[Federal Register Volume 74, Number 182 (Tuesday, September 22, 2009)]
[Notices]
[Pages 48275-48280]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-22693]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Office of Biotechnology Activities; Recombinant DNA Research: 
Actions Under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules (NIH Guidelines)

AGENCY: National Institutes of Health (NIH), Department of Health and 
Human Services (HHS).

ACTION: Notice of changes to the NIH Guidelines.

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SUMMARY: Concerns about the emergence of a pandemic influenza virus 
have spurred research on influenza viruses that have either caused 
pandemics or are believed to have the potential to cause a pandemic. 
These viruses include human H2N2 virus, which circulated from 1957-
1968, the 1918-1919 H1N1, which caused the deadliest pandemic in the 
past century, and the Highly Pathogenic Avian Influenza (HPAI) H5N1 
virus that is thought to have pandemic potential. The public health 
benefits of this research include developing a better understanding of 
the pathogenicity of pandemic influenza viruses, their virulence 
mechanisms, mechanisms of host adaptation, and ultimately the 
development of vaccines and antiviral drugs. These benefits are 
balanced against the potential risks that might include the inadvertent 
release of a highly transmissible and potentially virulent influenza 
virus. Consequently, explicit and uniform biosafety containment 
practices are critical to the safe conduct of research with these 
agents. The NIH Guidelines provide a framework for assessing the risks 
of such research. However, after extensive consultation with the NIH 
Recombinant DNA Advisory Committee (RAC), experts in biosafety and 
influenza, the Centers for Disease Control and Prevention (CDC), and 
the U.S. Department of Agriculture (USDA), the NIH Office of 
Biotechnology Activities (OBA) concluded that more specific guidance in 
the NIH Guidelines is warranted to promote uniform biosafety practices 
for recombinant research with these viruses.
    The resulting amendments are ``Minor Actions'' under Section IV-C-
1-(b)-2 of the NIH Guidelines and, therefore, will be implemented 
immediately upon publication in the Federal Register. While a Minor 
Action only requires consultation with the RAC chair and one or more 
RAC members, as necessary, as noted above, these changes were developed 
after extensive consultation with the full RAC and other experts and 
were discussed at three public RAC meetings. The RAC voted on March 4, 
2009 to recommend these changes. They are being published to inform the 
scientific and biosafety communities, as well as to solicit continued 
scientific input should further revisions be needed.
    The NIH Guidelines are being changed to provide the following 
biosafety guidance for research with potentially pandemic influenza 
viruses:
     Designation of human H2N2 viruses that circulated from 
1957-1968 (human H2N2 (1957-1968)), the fully reconstructed 1918-1919 
H1N1 influenza virus (1918 H1N1), and Highly Pathogenic Avian Influenza 
(HPAI) H5N1 within the Goose/Guangdong/96-like H5 lineage (HPAI H5N1) 
as Risk Group 3 agents. Risk Group 3 agents have the potential to cause 
serious or lethal disease in humans for which preventative and 
therapeutic measures may be available. Up until this revision, all 
influenza viruses (Orthomyxoviruses) were Risk Group 2 agents, which 
are agents that are associated with human disease that is rarely 
serious and for which preventative and therapeutic agents are often 
available.
     Requirement for enhanced biosafety practices, including 
the use of powered air purifying respirators (PAPRs) and other personal 
protective equipment to prevent laboratory worker exposure and minimize 
the risk of spread outside of the laboratory.
     Guidance on the containment for research with influenza 
viruses generated by recombinant methods (e.g., generation by reverse 
genetics of chimeric viruses with reassorted segments, introduction of 
specific mutations) containing one or more genes and/or segments from 
human H2N2 (1957-1968), 1918 H1N1 or HPAI H5N1. For 1918 H1N1, the NIH 
Guidelines will require Biosafety Level 3 enhanced containment for all 
influenza viruses that contain one of more genes and/or segments from 
1918 H1N1 because of the uncertainty about the virulence factors for 
this agent.
     Guidance on occupational health practices, including 
policies regarding the use of prophylactic antiviral agents and 
isolation of laboratory workers who are exposed to one of these 
viruses.

DATES: The public is encouraged to submit written comments on this 
action. Comments may be submitted to OBA in paper or electronic form at 
the OBA mailing, fax, and e-mail addresses shown below under the 
heading FOR FURTHER INFORMATION CONTACT. All comments should be 
submitted by September 22, 2010. All written comments received in 
response to this notice will be available for public inspection in the 
NIH OBA office, 6705 Rockledge Drive, Suite 750, MSC 7985, Bethesda, MD 
20892-7985, weekdays between the hours of 8:30 a.m. and 5 p.m. and may 
be posted to OBA's Web site.

