnosis of influenza on the basis of symptoms 
alone is limited because symptoms from illness caused by other 
pathogens can overlap considerably with influenza. The amount of time 
required to attain results from diagnostic tests varies from minutes to 
several days, with accuracy often being the trade-off for rapid 
results. Existing point-of-care tests can provide results rapidly and 
determine if the patient is infected with seasonal influenza viruses A 
or B but cannot identify avian influenza H5N1.[Footnote 42] A viral 
culture test can provide specific information on circulating strains 
and subtypes of influenza viruses in 2 to 10 days but may require 
longer for more detailed analysis. In addition, the need to conduct 
viral culture tests in laboratories with enhanced safety levels can 
also restrict their usefulness. HHS recommends an H5 polymerase chain 
reaction test, which can be done without the specialized laboratory 
facilities required by viral culture tests, for the diagnosis of H5N1 
influenza. This test is FDA-approved and is used by public health 
laboratories throughout the United States and in many parts of the 
world.

Limited Support for Clinical Trials:

Limited support for clinical trials could hinder their ability to 
improve understanding of the use of antivirals and vaccines against a 
pandemic strain. Clinical trials improve the understanding of 
effectiveness, timing of administration, duration of treatment, optimal 
dosage, safety, and the balance of risks and benefits of antivirals and 
vaccines. Improved understanding gained through clinical trials would 
assist with updating international guidance on antiviral use. The 
current estimates on the effectiveness of antivirals in a pandemic are 
largely based on their use in treating and preventing influenza illness 
caused by seasonal influenza strains circulating at the times the 
studies were performed. However, the viral characteristics of a 
pandemic strain may be different. Similarly, clinical trials are an 
essential step in vaccine development and are used for testing the 
safety and effectiveness of vaccines. For instance, clinical trials 
could test for the optimal dosage of vaccines developed against a 
potential pandemic strain.[Footnote 43] However, few governments are 
assisting vaccine manufacturers with funding and technical support for 
clinical trials.

Limited Production, Distribution, and Administration Capacity Could 
Constrain the Availability of Antivirals and Vaccines:

The availability of antivirals and vaccines is constrained by limited 
production, distribution, and administration. Vaccine manufacturers' 
liability concerns might also limit their willingness to manufacture 
these drugs and make them available in certain countries.

Constraints on Antiviral and Vaccine Production:

Current antiviral production is inadequate to reach WHO estimates for 
the number of antivirals needed to contain a pandemic. While WHO has 
not set a target for national antiviral stockpiles, it stated in 2007 
that it is unlikely that sufficient quantities of antivirals will be 
available in any country at the onset of a pandemic. WHO estimates that 
the quantity of antivirals required to forestall a pandemic would be 
enough treatment courses for 25 percent of the population.[Footnote 44] 
In addition, there would need to be enough preventative courses to last 
20 days for the remaining 75 percent of the population in the outbreak 
containment zone.[Footnote 45] While Roche, the primary manufacturer of 
Tamiflu, has expanded production, it has stated that the demand for 
Tamiflu will need to further increase before there are any new 
increases in production.

While vaccination is considered to be the best defense against 
influenza, it is unlikely that a vaccine targeted to the pandemic 
strain will be available in time to forestall the onset of a pandemic. 
HHS has reported that 20 to 23 weeks are currently required from the 
start of a pandemic to the availability of a well-matched vaccine; WHO 
expects that once a pandemic strain emerges, it is likely that it will 
spread globally within approximately 3 months.[Footnote 46] Figure 1 
shows how WHO, its Collaborating Centres around the world, and 
pharmaceutical manufacturers would proceed to develop and produce 
vaccines designed to protect against a newly emerged pandemic strain, 
and how long it would take for the vaccines to become available.

Figure 1: Pandemic Vaccine Production Timeline:

[See PDF for image] 

This figure illustrates the Pandemic Vaccine Production Timeline, as 
follows: 

Month 1: Pandemic strain emerges in country of origin; 
* Detection of outbreak; 
* Isolation of virus; 
* Shipment to WHO labs. 

Month 2: Develop virus reference; 
* Development of reference virus by WHO Collaborating Centres. 

Month 3: Prepare for production; 
* Manufacturers adapt seed virus for mass production; 
* Develop reagents. 

Month 4: Produce and test vaccines; 
* Pandemic has spread worldwide; 
* Production begins. 

Month 5: Produce and test vaccines; 
* First vaccines become available. 

Month 6: Produce and test vaccines; 
* First vaccines become available. 

Month 7: Produce and test vaccines; 
* First vaccines become available. 

Source: GAO analysis of HHS, IFPMA, and WHO data. 

[End of figure] 

Some health authorities have suggested that increased seasonal 
vaccination could play a limited role in forestalling the emergence of 
a pandemic by limiting the opportunities for human and animal influenza 
strains to combine and form a pandemic strain, but it is likely that 
the limited availability of seasonal vaccination would limit its role 
in forestalling an influenza pandemic. Seasonal vaccine would not 
prevent individuals from becoming infected with animal influenza. 
However, in the case of an H5N1 strain, promoting seasonal vaccination 
prior to the emergence of a pandemic strain, particularly among health 
care workers and others in contact with human cases of H5N1 infection 
and infected poultry, could reduce the likelihood of H5N1 and seasonal 
influenza coinfection in humans.[Footnote 47] Experts fear that such co-
infection could lead to the emergence of a reassorted influenza strain 
that has the transmissibility of the human seasonal strain and the 
virulence of the H5N1 strain, thus resulting in a pandemic. However, 
large-scale global seasonal influenza vaccination would be difficult to 
implement because of the lack of influenza vaccination programs in many 
countries. Additionally, seasonal vaccination of humans would not 
prevent influenza reassortment within animals.

According to WHO, current annual global production capacity for 
trivalent seasonal vaccines is approximately 565 million doses; these 
doses would only be enough to vaccinate about 9 percent of the world's 
population of 6.6 billion people.[Footnote 48] WHO has also stated that 
the current demand for and supply of seasonal influenza vaccine is 
approximately equal. Thus, without additional production, either by 
current manufacturers scaling up their production or by increasing the 
number of manufacturers, the supply of seasonal vaccine would not be 
able to meet the increased demand that would stem from the promotion of 
seasonal vaccination. In fact, due to limitations in vaccine production 
capacity, even countries with existing seasonal vaccine programs have 
experienced shortages. For example, the United States experienced 
vaccine shortages as recently as the 2004-2005 influenza season due to 
production problems experienced by one manufacturer.[Footnote 49]

This limited vaccine production capacity would also limit the 
availability of a pandemic vaccine in the event of a pandemic since the 
processes used to manufacture seasonal and pandemic vaccines are 
similar and the manufacturing would take place in the same facilities. 
If a monovalent vaccine (that is, a vaccine that contains only one 
influenza strain) were produced for a pandemic strain, experts estimate 
that approximately three times the number of trivalent doses could be 
produced. Consequently, if annual production capacity is sufficient to 
produce 565 million doses of trivalent vaccine, 1.695 billion doses of 
monovalent vaccine could be produced each year. However, the actual 
number of doses that could be produced would depend on a number of 
factors including how well the virus strain grows in eggs and the 
dosage required. For instance, if a dose larger than 15 micrograms--the 
dose required for current seasonal vaccine--was needed, fewer doses 
could be produced. Testing on a sanofi pasteur H5N1 vaccine approved by 
FDA in April 2007 indicates that a single 15 microgram dose would not 
be sufficient to confer immunity. Instead, the testing indicated that 
45 percent of individuals who received two 90 microgram doses of this 
vaccine--or twelve times as much--developed an immune response expected 
to reduce the risk of getting influenza. If this dosage were required 
during a pandemic, instead of having the capability to vaccinate 1.695 
billion people, only 141,250,000 (one-twelfth as many) could be 
vaccinated. This would likely be well below global demand, given a 
global population of 6.6 billion people.

The location of vaccine manufacturing facilities could also limit the 
role that vaccines would play in forestalling an influenza pandemic. 
Experts fear that the concentration in a few countries of vaccine 
production capacity could, in the event of a pandemic, lead to vaccine 
shortages in countries without domestic manufacturing capacity. 
According to WHO, 90 percent of vaccine production capacity is 
concentrated in Europe and North America.[Footnote 50] Currently, only 
one manufacturer's entire seasonal influenza vaccine production 
facilities are located completely within the United States. There is 
concern among experts that countries without domestic manufacturing 
capacity would not have access to vaccines in the event of a pandemic 
if the countries with domestic manufacturing capacity prohibited the 
export of vaccine until their own needs were met. Many countries 
experiencing H5N1 influenza outbreaks, such as Cambodia and Indonesia, 
do not have domestic manufacturers that produce influenza vaccines, and 
according to WHO, would require financial and technical support from 
the international community to create a domestic pharmaceutical 
infrastructure.[Footnote 51]

Constraints on Distribution and Administration:

Limited global, national, and local-level distribution and 
administration capacity could restrict the availability of antivirals 
at the site of outbreaks for use in forestalling the onset of a 
pandemic. Distribution and administration capacities require plans, 
delivery networks, facilities suitable for administering the drugs, 
trained personnel, and funding to get antivirals to where they are 
needed and administer them promptly. As discussed earlier, experience 
with seasonal influenza indicates that antivirals are most effective in 
treating influenza if they are taken within 48 hours of the onset of 
symptoms. This requires an efficient distribution network to get the 
drugs to where they are needed.

Antiviral distribution networks are poor or nonexistent in some 
countries. We previously reported that as of October/November 2005, 10 
of 17 countries reviewed did not have distribution plans for the 
release of antiviral stockpiles and there was insufficient information 
available to reach conclusions for 4 others.[Footnote 52] Studies of 
national pandemic preparedness plans in Europe and the Asia-Pacific 
region found that most did not adequately address how antivirals would 
be transported to locations where they are needed and how they would be 
administered to individuals.[Footnote 53] Thirteen of the 21 European 
plans had guidance on priority groups for treatment with antivirals, 
but none described the process by which individuals belonging to 
priority groups would be identified.[Footnote 54] Most of the plans in 
Asian-Pacific countries did not identify such priority groups. The 
timely administration of antivirals would also likely be constrained if 
there is a scarcity of trained professionals as well as packaging and 
instructions that are printed in languages foreign to those 
administering the drugs. In addition, countries that depend upon 
outside sources to provide antivirals might not have these drugs 
available in time to contain an outbreak. Many countries do not have 
national stockpiles of antivirals and are dependent on outside sources 
to provide these drugs for distribution in the event of an outbreak. 
Antiviral stockpiling is expensive, and it may not be feasible for many 
countries to establish their own national stockpiles.

Similarly, the availability of vaccines could be affected by 
limitations in countries' capacity for distributing and administering 
vaccines. For example, a lack of supplementary medical supplies (such 
as syringes) could impede the administration of vaccines. Countries' 
experience with seasonal vaccination programs indicates potential 
problems in the event of a pandemic. IFPMA has noted that many 
developing countries have insufficient health care systems to deliver 
vaccines. Most countries have little seasonal influenza vaccine 
distribution infrastructure and lack financial and human resources to 
implement national seasonal influenza vaccination programs. In 2005, 
WHO reported that about 50 of the 193 countries in the world, mainly 
those that are industrialized and some countries in rapid economic 
development, offer influenza vaccination to nationally defined high- 
risk groups.[Footnote 55] However, even in industrialized nations such 
as the United States, vaccine distribution and administration issues 
arise. For example, during the vaccine shortage in the 2004-2005 
influenza season, CDC developed a plan to allocate the available 
vaccine among states. However, the formula for allocating each state's 
allocation was imperfect, resulting in some states having more vaccine 
than needed to cover demand and other states having too 
little.[Footnote 56]

Manufacturers' Liability Concerns:

Manufacturers' concerns regarding product liability in individual 
countries could also hinder the global availability of vaccines. 
Experts and vaccine manufacturers have said that the lack of liability 
protection increases liability concerns for manufacturers, which may 
hinder their willingness to manufacture and distribute vaccines in 
countries where they might be held liable for any adverse effects that 
occurred from their administration. Concerns regarding potential 
liability for the vaccines could hinder efforts by WHO to get companies 
to donate vaccines to countries where they are not licensed.[Footnote 
57] Industry representatives have stated that manufacturers would need 
advance assurance that governments would provide liability protection.

U.S. Government and International Partners' Efforts Are Under Way to 
Address Constraints on Use of Antivirals and Vaccines, but Certain 
Efforts Face Limitations:

The United States, its international partners, and the pharmaceutical 
industry are investing substantial resources in efforts to address the 
uncertain effectiveness and limited availability of antivirals and 
vaccines. Efforts to make effective antivirals and vaccines more 
available include (1) improving disease surveillance on an 
international scale in order to monitor the evolution of influenza 
strains and the effectiveness of antivirals and vaccines against those 
strains, (2) increasing global demand for antivirals and vaccines to 
encourage production and spur research and development, and (3) 
increasing global distribution and administration capacity. However, 
some of these efforts face funding and logistical limitations and will 
take several years to complete.

Efforts Are Under Way to Improve Surveillance in Order to Increase the 
Effectiveness of Antivirals and Vaccines:

The U.S. government and its international partners are supporting 
efforts to increase the effectiveness of antivirals and vaccines by 
improving influenza surveillance. International surveillance is 
required for monitoring strain evolution in humans and animals to 
detect the emergence of new influenza strains and evaluate the 
continued effectiveness of antivirals and vaccines as the virus 
evolves. Governments, international organizations, manufacturers, and 
scientists have initiatives under way to improve international 
surveillance by improving disease surveillance in humans, creating 
animal surveillance networks, improving animal and human sample sharing 
and analysis, increasing international collaboration in monitoring 
influenza strains, and improving diagnostic capabilities.

