[Federal Register Volume 78, Number 35 (Thursday, February 21, 2013)]
[Notices]
[Pages 12074-12082]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-03974]


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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 with influenza viruses that have the potential to 
cause a pandemic, such as highly pathogenic avian influenza (HPAI) H5N1 
viruses. In 2012, two published studies funded by the National 
Institutes of Health (NIH) examined genetic changes that would allow 
HPAI H5N1 viruses to transmit by respiratory droplets among ferrets, an 
animal model that is often used to predict transmission and 
pathogenicity of influenza viruses in humans. This research raised 
concerns regarding the potential for HPAI H5N1 viruses to evolve and 
lead to a global pandemic. If transmission of a genetically engineered 
HPAI H5N1 virus among ferrets by respiratory droplets indicates that 
HPAI H5N1 viruses could evolve to transmit efficiently among humans by 
respiratory droplets, the public health risk of such a virus would be 
greater than that of the HPAI H5N1 virus currently circulating in 
poultry and wild birds, which does not easily transmit among humans. 
The NIH Recombinant DNA Advisory Committee (RAC) was asked to review 
the biosafety requirements for recombinant research with HPAI H5N1 
virus contained in the October 2011 NIH Guidelines and determine 
whether these conditions and practices are adequate to address research 
with HPAI H5N1 viruses that transmit among mammals by respiratory 
droplets, as demonstrated in an appropriate animal model or clinically 
in humans (referred throughout this document as mammalian-transmissible 
HPAI H5N1). On January 24, 2013, the RAC held a public meeting, 
together with influenza experts, as well as experts from the Centers 
for Disease Control and Prevention (CDC), the Biomedical Advanced 
Research and Development Authority (BARDA), HHS, the Food and Drug 
Administration (FDA), the World Health Organization (WHO), and the U.S. 
Department of Agriculture (USDA). The RAC recommended additional 
enhancements for research on mammalian-transmissible HPAI H5N1 virus to 
supplement the biosafety requirements for HPAI H5N1 that are already 
delineated in the NIH Guidelines. These enhancements include changes to 
the facility and biosafety equipment and practices, including 
occupational health practices. Based on the recommendations of the RAC, 
the NIH Office of Biotechnology Activities (OBA) concluded that more 
specific guidance regarding recombinant research with mammalian-
transmissible HPAI H5N1 virus is warranted.
    The resulting amendments to the NIH Guidelines 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 a public RAC 
meeting. Publication in the Federal Register will inform the scientific 
and biosafety communities, as well as solicit continued scientific 
input should revisions be needed in the future.

DATES: The public is encouraged to submit written comments on this 
action. Comments may be submitted to the OBA in paper or electronic 
form at the OBA mailing, fax, and email addresses shown below under the 
heading For Further Information. All comments should be submitted by 
March 25, 2013. All written comments received in response to this 
notice will be available for public inspection in the NIH OBA, 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 the 
OBA's Web site.

FOR FURTHER INFORMATION CONTACT: If you have questions, or require 
additional information about these changes, please contact the OBA by 
email at [email protected], or telephone at 301-496-9838. Comments may be 
submitted to the same email 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 contacting NIH 
OBA by email at [email protected].

SUPPLEMENTARY INFORMATION

Background

    The NIH is a major funder of research on influenza viruses, much of 
which involves recombinant DNA technology. One important area of 
research is focused on currently circulating HPAI H5N1 influenza 
viruses. These avian influenza viruses primarily infect and kill 
poultry and other susceptible species. Currently, almost all HPAI H5N1 
infections in humans have been linked to a person having close contact 
with infected poultry; the virus does not seem to transmit readily 
among humans. In the approximately 600 human cases of infection with 
HPAI H5N1 virus reported to the WHO to date, apparent human-to-human 
transmission is limited to small, familial clusters (see e.g., Kandun, 
I.N. et al. Three Indonesian Clusters of H5N1 Virus Infection in 2005, 
N Engl. J. M. 355: 2186-94 (2006)), without sustained chains of 
transmission in the community. However, the mortality rate for the 
human infections reported to WHO is almost 60% [http://www.who.int/influenza/human_animal_interface/EN_GIP_20130201CumulativeNumberH5N1cases.pdf]. The high mortality rate for 
these clinical infections is of great concern, especially if such a 
virus developed the ability to transmit efficiently among humans.
    The public health benefits of research on potentially pandemic 
influenza viruses include identification of genetic changes that 
contribute to host adaptation, transmissibility, and virulence. Such 
information can be used to enhance surveillance as well as contribute 
to the 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 personnel and the public.
    In 2009, the NIH Guidelines were amended to address research with 
certain influenza viruses with increased pandemic potential, including 
the reconstructed 1918 H1N1 virus and