FOR FURTHER INFORMATION: If you have questions, or require additional 
information about these changes, please contact OBA by e-mail at 
[email protected], or telephone at 301-496-9838. Comments may be submitted 
to the same e-mail address or by fax at 301-496-9839 or by mail to the 
Office of Biotechnology Activities, National Institutes of Health, 6705 
Rockledge Drive, Suite 750, MSC 7985, Bethesda, Maryland 20892-7985. 
Background information may be obtained by

[[Page 48276]]

contacting NIH OBA by e-mail at [email protected].

SUPPLEMENTARY INFORMATION:

Background

    Recently, NIH support for research with influenza viruses involving 
recombinant DNA technology has significantly increased. The development 
of new laboratory methods, such as reverse genetics, has allowed for 
easier and more rapid generation of infectious influenza viruses from 
DNA plasmids, e.g. reassortant viruses. An increasing proportion of 
such research has focused on pandemic or potentially pandemic viruses. 
These include previously pandemic viruses that are not currently 
circulating in the human population, such as the human H2N2 virus that 
caused a pandemic resulting in approximately 66,000 excess deaths in 
the U.S. in 1957 and the 1918 H1N1 virus, which caused 20-40 million 
excess deaths worldwide. Another focus of research is currently 
circulating highly pathogenic avian influenza viruses (HPAI) that may 
have potential to cause a human pandemic if efficient human-to-human 
transmission were to develop. Over 400 cases worldwide of human 
infection with the HPAI H5N1 virus have been reported to date with 
approximately 60% mortality rate; however, evidence of human-to-human 
transmission has been limited to small, familial clusters.
    The public health benefits of research on potentially pandemic 
influenza viruses include identification of viral proteins that 
contribute to host adaptation and virulence to increase understanding 
of the pathogenicity of influenza viruses during pandemics, development 
of vaccine candidates, and identification of targets for antiviral 
drugs. While research into influenza viral virulence mechanisms and the 
development of vaccines and antiviral drugs are public health 
priorities, it is equally important that the research be performed 
under appropriate biocontainment to protect the health of laboratory 
researchers and the public.
    There are currently other biosafety requirements for certain types 
of research with these viruses. The CDC/NIH Biosafety in 
Microbiological and Biomedical Laboratories (5th edition) (BMBL) 
recommends Biosafety Level 3 with additional personal protection 
equipment designed to minimize the risk of laboratory acquired 
infection for research with the reconstructed replication competent 
forms of 1918 H1N1 (i.e. Biosafety Level 3 enhanced). Reconstructed 
replication competent forms of 1918 pandemic influenza virus H1N1 were 
designated HHS/CDC Select Agents in 2005 (70 FR 61047). The BMBL also 
recommends Biosafety Level 3 containment level for research with the 
full human H2N2 virus (1957-1968) with enhancements designed to prevent 
laboratory acquired respiratory infection.
    HPAI H5N1 influenza viruses are USDA Select Agents (9 CFR 
121.3(b)). The USDA's Animal and Plant Health Inspection Service 
(APHIS) regulates as a Select Agent avian influenza viruses (and 
constructs thereof pursuant to 9 CFR 121.3(c)(3)) that demonstrate a 
high pathogenicity index in chickens, contain a specific poly-basic 
amino acid motif at the hemagglutinin (HA) gene cleavage site (or have 
an amino acid sequence at the cleavage site of the HA gene that is 
compatible with other highly pathogenic avian influenza viruses) and 
show growth characteristics of influenza virus in the presence and 
absence of trypsin. Avian influenza viruses that demonstrate evidence 
of attenuation in poultry can be excluded pursuant to 9 CFR 121.3(e). 