WHO's revised International Health Regulations seek to improve 
worldwide disease surveillance in humans.[Footnote 58] The revised 
Regulations were adopted in May 2005 and effective on June 15, 
2007,[Footnote 59] require that member states report all events that 
constitute a public health emergency of international concern, such as 
those caused by new and reemerging diseases with epidemic potential 
like H5N1 influenza.[Footnote 60] The Regulations set out the basic 
public health capacities a country must develop, strengthen, and 
maintain to detect, report, and respond to public health risks and 
potential public health emergencies of international concern. For 
example, at the national level a country is required to be able to 
assess all reports of urgent events within 48 hours. Each country must 
assess its ability to meet the core surveillance capacities by June 
2009 and has until June 2012 to develop these capacities.[Footnote 61]

Among activities to improve influenza surveillance in animals, in May 
2005 the World Organisation for Animal Health (OIE) and the Food and 
Agriculture Organization of the United Nations (FAO) created the OIE/ 
FAO Network of Expertise on Avian Influenza (OFFLU), an international 
veterinary counterpart to WHO's human Global Influenza Surveillance 
Network.[Footnote 62] OFFLU supports international efforts to monitor 
and control H5N1 in poultry and other bird species through the 
collection and sharing of influenza virus samples from infected 
animals. Increased animal surveillance could speed the diagnosis and 
reporting of novel influenza strains. One of OFFLU's goals is to put 
influenza sequences in the public domain for the benefit of research 
and development, and OFFLU is actively supported in this endeavor by 
the U.S. government.[Footnote 63] Influenza sequencing reveals complete 
genetic blueprints of influenza viruses, information which is used to 
develop vaccines and to monitor the emergence of antiviral-resistant 
influenza strains. Additionally, sequencing provides information that 
might indicate that a virus has changed in such a way to become more 
transmissible among humans. OFFLU collects animal influenza samples and 
shares them with NIH for sequencing and with CDC for antigenic 
analysis.[Footnote 64] NIH sequences the samples and funds the costs of 
sequencing these samples. NIH then makes the completed sequences 
available in the public domain. Through its Influenza Genome Sequencing 
project, NIH makes available to the entire scientific community over 
the Internet the genetic sequences of human and animal influenza 
viruses. As of December 13, 2007, 2,807 human and animal influenza 
viruses have been completely sequenced. In addition to this project, 
CDC and NIH have provided materials to countries affected by H5N1 to 
test animal influenza virus strains. In the event of a pandemic, CDC 
and NIH have also offered them assistance in sequencing influenza 
viruses.

An additional effort to improve surveillance through sample sharing is 
the Global Initiative on Sharing Avian Influenza Data, formed in August 
2006 by a group of scientists from over 40 countries. Genetic sequence 
data collected through this initiative will be deposited in a publicly 
available database and then after a specified period of time will be 
released automatically to publicly funded databases participating in 
the International Sequence Database Collaboration or in other publicly 
available databases. This initiative will work to overcome restrictions 
which have previously prevented influenza information sharing, with the 
hope that more shared information will help researchers understand how 
viruses spread, evolve, and can potentially lead to a pandemic. This 
initiative is open to all scientists, provided they agree to share 
their own data, credit the use of others' data, analyze findings 
jointly, and publish results collaboratively.

In addition to OFFLU, a surveillance system for animal diseases that 
are transmissible to humans has also been established and many 
countries have improved their surveillance of animal diseases. FAO, 
OIE, and WHO launched the Global Early Warning and Response System for 
Major Animal Diseases, including Zoonoses (GLEWS) in July 2006 to 
improve the early warning and response capacity of the three 
organizations to animal diseases, including those that can spread to 
humans.[Footnote 65] GLEWS is the first joint early warning and 
response system conceived with the aim of predicting and responding to 
such diseases. WHO has stated that from a public health perspective, 
early warnings of animal outbreaks that have a known potential to 
spread to humans will enable the initiation of control measures that 
can prevent human morbidity and mortality. The United Nations System 
Influenza Coordinator and the World Bank have reported that many 
countries have improved their animal disease surveillance systems. They 
noted that better disease surveillance systems, along with improved 
laboratory capacity and increased access to epidemiological expertise, 
account for improved detection of H5N1 and other influenza viruses.

In April 2007, NIH announced that it was awarding $23 million per year 
for 7 years to establish six Centers of Excellence for Influenza 
Research and Surveillance. The mission of the centers is to expand 
NIH's influenza research program, both in the United States and 
internationally, to determine how these viruses cause disease as well 
as how the human immune system responds to them. Specific activities 
include expanding animal influenza surveillance and studying how 
pandemic viruses emerge.

Governments, including the U.S. government, and manufacturers are 
undertaking efforts to increase international collaboration to monitor 
the evolution of influenza strains. Through a collaborative global 
network, CDC's WHO Collaborating Centre is monitoring the H5N1 virus to 
track its geographic spread and to identify and analyze changes in the 
virus. CDC is providing funds for the shipment of influenza samples to 
WHO Collaborating Centres for analysis. As part of its surveillance 
role, CDC conducts antiviral susceptibility testing on seasonal and 
novel influenza viruses and has been able to identify changes in the 
sequence of H5N1 virus samples that could affect their susceptibility 
to existing antiviral medications. For example, in January 2007 CDC 
testing found an H5N1 virus sample from Egypt with reduced 
susceptibility to Tamiflu. FDA, CDC and other WHO Collaborating 
Centres, other WHO laboratories, and national regulatory authorities 
have also used information on H5N1 strain evolution to recommend 
representative strains for use in the development of pre-pandemic 
vaccines and to develop H5N1 reference viruses which are shared with 
manufacturers. Manufacturers are also supporting the independent 
Neuraminidase Inhibitor Susceptibility Network, which includes 
government officials and works in collaboration with WHO to monitor 
influenza viruses for any signs of strains that have developed 
resistance to this class of antivirals.

Concerns regarding the failure of certain countries to share human and 
animal influenza samples and the availability of vaccines developed 
from these samples have led to efforts to promote sample sharing. In 
February 2007, Indonesia announced that it would no longer share H5N1 
samples with WHO because the resulting vaccines produced by private 
companies were unlikely to be available to developing countries such as 
Indonesia. At times, the Indonesian government has also expressed a 
desire for royalties from any invention derived from an influenza 
sample isolated within its borders. In March 2007, WHO said that an 
agreement had been reached and that Indonesia would resume sharing H5N1 
samples immediately. However, sample sharing did not resume until May 
2007 when, at the World Health Assembly meeting, 17 developing 
countries introduced a resolution demanding equitable access to 
vaccines made from H5N1 samples the countries provide.[Footnote 66] At 
that time, Indonesia provided three samples from two patients to WHO. 
Later at that meeting, the World Health Assembly requested that WHO 
formulate mechanisms and guidelines aimed at ensuring the fair and 
equitable distribution of pandemic influenza vaccines at affordable 
prices in the event of a pandemic. Following this, in June 2007 the 
health ministers of the Asia-Pacific Economic Cooperation stated they 
planned to share influenza virus specimens in a timely manner.[Footnote 
67] However, HHS officials told us that concerns remain. In July 2007, 
HHS reported to us that Indonesia had not shared any seasonal or H5N1 
influenza samples since those it sent to WHO in May 2007. HHS also 
noted that the Asia-Pacific Economic Cooperation agreement is not being 
followed. A WHO official has also expressed concern. In August 2007, he 
stated that by not sharing virus samples, Indonesia is endangering the 
world's health as well as its own. Also in August 2007, Indonesian 
health officials stated that the county will continue to withhold H5N1 
samples at least until a new virus-sharing agreement is developed at an 
international meeting in November 2007.[Footnote 68] Later in August 
Indonesia sent two samples to CDC for testing, although concerns remain 
whether Indonesia will share or continue to withhold samples in the 
future. At the November 2007 meeting, no agreement on sample sharing 
was reached. Indonesia advocated an accord stating that for every virus 
sample sent out of a country, there should be an agreement specifying 
that the sample be used only for diagnostic purposes. Commercial use of 
the virus would require permission of the country that provided the 
sample.

Improved understanding of influenza viruses could improve surveillance 
and, in turn, vaccine development. Scientists at NIH, along with a 
collaborator at Emory University, have identified mutations that would 
help a strain of the H5N1 virus spread easily from person-to-person. 
This knowledge could contribute to better surveillance of naturally 
occurring influenza outbreaks because efforts could be focused on 
identifying viruses with mutations that lead to increased 
transmissibility among humans. This could permit the development of 
vaccines prior to a pandemic, and possibly help contain a pandemic at 
its outset.

WHO and CDC are undertaking a number of activities in order to improve 
diagnostic capability worldwide. WHO reported providing equipment and 
training to staff working within national laboratories and is providing 
experts to give hands-on support. At the regional level, it reported 
enhancing the laboratory network with the facilities and expertise to 
analyze H5 samples so that every country has access to a regional H5 
laboratory.[Footnote 69] This H5 laboratory network has provided 
support to countries in shipping samples and providing confirmation of 
suspected H5N1cases. According to WHO, four laboratories in Africa have 
been upgraded so that they can conduct H5 diagnosis. For the long term, 
WHO is working to build and strengthen local H5 diagnostic capability. 
In addition, CDC officials stated that among its activities the agency 
provides financial and technical assistance to 35 countries, WHO, and 
WHO regional offices in order to improve influenza laboratory 
diagnostic capability. CDC is also providing training for laboratory 
workers and epidemiologists in order to expand laboratory diagnostic 
capabilities and develop rapid response teams that could quickly 
detect, report, and control outbreaks caused by novel influenza 
viruses. CDC officials have also provided laboratory support and 
diagnostic reagents to countries investigating H5N1 outbreaks.

Research is being conducted to improve rapid, diagnostic tests for 
influenza. In order to forestall a pandemic, it is critical to be able 
to identify people with H5N1 quickly. A reliable, rapid diagnostic test 
is needed for epidemiological assessments, traveler screening, and 
clinical care. Currently, rapid tests cannot distinguish between 
strains and subtypes of influenza viruses. To address this shortcoming, 
in December 2006, CDC awarded four companies a total of $11.4 million 
in contracts to develop new viral diagnostic tests with quicker and 
more reliable results that could be used at, for example, a patient's 
bedside or a port of entry (see table 3). CDC hopes for FDA approval 
and commercialization of these products in 2 to 3 years. In addition, 
tests designed for large reference and public health laboratories are 
also being developed.[Footnote 70] In February 2006, FDA approved a 
test developed by CDC that identifies H5 but not the strain within 4 
hours once testing begins. Previously, it would have taken 2 to 3 days. 
If the virus is identified as H5, tests are then conducted to identify 
the strain. FDA has shared this technology with WHO and its 
Collaborating Centres.

Table 3: HHS Contracts Awarded to Companies in December 2006 to Develop 
Rapid Diagnostic Tests for Influenza:

Recipient: Cepheid; 
Amount (dollars in millions): $2.4.

Recipient: Iquum[A]; 
Amount (dollars in millions): 3.8.

Recipient: MesoScale; 
Amount (dollars in millions): .7.

Recipient: Nanogen; 
Amount (dollars in millions): 4.5.

Recipient: Total; 
Amount (dollars in millions): $11.4.

Source: CDC.

[A] According to HHS, the Iquum contract was terminated in May 2007 due 
to technical issues. 

[End of table] 

Research is also under way to improve other types of diagnostic tests 
for influenza. For example, using funding from NIH, scientists at the 
University of Colorado at Boulder and CDC have developed a test that is 
based on a single influenza virus gene that could allow scientists to 
quickly identify influenza viruses, including H5N1. This test offers 
several advantages over available tests including being based on a gene 
that, unlike hemagglutinin and neuraminidase, does not mutate 
constantly. Consequently, the researchers believe that this test will 
be more useful than other tests because it will provide accurate 
results even if the hemagglutinin and neuraminidase genes mutate. 
However, WHO has cautioned that the availability of such tests are at 
least 4 years away.

Efforts Are Under Way to Increase Demand for Antivirals and Vaccines to 
Encourage Production and Spur Research and Development:

Efforts to expand seasonal vaccination and build national stockpiles of 
antivirals and pre-pandemic vaccines are under way to encourage 
increased demand for these drugs. Demand for seasonal influenza 
treatment drives global production capacity for antivirals and all 
types of influenza vaccines. Increasing demand through government 
support provides incentives for manufacturers to develop more effective 
antivirals and vaccines.

Efforts to Increase Demand to Encourage Production:

While the primary benefit of increased seasonal vaccination would be 
the enhanced protection against seasonal influenza, WHO has stated that 
increased demand for seasonal vaccines would spur manufacturers to 
increase their vaccine manufacturing capacity. One of WHO's goals is to 
increase seasonal vaccine coverage in countries that already use 
seasonal vaccine to 75 percent of target populations by 2010, which 
would require an increase in global vaccine production to 560 million 
doses to cover use in these countries only.[Footnote 71] Some countries 
with seasonal influenza vaccination programs had increased their use of 
seasonal vaccines prior to WHO setting vaccination goals, thus 
providing incentives for manufacturers to increase overall vaccine 
production capacity. In October 2007, WHO stated that seasonal 
influenza vaccine capacity is expected to rise to 1 billion doses 
annually in 2010, provided sufficient demand exists.

Increased demand for antivirals and pre-pandemic vaccines also stems 
from orders placed by countries to build national stockpiles. According 
to Roche, as of April 2007, more than 80 countries had ordered Tamiflu 
for their own national antiviral stockpiles. Some countries, including 
Australia, France, and the United States, are also ordering Relenza to 
supplement their Tamiflu stockpiles. The United States had 36.6 million 
neuraminidase treatment courses in its federal stockpiles as of August 
6, 2007, consisting of 30.8 million treatment courses of Tamiflu and 
5.8 million treatment courses of Relenza. It also had 3.6 million 
treatment courses of rimantadine, an adamantane, on-hand for a total 
stockpile of 40.2 million antiviral treatment courses. Approximately 
100,000 additional Tamiflu treatment courses and 700,000 additional 
Relenza treatment courses are currently on order for the stockpile. The 
U.S. goal at the national level is to have a federal stockpile of 50 
million antiviral treatment courses. In addition, states and other 
entities had stockpiles totaling 12.9 million treatment courses of 
Tamiflu and 1.6 million treatment courses of Relenza as of August 6, 
2007. Similarly, Australia, Japan, the United States, and countries in 
Europe have been establishing stockpiles of pre-pandemic vaccines. For 
example, in 2005, sanofi pasteur agreed to produce 1.4 million doses of 
H5N1 pre-pandemic vaccine for France's stockpile. It is also providing 
H5N1 pre-pandemic vaccines for national stockpiling in the United 
States and Italy. In addition, GlaxoSmithKline Biologicals and Novartis 
Vaccines and Diagnostics are also producing H5N1 pre-pandemic vaccine 
for the U.S. national stockpile. The United States has stockpiled 
enough H5N1 pre-pandemic vaccine to cover about 7 million people. The 
United States' goal is to have a pre-pandemic vaccine stockpile of 
treatment courses for 20 million persons.[Footnote 72] However, 
developing countries may not be able to build such antiviral and 
vaccine stockpiles.