[[Page 12075]]

HPAI H5N1 viruses of the Goose/Guangdong/96-like H5 lineage, the 
lineage responsible for human cases to date. Specifically, HPAI H5N1 
viruses were classified as Risk Group 3 agents in Appendix B-III-D, 
i.e., agents that are able to cause serious or lethal disease, but for 
which preventative and therapeutic agents may be available (high 
individual risk, low community risk). In making that decision, the OBA 
noted that for HPAI H5N1 virus, the individual risk of serious or 
lethal disease is quite high; however, the community risk is currently 
considered low, as there is only limited evidence of human-to-human 
transmission.
    Since 2009, the NIH Guidelines have set containment for HPAI H5N1 
virus research at Biosafety Level (BL) 3 with additional enhancements. 
These enhancements include additional personal protective equipment 
(e.g., powered air-purifying respirators, protective suits) and 
practices and procedures (e.g., clothing changes, showers when 
appropriate) that are not required at BL3 containment. In addition, the 
NIH Guidelines require implementation of specific practices to avoid 
inadvertent cross-contamination with other influenza viruses being 
studied in the same laboratory. The NIH Guidelines require periodic 
training for these enhanced practices. To address the potential public 
health risks of a laboratory exposure, the NIH Guidelines also set 
forth detailed occupational health requirements for research with each 
virus, including how to respond to known laboratory exposures or to the 
development of an influenza-like illness in laboratory workers.
    Of note, there are other regulatory requirements governing research 
with HPAI H5N1 virus. The HPAI H5N1 influenza viruses are USDA Select 
Agents (9 C.F.R. 121.3(b)). The USDA Animal and Plant Health Inspection 
Service (APHIS) regulates as a Select Agent avian influenza viruses 
that demonstrate a high pathogenicity in chickens and contain a 
specific polybasic 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 comparable to other highly pathogenic avian 
influenza viruses) (9 CFR 121.3(c)(3)). Avian influenza viruses that 
demonstrate evidence of attenuation in poultry can be excluded from the 
Select Agent list pursuant to 9 C.F.R. 121.3(e). The biosafety 
containment level recommended for most research with HPAI H5N1 viruses 
that are Select Agents is a minimum of BL3 enhanced or Animal Biosafety 
Level 3 (ABSL3) enhanced. Influenza viruses containing genes from an 
HPAI virus, which are not classified as Select Agents by the USDA, are 
still regulated by that Agency through ``permitting'' regulations (9 
CFR part 122) that govern imports and interstate movements of the 
viruses. In addition, on October 17, 2012, the CDC issued a request for 
information and comment regarding whether HPAI H5N1 viruses containing 
an HA from the Goose/Guangdong/1/96 lineage should become an HHS Select 
Agent (77 FR 63783). Additional containment practices may apply under 
the Select Agent regulations and the OBA will defer to the requirements 
of the regulatory agencies on restricted experiments [9 CFR 121.13, 45 
CFR 73.13], for example, the introduction of antiviral resistance into 
HPAI H5N1 influenza viruses.
    In light of recent publications [Imai, M. et al., Nature 486:420-
428 (2012), Herfst, S. et al., Science 336:1534-1541 (2012)] reporting 
genetic changes that may enhance the ability of the HPAI H5N1 virus to 
transmit by respiratory droplets among mammals, the RAC was asked to 
revisit the biosafety recommendations in the October 2011 NIH 
Guidelines for research with HPAI H5N1 virus to determine whether these 
are adequate to address recombinant DNA research with mammalian-
transmissible HPAI H5N1 viruses. On January 24, 2013, the RAC met in a 
public meeting, together with influenza experts, as well as experts 
from the CDC, BARDA, FDA, WHO, and USDA. The RAC concluded that all 
HPAI H5N1 viruses, including mammalian-transmissible viruses, are RG3 
agents because vaccines and antivirals may be available for the 
treatment and/or prevention of disease. However, because a mammalian-
transmissible virus may present increased risk to the community, 
additional enhancements to the current biosafety containment and 
practices were recommended.
    The OBA accepts the recommendations of the RAC and the NIH 
Guidelines have been amended to include the following enhancements for 
research with mammalian-transmissible HPAI H5N1 virus:
     Enhancements of BL3 facilities to include (1) HEPA 
filtration of exhaust air and air handling systems that are designed to 
avoid airflow reversal during failure, with periodic verification and 
at least annual verification of the HEPA filters and (2) backup power 
for critical controls and instrumentation necessary to maintain 
containment;
     Specific guidance on liquid and animal waste disposal;
     A requirement that antiviral susceptibility be maintained 
in laboratory strains of mammalian-transmissible HPAI H5N1 influenza 
unless specifically authorized by the NIH or another regulatory agency, 
such as the CDC or USDA in their role administering the Select Agent 
regulations;
     Additional practices to avoid self-contamination or 
inadvertent release of the viruses by a laboratory worker, including 
the requirement for two individuals to be in the lab when certain 
research is being conducted;
     Enhancements to current occupational health requirements: 
(1) That HPAI H5N1 licensed vaccines should be taken, if available, (2) 
mandatory collection and storage of serum samples, (3) isolation of 
workers out of the community, in a medical or other appropriate 
facility if they have had a potential ``high-risk'' exposure to the 
virus, or for those who develop influenza-like illness after being in a 
laboratory in which research with the virus is being conducted, (4) 
active surveillance programs for influenza-like illness, (5) a 
prohibition for home supplies of antiviral agents to avoid self-
medication without reporting of illness; and
     A requirement that each laboratory worker sign a document 
acknowledging that (s)he understands and agrees to adhere to biosafety, 
biosecurity, and occupational health requirements and also agrees to 
report any potential exposures or accidents, including those made by 
other individuals in the laboratory.
    In addition to these enhancements, all biosafety containment and 
practices for research with HPAI H5N1 viruses are applicable to 
research with mammalian-transmissible strains, and additional 
containment and practices for mammalian-transmissible HPAI H5N1 are 
specified in the NIH Guidelines. Institutions may, of course, decide to 
adopt the practices required for research with mammalian-transmissible 
HPAI H5N1 viruses for all research with HPAI H5N1 viruses.
    The RAC made several general recommendations to help guide 
biosafety assessments for research with HPAI H5N1 influenza viruses, as 
well as research with emerging influenza viruses that have the 
potential to lead to a human pandemic because the general population is 
not expected to have immunity to such viruses (e.g., an H9 avian 
influenza virus). The OBA concurs with these general risk assessment 
principles and will incorporate these recommendations into a general 
guidance document for research with influenza, taking into