The biosafety containment level recommended for most Select Agent 
research with these viruses is a minimum of Biosafety Level 3 enhanced 
or Animal Biosafety Level 3 (ABSL3) enhanced. Influenza viruses 
containing genes from highly pathogenic avian influenza virus that are 
not classified as Select Agents by USDA are still regulated by that 
agency through ``permitting'' regulations (9 CFR 122), which govern 
imports and interstate movements of the viruses.
    The current (April 2002) NIH Guidelines classify influenza viruses 
A, B, and C as Risk Group 2 agents in Appendix B. No distinction is 
made between potentially pandemic strains of influenza and other lower 
risk influenza viruses. According to the NIH Guidelines, an initial 
risk assessment is based on the Risk Group (RG) of the parent agent; 
however, appropriate containment is set following consideration of the 
specific agent and how it is to be manipulated. The NIH Guidelines 
emphasize that containment levels for recombinant research may be 
raised or lowered relative to the RG classification of the parent agent 
after a comprehensive risk assessment.
    Up until today, the NIH Guidelines had not been amended to address 
specifically recombinant influenza viruses that contain genes and/or 
segments from human H2N2 (1957-1968), 1918 H1N1 and HPAI H5N1 viruses. 
Therefore, to clarify and augment the current biosafety guidance in the 
NIH Guidelines for research with potentially pandemic influenza 
viruses, and to harmonize with the BMBL and other regulatory policies, 
NIH/OBA in consultation with the RAC and outside experts, including the 
CDC and USDA, reviewed and revised the Risk Group designations for 
potentially pandemic influenza viruses human H2N2 (1957-1968), 1918 
H1N1, and HPAI H5N1 and developed additional containment and 
occupational health guidance for research involving recombinant 
influenza viruses containing genes from these influenza viruses.
    In determining the Risk Group (RG) classification for human H2N2 
(1957-1968), 1918 H1N1 and HPAI H5N1, the RAC considered the definition 
of risk groups in Appendix B. Risk Group 3 agents are those ``that are 
associated with serious or lethal disease for which preventative or 
therapeutic interventions may be available (high individual risk but 
low community risk).'' Each strain was considered to be a risk for 
serious or lethal disease, although it was recognized that the case 
fatality rate for HPAI H5N1 is very high, over 50 percent, whereas the 
case fatality rate for 1918 H1N1 is considerably lower in the range of 
1-2 percent. Human H2N2 caused a much milder pandemic compared to 1918 
H1N1, but because it has not circulated for over forty years, a large 
population will likely not have immunity to the virus and therefore is 
at risk of serious disease. ``Preventative or therapeutic interventions 
may be available'' for infection with each of these viruses as there is 
evidence that the antiviral agents used against seasonal influenza are 
effective for prophylactic and therapeutic use for each virus and 
antibiotics are available for secondary bacterial pneumonias should 
they develop. Virus specific vaccines are not currently available to 
prevent infection. However, they are being developed and stockpiled for 
HPAI H5N1, and sources exist for the possible development of 1918 H1N1 
or human H2N2 (1957-1968) vaccines for laboratory workers who might be 
exposed or in the unlikely event of a release of the virus into the 
general population. In the case of human H2N2 (1957-1968), some pre-
existing immunity is likely in the population that was exposed to human 
H2N2 while these viruses circulated from 1957-1968 or from cross-
reactivity with N2 in the currently circulating H3N2 strain. For 1918 
H1N1, partial immunoprotection may exist from previous exposure or 
vaccination with recently circulating H1N1 strains, but definitive data 
are lacking. An important additional consideration for