Antiviral manufacturers have expanded their production capabilities. 
Roche expanded its Tamiflu production so that it could produce 400 
million treatment courses of Tamiflu by the end of 2006. Roche noted 
that this represents an approximate 15 fold increase over its 
production capacity of 27 million treatment courses in 2004. In April 
2007, Roche stated that its production capacity now exceeded government 
and corporate orders for Tamiflu received to date.[Footnote 73] To 
increase capacity, Roche expanded production from one facility to eight 
Roche sites, including the United States where 80 million Tamiflu 
treatment courses can now be produced. In addition, Roche now has 19 
external manufacturing partners that perform particular functions in 
the manufacturing process. Roche has also granted sublicenses to 
selected drug companies in China and India to allow them to produce 
Tamiflu in its generic form, oseltamivir, which will increase the 
amount of that antiviral available globally. In Africa, Roche granted a 
sublicense to a South African company allowing it to produce 
oseltamivir to increase production and speed up availability of the 
drug for use against a pandemic strain in Africa.[Footnote 74] 
GlaxoSmithKline, the manufacturer of Relenza, is undertaking efforts to 
boost Relenza production. While less than 1 million treatment courses 
of Relenza were produced in 2005, GlaxoSmithKline stated in May 2006 
that it planned to increase production capacity in its existing 
facilities in North America, Europe, and Australia. It increased 
production to 15 million treatment courses in 2006 and plans to produce 
40 million treatment courses in 2007. GlaxoSmithKline also stated that 
it is willing to license other manufacturers to produce Relenza in its 
generic form, zanamivir. In September 2006, GlaxoSmithKline announced a 
licensing agreement with a Chinese drug company to produce the 
antiviral and sell it in China, Indonesia, Thailand, Vietnam, and other 
developing countries.

Governments and manufacturers are also working to increase the global 
production of vaccines by helping to build production facilities and 
supplying the technology and resources necessary to produce influenza 
vaccines. In September 2006, WHO stated that worldwide vaccine 
production capacity is expected to increase by 280 million trivalent 
doses in the next 2 to 3 years.

* The U.S. government has offered assistance to countries trying to 
create the infrastructure necessary for vaccine production. For 
example, HHS has provided countries with reagents, the chemicals 
required to assess vaccine effectiveness, and training for testing 
vaccines. It also works with countries to help them develop their own 
reagents and tests for use in clinical trials and other research.

* WHO's Global pandemic influenza action plan to increase vaccine 
supply, dated September 2006, proposes building new production plants 
in both developing and industrialized countries as one means to 
increase production capacity.[Footnote 75]

* In October 2006, HHS announced a grant of $10 million to WHO to 
support influenza vaccine development and manufacturing infrastructure 
in other countries, while Japan has contributed $8 million. In April 
2007, WHO announced that it was awarding grants to six countries to 
help them develop the capacity to make influenza vaccine.[Footnote 76] 
Two of the projects will be in Latin America and four in Asia. Three of 
the Asian countries receiving grants--Indonesia, Thailand, and Vietnam-
-have had cases of persons infected with H5N1 influenza. Manufacturers 
have also committed substantial funds to increase their own vaccine 
production capacity.[Footnote 77]

* Additionally, sanofi pasteur signed a technology transfer arrangement 
with the governments of Thailand, Mexico, and Brazil.

* In June 2007, HHS awarded a $77.4 million contract to sanofi pasteur 
and a $55.1 million contract to MedImmune to renovate existing vaccine 
manufacturing facilities in the United States and to provide warm-base 
operations for manufacturing pandemic influenza vaccines. In warm-base 
operations, a facility does not shut down. HHS stated that these 
changes will increase production capacity and permit year-round 
production of pre-pandemic influenza vaccines for the national 
stockpile, which is currently limited to 3 months per year.

* In July 2007, sanofi pasteur announced that it had completed 
construction of a new influenza vaccine manufacturing facility in the 
United States. It also noted that it was expanding its influenza 
vaccine manufacturing capacity in France.

Encouraging Further Research and Development:

Increased demand through government support has provided incentives for 
manufacturers to develop more effective antivirals and vaccines. 
Manufacturers are conducting research on new antivirals and on 
improving the use of existing antivirals. Manufacturers are also 
working to improve the effectiveness of vaccines to combat pandemic 
influenza through such activities as developing pre-pandemic vaccines, 
examining cell-based production technology, studying substances that 
can be added to vaccines to improve effectiveness, and conducting 
research on vaccines that would provide protection against multiple 
influenza strains. These studies could be used to help define 
additional studies and resources that might be needed to assess the 
safety, effectiveness, and risk and benefit of products, and 
appropriate use of proposed new products or new uses of existing 
products.

Research on and Development of Antivirals:

Development of new antivirals is particularly important due to concern 
over the emergence of antiviral-resistant influenza strains that could 
render existing antivirals ineffective. Manufacturers are developing 
and testing new antivirals, and the U.S. government is providing 
support to manufacturers that are developing new antivirals. In 2005, 
HHS announced plans to spend $400 million to develop new antiviral 
drugs. In January 2007, HHS awarded a 4-year $103 million contract to 
BioCryst Pharmaceuticals, Inc., to support development of a new 
antiviral, peramivir.[Footnote 78] Sankyo Co., Ltd., of Japan and Biota 
Holdings Limited of Australia are working together to develop new 
antivirals called long-acting neuraminidase inhibitors. These companies 
have received a $5.6 million grant from HHS to accelerate the 
development of these antivirals.

In addition to developing new antivirals, governments and manufacturers 
are exploring ways in which existing antivirals could be used to treat 
influenza more effectively and efficiently. For example, researchers 
are examining the potential use of antiviral combination therapy, which 
would entail the use of more than one antiviral to treat an influenza 
infection. Combination antiviral therapy may be more effective and 
could reduce the likelihood that an antiviral-resistant strain might 
emerge because, for example, there may be less chance that a strain 
resistant to both antivirals would emerge. Researchers are also 
examining the use of antivirals with other types of pharmaceuticals. 
NIH, the Department of Defense, and the Department of Veterans Affairs 
are collaborating on a study to determine if Tamiflu used in 
combination with the drug probenecid can stretch the supply of 
Tamiflu.[Footnote 79] The aim of these studies is to determine whether 
the combination of these drugs results in Tamiflu remaining in the body 
longer, thus reducing the amount of Tamiflu that an individual would 
need to take and effectively increasing the supply of the drug. NIH has 
also provided funding to the South East Asian Influenza Clinical 
Research Network, to improve understanding and clinical management of 
influenza through clinical research, as well as to increase clinical 
research capacity in participating countries (Indonesia, Thailand, and 
Vietnam). One ongoing study will compare the safety and effectiveness 
of standard-and high-dose Tamiflu in treating animal and severe 
seasonal influenza in hospitalized children and adults. Planned studies 
include the evaluation of the safety and tolerability of the long-term 
use of Tamiflu and Relenza to prevent influenza in health care workers 
and a study of the safety and effectiveness of using intravenous 
Relenza for the treatment of H5N1 infection in adults and children.

Research on and Development of Pre-Pandemic Vaccines:

Manufacturers, sometimes with the assistance of governments, are 
working to develop pre-pandemic vaccines. These vaccines might provide 
some protection against a pandemic strain and also give manufacturers 
experience in producing effective vaccines for a potential pandemic 
strain. The United States has been the primary government sponsor of 
these efforts although other countries have sponsored some studies; 
other studies have been conducted without government support. The 
United States has supported studies of vaccines developed by Baxter 
International, Inc., MedImmune, Novartis, and sanofi pasteur.

WHO has reported two ways in which a pre-pandemic vaccine could be 
used. First, such a vaccine could be used to protect selected 
populations at risk of being infected by viruses currently circulating 
among poultry. Second, it could be used to immunize general populations 
or selected groups (e.g., health care workers) against a potential 
pandemic strain. However, WHO points out that the pandemic virus may be 
quite different than what people are immunized against and therefore 
the pre-pandemic vaccine may not be protective.

Pre-pandemic vaccine might also be used as part of a "prime-boost" 
series in which two doses of vaccine based on different strains would 
be given. The first vaccine would be a pre-pandemic vaccine that would 
prime the immune system for a second vaccine. The second vaccine would 
match the pandemic strain. It is hoped that together the two doses 
would result in immunity. However, the data needed to support such an 
approach have not been fully developed.

In April 2007, FDA licensed the first pre-pandemic vaccine for human 
use in the United States against H5N1 based on the results of a 
clinical trial conducted by NIH, although the results revealed 
limitations. FDA approved the vaccine for the immunization of persons 
18 to 64 years of age at increased risk of exposure to the H5N1 
influenza subtype. The vaccine, manufactured by sanofi pasteur, will 
not be marketed commercially. Instead, the vaccine has been purchased 
by the federal government for inclusion in the United States stockpile 
for distribution if needed.[Footnote 80] However, NIH's clinical trial 
showed limitations of the vaccine. First, in previously unexposed 
populations, two 90 microgram doses are needed to elicit the levels of 
immune responses usually thought to be adequate to provide protection 
instead of the single 15 microgram dose of seasonal influenza vaccine 
that is needed for protection against a seasonal influenza strain. 
Second, even with this larger dosing regimen, vaccination results in an 
immune response thought to be protective in only 45 percent of those 
receiving the vaccine. Studies of seasonal vaccines in healthy persons 
have demonstrated that effectiveness against well-matched strains is 70 
to 90 percent.[Footnote 81] In addition, experts have noted that such a 
high vaccine dose could result in an unusually high rate of adverse 
reactions. NIH, along with other federal agencies, sanofi pasteur, and 
other manufacturers, continue to work on the development of vaccines 
that will stimulate enhanced immune response at lower doses of vaccine.

GlaxoSmithKline and Novartis have both announced that they have 
submitted pre-pandemic H5N1 vaccines for approval in Europe.

Research on and Development of Cell-Based Production Technology:

To speed development and production of new technologies for influenza 
vaccines, the U.S. government and manufacturers are pursuing the 
development of cell-based vaccine production technology as an 
alternative method to current egg-based production.[Footnote 82] Egg- 
based vaccine production cannot be scaled up quickly and egg supplies 
can be compromised in the event of an influenza outbreak.[Footnote 83] 
According to HHS, cell-based technology could be scaled up quickly 
because cells can be frozen in advance and large volumes grown quickly, 
thus providing surge capacity in the event of a pandemic. In April 
2005, HHS awarded a $97 million 5-year contract to sanofi pasteur for 
development of a cell-based influenza vaccine. Subsequently, HHS 
awarded more than $1 billion in contracts to accelerate development and 
production of cell-based production technologies for influenza vaccines 
within the United States. (See table 4.) HHS officials told us that 
this funding provided companies with the incentive to invest in this 
technology. In the past, companies did not want to invest in cell-based 
production technologies because it would not increase efficiency as 
both cell-and egg-based production would yield similar amounts of 
vaccine. FDA issued draft guidance in September 2006 to assist 
manufacturers in developing cell-based vaccines. In other countries, 
companies are making similar although smaller investments than in the 
United States, usually without government support.

Progress has already been made on the development of cell-based 
influenza vaccines. For example, Solvay Pharmaceuticals received 
authorization to market its cell-culture influenza vaccine in the 
Netherlands in 2001. However, this vaccine has not yet been marketed. 
In June 2007, the European Union approved a cell-culture-derived 
seasonal influenza vaccine manufactured by Novartis. The company has 
stated that it expects to submit an application for approval to market 
the vaccine in the United States in 2008.[Footnote 84]

Table 4: HHS Contracts Awarded in May 2006 to Develop Cell-Based 
Vaccines:

Recipient[A]: Solvay Pharmaceuticals; 
Amount (dollars in millions): $298.59.

Recipient[A]: GlaxoSmithKline Biologicals; 
Amount (dollars in millions): 274.75.

Recipient[A]: Novartis Vaccines and Diagnostics; 
Amount (dollars in millions): 220.51.

Recipient[A]: MedImmune; 
Amount (dollars in millions): 169.46.

Recipient[A]: DynPort Vaccine; 
Amount (dollars in millions): 40.97.

Recipient[A]: Total; 
Amount (dollars in millions): $1,004.28.

Source: HHS.

[A] In April 2005 HHS awarded a $97 million 5-year contract to sanofi 
pasteur to develop a cell-based vaccine.

[End of table] 

Research on and Development of Adjuvants:

HHS has awarded contracts to manufacturers to research and develop 
influenza vaccines that use adjuvants. An adjuvant is a substance added 
to a vaccine to improve its effectiveness so that less vaccine is 
needed to provide protection. When added to a vaccine, adjuvants can 
stretch the vaccine supply by decreasing the amount of vaccine needed 
per person while still providing the same level of protection. 
Adjuvants have been used in other vaccines, but not in influenza 
vaccines. GlaxoSmithKline, Novartis, and sanofi pasteur have announced 
study results that show that adjuvanated influenza vaccines produced 
possible protective immunity at lower doses than did nonadjuvanated 
vaccines. For example, Novartis has reported that its adjuvanated 
vaccine produced a strong immune response against H5N1, H5N3, and H9N2, 
but that its vaccine without adjuvant produced a poor response. In 
January 2007, HHS announced that it had awarded contracts totaling 
$132.5 million to three vaccine manufacturers for the development of 
H5N1 vaccines using an adjuvant. (See table 5.)

Table 5: HHS Contracts Awarded in January 2007 to Develop Influenza 
Vaccines Containing an Adjuvant:

Recipient: GlaxoSmithKline Biologicals; 
Amount (dollars in millions): $63.3.

Recipient: Novartis Vaccines and Diagnostics; 
Amount (dollars in millions): 54.8.

Recipient: Iomai Corporation; 
Amount (dollars in millions): 14.4[A].

Recipient: Total; 
Amount (dollars in millions): $132.5.

Source: HHS.

[A] Iomai Corporation would be eligible to receive an additional $114 
million upon successful completion of Phase I trials. Phase I trials 
are the first stage of testing new drugs or treatments in people and 
normally include a small (less than 100) group of healthy volunteers.