[[Page 12076]]

account any comments received on this notice:
     While acknowledging the limits of any animal model to 
predict disease in humans accurately, the ferret remains the best model 
for assessing the pathogenicity and transmissibility of an influenza 
virus in mammals. Therefore, containment decisions for influenza 
viruses should be made based on the assumption that transmissibility 
and pathogenicity in this model are predictive of the disease in 
humans.
     It is difficult to predict which experiments may generate 
a mammalian-transmissible virus; however, given the pathogenicity of 
HPAI H5N1 viruses, if the experimental procedures are such that it 
could reasonably be anticipated to generate aerosols and create a 
mammalian transmissible HPAI H5N1 virus, such as serial passaging of an 
HPAI H5N1 virus in animals, these studies should be conducted at BL3 
with all of the enhancements required for research with HPAI H5N1 
mammalian-transmissible virus.
     Likewise, while the risk of generating a mammalian-
transmissible, pathogenic influenza virus cannot always be predicted at 
the beginning of the experiment, enhanced BL3 containment and practices 
should be considered for research with any influenza virus if: (1) The 
virus has a high potential to cause disease in humans, as demonstrated 
in the ferret model, (2) there is little or no community immunity 
(i.e., a virus with a high pandemic risk), and (3) the research is 
designed to increase the ability of that influenza virus to be 
transmissible among mammals. A risk assessment will determine whether 
the most appropriate BL3 enhanced containment practices are those for 
RG3 influenza viruses, or include, in addition, the specific 
enhancements for mammalian-transmissible HPAI H5N1 virus.
     One should also consider BL3 enhanced containment and 
practices for experiments involving any influenza virus for which there 
is little or no community immunity (high pandemic risk), if the 
experiment is designed to increase transmissibility in mammals by 
respiratory droplets, as the ability to transmit efficiently among 
humans is a critical attribute of pandemic influenza viruses.