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HPAI H5N1 RG classification was that, while the individual risk of 
serious or lethal disease is quite high, the community risk is 
currently considered low, as there is only limited evidence for human-
to-human transmission. Based on these considerations, influenza viruses 
1918 H1N1, human H2N2 (1957-1968), and highly pathogenic avian 
influenza H5N1 viruses within the Goose/Guangdong/96-like H5 lineage 
will be classified as Risk Group 3 agents in Appendix B-III-D. All 
viruses within HPAI H5N1 lineages that have been associated with human 
disease, whether it is mild or severe and fatal, will be classified as 
RG3 agents. Thus BL3 enhanced containment will apply to a virus 
evolving from the current lineages that causes milder disease in 
humans, which could indicate adaptation to the human host.
    Because the generation of influenza viruses by reassorting RNA 
segments by recombinant techniques (i.e., reverse genetics) does not 
take place in a single host-vector system, OBA has received questions 
about which sections of the NIH Guidelines apply to such research with 
influenza viruses. Sections III-D-1 or III-D-2 (research that falls 
under Section III-D requires Institutional Biosafety Committee approval 
before initiation) refer to specific host-vector systems and, 
therefore, do not specifically address this research. To clarify this, 
an additional section has been added: Section III-D-7-Experiments 
Involving Influenza Viruses. This section will apply to recombinant 
research with influenza viruses (e.g., chimeric viruses with reassorted 
segments generated by reverse genetics, viruses in which specific 
mutations are introduced).
    Additional biosafety guidance for research with 1918 H1N1, HPAI 
H5N1 within the Goose/Guangdong/96-like H5 lineage and human H2N2 
(1957-1968) has been included in Appendix G-II-C-5. Biosafety Level 3 
Enhanced for Research Involving Risk Group 3 Influenza Viruses. In 
addition to the standard BL3 containment and practices, the RAC 
recommended specific enhancements for research with these viruses 
including personal protective equipment (e.g., powered air-purifying 
respirators, protective suits), practices and procedures (e.g., 
clothing changes, showers when appropriate). In addition, the RAC made 
specific recommendations on training for these enhanced practices. 
Guidance is also provided for avoidance of inadvertent cross-
contamination during research. To address the potential public health 
risks of a laboratory exposure, this section also includes 
recommendations for development of a detailed occupational health plan 
for research with each virus, including how to respond to known 
laboratory exposures or development of an influenza-like illness in 
laboratory workers. The community risk from an inadvertent laboratory 
release of a virus with human H2N2 (1957-1968) or 1918 H1N1 is expected 
to be higher than for HPAI H5N1. Consequently, the occupational health 
recommendations for the response to a known laboratory exposure differ 
depending on whether the exposure was to HPAI H5N1, a virus that 
currently does not efficiently transmit human-to-human, or to either 
human H2N2 (1957-1968) or 1918 H1N1, both of which have previously 
caused pandemics, therefore demonstrating efficient human-to-human 
transmission. These recommendations regarding occupational health are 
also included in Appendix G-II-C-5.
    During development of the occupational health recommendations, the 
RAC discussed the use of pre-exposure prophylaxis with antiviral agents 
(e.g., oseltamivir) for research with 1918 H1N1. Initially, the RAC had 
proposed recommending a practice that is in place at the CDC (the first 
lab to work with 1918 H1N1), namely that researchers working with 1918 
H1N1 take pre-exposure prophylaxis with the antiviral oseltamivir for 
their protection, and to further limit the risk to the public. In 
addition, the Intragovernmental Select Agents and Toxins Technical 
Advisory Committee (ISATTAC), an advisory body to the USDA and CDC 
Select Agent Programs, recommended that the CDC Select Agent Program 
require pre-exposure prophylaxis for research with 1918 H1N1 at BL3 
enhanced but not at BL4 containment. This recommendation was adopted by 
the CDC Select Agent Program. However, as research on 1918 H1N1 
progressed and more was learned about the virus, other influenza 
researchers expressed concerns that the risks of long-term use of 
antiviral drugs would not be balanced by potential benefit to the 
investigator or the public.
    To address this issue, the RAC and ISATTAC convened a Safety 
Symposium on Public Health and Biosafety Practices for Research with 
1918 H1N1 Influenza Virus on December 2, 2008 (a Webcast of the meeting 
is available at http://oba.od.nih.gov/rdna_rac/rac_past_meetings_2000.html). The discussion at the safety symposium focused on the 
scientific data regarding the efficacy of prophylactic administration 
and use of oseltamivir for extended periods of time, as well as public 
health and ethical issues. The RAC concluded that while prophylaxis can 
reduce the likelihood of an individual laboratory worker developing 
symptoms or complications should they become infected, it will not 
eliminate the risk of transmission to the community. Further, although 
the medications are generally safe, there are risks, and data on long-
term use (beyond 6 weeks) are limited. Therefore, the RAC concluded 
that the data do not support mandating pre-exposure prophylaxis. 
Instead, the RAC recommended that the use of antiviral agents as pre-
exposure prophylaxis be discussed with laboratory workers and used on a 
case-by-case basis, after a risk assessment and appropriate counseling 
of the laboratory worker about the risks and potential benefits. 
Antiviral agents are recommended for post-exposure prophylaxis after 
medical evaluation.
    While most research with these viruses will be conducted at BL3 
with specific enhanced practices, the RAC also considered whether 
certain research could be safely conducted at lower containment. After 
consulting with experts in influenza virology, the RAC concluded that 
due to the multigenic determinants of virulence observed in influenza 
viruses, it is difficult to predict the phenotype of recombinant 
influenza viruses created by reassorting segments from multiple strains 
of influenza viruses. As the current data are insufficient to generate 
a predictive framework upon which to base the risk assessment, a case-
by-case evaluation is more appropriate.
    Section III-D-7 will specify when an IBC may determine containment 
for certain research (e.g., research with H2 HA in cold-adapted, live 
attenuated vaccine strains, or research with chimeric influenza viruses 
containing a minority of genes and/or segments from HPAI H5N1) and when 
requests to lower containment must be considered by the NIH (e.g., 
research with recombinant viruses containing any gene and/or segment 
from 1918 H1N1).
    Because the revisions outlined herein are considered Minor Actions 
as defined in Section IV-C-1-b-(2) of the NIH Guidelines, public and 
Federal Agency comment is not required and the changes are to be 
implemented immediately. However, in order to promote transparency and 
to gather ongoing input from scientific community, OBA is publishing 
these changes in the Federal Register with opportunity for public 
comment. The NIH Guidelines are intended to be an evolving document 
that may be modified to address new developments