[End of table] 

In addition to potentially stretching the vaccine supply, there is 
evidence that when adjuvants are added to a vaccine, that vaccine might 
also provide protection against strains to which it is not fully 
matched. Research by Novartis demonstrated that its H5N3 vaccine 
generated a better immune response against H5N1 strains with an 
adjuvant than without it. Similarly, a GlaxoSmithKline vaccine with 
adjuvant provided protection against two diverse H5N1 influenza strains.

Research on and Development of Universal Vaccines and Other Vaccines 
That Protect Against Multiple Influenza Strains:

Current efforts to develop a universal influenza vaccine are intended 
to address constraints on both the effectiveness and availability of 
vaccines. A universal vaccine would protect against multiple virus 
strains.[Footnote 85] Availability of universal influenza vaccines 
would eliminate the current process required to reformulate seasonal 
influenza vaccines each year. Consequently, if vaccines effective 
against pandemic influenza could be available when a pandemic strain 
emerged, there would not be a 20-to 23-week period between 
identification of the pandemic strain and the ability to produce an 
effective vaccine. The recent threat of a human pandemic arising from 
H5N1 has spurred new funding for manufacturers currently attempting to 
develop universal influenza vaccines. In October 2005, a consortium of 
companies and universities announced that it had received a 2-year $1.4 
million grant from the European Union to support the Universal Vaccine 
project. The aim of this project is to develop an easily-administered 
nasal vaccine that provides life-long protection against influenza. 
Manufacturers such as Merck and Cytos Biotechnology are also working to 
develop a universal vaccine. NIH is working to bring universal vaccine 
candidates through the pre-clinical development stage.

Despite the recent increase in funding, experts caution that a 
completely universal influenza vaccine is years away.[Footnote 86] 
Therefore, some researchers and manufacturers are developing live 
attenuated vaccines that might protect against a matched strain as well 
as mutated strains that typically emerge from year to year.[Footnote 
87] These live attenuated vaccines would not be completely universal, 
but are easier to develop than universal vaccines and may provide 
broader protection than current vaccines that match a specific 
influenza strain. For example, MedImmune's current seasonal FluMist 
vaccine, which is a live attenuated vaccine, proved effective in 
children against the H3N2 strain to which it was fully matched as well 
as against H3N2 strains for which there was a mismatch in studies in 
children. However, this may not be the case in adults. Evidence 
suggests that a live attenuated vaccine was less effective in 
protecting against mismatched strains in healthy adults than was the 
inactivated trivalent vaccine. In September 2005, HHS announced that it 
would work with MedImmune to develop at least one vaccine for each of 
the 16 identified hemagglutinin influenza proteins. According to 
experts, it is not clear whether live attenuated virus vaccines matched 
only for the hemagglutinin protein (e.g., H5 or H7) would work as well 
against a pandemic strain as would a vaccine matched to the particular 
strain. However, as in the case of pre-pandemic vaccines, even if 
limited in their effect these vaccines might help reduce mortality 
during a pandemic while a fully matched vaccine is developed. HHS 
officials noted that the protection offered by live attenuated vaccines 
against multiple strains of different subtypes has yet to be 
established. It has also been noted that even if an acceptable live 
attenuated H5N1 vaccine is developed, it could not be used as a pre- 
pandemic vaccine. There is concern that it could reassort with a 
circulating seasonal influenza virus and thereby increase its 
transmissibility among humans.

Similarly, research has been conducted using vaccines made from whole 
influenza virus rather than just parts of the virus. Studies from two 
vaccine manufacturers, Baxter and Biken, have independently suggested 
that whole virus vaccines provide protection against multiple strains 
of the H5N1 virus and require a smaller dose than do vaccines made from 
parts of the virus. Consequently, the use of whole virus vaccine might 
not only increase the number of influenza strains against which one is 
protected, but also increase the number of doses available.

To Increase Availability, Governments and International Organizations 
Have Worked with Manufacturers to Improve Distribution of and 
Administration Capacity for Antivirals and Vaccines:

Increasing global availability of antivirals and vaccines includes 
improving the global capacity for their distribution and 
administration. These efforts also include establishing global and 
regional antiviral stockpiles and addressing restrictions that 
different national regulations place on drug manufacture and approval.

WHO, countries, and pharmaceutical manufacturers have established 
global and regional antiviral stockpiles to enhance the availability 
and quick distribution of antivirals to the site of outbreaks. In 
August 2005, Roche donated 3 million treatment courses of Tamiflu to 
WHO for a global stockpile to contain or slow the spread of a pandemic 
at its origin.[Footnote 88] According to Roche officials, the size of 
the stockpile was based on studies that indicated that 3 million 
treatment courses would be sufficient to stop the spread of a pandemic 
strain at its source. Roche will be responsible for the delivery of 
Tamiflu from these stockpiles to the international airport closest to 
the outbreak, where it will transfer the Tamiflu to WHO. It will then 
be the responsibility of the affected countries to distribute the 
donated antivirals within their country to contain outbreaks. 
Subsequently, in January 2006 Roche announced the donation of an 
additional 2 million treatment courses to WHO for the establishment of 
regional stockpiles. In March 2007, WHO stated that these drugs are for 
the use of countries currently experiencing human outbreaks of animal 
influenza. Supplies from this second donation have already been sent to 
those countries. Additionally, some countries have taken the lead in 
funding regional stockpiles. Japan has provided 500,000 treatment 
courses of Tamiflu for a regional stockpile for Asia. Japan is also 
funding the delivery of antivirals from that regional stockpile to the 
capitals of affected Asian nations. Discussions are under way for HHS 
to assist in this antiviral stockpiling. For example, there are 
discussions about sharing antivirals from the United States stockpile, 
but these drugs could be recalled for domestic use if outbreaks could 
not be contained or if an outbreak occurred in North America. In May 
2006, HHS sent a stockpile of approximately 260,000 treatment courses 
of Tamiflu to Asia to be pre-positioned for international containment 
efforts in the event of a pandemic influenza outbreak in that 
region.[Footnote 89]

The United Nations System Influenza Coordinator and the World Bank 
reported in December 2007 that individual countries have also purchased 
or are planning to purchase antivirals but that coverage in many 
countries remains limited. Sixty-eight percent of countries worldwide 
have purchased antivirals and an additional 22 percent plan to purchase 
them. However, the agencies also note that 36 percent of countries 
report that that their supply of antivirals covers less than 1 percent 
of their population while another 37 percent report that their 
antiviral supply covers from 1 to 20 percent of their populations.

Individual countries and WHO are also establishing pre-pandemic 
influenza vaccine stockpiles. Several industrialized countries, 
including the United States, have established pre-pandemic influenza 
vaccine stockpiles to vaccinate critical workforce and primary health 
care workers at the onset of a pandemic. WHO is working to establish a 
pre-pandemic vaccine stockpile. Such a stockpile could help to 
alleviate developing countries' concerns about their lack of access to 
H5N1 vaccines developed using virus samples provided by them. In April 
2007, a WHO expert committee wrote that there is sufficient scientific 
support for creating a stockpile of H5N1 vaccine for use in countries 
without influenza vaccine production capacity or the ability to 
purchase stockpiles of H5N1 vaccines. The committee noted that there is 
some evidence that current H5N1 vaccines produce a protective immune 
response against other H5N1 viruses as well. Following this, in May 
2007, the World Health Assembly passed a resolution requesting WHO to 
establish an international stockpile of vaccines for H5N1 or other 
influenza viruses of pandemic potential. In June 2007, GlaxoSmithKline 
announced that it would contribute 50 million doses of its H5N1 vaccine 
to the stockpile, enough to vaccinate 25 million people. Also in June, 
WHO stated that three additional companies had indicated their 
willingness to make some of their H5N1 vaccine available for the 
stockpile.

In an effort to facilitate access to various vaccines, FDA and its 
international counterparts, in collaboration with WHO, are developing a 
standard set of data requirements to support the licensure of pandemic 
and pre-pandemic vaccines. Each country has its own requirements for 
the development and licensure of vaccines for human use (which include 
testing in clinical trials).[Footnote 90] If demand were to surge as 
might happen in the event of a pandemic, the time needed to go through 
the regulatory process to gain approval for a new vaccine could 
constrain its availability.[Footnote 91] FDA and its international 
counterparts, in conjunction with WHO, participate in international 
working groups that examine regulations for the development and 
manufacturing of influenza vaccines.

Some governments are also exploring other avenues to speed up their 
domestic regulatory process to enhance pandemic preparedness. 
Currently, FDA's goal is to complete the review of a "standard" 
application in the United States for vaccine licensure within 10 
months. However, the goal for review of a "priority" license 
application is 6 months. Priority reviews are given to those vaccines 
that have the potential for providing significant preventive, 
diagnostic, or therapeutic advancement as compared to existing 
treatments for a serious or life-threatening disease. In addition, FDA 
has processes intended to shorten the time needed for commercial 
development and FDA review in certain circumstances. For example, 
because it can take many years to determine whether a drug provides 
real improvement for patients--such as living longer or feeling better-
-FDA has a process known as "accelerated approval." Under accelerated 
approval, applications are reviewed using a substitute measurement of 
effectiveness that is considered likely to predict patient benefit.

Similarly, the European Union is pursuing approval for pre-pandemic 
vaccines as a mechanism to expedite approval for a pandemic 
vaccine.[Footnote 92] Prior to the onset of a pandemic, these pre- 
pandemic vaccines undergo safety and effectiveness testing and are 
submitted for approval. In the event of a pandemic, this approved pre- 
pandemic vaccine would then be reformulated to match the pandemic virus 
and expedited approval for the reformulated vaccine would be sought. 
Because the application would only pertain to a variation on the 
earlier, approved, pre-pandemic vaccine, regulatory approval is 
expected to be faster.[Footnote 93] Both GlaxoSmithKline and Novartis 
have had pre-pandemic vaccines approved by the European Union under 
this mechanism. In addition, GlaxoSmithKline, Novartis, and sanofi 
pasteur have submitted additional vaccines for approval under this 
process.

Certain Efforts to Increase the Effectiveness and Availability of 
Antivirals and Vaccines Face Limitations and Will Take Several Years:

While efforts are under way to alleviate constraints upon the 
effectiveness and availability of antivirals and vaccines, certain 
efforts face limitations and will take several years to complete. The 
strengthening of animal and human surveillance systems is vital to 
increasing the effectiveness of antivirals and vaccines. However, 
according to OFFLU officials, that network lacks sufficient funding to 
hire staff needed to analyze influenza strains. Officials fear that 
without this staff, scientists might not continue to submit samples to 
OFFLU--which are analyzed and presented in public databases--out of 
concern that they would not be analyzed. FAO, OIE, and WHO have stated 
that greater support of OFFLU is required in order for it to fulfill 
its functions. Experts have noted that public access to databases that 
contain influenza sequence information is vital to understanding the 
spread and evolution of influenza viruses and, therefore, to the 
research and development of influenza treatments.

International support for clinical trials--necessary for developing and 
evaluating the effectiveness of antivirals and vaccines--is largely 
provided by only four countries: the United States, Australia, Japan, 
and the United Kingdom. The United States supports clinical trials for 
antivirals and vaccines being developed by global manufacturers, but 
experts state that more widespread and consistent international support 
is needed. Clinical trials are also required to test effectiveness and 
cross-protection provided by pre-pandemic vaccines. The United States, 
Australia, Japan, and the United Kingdom have provided the most support 
for pandemic vaccine development. However, only the United States 
provides substantial support to both domestic and international 
manufacturers for such trials. According to IFPMA representatives, the 
United States' efforts are the primary governmental source for funding 
clinical trials for these vaccines.

Increasing demand for vaccines is likely to continue to pose 
difficulties because a number of countries will still need to balance 
concerns about a potential pandemic against other existing public 
health concerns. Low demand for vaccines to treat seasonal influenza is 
due in part to the low priority placed on seasonal influenza by many 
countries. As discussed earlier, current global demand for seasonal 
influenza vaccines is lower than global need, which is the amount 
required to cover individuals under medical guidelines for influenza 
vaccination.[Footnote 94] Manufacturers have been reluctant to invest 
in the development and production of vaccines due to this low demand 
and disincentives such as low profits. One reason for low demand is 
that seasonal influenza programs compete with many other public health 
priorities for limited budgets in developing countries. For example, 
Indonesia, one of the countries experiencing human H5N1 outbreaks, is 
also dealing with other diseases as well as the aftermath of a tsunami, 
volcanic eruptions, and earthquakes. Some developing countries are 
willing to implement seasonal influenza vaccination programs but 
require outside funding to do so. One objective of WHO's Global 
pandemic influenza action plan to increase vaccine supply is to 
increase seasonal vaccine use. According to WHO, a minimum of $300 
million is required to do this.[Footnote 95] Similarly, efforts to 
increase vaccine production capacity can also be problematic. Citing 
Vietnam as an example, NIH officials told us that countries may have 
been too overwhelmed with H5N1 outbreaks to accept offers of assistance 
to develop vaccine production infrastructure.

Although efforts are under way to increase antiviral and vaccine 
manufacturers' production capacity by building new facilities, these 
new facilities are not expected to be ready to produce antivirals and 
vaccines for several years. According to manufacturers, it will take at 
least 5 years to build new vaccine manufacturing facilities and receive 
regulatory approval. WHO stated that it will take the six countries 
that received grants to develop vaccine production capacity at least 3 
to 5 years to begin producing vaccine. Additionally, Roche granted 
sublicenses to selected drug companies in developing countries for the 
production of generic versions of Tamiflu. However, these agreements 
will not immediately alleviate any shortages due to the complicated 
production process for Tamiflu. Roche has estimated that it would take 
2 to 3 years for a new facility to produce Tamiflu on a large scale. It 
has also stated that, even with all the materials necessary for 
production available, it takes 6 to 8 months to produce Tamiflu. 
Similarly, GlaxoSmithKline has stated that it would take a minimum of 6 
to 9 months to increase production capacity for Relenza. WHO has stated 
that it is unlikely that sufficient quantities of antivirals will be 
available in any country at the onset of a pandemic. Further, in 
November 2006, Roche stated that because of high demand and long 
manufacturing lead times for Tamiflu, it is highly unlikely that it 
would be able to fill large Tamiflu orders on short notice. 
Demonstrating the importance of demand in driving production capacity, 
Roche announced in April 2007 that it planned to reduce Tamiflu 
production because it now exceeded demand for the drug. Roche officials 
stated that if demand were to increase, it would take 4 months to 
return the production level to 400 million treatment courses annually.