Amendments to the NIH Guidelines

    In order to ensure that biosafety for research involving mammalian-
transmissible HPAI H5N1 virus is addressed appropriately, the OBA has 
made changes to the following sections of the NIH Guidelines:
    In order to make it clear that all facility, procedures and 
practices for research with HPAI H5N1 viruses also apply to research 
with mammalian-transmissible HPAI H5N1 viruses, Section III-D-7 is 
amended to include a specific reference to mammalian-transmissible HPAI 
H5N1 virus.
    The Section III-D-7 previously stated:

Section III-D-7. Experiments Involving Influenza Viruses

    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 is amended to state:

Section III-D-7. Experiments Involving Influenza Viruses

    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 virus (1918 H1N1), human H2N2 virus (1957-1968) and 
highly pathogenic avian influenza H5N1 virus strains within the Goose/
Guangdong/96-like H5 lineage (HPAI H5N1), including, but not limited to 
strains of HPAI H5N1 virus that are transmissible among mammals by 
respiratory droplets, as demonstrated in an appropriate animal model or 
clinically in humans, (hereinafter referred to as mammalian-
transmissible HPAI H5N1 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) unless indicated 
below.

Laboratory Practices and Facilities

    Appendix G-II-C outlines the requirements for BL3 facilities and 
containment practices. All of the requirements in G-II-C apply to 
research with HPAI H5N1 virus. For research with mammalian-
transmissible HPAI H5N1 viruses, the OBA is adding additional facility 
requirements, specific guidelines for waste disposal, and a requirement 
that baseline serum samples shall be collected.
    Appendix G-II-C-2-n previously stated:
    Appendix G-II-C-2-n. All wastes from laboratories and animal rooms 
are appropriately decontaminated before disposal.
    As amended:
    Appendix G-II-C-2-n. All wastes from laboratories and animal rooms 
are appropriately decontaminated before disposal. For research 
involving mammalian-transmissible HPAI H5N1 virus, liquid effluents 
should be chemically disinfected or heat-treated, or collected and 
processed in a central effluent decontamination system. Decontamination 
of shower and toilet effluents is not required, provided appropriate 
practices and procedures are in place for primary containment of 
mammalian-transmissible HPAI H5N1 virus. Animal tissues, carcasses, and 
bedding originating from the animal room must be decontaminated by an 
effective and validated method (e.g., use of an autoclave) preferably 
before leaving the containment barrier. If waste must be transported, 
special practices should be developed for transport of infectious 
materials to designated alternate location(s) within the facility.
    Appendix G-II-C-2-r states that baseline serum samples should be 
collected for all laboratory and other at-risk personnel and stored. 
Collection of baseline serum samples is mandatory for personnel 
performing research with mammalian-transmissible HPAI H5N1 virus. In 
addition, the OBA has clarified the time-frame for storage of samples.
    Appendix G-II-C-2-r previously stated:
    Baseline serum samples for all laboratory and other at-risk 
personnel should be collected and stored. Additional serum specimens 
may be collected periodically depending on the agents handled or the 
function of the laboratory.

[[Page 12077]]

    The revised section is amended to read as follows:
    Appendix G-II-C-2-r. Baseline serum samples for all laboratory and 
other at-risk personnel should be collected and stored in accordance 
with institutional policy and at least for the time period in which the 
personnel continues to work with the agent at biosafety level 3 
containment. Such samples must be collected and stored for laboratory 
and other at-risk personnel who will work with mammalian-transmissible 
HPAI H5N1 virus. Additional serum specimens may be collected 
periodically depending on the agents handled or the function of the 
laboratory.