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in research. As the influenza virology field advances, new data will 
emerge to inform risk assessments for research with these viruses. The 
public is encouraged to submit written comments, in particular on the 
following question regarding containment for 1918 H1N1:
     What data can be used to confidently predict an influenza 
virus containing one or more genes from the 1918 H1N1 virus can be 
worked with safely at biosafety containment level lower than Biosafety 
level 3 enhanced? Are there animal models of infection that are 
consistent and predictive of attenuation or loss of virulence in 
humans? What data should be used to assess attenuation in animal 
model(s)? What criteria should be used to evaluate a request for 
reduction of containment?
    When data are available to answer these questions, or new data 
emerges regarding other aspects of these changes, the framework will be 
reevaluated.

Amendments to the NIH Guidelines

    In order to ensure that biosafety considerations for research with 
human H2N2 (1957-1968), 1918 H1N1 and HPAI H5N1 are addressed 
appropriately, the NIH/OBA has made the following changes to the NIH 
Guidelines:

Section III-D-7. Experiments Involving Influenza Viruses

    This section will apply to recombinant experiments with influenza 
viruses that contain genes and/or segments from human H2N2 (1957-1968), 
HPAI H5N1, and 1918 H1N1 (e.g., chimeric viruses with reassorted 
segments generated by reverse genetics, viruses in which specific 
mutations are introduced). Because the generation of viruses by 
reassortment of RNA segments does not involve a single host-vector 
system, such experiments do not fit neatly into Sections III-D-1 or 
III-D-2. The new Section III-D-7 states: ``Experiments with influenza 
viruses generated by recombinant methods (e.g., generation by reverse 
genetics of chimeric viruses with reassorted segments, introduction of 
specific mutations) shall be conducted at the biosafety level 
containment corresponding to the risk group of the virus that was the 
source of the majority of segments in the recombinant virus (e.g., 
experiments with viruses containing a majority of segments from a RG3 
virus shall be conducted at BL3). Experiments with influenza viruses 
containing genes or segments from 1918-1919 H1N1 (1918 H1N1), human 
H2N2 (1957-1968) and highly pathogenic avian influenza H5N1 strains 
within the Goose/Guangdong/96-like H5 lineage (HPAI H5N1) shall be 
conducted at BL3 enhanced containment (see Appendix G-II-C-5, Biosafety 
Level 3 Enhanced for Research Involving Risk Group 3 Influenza Viruses) 
unless indicated below.''
    Section III-D-7-a. Human H2N2 (1957-1968). Experiments with 
influenza viruses containing the H2 hemagglutinin (HA) segment shall be 
conducted at BL3 enhanced (see Appendix G-II-C-5, Biosafety Level 3 
Enhanced for Research Involving Risk Group 3 Influenza Viruses). 
Experiments with the H2 HA gene in cold-adapted, live attenuated 
vaccine strains (e.g., A/Ann Arbor/6/60 H2N2) may be conducted at BL2 
containment provided segments with mutations conferring temperature 
sensitivity and attenuation are not altered in the recombinant virus. 
Experiments with Risk Group 2 influenza viruses containing genes from 
human H2N2 (1957-1968) other than the HA gene can be worked on at BL2.
    Section III-D-7-b. Highly Pathogenic Avian Influenza H5N1 strains 
within the Goose/Guangdong/96-like H5 lineage (HPAI H5N1). Experiments 
involving influenza viruses containing a majority of genes and/or 
segments from a HPAI H5N1 influenza virus shall be conducted at BL3 
enhanced containment, (see Appendix G-II-C-5, Biosafety Level 3 
Enhanced for Research Involving Risk Group 3 Influenza Viruses). 
Experiments involving influenza viruses containing a minority of genes 
and/or segments from a HPAI H5N1 influenza virus shall be conducted at 
BL3 enhanced unless a risk assessment performed by the IBC determines 
that they can be conducted safely at biosafety level 2 and after they 
have been excluded pursuant to 9 CFR 121.3(e). OBA is available to IBCs 
to provide consultation with the RAC and influenza virus experts when 
risk assessments are being made to determine the appropriate 
biocontainment for experiments with influenza viruses containing a 
minority of gene/segments from HPAI H5N1. Such experiments may be 
performed at BL3 enhanced containment or containment may be lowered to 
biosafety level 2, the level of containment for most research with 
other influenza viruses. (USDA/APHIS regulations and decisions on 
lowering containment also apply.) In deciding to lower containment, the 
IBC should consider whether, in at least two animal models (e.g., 
ferret, mouse, Syrian golden hamster, cotton rat, non-human primates), 
there is evidence that the resulting influenza virus shows reduced 
replication and virulence compared to the parental RG3 virus at 
relevant doses. This should be determined by measuring biological 
indices appropriate for the specific animal model (e.g., severe weight 
loss, elevated temperature, mortality or neurological symptoms).
    Section III-D-7-c. 1918 H1N1. Experiments involving influenza 
viruses containing any gene or segment from 1918 H1N1 shall be 
conducted at BL3 enhanced containment (see Appendix G-II-C-5, Biosafety 
Level 3 Enhanced for Research Involving Risk Group 3 Influenza 
Viruses).
    Section III-D-7-d. Antiviral Susceptibility and Containment. The 
availability of antiviral drugs as preventive and therapeutic measures 
is an important safeguard for experiments with 1918 H1N1, HPAI H5N1, 
and human H2N2 (1957-1968). If an influenza virus containing genes from 
one of these viruses is resistant to both classes of current antiviral 
agents, adamantanes and neuraminidase inhibitors, higher containment 
may be required based on the risk assessment considering 
transmissibility to humans, virulence, pandemic potential, alternative 
antiviral agents if available, etc. Experiments with 1918 H1N1, human 
H2N2 (1957-1968) or HPAI H5N1 that are designed to create resistance to 
neuraminidase inhibitors or other effective antiviral agents (including 
investigational antiviral agents being developed for influenza) would 
be subject to Section III-A-1 (Major Actions) and require RAC review 
and NIH Director approval. As per Section I-A-1 of the NIH Guidelines, 
if the agent is a Select Agent, the NIH will defer to the appropriate 
Federal agency (HHS or USDA Select Agent Divisions) on such 
experiments.