Although global, regional, and national stockpiles of antivirals are 
being established, little progress has been made in improving the 
capacity for distributing the stockpiled antivirals to the site of 
outbreaks around the world, particularly within developing countries. 
According to Asian Development Bank officials, the logistics of 
distributing antivirals in the event of a pandemic would be of greater 
concern than the limited supply of antivirals. Although the cost and 
logistics of transporting antivirals from a stockpile to a country's 
capital are addressed to some extent by WHO and those countries and 
manufacturers that have donated antivirals, issues of transportation 
from the capital to a province or distant region remain unaddressed by 
many national governments. WHO has established protocols for countries 
to request Tamiflu for containment purposes from its global stockpile. 
Roche, the donor of the WHO global stockpile, will deliver the drugs to 
the international airport nearest the crisis and hand them over to WHO. 
National authorities would then be responsible for the storage, 
transportation, and administration of those drugs within their borders. 
To do so effectively, governments must have plans in place prior to an 
outbreak as well as adequate resources to implement them. The U.S. 
government has assisted countries in developing such plans. In June 
2007, WHO officials reported that over 178 countries have drafted or 
finalized their preparedness plans. However, WHO has noted that not all 
plans have incorporated its rapid containment protocol.

Agency Comments and Our Evaluation:

HHS, the Department of State and WHO provided comments on a draft of 
this report. The comments from HHS and the Department of State are 
reproduced in appendixes I and II. WHO provided comments via e-mail and 
stated that the report was comprehensive and useful.

In its comments, HHS said that we had lost the larger context of all 
efforts with respect to pandemic preparedness and that HHS's antiviral 
and vaccine strategies and implementation plans are not captured. 
Expressing concern about our focus on antivirals and vaccines, HHS said 
that these are only one piece of the agency's broader scope of work on 
this topic. It cautioned that the use of antivirals and vaccines in 
response to a pandemic is part of a larger, integrated whole, so 
viewing them outside of the broader context is likely to raise other 
questions and issues. HHS said that we were assuming that antivirals 
and vaccines are the only tools necessary to forestall a pandemic. HHS 
commented on the uncertainty of success associated with measures such 
as stockpiling antivirals, stating that one must not assume that 
establishing antiviral stockpiles has solved the problem. HHS noted 
that if a potential pandemic is identified early, efforts at 
containment should and will be attempted. It further commented that if 
containment fails, the effort may still have the effect of slowing the 
pandemic's rate of spread while if it succeeds, a pandemic may be at 
least temporarily averted. In its comments, HHS stated that as a 
preventive health measure only a vaccine will have the capability of 
dramatically changing the course of an influenza pandemic.

We do not agree that we have lost the larger context of efforts to 
prepare for a pandemic. This work was done in response to a 
congressional request that we study the role that antivirals and 
vaccines could play in forestalling a pandemic. While this was the 
focus of this engagement specifically, we are well aware that 
antivirals and vaccines are just two of many possible measures that 
could be taken in response to an influenza pandemic. As HHS notes in 
its comments, we have issued other reports on various aspects of 
pandemic preparedness (see the Related GAO Products section of this 
report) and we have ongoing work on numerous other aspects of this 
issue. We stated on page 2 of the draft report provided to HHS for 
comment that antivirals and vaccines may play a role in forestalling a 
pandemic, but we did not suggest that they were the only available 
response measures. Nonetheless we have added language to the report to 
make it clearer still that antivirals and vaccines are just two of a 
variety of available countermeasures that are being contemplated by 
WHO, HHS, and other agencies charged with the responsibility of 
protecting the public in the event of a pandemic. However, a discussion 
of the full range of possible responses to an influenza pandemic 
currently being contemplated by HHS and other organizations and 
agencies is beyond the scope of this report.

HHS also expressed concern with our discussion of "forestalling" a 
pandemic, suggesting that the premise that a pandemic can be 
forestalled is not one widely held by the public health or scientific 
community and is misguided and misleading. They said that few believe 
that a developing pandemic can be stopped in its tracks. In elaborating 
on this point, HHS suggested that the concept that antivirals and 
possibly vaccines might be used to stop an incipient pandemic or to 
slow the spread should be explicitly stated instead of using the word 
forestalled in a way that is very likely to be misinterpreted. They 
note that theoretically, the only way to truly forestall a human 
pandemic would be to eliminate the avian reservoir from which a future 
pandemic is likely to emerge.

In the draft of this report provided to HHS for comment, we defined the 
word "forestalling" to mean "preventing or at least delaying." We use 
this term to suggest that, while preventing a pandemic would be the 
desired result of any response effort, delaying the pandemic would 
perhaps be the more likely yet still desired result. It is not clear 
why the level of concern expressed by HHS in its comments on our use of 
the word "forestall" is being raised at this time. We issued a report 
in June 2007 that discussed efforts to forestall an influenza pandemic, 
including the word "forestall" in the report title, on which HHS 
provided written comments. At that time, HHS expressed no concern with 
the term. In addition WHO has used the word in describing its efforts 
to respond to a pandemic and our definition is consistent with WHO's 
use of the term.

Moreover, we fail to see significant differences in the meaning of the 
word "forestall" as compared to other terms and concepts contained in 
other parts of HHS's comments on this report and other public comments. 
For example, in its comments, HHS discussed a goal to "minimize the 
impact" of a pandemic. They expressed the desire that we explicitly 
state the concept of "stopping or slowing the spread of" an incipient 
pandemic, rather than using the word forestall, defined as "prevent or 
delay," which HHS believes is likely to be misinterpreted by the 
readership. Later in its comments, HHS stated that a pandemic may be 
"temporarily averted" or slowed. HHS stated in its letter that a 
vaccine could "dramatically change the course" of a pandemic. While we 
believe that these concepts are consistent with our use of the term 
forestall when describing efforts to respond to a pandemic in such a 
way as to avert, slow, mitigate, or change the course of a pandemic, we 
have revised the report and defined forestall to mean containing, 
delaying, or minimizing the impact of the onset of a pandemic. We have 
also added discussion to the report to further clarify our use of the 
term, making it clear that success in these efforts is uncertain and 
that it is unlikely that a pandemic can be entirely prevented.

HHS provided other general comments on the structure and organization 
of the report. HHS expressed concern that we have provided an 
inadequate amount of information about influenza diagnostic tests. They 
said that our emphasis on OFFLU is out of proportion to the role it 
plays in recognizing when a new virus with pandemic potential has begun 
to spread in humans. They further suggest that we do not adequately 
distinguish between seasonal, pre-pandemic, and pandemic vaccines. 
Finally, HHS stated that some information in the draft is out of date 
and that they corrected many factual errors in their technical comments.

We have evaluated HHS's other comments on the structure and 
organization of the report. Both their general and technical comments 
suggested that we have overemphasized some issues while 
underemphasizing others. They also touched upon areas where HHS does 
not believe that we adequately distinguished between various aspects of 
influenza response; for example, HHS commented that we do not 
adequately distinguish between seasonal and pandemic influenza but also 
noted that much of what is believed to be true about pandemic influenza 
is based upon experience with seasonal influenza. We made changes to 
the report where HHS's general and technical comments could enhance 
clarity and completeness. However, this report was intended to describe 
the challenges and limitations of efforts to respond to an impending 
pandemic using antivirals and vaccines; it was not intended to capture 
a complete inventory of the most current scientific knowledge and 
developments regarding these two countermeasures. In some cases, rapid 
scientific advances may have outpaced the timing of this report such 
as, for example, the initiation of a new area of research not 
specifically identified in the report. In other cases, there is no 
consensus on the appropriate use and likely results of various medical 
countermeasures, including different types of antivirals and vaccines.

Further, while we updated the report to reflect changes that occurred 
while the draft report was with the agencies for comment, we disagree 
with HHS that the draft contained many factual errors. In its comments, 
HHS updated the information in the report in several areas, provided 
additional information on some points, and suggested different areas of 
emphasis in others. HHS suggested different wording in several 
instances that would have made our description of certain concepts 
extremely technical and not easily understood by persons not expert in 
the field. In those instances, we often chose not to make the change 
suggested by HHS. There were few instances of corrections of facts. 
Moreover, in a meeting discussing the draft, an HHS official was 
complimentary of the accuracy and completeness of the report.

The Department of State suggested in its comments that the report 
should be restructured to separate discussion of antivirals and 
vaccines. The comments state that these medical countermeasures are 
very different from each other in their application, utility, and the 
challenges the U.S. government faces in development and production of 
sufficient quantities. They further commented that while the report 
extensively discusses the challenges in production of adequate 
quantities of medical countermeasures, it does not give adequate 
consideration to the challenges of establishing protocols that would 
guide the international community in the use of whatever vaccines and 
antivirals are available. They also suggested that our use of the word 
"forestall" is somewhat ambiguous and should be clarified.

While we did not separate the discussion of antivirals and vaccines as 
the Department of State suggested, we revised the draft to ensure that 
discussion of antivirals and vaccines are clearly distinguished from 
one another. While antivirals and vaccines are very different from each 
other, we believe that the issues involved in identifying where they 
are needed, manufacturing sufficient quantities, shipping them to where 
they are needed, and administering them safely, are similar enough to 
merit discussing them together. We agree that the issue of establishing 
protocols to guide the international community in the use of antivirals 
and vaccines is an important one. However, this issue was discussed in 
the draft report and the Department of State did not articulate in its 
comments what information needs to be added.

The Department of State's concerns about our use of the word 
"forestall" are unclear. In making this comment, the Department of 
State suggests that we refer to the North American Plan for Avian and 
Pandemic Influenza, approved by the United States, Canada, and Mexico. 
The comments quote the plan, which states that "The North American Plan 
will enhance collaboration in order to ï¿½ prevent or slow the entry of a 
novel (pandemic) strain of human influenza to North America." We fail 
to see the meaningful difference between the words, "prevent or slow" 
in the plan and "prevent or delay," which is the meaning of the word 
"forestall." However, as stated earlier, we added discussion to the 
report to clarify our use of the word "forestall."

We incorporated technical comments provided by HHS, the Department of 
State, and WHO, as appropriate throughout the report.

As arranged with your offices, unless you publicly announce the 
contents of this report earlier, we plan no further distribution of it 
until 30 days after its issue date. At that time, we will send copies 
of this report to the Secretary of Health and Human Services, the 
Secretary of State, the Commissioner of the U.S. Food and Drug 
Administration, the Director of the Centers for Disease Control and 
Prevention, the Director of the National Institutes of Health, the 
Director of the Office of Global Health Affairs, the Special 
Representative on Avian and Pandemic Influenza at the U.S. Department 
of State, and to interested congressional committees. We will also make 
copies available to others upon request. In addition, the report will 
be available at no charge on GAO's Web site at [hyperlink, 
http://www.gao.gov].

If you or your staff have any questions about this report, please 
contact Marcia Crosse at (202) 512-7114 or [email protected] or David 
Gootnick at (202) 512-3149 or [email protected]. Contact points for our 
Offices of Congressional Relations and Public Affairs may be found on 
the last page of this report. GAO staff who made major contributions to 
this report are listed in appendix III. 

Singed by: 

Marcia Crosse: 
Director, Health Care:

Signed by: 

David Gootnick: 
Director, International Affairs and Trade:

[End of section]

Appendix I: Comments from the Department of Health and Human Services:

Department Of Health & Human Services: 
Office of the Assistant Secretary for Legislation: 
Washington, DC 20201: 

September 17, 2007: 

Marcia Crosse: 
Director, Health Care: 
U.S. Government Accountability Office: 
Washington, DC 20548: 

Dear Ms. Crosse: 

Enclosed are the Department's comments on the U.S. Government 
Accountability Office's (GAO) draft report entitled, "Influenza 
Pandemic: Efforts Under Way to Address Constraints on Using Antivirals 
and Vaccines to Forestall a Pandemic (GAO 07-1052).

The Department provided several technical comments directly to your 
staff.

The Department appreciates the opportunity to review and comment on 
this report before its publication. 

Sincerely, 

Signed by: 

Rebecca Hemarel for Vincent J. Ventimiglia: 
Assistant Secretary for Legislation: 

[End of letter] 

General Comments Of The Department Of Health And Human Services (HHS) 
on The Government Accountability's Office's (GAO) Draft Report 
Entitled: Influenza Pandemic: Efforts Under Way To Address Constraints 
On Using Antivirals And Vaccines To Forestall A Pandemic (GAO-07-1052): 

HHS appreciates GAO's work on several different reports concerning the 
important topic of influenza pandemic preparedness. Although we 
recognize that the topics of vaccines and antivirals are very important 
in their own right, GAO-07-1052 clearly has lost the larger context of 
all efforts with respect to pandemic preparedness, and the presentation 
of the antiviral and vaccine strategies and implementation plans are 
not captured. While this context can (and should) be restored to this 
document, from the outset, the premise that a pandemic can be 
"forestalled" is not one widely held by the public health or scientific 
community. GAO should revisit this premise as it is misguided and 
misleading. 

While the H5N1 influenza virus is in the news less often than it was 
just a year ago, we remain on alert for a human influenza pandemic (WHO 
Phase 3, Pandemic Alert) with the virus now responsible for animal 
outbreaks and killed hundreds of millions of chickens in 60 countries, 
up from just a dozen two years ago. Worldwide, over 300 human cases 
have been confirmed in 12 of those countries. For those who have been 
infected, the disease is very serious ï¿½ overall 61 % of the human cases 
have been fatal. During this period, the H5N1 virus has evolved. 
Currently, the H5N1 viruses can be divided into two distinct clades -- 
clade 1 and clade 2 ï¿½ with the latter branching into three subclades. 
While this is especially relevant to the selection of a vaccine target, 
it reinforces the plasticity of this RNA virus and serves as a constant 
reminder that with this virus becoming endemic among many avian species 
around the world, with each viral replication cycle comes the 
possibility that the next generation of virus could be the one that 
sparks a human pandemic. 

Yet despite all that it has shown us in the past several years, 
scientists do not know whether this virus is capable of sparking a 
pandemic and if so, how severe it might be. Recent reviews of the 
natural history of past pandemics and our expanded investments in the 
scientific underpinnings of this virus provide new insights into how we 
might minimize the impact of a pandemic and, for the first time in 
history we have the potential to do this. However, unlike the SARS 
virus, a different respiratory virus that recently showed us the 
potential for rapid global spread of disease in the 21st century, 
unless the circumstances arc ideal, few believe that a developing 
pandemic can be stopped in its tracks. 