Facilities

    Additional facility enhancements are required for research with 
mammalian-transmissible HPAI H5N1 virus. These enhancements include 
HEPA filtration of exhaust air and specific requirements for the air 
handling systems. In addition, facilities working with mammalian-
transmissible HPAI H5N1 virus must have backup power for critical 
controls. These changes are outlined in a revised Appendix G-II-C-4 
Laboratory Facilities (BL3).
    Specifically, Appendix G-II-C-4-i previously stated:
    Appendix G-II-C-4-i. A ducted exhaust air ventilation system is 
provided. This system creates directional airflow that draws air into 
the laboratory through the entry area. The exhaust air is not 
recirculated to any other area of the building, is discharged to the 
outside, and is dispersed away from the occupied areas and air intakes. 
Personnel shall verify that the direction of the airflow (into the 
laboratory) is proper. The exhaust air from the laboratory room may be 
discharged to the outside without being filtered or otherwise treated.
    The amended section clarifies that air flow is from uncontaminated 
spaces for all labs and adds the following additional requirements for 
research with mammalian-transmissible HPAI H5N1:
    Appendix G-II-C-4-i. A ducted exhaust air ventilation system is 
provided. This system creates directional airflow that draws air into 
the laboratory from uncontaminated spaces surrounding the laboratory. 
The exhaust air is not recirculated to any other area of the building, 
is discharged to the outside, and is dispersed away from occupied areas 
and air intakes. Personnel shall verify that the direction of the 
airflow (into the laboratory) is proper. The exhaust air from the 
laboratory room may be discharged to the outside without being filtered 
or otherwise treated unless research is being conducted with mammalian-
transmissible HPAI H5N1 virus. For research with mammalian-
transmissible HPAI H5N1 virus, exhaust air must be HEPA filtered and 
there must be sealed ductwork from the containment barrier to the 
filter. In addition, the air handling system shall be designed such 
that under failure conditions, the airflow will not be reversed and 
periodic verification, with annual verification of the HEPA filters, 
shall be performed. Finally, backup power shall be available for 
critical controls and instrumentation necessary to maintain 
containment.

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

    Appendix G-II-C-5 provides additional 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. All of the practices and 
occupational health measures described in Appendix G-II-C-5 apply to 
research with mammalian-transmissible HPAI H5N1 virus. Additional 
requirements for research with mammalian-transmissible HPAI H5N1 virus 
are specified. In addition to updating the following sections to 
include specific recommendations for research with mammalian-
transmissible HPAI H5N1 virus, this section will specifically reference 
the additional practices and facilities requirements for mammalian-
transmissible HPAI H5N1 virus discussed above.
    Previously Appendix G-II-C-5 was just a title.

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

    It is amended to read as follows:

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

    (See Appendices G-II-C-2-n, G-II-C-2-r, and G-II-C-4-i for 
additional guidance for facilities, waste handling, and serum 
collection for research involving mammalian-transmissible HPAI H5N1 
virus.)

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

    Personal Protective Equipment (PPE) and Practices. Research with 
HPAI H5N1 virus must be conducted using powered air purifying 
respirators (PAPRs), double gloves, wrap-around gowns, and shoe 
coverings. The RAC recommended that laboratory workers doing research 
with mammalian-transmissible strains of HPAI H5N1 virus also (1) Use 
protective sleeves over the gown when working in a biosafety cabinet, 
(2) spray or wipe down their personal protective equipment, in 
particular their PAPRs, with a disinfectant that has activity against 
influenza virus prior to leaving containment, and (3) always take a 
shower before leaving the facility. In addition, at least two 
individuals should be present in the lab at all times while certain 
research is conducted and removal of PPE, prior to the shower, should 
be observed. This system is aimed at promoting adherence to all 
containment practices, including correct removal of PPE to avoid self-
contamination. Finally, as part of proper training, the laboratory 
workers shall sign a document acknowledging their understanding of, and 
intent to adhere to biosafety, biosecurity, and occupational health 
requirements and that they agree to report any exposures or accidents, 
including those that do not involve the worker. The OBA agrees with 
these recommendations, and they are implemented through amendments to 
the following sections.
    Appendix G-II-C-5-a-(1) previously stated:
    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.
    The revised Appendix G-II-C-5-a-(1) now states:

[[Page 12078]]