Appendix B. Classification of Human Etiologic Agents on the Basis of 
Hazard

    Currently all influenza viruses types A, B, and C are classified as 
Risk Group 2 agents. Appendix B-II-D currently states:

Appendix B-II-D. Risk Group 2 (RG2)--Viruses

Orthomyxoviruses

--Influenza viruses types A, B, and C.
--Other, tick-borne orthomyxoviruses as listed in the reference source 
(see Section V-C, Footnotes and Reference of Sections I through IV).

    The revised Appendix B-II-D states:

[[Page 48279]]

Orthomyxoviruses

--Influenza viruses types A, B, and C (except those listed in Appendix 
B-III-D (RG3)).
--Tick-borne orthomyxoviruses.

    The phrase ``as listed in the reference source (see Section V-C, 
Footnotes and References of Sections I through IV)'' will be deleted 
from the revised Appendix B-II-D due to the fact that tick-borne 
orthomyxoviruses are not listed in the current version of the reference 
source.
    The following is added to Appendix B-III-D. Risk Group 3 (RG3)--
Viruses and Prions

Orthomyxoviruses

--Influenza viruses 1918-1919 H1N1 (1918 H1N1), human H2N2 (1957-1968), 
and highly pathogenic avian influenza H5N1 strains within the Goose/
Guangdong/96-like H5 lineage (HPAI H5N1).

Appendix G-II-C-5. Biosafety Level 3 Enhanced for Research Involving 
Risk Group 3 Influenza Viruses

    Appendix G-II-C-5 provides additional and specific biosafety 
guidance for research with 1918 H1N1, human H2N2 (1957-1968), and HPAI 
H5N1 viruses and is intended to supplement the guidance provided in 
Appendix G. Physical Containment and Appendix Q. Physical and 
Biological Containment for Recombinant DNA Research Involving Animals, 
which applies to large research animals. Any enhancements to standard 
BL3 facilities, practices, and procedures that are described in 
Appendix G-II-C-5-a shall be considered specific for research with the 
Risk Group 3 influenza viruses. Risk assessments for research with 
other agents may also determine that enhancements to standard 
containment are necessary, but such enhancements must be determined for 
the specific agents and experiments being proposed.
    Influenza viruses that contain the hemagglutinin gene from a HPAI 
avian influenza are Select Agents and research with such viruses is 
regulated by the USDA. The fully reconstructed 1918 H1N1 virus is a 
Select Agent regulated by the HHS/CDC and certain experiments with 
genes and/or segments from 1918 may be regulated by HHS/CDC. Therefore, 
additional containment practices may apply and OBA will defer to the 
regulatory decisions of these agencies. Research with reassortant 
influenza viruses containing segments or genes from HPAI H5N1 will also 
require a permit from USDA/APHIS specifying containment and may require 
additional practices beyond those described in the NIH Guidelines.