The majority of human cases to date can be attributed to exposure to 
infected poultry. However, there have been episodes where it appears 
likely that humans were the source of the infection in other humans, 
but efficient and sustained transmission from person-to-person-to-
person did not occur. Although there arc many uncertainties about the 
future of the H5N1 virus itself, based on what we have learned about 
pandemics in the past and what we now know about the molecular 
evolution of influenza viruses the only certainty about influenza 
pandemic is that will continue to occur since novel influenza viruses 
will continue to emerge and will continue to be a threat. Therefore, we 
must prepare. Because of what is at stake, it is appropriate that the 
Congress asked GAO to assess our progress. 

Our preparations are broad and deep. As outlined in the National 
Strategy for Pandemic Influenza, they affect all Departments and 
Agencies, State, Local and Tribal Governments, communities, families 
and individuals. Therefore, we appreciate that GAO is reviewing many 
aspects of the nation's pandemic preparedness activities and recognize 
that this report, focused on vaccines and influenza antiviral drugs is 
only one piece of a their broader scope of work on this topic. However, 
we caution that analysis of vaccines and antiviral drugs is part of a 
larger, integrated whole, so viewing them outside of the broader 
context is likely to raise other questions and issues. 

We believe that the current draft of GAO-07-1052 suffers from the 
following deficiencies: 

A limited exploration, understanding and statement of fact regarding 
the overall U.S. Government (USG) strategy for the use of influenza 
vaccines and antivirals before and during a pandemic: 

* The USG approach to pandemic preparedness is a very dynamic one and 
has advanced significantly in the last six months, in part because 
important substantive new data has emerged concerning the use of 
adjuvants with pre-pandemic vaccines. While we recognize that any 
report will necessarily be somewhat out of date by the time it is 
published, this report lacks essential information to properly inform 
the intended audience. 

* The "mix and match" stockpiling strategy now in place must be 
included. 

A fundamental misunderstanding concerning forestalling a pandemic using 
vaccines and antivirals: 

* The concept that antivirals (and possibly vaccines under certain very 
specific circumstances) might be used to stop an incipient pandemic or 
to slow the spread should be explicitly stated instead of using the 
word forestalled in a way that is very likely to be misinterpreted by 
the readership. Further, GAO should acknowledge that there is not 
experience in preventing an incipient pandemic. 

* The emergence of a virus with the ability to be transmitted from 
human-to-human in an efficient and sustained manner cannot be 
forestalled by using vaccines and antivirals. 

* Because avian viruses such as H5N1 are a likely source of pandemics, 
without effectively eliminating the virus in avian populations, the 
potential threat to humans will likely persist. Thus theoretically the 
only way to truly forestall a human pandemic would be to eliminate the 
avian reservoir. This concept is not included in GAO-07-1052. 

Our preparations also involve the development and analysis of new 
science relevant to vaccines and antivirals and a number of novel 
influenza viruses (including H5N1 virus). We are also concerned that 
this report fails to draw bright lines between what we know about 
seasonal influenza, the novel forms of influenza virus that have 
already appeared, and pandemics. What we know about how antiviral drugs 
and influenza vaccines perform is largely drawn from our long 
experience with these products during seasonal influenza. For example, 
the neuraminidase inhibitor drugs (oseltamivir and zanamavir) were 
initially licensed for use by the FDA for the treatment of 
uncomplicated seasonal influenza and if administered within 48 hours of 
the onset of symptoms, their impact was to reduce the time to freedom 
from illness by 1.5 days compared to placebo. How they will perform 
against a pandemic influenza virus cannot be predicted, but as there 
are currently no better options, stockpiles are being established. 

In addition, we are also concerned by the expectation that GAO has set 
in its assumption that a pandemic can be forestalled and that vaccines 
and antivirals are only tools necessary to do so. While preventing a 
pandemic from occurring is the goal that all strive for, whether it can 
actually be achieved is not known. Mathematical models of the spread of 
a novel influenza virus hold out the hope that under the right 
circumstances ï¿½ early identification of the emergence of a pandemic 
outside of a densely populated urban setting ï¿½ an emerging pandemic 
might be contained, assuming that antiviral drugs that are used are 
available, effective both as treatment and as prophylaxis, are used 
strategically and can get to where they need to be before a pandemic 
spark becomes a forest fire. 

Led by the World Health Organization and in concert with our global 
partners, the strategy for such a rapid response is being refined (WHO 
Pandemic Influenza Draft Protocol for Rapid Response and Containment, 
May 30, 2006). Antiviral drugs may well be an important component and 
make such an effort most effective but their availability alone is 
insufficient to accomplish the task. Therefore, we caution those who 
may conclude that the establishment of national and global stockpiles 
of antiviral drugs has solved the problem. 

If a potential pandemic is identified early attempts at containment 
should and will be attempted. Such an effort would be in the best 
interest of both the affected country, and of benefit to global health 
security if it is successful in containing or slowing down the 
development of an emerging pandemic. Yet, there is no assurance a 
containment effort will succeed. In the likely event containment fails, 
the effort may still have the effect of slowing the pandemic's rate of 
spread. If containment succeeds, a pandemic may be at least temporarily 
averted. 

In contrast, as a truly preventive health measure only a vaccine will 
have the capability of dramatically changing the course of an influenza 
pandemic. Emerging vaccine production technologies (e.g., cell culture) 
and new approaches to the vaccine development (e.g., vaccine adjuvants 
and recombinant vaccines) may well influence the time it takes to 
develop and produce a pandemic vaccine. Many of these approaches are 
very promising and studies being conducted by HHS and those of many 
vaccine companies will provide the data to better judge which of these 
approaches are the most likely to be effective, but these vaccines are 
not yet sufficiently advanced to prevent a pandemic in its tracks if it 
occurred tomorrow. 

The addition of a very small amount of information about influenza 
diagnostic test development is confusing within the context of the 
subject and structure of the document: 

* The efforts to develop diagnostic tests go well beyond the 
information presented here which is not factually correct as noted in 
the editorial comments. This section should be excised or expanded to 
be complete and factually correct. 

The emphasis on OFFLU is totally out of proportion to the role they 
play in recognizing when a new virus with pandemic potential has begun 
to spread in humans. This recognition will occur on the international 
and domestic human influenza arena, not in the veterinary context: 

* OFFLU is given great emphasis in this document on page 33 and again 
on page 52. It must be understood that OFFLU does not monitor human 
infections and plays a limited role in international surveillance for 
influenza viruses that infect humans. 

* The role of human influenza surveillance is neglected in this 
document relative to the importance of the detection and monitoring of 
person-to-person spread of a new pandemic virus. This detection will 
trigger the use of vaccines and antivirals. HHS will append a 
spreadsheet outlining all of the international activities for influenza 
surveillance and capacity building relevant to human health 
accomplishments which dwarf what OFFLU has done in the context of 
pandemic preparedness. 

* The emphasis on OFFLU is just one example where the auditors spoke 
with an articulate person from this organization but were unable to put 
the information into the proper context of the threat of pandemic 
influenza and what the USG and others are doing globally. 

Structural weakness in the document that will confuse the Congressional 
audience about the differences between seasonal and pre-pandemic or 
pandemic vaccines: 

* The concept that vaccines could be used to help with limiting the 
spread of an incipient influenza pandemic is a rather new one and has 
not been fully explored and over emphasis is placed on vaccines within 
this context. 

* The use of pre-pandemic vaccines is also controversial but one that 
is not explored factually in this document. 

Although seasonal, pre-pandemic and pandemic vaccines are defined on 
page 10, the authors are not consistent throughout the document in 
defining for their audience the use and target populations for these 
vaccines. 

Information that is out of date: 

* Some information dates from 2005 and other dates from 2006 and these 
pieces of information are out of date and misrepresent the current 
status. 

Many factual errors are in GAO-07-1052: 

* Many errors of fact are corrected in the technical comments which are 
provided to GAO in a separate document. In addition, we have attempted 
to point out areas where additional fact finding should be done by the 
auditors in order to present to Congress an accurate and more complete 
picture of USG activities. 

We hope that this information as well as the technical comments 
attached to this response is useful to you. Please do not hesitate to 
contact us if we can be of further assistance. 

[End of section] 

Appendix II: Comments from the Department of State: 

United States Department of State: 
Assistant Secretary for Resource Management and Chief Financial 
Officer: 
Washington, D.C. 20520: 

Ms. Jacquelyn Williams-Bridgers: 
Managing Director International Affairs and Trade: 
Government Accountability Office: 
441 G Street, NW: 
Washington, D.C. 20548-0001: 

September 18, 2007: 

Dear Ms. Williams-Bridgers: 

We appreciate the opportunity to review your draft report, "Influenza 
Pandemic: Efforts Under Way to Address Constraints on Using Antivirals 
and Vaccines to Forestall a Pandemic," GAO Job Code 290618. 

The enclosed Department of State comments are provided for 
incorporation with this letter as an appendix to the final report. 

If you have any questions concerning this response, please contact Dan 
Singer, Senior Policy Advisor, Office of Avian Influenza Action Group, 
at (202) 312-9780. 

Sincerely, 

Signed by: 

Sid Kaplan (Acting): 

cc: GAO ï¿½ Thomas Conahan: 
G/AIAG ï¿½ John Lange: 
State/OIG ï¿½ Mark Duda: 

[End of letter] 

Department of State Comments on GAO Draft Report: 

Influenza Pandemic: Efforts Underway to Address Constraints on Using 
Antivirals and Vaccines to Forestall a Pandemic (GAO-07-1052, GAO Code 
290618): 

Thank you for the opportunity to review and comment on the draft report 
"Influenza Pandemic: Efforts Underway to Address Constraints on Using 
Antivirals and Vaccines to Forestall a Pandemic." 

The report in its current draft would benefit from major restructuring. 
One particular problem is the frequent jump in the text from discussion 
of antivirals to discussion of vaccines. These medical countermeasures 
are very different from each other in their application, utility, and 
the challenges the U.S. Government faces in development and production 
of sufficient quantities. The paper would be clearer if all issues 
pertaining to antivirals were discussed, then all issues pertaining to 
vaccines, with appropriate sections before and after to deal with a few 
cross-cutting issues. 

The use of the word "forestall" is somewhat ambiguous and should be 
clarified, since the definitions of forestall include such distinct 
concepts as to prevent or to hinder (delay). It may be useful to note 
that the North American Plan for Avian and Pandemic Influenza, approved 
by the United States, Canada and Mexico, makes clear the distinction 
between: (1) containing an incipient pandemic and thereby preventing a 
global pandemic; and, if containment fails, (2) delaying the arrival of 
the pandemic influenza in this region. The Plan states, "The North 
American Plan will enhance collaboration in order to...prevent or slow 
the entry of a novel strain of human influenza to North America." 

The report discusses extensively the challenges in production of 
adequate quantities of medical countermeasures. Proportionally, it does 
not give adequate consideration to the challenges of establishing 
protocols which would guide the international community in the use of 
whatever vaccines and antivirals are available. At the moment, there is 
not an international consensus on how antivirals or vaccine would be 
deployed, at what stage, and to whom, and this is a larger issue than 
the problem of clinical trials, which is addressed in the report. The 
development of international guidance for the use of antivirals and 
especially pre-pandemic vaccines could be addressed in the document, 
along which what the U.S. Government is doing to promote the 
development of such guidance (such as funding the World Health 
Organization (WHO) to write the guidance, providing staff to WHO, and 
directly promoting our own views, such as the guidelines on community 
mitigation during a pandemic.) 

[End of section] 

Appendix III: GAO Contacts and Staff Acknowledgments: 

GAO Contacts: 

Marcia Crosse, (202) 512-7114 or [email protected]: 

David Gootnick, (202) 512-3149 or [email protected]: 

Acknowledgments: 

In addition to the contacts above, Thomas Conahan, Assistant Director; 
Celia Thomas, Assistant Director; Robert Copeland; Etana Finkler; David 
Fox; Cathy Hamann; R. Gifford Howland; Michael McAtee; Jasleen Modi; 
Syeda Uddin; and George Bogart made key contributions to this report. 

[End of section] 

Related GAO Products: 

Influenza Vaccine: Issues Related to Production, Distribution, and 
Public Health Messages. GAO-08-27. Washington, D.C.: October 31, 2007. 

Influenza Pandemic: Opportunities Exist to Address Critical 
Infrastructure Protection Challenges That Require Federal and Private 
Sector Coordination. GAO-08-36. Washington, D.C.: October 31, 2007. 

Influenza Pandemic: Further Efforts are Needed to Ensure Clearer 
Federal Leadership Roles and an Effective National Strategy. GAO-07- 
781. Washington, D.C.: August 14, 2007. 

Influenza Pandemic: DOD Combatant Commands' Preparedness Efforts Could 
Benefit from More Clearly Defined Roles, Resources, and Risk 
Mitigation. GAO-07-696. Washington, D.C.: June 20, 2007. 

Influenza Pandemic: Efforts to Forestall Onset Are Under Way; 
Identifying Countries at Greatest Risk Entails Challenges. GAO-07-604. 
Washington, D.C.: June 20, 2007. 

Avian Influenza: USDA Has Taken Important Steps to Prepare for 
Outbreaks, but Better Planning Could Improve Response. GAO-07-652. 
Washington, D.C.: June 11, 2007. 

The Federal Workforce: Additional Steps Needed to Take Advantage of 
Federal Executive Boards' Ability to Contribute to Emergency 
Operations. GAO-07-515. Washington, D.C.: May 4, 2007. 

Financial Market Preparedness: Significant Progress Has Been Made, but 
Pandemic Planning and Other Challenges Remain. GAO-07-399. Washington, 
D.C.: March 29, 2007. 

Influenza Pandemic: DOD Has Taken Important Actions to Prepare, but 
Accountability, Funding, and Communications Need to be Clearer and 
Focused Departmentwide. GAO-06-1042. Washington, D.C.: September 21, 
2006. 

Influenza Pandemic: Applying Lessons Learned from the 2004-05 Influenza 
Vaccine Shortage. GAO-06-221T. Washington, D.C.: November 4, 2005. 

Influenza Vaccine: Shortages in 2004-05 Season Underscore Need for 
Better Preparation. GAO-05-984. Washington, D.C.: September 30, 2005. 

Influenza Pandemic: Challenges in Preparedness and Response. GAO-05- 
863T. Washington, D.C.: June 30, 2005. 