    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 (disposable) are worn. For research with 
mammalian-transmissible HPAI H5N1 virus, protective sleeves shall be 
worn over the gown while working in a biosafety cabinet.
    (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, with the exception 
that showers prior to exiting the laboratory are required for all 
research with mammalian-transmissible HPAI H5N1 virus, including care 
of animals infected with mammalian-transmissible HPAI H5N1 virus.
    (6) For research with mammalian-transmissible HPAI H5N1 virus, 
prior to leaving containment, personal protective equipment shall be 
sprayed or wiped down with a disinfectant that has activity against 
influenza viruses.
    (7) In order to promote adherence to proper practices, including 
proper removal of personal protective equipment, and reporting of any 
loss of containment or exposures, at least two individuals should be in 
the laboratory at all times when research with mammalian-transmissible 
HPAI H5N1 virus involves experimental procedures with animals or 
sharps, or when procedures are being conducted whereby the generation 
of aerosols is reasonably anticipated. Removal of personal protective 
equipment should be observed.
    Appendix G-II-C-5-a-(2) previously stated:
    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.
    The revised Appendix G-II-C-5-a-(2) now states:
    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, are required. For research with mammalian-transmissible HPAI 
H5N1 virus, laboratory workers shall be required to sign a document 
acknowledging their understanding of and intent to adhere to biosafety, 
biosecurity, and occupational health requirements. This document shall 
include a statement that the laboratory worker agrees to report any 
exposures or accidents, including those by other individuals in the 
lab.
    Anti-viral susceptibility. Currently, there is one FDA-licensed 
vaccine against a single clade of HPAI H5N1 virus, although others with 
adjuvants to induce broader and more prolonged immune responses are in 
clinical trials. As vaccines are not 100 percent effective and the 
mortality rate for HPAI H5N1 virus infections in humans is currently 
close to 60 percent, the RAC concluded that the availability of 
effective antiviral agents is a critical pre-requisite for conducting 
this research at BL3 enhanced containment. Therefore, as stated in 
Section III-D-7-d, any experiment that attempts to create a mammalian-
transmissible virus that is also resistant to neuraminidase inhibitors, 
including oseltamivir, or other effective antivirals agents (including 
investigational antiviral agents), would need to be reviewed by the 
appropriate federal authorities, i.e., the NIH Director or Select Agent 
Program officials. It is also important to maintain antiviral 
sensitivity throughout experiments with mammalian-transmissible HPAI 
H5N1 virus. Therefore, the Appendix G-II-C-5-a-(5) has been amended to 
address this issue.
    Appendix G-II-C-5-a-(5) previously stated:
    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.
    The revised Appendix G-II-C-5-a-(5) now states:
    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. 
If susceptibility to neuraminidase inhibitors or other effective 
antiviral agents is lost as a result of genetic modification or serial 
passage of a mammalian-transmissible HPAI H5N1 virus, then any research 
with this antiviral agent-resistant virus shall be stopped and research 
shall only proceed after review by the NIH (as outlined in Section III-
A-1-a) or the appropriate federal regulatory agency.
    Occupational Health Measures. The NIH Guidelines contain detailed 
occupational health requirements for research with HPAI H5N1 virus. 
Each institution is required to develop an occupational health plan 
that includes a requirement for seasonal flu vaccine, a plan to report 
all incidents (i.e., spills, accidents and potential exposures), and 
procedures to isolate and treat those who develop influenza-like 
illness (e.g., fever or respiratory illness) or those who have an 
accident in the laboratory that places them at high risk of exposure to 
the virus. The RAC made additional recommendations for research with 
mammalian-transmissible HPAI H5N1 virus to minimize the potential 
public health risks that could result from a laboratory worker becoming 
infected with one of these viruses and entering the community. If a 
laboratory worker has a respiratory or mucous membrane exposure to a 
mammalian-transmissible HPAI H5N1 virus, that worker shall be isolated 
in a hospital room or other designated facility away from the public 
until infection can be ruled out, as is required in the NIH Guidelines 
for research with the 1918 H1N1 influenza virus. The RAC also 
recommended that if a licensed vaccine against HPAI H5N1 virus is 
available, and there are no medical contraindications, it should be 
taken by all laboratory workers performing research with mammalian-
transmissible HPAI H5N1, and a post-vaccination serum sample shall be 
collected for evaluation of immune responses and stored. Antiviral 
agents for treating potential exposures shall only be provided after 
medical evaluation; home supplies shall not be provided to avoid self-
treatment of influenza-like illness without seeking medical care. 
Finally, an active surveillance program to identify laboratory workers 
with influenza-like illness shall be undertaken. To implement these 
changes, the following sections are amended.
    Appendix G-II-C-5-c outlines the requirement for an influenza-
specific occupational health plan that needs to be developed prior to 
work with any