Appendix G-II-C-5-a. Containment, Practices, and Training for Research 
with Risk Group 3 Influenza Viruses (BL3 Enhanced)

    Appendix G-II-C-5-a-(1). In addition to standard BL3 practices, the 
following additional personal protective equipment and practices shall 
be used:
    (1) Powered Air-purifying Respirators (PAPR) are worn.
    (2) Street clothes are changed to protective suit (e.g., wrap-back 
disposable gown, olefin protective suit).
    (3) Double gloves are worn.
    (4) Appropriate shoe coverings are worn (e.g., double disposable 
shoe coverings, single disposable shoe coverings if worn with footwear 
dedicated to BL3 enhanced laboratory use, or impervious boots or shoes 
of rubber or other suitable material that can be decontaminated).
    (5) Showers prior to exiting the laboratory should be considered 
depending on risk assessment of research activities.
    Appendix G-II-C-5-a-(2). As proper training of laboratory workers 
is an essential component of biosafety, retraining and periodic 
reassessments (at least annually) in BL3 enhanced practices, especially 
the proper use of respiratory equipment, such as PAPRs, and clothing 
changes is required.
    Appendix G-II-C-5-a-(3). Reporting of all spills and accidents, 
even if relatively minor, is required as described in Appendix G-II-C-
2-q.
    Appendix G-II-C-5-a-(4). To avoid inadvertent cross contamination 
of 1918 H1N1, HPAI H5N1 or human H2N2 (1957-1968):
    (1) Containment facilities and practices appropriate for highest 
risk group virus shall be used at all times with lower risk group 
viruses, when studied in the same laboratory room.
    (2) Tissue cultures with these viruses shall be conducted at 
separate times (temporal spacing) in the same room.
    (3) Separate reagents shall be used to minimize risk of cross 
contamination.
    (4) A laboratory worker shall not perform concurrent influenza 
virus experiments that carry the risk of unintended reassortment among 
1918 H1N1, human H2N2 (1957-1968), HPAI H5N1 and other human influenza 
viruses.
    (5) Two or more laboratory workers shall not perform within the 
same work area simultaneous influenza virus experiments that carry the 
risk of unintended segment reassortment between 1918 H1N1, or HPAI 
H5N1, or human H2N2 (1957-1968) and other human influenza viruses.
    (6) Between experiments good biosafety decontamination practices 
(e.g., surface and biosafety cabinet surface decontamination according 
to standard BL3 procedures) shall be used and there shall be a thirty 
minute wait period after decontamination before equipment is used for 
experiments with any other influenza A viruses.
    (7) Between experiments, in addition to decontamination of the work 
area, clothing changes and PAPR disinfection shall be performed prior 
to handling a different influenza virus in the same work area. (Shower-
out capability may be required by USDA/APHIS for certain experiments 
with HPAI H5N1.)
    Appendix G-II-C-5-a-(5). Continued susceptibility of the 
reassortant influenza viruses containing genes and/or segments from 
1918 H1N1, HPAI H5N1, and human H2N2 (1957-1968) to antiviral agents 
shall be established by sequence analysis or suitable biological 
assays. After manipulation of genes that influence sensitivity to 
antiviral agents, susceptibility to these agents shall be reconfirmed.

Appendix G-II-C-5-b. Containment for Animal Research

    Guidance provided in Appendix G-II-C and Appendix Q-II-C is 
applicable with the following emphasis on standard BL3 or BL3-N 
containment or additional enhancements.
    Appendix G-II-C-5-b-(1). Research with small animals shall be 
conducted in a class II biosafety cabinet. Small animals such as 
rodents (e.g. mice, hamsters, rats, guinea pigs) can be housed within a 
negative pressure BL3 animal suite using high-density individually 
vented caging (IVC) systems that independently supply HEPA-filtered and 
directional air circulation. Other animals (e.g. rabbits, ferrets) that 
are of a size or have growth or caging requirements that preclude the 
use of high-density IVC systems are to be housed in negative pressure 
bioisolators.
    Appendix G-II-C-5-b-(2). Large animals such as non-human primates 
shall be housed in primary barrier environments according to BL3-N 
containment requirements (see Section Q-II-c).
    Appendix G-II-C-5-b-(3). Specialized training and proven competency 
in all assigned practices and procedures shall be required for 
laboratory staff, including staff involved in animal care.
    Appendix G-II-C-5-b-(4). For HPAI H5N1 research, the NIH Guidelines 
defer to USDA/APHIS recommendations

[[Page 48280]]

for biocontainment practices for loose housed animals.