Influenza Pandemic: Challenges Remain in Preparedness. GAO-05-760T. 
Washington, D.C.: May 26, 2005. 

Flu Vaccine: Recent Supply Shortages Underscore Ongoing Challenges. GAO-
05-177T. Washington, D.C.: November 18, 2004. 

Emerging Infectious Diseases: Review of State and Federal Disease 
Surveillance Efforts. GAO-04-877. Washington, D.C.: September 30, 2004. 

Emerging Infectious Diseases: Asian SARS Outbreak Challenged 
International and National Responses. GAO-04-564. Washington, D.C.: 
April 28, 2004. 

Global Health: Challenges in Improving Infectious Disease Surveillance 
Systems. GAO-01-722. Washington, D.C.: August 31, 2001. 

Flu Vaccine: Supply Problems Heighten Need to Ensure Access for High- 
Risk People. GAO-01-624. Washington, D.C.: May 15, 2001. 

Influenza Pandemic: Plan Needed for Federal and State Response. GAO-01- 
4. Washington, D.C.: October 27, 2000. 

[End of section] 

Footnotes: 

[1] WHO is the United Nations agency for health. It is responsible for 
coordinating the global response to human cases of H5N1, monitoring the 
spread of the disease, and determining when a virus has caused a global 
pandemic. It also provides the international community with guidelines, 
procedures, and recommendations on addressing infectious disease 
outbreaks, including H5N1. 

[2] Antivirals can prevent or reduce the severity of a viral infection, 
such as influenza. Vaccines are used to stimulate the production of an 
immune system response to protect the body from disease. 

[3] The Asian Development Bank provides funding and technical 
assistance aimed at improving the welfare of people in the Asia-Pacific 
region. WHO has stated the Asian Development Bank has become a major 
partner in providing financial assistance to support WHO's pandemic 
response activities. 

[4] Members of the IFPMA Influenza Vaccine Supply International Task 
Force represent more than 95 percent of worldwide influenza vaccine 
production. 

[5] GAO, Influenza Pandemic: Efforts to Forestall Onset Are Under Way; 
Identifying Countries at Greatest Risk Entails Challenges, GAO-07-604 
(Washington, D.C.: June 20, 2007). 

[6] Seasonal influenza is an outbreak of influenza that occurs every 
year. There are two influenza seasons, one in the northern hemisphere 
and one in the southern hemisphere. The influenza season in the 
northern hemisphere is from November to April while the influenza 
season in the southern hemisphere is from May to October. An epidemic 
is the occurrence in a community or region of cases of an illness in 
excess of what is normally expected. 

[7] People aged 65 years and older, people of any age with chronic 
medical conditions, children younger than 2 years, and pregnant women 
are generally more likely than others to develop severe complications 
from seasonal influenza. 

[8] In addition to humans, influenza A viruses can infect a variety of 
other animals including horses, pigs, sea mammals, and birds. In this 
report, we differentiate between human influenza and animal influenza. 
Evidence suggests that all human influenza A viruses originate from 
influenza A viruses in wild waterfowl. 

[9] Sixteen types of HA or H (hemagglutinin) proteins and 9 types of NA 
or N (neuraminidase) proteins have been identified. Each combination of 
these proteins (for example, H5N1) is known as a subtype. 

[10] Pandemic influenza can emerge through two principal mechanisms: 
reassortment and adaptive mutation. Reassortment is the mixing of human 
influenza and animal influenza viruses within an animal or human to 
create a new human influenza A subtype. Adaptive mutation involves 
changes in the virus whereby a virus gradually acquires the changes 
needed to improve its transmissibility among humans. If such changes 
result in a new influenza A virus subtype that can infect humans and 
spread easily from person to person, an influenza pandemic can occur. 

[11] Pandemics vary in severity. For example, the pandemic of 1918-1919 
was more severe than the last two pandemics (in 1957 and 1968). 

[12] In the past, influenza pandemics have spread worldwide within 6 to 
9 months. However, WHO has stated that given the current volume of 
international travel, it is likely that a pandemic would spread more 
quickly. 

[13] H5N1 influenza is caused by influenza viruses that occur naturally 
among wild birds. All types of birds are susceptible to the virus, but 
outbreaks occur most often in chickens and turkeys. The H5N1 subtype is 
deadly to domestic fowl. Currently, humans are only rarely affected. 

[14] While H5N1 is considered the most likely subtype to cause a 
pandemic at this time, experts have also cited the subtypes H2N2, H7N7, 
and H9N2 as having pandemic potential. 

[15] The case fatality rate is defined as the number of people who die 
of a disease divided by the number of people who have the disease. 

[16] According to HHS and WHO, there have been a limited number of 
human cases in which human-to-human transmission cannot be ruled out. 
However, H5N1 has not yet demonstrated an ability to spread efficiently 
among humans. 

[17] An antibody is a molecule produced by the immune system that helps 
fight infections. 

[18] The ability of influenza vaccine to protect a person depends on 
the age and health status of the person getting the vaccine, and the 
similarity or "match" between the virus strains in the vaccine and 
those in circulation. When the vaccine and circulating virus are well- 
matched, influenza vaccines will prevent illness in approximately 70 to 
90 percent of healthy adults under the age of 65. The protection drops 
to about 30 to 40 percent for the elderly. Vaccine effectiveness can 
also be lower for individuals with underlying medical conditions such 
as compromised immune systems. 

[19] We use the term seed virus to indicate the modified virus from 
which subsequent vaccine production for that strain is derived. 

[20] The time required to produce vaccines depends, in part, on the 
number of viral strains in the vaccine, satisfactory growth and yield 
of the virus in chicken eggs, the number of doses required to build 
immunity, and access to raw materials. All other things being equal, 
vaccines that include a single strain can be produced in less time and 
in greater quantities than vaccines containing multiple strains because 
no additional time is needed to produce and combine additional strains. 
Other factors that affect timing include testing by FDA and 
manufacturers to determine vaccine strength and the development of a 
reagent for such testing. A reagent is a substance used in a chemical 
reaction to detect, measure, examine, or produce other substances. 
Reagents are used to determine the purity and strength of influenza 
vaccine, and must be developed each year for the specific new vaccine. 

[21] A pre-pandemic vaccine may have both pre-pandemic and pandemic 
use. For example, a pre-pandemic vaccine might be given to those at 
high risk of exposure prior to a pandemic. The same vaccine might also 
be used to vaccinate critical workforce and primary health care workers 
in the early stages of a declared pandemic when a matched pandemic 
vaccine is not available. 

[22] Research is also currently underway to develop what is called a 
universal vaccine, which would protect against multiple influenza 
strains. However, such a vaccine does not currently exist. 

[23] The five vaccines and their manufacturers were Fluarix 
(GlaxoSmithKline Biologicals), FluLaval (ID Biomedical Corporation, a 
subsidiary of GlaxoSmithKline Biologicals), FluMist (MedImmune 
Vaccines, Inc.), Fluvirin (Novartis Vaccines and Diagnostics, Inc.), 
and Fluzone (sanofi pasteur, Inc.) The policy of sanofi pasteur is to 
spell its name without capital letters. 

[24] The switch to pandemic vaccine production is a decision that 
manufacturers will make together with public health officials. This 
switch will impact the availability of the following year's seasonal 
vaccine since production facilities will be used to produce pandemic 
vaccine instead of seasonal vaccine. If such a decision is made and the 
pandemic does not occur, the pandemic vaccine will not likely protect 
against the following year's seasonal influenza. However, if a pandemic 
does occur and the decision is late, then that will add to the delay in 
the availability of a pandemic vaccine. 

[25] Adamantanes, also known as M2-ion channel inhibitors, are less 
expensive than neuraminidase inhibitors. Amantadine and rimantadine are 
no longer under patent protection and are referred to by their 
scientific (that is, generic) names. 

[26] Tamiflu and Relenza are both under patent protection in some 
countries, including the United States, and therefore are referred to 
by their brand names instead of their scientific names, oseltamivir and 
zanamivir, respectively. 

[27] Antiviral resistance is the result of viruses changing in ways 
that reduce or eliminate the effectiveness of antiviral agents to treat 
or prevent infections. Antiviral resistance can emerge due to genetic 
changes in the virus from either natural mutation or as a result of the 
use of antivirals, including antiviral misuse such as not completing 
the full treatment course. According to HHS, antiviral resistance is 
one of several factors that could limit the effectiveness of 
antivirals. In addition, not all viral changes leading to reduced 
effectiveness of antivirals would generally be termed resistance. In 
this report, we use resistance to refer to changes in the virus that 
result in reductions in the effectiveness of antivirals in responding 
to influenza outbreaks. 

[28] However, concerns regarding Tamiflu and Relenza have recently 
increased. On November 13, 2006, FDA announced a change to the 
prescribing information for Tamiflu to include a precaution about 
neuropsychiatric events. The revision is based on postmarketing reports 
(mostly from Japan) of self-injury and delirium with the use of Tamiflu 
in patients with influenza. The reports were primarily among pediatric 
patients. On November 27, 2007, FDA's Pediatric Advisory Committee 
recommended stronger warning labels for both Tamiflu and Relenza 
because of reports of neuropsychiatric problems in children and teens. 

[29] The patent holders for Tamiflu and Relenza, Gilead Sciences and 
Biota Holdings Limited, respectively, have licensed these drugs to 
Roche and GlaxoSmithKline. 

[30] Tamiflu and Relenza are both patent protected in some countries, 
which limits the manufacture, use, sale, offering to sell, and 
importation of these drugs in those countries. Both Tamiflu and Relenza 
are patent protected in the United States. However, they are not patent 
protected everywhere. For example, generic drug makers in Bangladesh, 
India, and Taiwan manufacture a generic version of Tamiflu. These 
products can be sold in countries without patent protection for 
Tamiflu. 

[31] In addition to the Departments of Agriculture, Defense, Health and 
Human Services, and State and the U.S. Agency for International 
Development, representatives from the Department of Homeland Security, 
the National Security Council, the Homeland Security Council, and U.S. 
intelligence agencies attend working group meetings. The Department of 
the Treasury has not been a regular participant. However, the 
Department of the Treasury has worked with U.S. executive directors at 
the World Bank, the Asian Development Bank, and other international 
financial institutions to encourage and support these entities' efforts 
to address influenza threats. 

[32] See Departments of Labor, Health and Human Services, and 
Education, and Related Agencies Appropriations Act, 2006, Pub. L. No. 
109-149, 119 Stat. 2833, 2857 (funds not limited to purposes related to 
pandemic or avian influenza); Department of Defense, Emergency 
Supplemental Appropriations to Address Hurricanes in the Gulf of 
Mexico, and Pandemic Influenza Act, 2006, Pub. L. No. 109-148, 119 
Stat. 2680, 2783, 2786; Emergency Supplemental Appropriations Act for 
Defense, the Global War on Terror and Hurricane Recovery, 2006, Pub. L. 
No. 109-234, 120 Stat. 479 (includes $30 million to be transferred to 
the U.S. Agency for International Development). HHS also received 
appropriations available for pandemic-influenza-related purposes, among 
other purposes, totaling $50 million in fiscal year 2004, $182 million 
in fiscal year 2005, and $100 million in fiscal year 2007. 2004: 
Consolidated Appropriations Act, 2004, Pub. L. No. 108-199, 118 Stat. 
3, 251; 2005: Consolidated Appropriations Act, 2005, Pub. L. No. 108-
447, 118 Stat. 2809, 3138, Emergency Supplemental Appropriations Act 
for Defense, the Global War on Terror, and Tsunami Relief, 2005, Pub. 
L. No. 109-13, 119 Stat. 231, 276, 280; 2007: Revised Continuing 
Appropriations Resolution, 2007, Pub. L. No. 110-5, 121 Stat. 8, 33. 
Many of these appropriations remain available until expended, that is 
without fiscal year limitation. 

[33] WHO, WHO Interim Protocol: Rapid operations to contain the initial 
emergence of pandemic influenza (Geneva: WHO, Oct. 2007), [hyperlink, 
http://www.who.int/entity/csr/disease/avian_influenza/guidelines/RapidCo
ntProtOct15.pdf] (accessed Oct. 27, 2007). This rapid containment 
strategy is one of the five major strategic actions that form the basis 
of the WHO strategic action plan for pandemic influenza. (Geneva: WHO, 
May 2007), [hyperlink, 
http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_
2006_2/en/index.html] (accessed July 19, 2007). In addition to these 
documents, we also have drawn on a number of other WHO documents 
dealing with forestalling a pandemic. 

[34] That strategy, released in November 2005, has three broad pillars: 
(1) preparedness and communications, (2) surveillance and detection, 
and (3) response and containment. In August 2007, the United States, 
Canada, and Mexico issued the North American Plan for Avian & Pandemic 
Influenza, which outlines how the three countries intend to work 
together to combat an outbreak of avian influenza or an influenza 
pandemic in North America. 

[35] An exception was the U.S. government decision to mass vaccinate 
the public against an outbreak of swine flu in New Jersey in 1976. That 
effort was halted when a small apparent risk emerged of contracting 
Guillain-Barre syndrome--an inflammatory disorder that can cause 
paralysis--from the swine flu vaccine, and there was no extensive 
spread of the influenza strain of concern. 

[36] WHO has stated that there are three opportunities for using 
antivirals. The first, and present situation, is when antivirals are 
used to treat infected patients and to prevent infection in close 
contacts, including family members and health care workers. The second 
is when surveillance indicates that the transmissibility of the virus 
among humans is beginning to become more efficient. In this 
circumstance, administration of antivirals to all members of a 
community in which clusters of cases are occurring might either stop 
the virus from further improving its transmissibility or delay 
international spread. The third opportunity is once a pandemic has been 
declared. Pending the availability of vaccines, antivirals will be the 
principal medical intervention for reducing morbidity and mortality. 

[37] The four WHO Collaborating Centres are located in the United 
States, Australia, Japan, and the United Kingdom. CDC is the 
Collaborating Centre in the United States. 

[38] Reagents are used to determine the purity and strength of 
influenza vaccine. 

[39] There does not appear to be agreement on the time needed to 
produce a pandemic vaccine. In a document distributed for a November 
2007 meeting on pandemic influenza preparedness, WHO stated that the 
total approximate time to produce an H5N1 vaccine is 28 to 52 weeks. 

[40] For an influenza virus, genetic sequencing reveals the complete 
genetic blueprint (sequence) of the virus. 

[41] GAO-07-604, 61. 