[[Page 12079]]

RG3 influenza virus, including HPAI H5N1 virus. In reviewing Appendix 
G-II-C-5-c, the RAC noted that clarification of the wording of Appendix 
G-II-C-5-c was needed to define what an incident includes and the time 
frames for reporting. This change will apply to all research with RG3 
influenza viruses, which includes HPAI H5N1 virus, as well as research 
with 1918 H1N1 and influenza viruses containing the HA from the H2N2 
virus that circulated from 1957-1968.
    Appendix G-II-C-5-c previously stated:
    Appendix G-II-C-5-c: 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.
    The revised Appendix G-II-C-5-c states:

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 shall include a description 
of the incident reporting system in place for incidents, which includes 
any loss of containment, spills, accidents, or potential exposures. The 
plan must specify that all incidents must be reported immediately to 
the appropriate institutional authorities, and no later than 24 hours 
to the appropriate public health authorities (e.g., the U.S. Department 
of Agriculture, the Centers for Disease Control and Prevention, NIH, 
local and state health authorities).
    Appendix G-II-C-5-c-(2) previously stated:
    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);
    (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).
    The revised Appendix G-II-C-5-(2) now states:
    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., a severe egg allergy), annual seasonal influenza vaccination as 
a prerequisite for research to reduce the risk of influenza-like 
illness that would require isolation and testing to rule out infection 
with experimental viruses and raise the risk for possible co-infection 
with circulating influenza strains.
    (2) Virus-specific vaccination, if available, should be offered and 
if a licensed HPAI H5N1 vaccine is available, and there are no medical 
contraindications, laboratory workers performing research with 
mammalian-transmissible HPAI H5N1 viruses should be vaccinated. A post-
vaccination serum sample shall be collected, assessed for immune 
response, and stored in accordance with institutional policy, at least 
for the time in which the laboratory worker continues to conduct HPAI 
H5N1 virus research.
    (3) Reporting of all respiratory symptoms and/or fever (i.e., 
influenza like illnesses). For research involving mammalian-
transmissible HPAI H5N1 virus, laboratory workers shall be actively 
monitored for influenza-like illness (i.e., fever and respiratory 
symptoms).
    (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) assays should be used 
for virus detection and 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).
    When the NIH Guidelines were revised in 2009, Appendix G-II-C-5-c-
(2) was added to specify the development of a detailed occupational 
health plan for research with each RG3 influenza virus. The community 
risk from an inadvertent laboratory release of an influenza virus 
containing the HA gene from human H2N2 (1957-1968) or gene from 1918 
H1N1, both of which have previously caused pandemics, was expected to 
be higher than for wild-type HPAI H5N1 virus, which does not 
efficiently transmit human-to-human. Consequently, the previous 
occupational health recommendations in the NIH Guidelines differed 
between HPAI H5N1 virus, and H2N2 (1957-1968) or 1918 H1N1 viruses. For 
1918 H1N1 and H2N2 (1957-1968) viruses, which were demonstrated to 
efficiently transmit from person-to-person, isolation outside of the 
community of a laboratory worker who was potentially infected with one 
of these viruses was determined to be an important public health 
measure to prevent a new pandemic with a laboratory-created virus. Home 
isolation was not considered a reliable public health measure as the 
laboratory worker could more easily leave their house or other people 
could enter the house. However, at the time the 2009 revisions were 
developed, HPAI H5N1 virus could not easily transmit among humans, and 
therefore, home isolation was permitted after exposure. Because the 
transmission of an influenza virus by respiratory droplets among 
ferrets indicates that this virus may also transmit among humans, the 
RAC recommended that isolation policies for exposures to HPAI H5N1 
viruses that are transmissible by respiratory droplets among ferrets be 
the same as for other RG3 influenza viruses that have the ability to 
transmit among humans. For the same reasons, home supplies of 
antivirals shall not be given to laboratory workers engaged in research 
with mammalian-transmissible HPAI H5N1 virus to prevent self-treatment 
of influenza-like illness or underreporting of potential exposures. In 
addition, since the phrase ``antiviral agents for post-exposure 
prophylaxis'' can be interpreted as recommending a specific approved 
dose, the term prophylaxis is removed because the appropriate dose is 
determined by the medical evaluation. The following