Appendix G-II-C-5-c. Occupational Health

    A detailed occupational health plan shall be developed in advance 
of working with these agents in consultation, as needed, with 
individuals with the appropriate clinical expertise. In addition, the 
appropriate public health authority shall be consulted (e.g. local 
public health officials) on the plan and a mock drill of this plan 
shall be undertaken periodically. The plan should include an incident 
reporting system and laboratory workers shall report all incidents.
    Appendix G-II-C-5-c-(1). Laboratory workers shall be provided with 
medical cards which include, at a minimum, the following information: 
characterization of the influenza virus to which they have been 
potentially exposed, and 24-hour contact numbers for the principal 
investigator and institution's occupational health care provider(s).
    Appendix G-II-C-5-c-(2). A detailed occupational health plan shall 
include:
    (1) Unless there is a medical contraindication to vaccination (e.g. 
severe egg allergy) annual seasonal influenza vaccination as 
prerequisite for research to reduce risk of influenza like illness 
requiring isolation and tests to rule out infection with experimental 
virus and possible co-infection with circulating influenza strains.
    (2) Virus specific vaccination, if available, should be offered;
    (3) Reporting of all respiratory symptoms and/or fever (i.e. 
influenza like illnesses); and
    (4) 24-hour access to a medical facility that is prepared to 
implement appropriate respiratory isolation to prevent transmission and 
is able to provide appropriate antiviral agents. Real-time reverse 
transcription-polymerase chain reaction (RT-PCR) procedures should be 
used to discriminate these viruses from currently circulating human 
influenza viruses. For exposures to viruses containing genes from 1918 
H1N1 or the HA gene from human H2N2 (1957-1968), specimens shall be 
sent to the CDC for testing (RT-PCR and confirmatory sequencing).
    Appendix G-II-C-5-c-(3). In preparing to perform research with 1918 
H1N1, human H2N2 (1957-1968), or HPAI H5N1, principal investigators 
should develop a clear plan specifying who will be contacted in the 
event of a potential exposure (during and after work hours) to conduct 
a risk assessment and make decisions as to the required response, 
including the need for and extent of isolation of the exposed worker. 
After any kind of potential exposure, a rapid risk assessment shall be 
performed by the principal investigator, health and biosafety officials 
and subsequent actions should depend on the appraised level of risk of 
respiratory infection for the individual and potential for transmission 
to others. A laboratory worker performing research with either an 
influenza virus containing the HA gene from human H2N2 or an influenza 
virus containing genes and/or segments from 1918 H1N1, shall be 
informed in advance that, in the case of a known laboratory exposure 
with a high risk for infection, e.g., involving the upper or lower 
respiratory tract or mucous membranes, the laboratory worker will need 
to be isolated in a predetermined facility, rather than home isolation, 
until infection can be ruled out by testing (e.g., negative RT-PCR for 
1918 H1N1 or human H2N2 (1957-1968)) of appropriately timed specimens. 
Laboratory workers shall be informed in advance that in the case of a 
known laboratory exposure to highly pathogenic avian influenza H5N1 
strains within the Goose/Guangdong/96-like H5 lineage with high risk 
for infection, they should be prepared to self isolate (for example at 
home) until infection can be ruled out by testing (e.g., negative RT-
PCR for HPAI H5N1) of appropriately timed specimens. The action taken 
for other types of exposures should be based on the risk assessment. In 
addition, based on the risk assessment: (1) Treatment with appropriate 
antiviral agents shall be initiated, and (2) the appropriate public 
health authorities shall be notified.
    Appendix G-II-C-5-c-(4). Influenza-like illness. If a laboratory 
worker, who had recent exposure (within ten days) to influenza viruses 
containing the human H2N2 HA gene or any gene from the 1918 H1N1 or 
HPAI H5N1 viruses, or to animals exposed to such viruses, demonstrates 
symptoms and/or signs of influenza infection (e.g., fever/chills, 
cough, myalgias, headache), then the lab worker shall report by phone 
to the supervisor/principal investigator and other individuals 
identified in the occupational health plan. The laboratory worker shall 
be transported to a healthcare facility that can provide adequate 
respiratory isolation, appropriate medical therapy, and testing to 
determine whether the infection is due to a recombinant influenza 
virus. The appropriate public health authorities shall be informed 
whenever a suspected case is isolated.
    Appendix G-II-C-5-c-(5). For 1918 H1N1 research, the use of 
antiviral agents (e.g., oseltamivir) for pre-exposure prophylaxis shall 
be discussed with laboratory workers in advance including a discussion 
of the data on the safety of long term exposure to these agents and 
their ability to reduce the risk of clinical disease and the limits of 
the data regarding protection of close contacts and the community.
    Appendix G-II-C-5-c-(6). Antiviral agents for post-exposure 
prophylaxis shall be provided only after medical evaluation. Home 
supplies shall not be provided in advance for research with 1918 H1N1 
or influenza viruses containing the HA gene from human H2N2.

    Dated: September 15, 2009.
Jacqueline Corrigan-Curay,
Acting Director, Office of Biotechnology Activities, National 
Institutes of Health.
[FR Doc. E9-22693 Filed 9-21-09; 8:45 am]
BILLING CODE 4140-01-P