[42] Point-of-care testing refers to a laboratory test that can be 
performed outside of a laboratory facility, with results available to 
doctors and patients within minutes. 

[43] The dosage for current seasonal vaccines is 15 micrograms per 
strain in the trivalent vaccine, for a total dosage of 45 micrograms. 
However, it is unknown what dosage would be effective against a 
pandemic strain. 

[44] A treatment course is the number of doses needed to treat a person 
that has been infected with an influenza virus. A treatment course for 
Tamiflu contains 10 capsules taken over the course of 5 days. 

[45] A preventative course would be given to individuals within the 
containment zone that may have been exposed to the virus. In this case, 
a preventative course for Tamiflu would be 20 capsules taken over the 
course of 20 days. 

[46] HHS, Pandemic Planning Update IV (Washington, D.C.: 2007). 

[47] Another benefit resulting from seasonal vaccination is that it 
would decrease the chance of confusing the diagnosis of cases of 
seasonal influenza with H5N1. 

[48] This represents an increase in capacity of 215 million doses over 
the 350 million dose capacity in 2006. 

[49] GAO, Influenza Vaccine: Shortages in 2004-05 Season Underscore 
Need for Better Preparation, GAO-05-984 (Washington, D.C.: Sept. 30, 
2005), 3. 

[50] According to IFPMA, many noninfluenza vaccines are manufactured in 
large volumes and used around the world, including in developing 
countries. This is not the case with influenza vaccine due primarily to 
low demand for seasonal influenza vaccines in such countries and the 
unpredictability of the occurrence of pandemic influenza. For these 
reasons, manufacturing capacity for seasonal influenza vaccines in 
developing countries has been limited and expansion is considered to be 
economically difficult. 

[51] Countries creating production infrastructure may require starting 
materials, such as reagents, to develop and produce vaccines and may 
need assistance in establishing new facilities. A reagent is a 
substance used in a chemical reaction to detect, measure, examine, or 
produce other substances. Reagents are used to determine the purity and 
strength of influenza vaccine. 

[52] GAO-07-604, 61. 

[53] Sandra Mounier-Jack and Richard J. Coker, "How Prepared is Europe 
for Pandemic Influenza? Analysis of National Plans," The Lancet, vol. 
367, no. 9520 (2006) and Richard Coker and Sandra Mounier-Jack, 
"Pandemic Influenza Preparedness in the Asia-Pacific Region," The 
Lancet, vol. 368, no. 9538 (2006). 

[54] In a follow-up study, the authors found that Europe had become 
better prepared for a pandemic. However, they noted that countries' 
plans on antivirals and vaccines varied and that operational planning 
remained weak. For example, they found that determining how to deliver 
antivirals within 48 hours to individual patients remained largely 
unresolved. Many countries are delegating this responsibility to local 
officials but are providing little guidance. Similarly, although most 
study countries had prioritized groups for receiving antivirals and 
vaccines, the details on how these policies would be implemented had 
not been put in place. See Sandra Mounier-Jack, Ria Jas, and Richard 
Coker, "Progress and Shortcomings in European National Strategic Plans 
for Pandemic Influenza," Bulletin of the World Health Organization, 
vol. 85, (2007). Published online ahead of print at [hyperlink, 
http://www.who.int/bulletin/published_ahead_of_print/en/index.html] 
(accessed Oct. 15, 2007). 

[55] Economic development refers to the process of raising the level of 
prosperity and material living in a society through increasing the 
productivity and efficiency of its economy. 

[56] See GAO-05-984, 17. In the United States, influenza vaccine 
production and distribution are largely private-sector activities. HHS 
has limited authority to control vaccine distribution directly. 
Manufacturers sell influenza vaccine to resellers (such as medical 
supply distributors and pharmacies), federal agencies, state and local 
public health departments, or directly to providers. Individuals can 
obtain an influenza vaccination at a number of places, including 
physicians' offices, public health clinics, nursing homes, and 
nonmedical locations such as workplaces or retail outlets. During the 
2004-2005 influenza season, CDC took actions in addition to the 
allocation plan discussed to deal with the vaccine shortage. For 
example, CDC developed a revised recommendation on who should be 
vaccinated, so that vaccine could be directed to those at high risk and 
to other priority groups, and worked with one manufacturer to increase 
production. 

If the Secretary of HHS determines and declares a public health 
emergency, the Public Health Service Act authorizes the Secretary to 
"take such action as may be appropriate" to respond. According to the 
act, to declare a pubic health emergency, the Secretary must determine 
that (1) a disease or disorder presents a public health emergency, or 
(2) a public health emergency, including significant outbreaks of 
infectious disease or bioterrorist attacks, otherwise exists. The 
federal government and some states are currently building 
pharmaceutical stockpiles that they would control. 

[57] If granted liability protection, manufacturers generally would not 
have to pay compensation to individuals injured by a vaccine. IFPMA's 
Influenza Vaccine Supply International Task Force issued a position 
statement in May 2006, calling for a waiver of liability for the 
manufacturing and use of pandemic vaccines. 

[58] The International Health Regulations are legally binding 
agreements on all 193 WHO member states who have not rejected them (or 
who have not raised reservations about them) and on all nonmember 
states of WHO that have agreed to be bound by them. Originally adopted 
in 1951 and named the International Sanitary Regulations, the 
Regulations were replaced by and renamed the International Health 
Regulations in 1969. Other than minor modifications in 1973 and 1981, 
the Regulations had not been revised again until the current revisions. 
The purpose and scope of the revised regulations are to prevent, 
protect against, control, and provide a public health response to the 
international spread of disease in ways that are commensurate with and 
restricted to public health risks, and which avoid unnecessary 
interference with international traffic and trade. Although the revised 
regulations do not include an explicit enforcement mechanism, WHO 
indicates that public knowledge and "peer pressure" within the global 
community are expected to provide powerful incentives for compliance. 

[59] The revised International Health Regulations went into effect for 
the United States on July 17, 2007. 

[60] Fifty-eighth World Health Assembly, agenda item 13.1, Revision of 
the International Health Regulations, May 23, 2005, [hyperlink, 
http://www.who.int/gb/ebwha/pdf_files/WHA58/A58_55-en.pdf] (accessed 
Nov. 16, 2007). 

[61] Despite the provisions not going into effect until June 2007, in 
May 2006 the World Health Assembly--the supreme decision-making body of 
WHO--requested that its member states comply immediately, on a 
voluntary basis, with provisions of the revised Regulations considered 
relevant to the risk posed by pandemic influenza. 

[62] OIE stands for Office International des Epizooties--the 
organization's original name, adopted at its founding in 1924. In 2003, 
the organization decided to begin using the common name World 
Organisation for Animal Health while retaining the OIE acronym. OIE is 
a multilateral organization but is not part of the United Nations. 

[63] By putting influenza sequences in the public domain rather than in 
restricted databases, more researchers have access to the information 
and can work to better understand how influenza viruses evolve, spread, 
and cause disease. 

[64] An antigen is any foreign substance that stimulates the body's 
immune system to produce antibodies. 

[65] Zoonoses are diseases that are transferable from animals to 
humans. 

[66] The World Health Assembly is the supreme decision-making body of 
WHO. 

[67] The Asia-Pacific Economic Cooperation consists of 21 economies 
including those of China, Indonesia, and Vietnam. 

[68] An official stated that the agreement must ensure that developing 
countries will receive equitable access to affordable vaccines made 
from the samples they share. 

[69] H5 is 1 of 16 hemagglutinin proteins that can make up an influenza 
virus. It can be combined with 1 of 9 types of neuraminidase proteins 
to form an influenza subtype. For example, H5N1 is an influenza 
subtype. 

[70] A reference laboratory conducts tests for other laboratories. A 
public health laboratory is a facility with the equipment and staff 
needed to conduct public health assessments and respond to emergency 
public health issues. 

[71] WHO has suggested that this be one component of a larger effort to 
increase vaccine production capacity. See WHO, Global pandemic 
influenza action plan to increase vaccine supply (Geneva: WHO, Sept. 
2006), [hyperlink, 
http://www.who.int/vaccinesocuments/DocsPDF06/863.pdf] (downloaded Oct. 
26, 2006). 

[72] The current HHS policy is to administer the H5N1 pre-pandemic 
vaccine stockpile to critical workforce members at the onset of an 
influenza pandemic caused by an H5N1-like virus. Studies are being 
conducted to determine if there may be value in immunizing more people 
at the onset of a pandemic. If so, the size of the pre-pandemic vaccine 
stockpile may be expanded. In addition, the Department of Defense is 
establishing, for military use, stockpiles of vaccines against H5N1 and 
other influenza subtypes with pandemic potential large enough to 
immunize approximately 1.35 million persons. 

[73] In April 2007, Roche reported that it had received orders or 
letters of intent from more than 80 countries for approximately 215 
million treatment courses of Tamiflu. It had also received orders from 
more than 250 corporations for about 5 million treatment courses. 

[74] These sublicensees cannot use the Tamiflu name and Roche does not 
ensure the quality of the products. 

[75] WHO has suggested that this be one component of a larger effort to 
increase vaccine production capacity. WHO estimates that $2 billion to 
$9 billion would be needed for all of these activities. See WHO, Global 
pandemic influenza action, [hyperlink, 
http://www.who.int/vaccinesocuments/DocsPDF06/863.pdf] (accessed Oct. 
26, 2006). 

[76] The six countries are Brazil, India, Indonesia, Mexico, Thailand, 
and Vietnam. 

[77] Sanofi pasteur has invested $150 million to create a new 
manufacturing facility in the United States that will allow it to 
double its influenza vaccine manufacturing capacity in time for the 
2008-2009 influenza season. Similarly, GlaxoSmithKline has committed 
more than $2 billion to increase its vaccine and antiviral production. 

[78] In September 2007, BioCryst Pharmaceuticals, Inc., reported the 
preliminary results of a study of the safety and effectiveness of 
peramivir in humans. The company noted that it was disappointed that 
the study did not meet its primary objective of reducing the time to 
lessen symptoms. However, it also stated that it had a plan to correct 
the issues identified in the study and planned to continue clinical 
trials. 

[79] Probenecid is used to treat chronic gout and gouty arthritis. 

[80] HHS noted that this vaccine may be used during the pre-pandemic 
period for those at increased risk of exposure to H5N1; however, it may 
also be used during the pandemic period because everyone would be 
considered at increased risk for exposure to H5N1 if the pandemic 
outbreak is of the H5N1 subtype. 

[81] The predicted effectiveness of the pre-pandemic vaccine is based 
on a measure of immune response. However, the measure is not a perfect 
surrogate for immunity and is known to be imperfect even for seasonal 
influenza. On the other hand, the effectiveness of seasonal influenza 
vaccines is based not on a surrogate measure, but on studies examining 
the actual level of protection offered from vaccination. 

[82] While cell-based production methods are new for influenza 
vaccines, they have been used for other vaccines such as chickenpox, 
hepatitis A, polio, and shingles. 

[83] Eggs for vaccine manufacturing come from producers that are 
located mainly in Europe, as are vaccine manufacturers. This creates 
vulnerabilities. For example, large egg suppliers based in the 
Netherlands were left without eggs for vaccine production after an H7N7 
influenza outbreak among chickens in that country in 2005. 

[84] Researchers are also pursuing other methods to develop vaccines. 
For example, DNA-based vaccines contain portions of the influenza 
virus' genetic material. Potentially, these vaccines could be produced 
more quickly than egg-based vaccines and provide protection against 
more than one influenza strain. The first human trial of a DNA vaccine 
to prevent H5N1 infection in people began in December 2006. In June 
2007, NIH awarded Vical Incorporated a $6 million grant to develop a 
DNA vaccine manufacturing process. 

[85] A universal vaccine would protect against both seasonal and 
pandemic influenza viruses. HHS has stated that successful development 
of a universal vaccine would mean that individuals would need only one 
influenza shot to protect them for many years (possibly for life). 

[86] In April 2007, WHO's Strategic Advisory Group of Experts on 
Immunization concluded that it was realistic to expect that vaccines 
offering protection against multiple influenza strains could be 
developed; however, no specific time frame was given. In May 2007, WHO 
said that a universal vaccine might not be available in the next 5 to 
10 years. 

[87] Live attenuated vaccines use a weakened form of the influenza 
virus to stimulate a protective immune response in the body. 

[88] The global stockpile is divided and located in Switzerland, the 
United Arab Emirates, and WHO regional offices. Prior to this, in 2004 
Roche had donated 125,000 treatment courses, which were used by WHO in 
Asian countries affected by H5N1. 

[89] However, if containment is not possible, the Tamiflu would be sent 
back to the U.S. stockpile of antiviral influenza medications. 

[90] For example, different countries can have varying requirements for 
clinical trials. 

[91] According to experts, global availability of antivirals and 
vaccines could be increased with coordination of different countries' 
regulatory processes. According to experts, one benefit would be that 
clinical trials might not have to be duplicated. 

[92] Vaccines approved under this process are only approved for use in 
a declared influenza pandemic. They are not approved for use prior to a 
pandemic. The objective of this mechanism is to have a marketing 
authorization in place that can be changed quickly in the event of a 
pandemic to include the virus strain responsible, once it has been 
identified. These are referred to as mock-up pre-pandemic influenza 
vaccines. 

[93] The goal is to approve the pandemic vaccine within 4 days after 
the application is submitted. The United Kingdom Vaccine Industry Group 
estimated that overall this process would allow a pandemic vaccine to 
be provided 2 to 4 months faster than if a pre-pandemic vaccine had not 
been approved. 

[94] WHO and many national health authorities recommend annual 
vaccination for a range of risk groups. These groups include those over 
a nationally defined age limit (often 65 years), those with specific 
chronic illnesses such as heart, lung, or kidney conditions including 
asthma and diabetes, and those suffering from immunosuppression, such 
as transplant patients and those with HIV. In addition, guidelines 
recommend vaccination for those who may transmit influenza to high-risk 
groups, such as health care workers and household contacts. 

[95] WHO estimates that a total of $3 billion to $10 billion will be 
required to implement its entire vaccine action plan. The other 
objectives of the plan are to increase influenza vaccine production 
capacity and to promote research and development for new influenza 
vaccines. In March 2007, WHO announced that in mid-2007 an independent 
steering committee with representation of both developing and 
industrialized countries would be formed to oversee implementation of 
the plan. Canada will provide support for the committee and its work. 

[96] GAO-07-604. 

[End of section] 

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