[[Page 12080]]

changes were made to Appendices G-II-C-5-c-(3), G-II-C-5-c-(4), and G-
II-C-5-c-(6).
    Appendix G-II-C-5-c-(3) stated:
    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.
    The revised Appendix G-II-C-5-c-(3) now states:
    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 or 
mammalian-transmissible HPAI H5N1 viruses, 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, human 
H2N2 (1957-1968), or HPAI H5N1) of appropriately timed specimens. 
Laboratory workers with a known laboratory exposure with high risk for 
infection during research with HPAI H5N1 virus strains that are not 
transmissible among mammals should be prepared to self-isolate (for 
example at home) until infection can be ruled out by testing (e.g., 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) is amended to clarify that this section 
applies to all individuals who enter a laboratory where research with 
RG3 influenza viruses is being conducted, including trainees and other 
employees, and not limited to those who have had a specific exposure 
due to loss of containment. Recognizing this clarification will likely 
lead to an increase in reporting of minor viral symptoms, we have also 
clarified that transportation to receive medical treatment and any 
decision on isolation is to be based on the risk assessment by the 
individuals identified in the occupational health plan.
    Appendix G-II-C-5-c-(4) previously stated:
    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-(4) is amended to state:
    Appendix G-II-C-5-c-(4). Influenza-like illness. If an individual 
has entered (within ten days) a laboratory conducting research with 
influenza viruses containing the human H2N2 HA gene or any gene from 
the 1918 H1N1 or HPAI H5N1 viruses, or housing animals exposed to such 
viruses, and the individual demonstrates symptoms and/or signs of 
influenza infection (e.g., fever/chills, cough, myalgia, headache), 
then he/she shall report by phone to the supervisor/principal 
investigator and other individuals identified in the occupational 
health plan. If needed, the person with influenza-like illness shall be 
transported to a healthcare facility, under the appropriate isolation 
conditions, 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-(6) previously stated:
    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.
    The revised G-II-C-5-c-(6) now states:
    Appendix G-II-C-5-c-(6). Antiviral agents for an exposure shall be 
provided only after medical evaluation. Home supplies shall not be 
provided in advance for research with 1918 H1N1, mammalian-
transmissible HPAI H5N1 or influenza viruses containing the HA gene 
from human H2N2.

[[Page 12081]]

Summary of Changes

    The following provides the revised language for amended sections 
discussed above:

Section III-D-7

    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 virus (1918 H1N1), human H2N2 virus (1957-1968) and 
highly pathogenic avian influenza H5N1 virus strains within the Goose/
Guangdong/96-like H5 lineage (HPAI H5N1), including, but not limited 
to, strains of HPAI H5N1 virus that are transmissible among mammals by 
respiratory droplets, as demonstrated in an appropriate animal model or 
clinically in humans (hereinafter referred to as mammalian-
transmissible HPAI H5N1 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) unless indicated 
below.

Appendix G-II-C-2-n

    All wastes from laboratories and animal rooms are appropriately 
decontaminated before disposal. For research involving mammalian-
transmissible HPAI H5N1 virus, liquid effluents should be chemically 
disinfected or heat-treated, or collected and processed in a central 
effluent decontamination system. Decontamination of shower and toilet 
effluents is not required, provided appropriate practices and 
procedures are in place for primary containment of mammalian-
transmissible HPAI H5N1 virus. Animal tissues, carcasses, and bedding 
originating from the animal room must be decontaminated by an effective 
and validated method (e.g., use of an autoclave) preferably before 
leaving the containment barrier. If waste must be transported, special 
practices should be developed for transport of infectious materials to 
designated alternate location(s) within the facility.

Appendix G-II-C-2-r

    Baseline serum samples for all laboratory and other at-risk 
personnel should be collected and stored in accordance with 
institutional policy and at least for the time period in which the 
personnel continues to work with the agent at biosafety level 3 
containment. Such samples must be collected and stored for laboratory 
and other at risk personnel who will work with mammalian-transmissible 
HPAI H5N1 virus. Additional serum specimens may be collected 
periodically depending on the agents handled or the function of the 
laboratory.

Appendix G-II-C-4-i

    A ducted exhaust air ventilation system is provided. This system 
creates directional airflow that draws air into the laboratory from 
uncontaminated spaces surrounding the laboratory. The exhaust air is 
not recirculated to any other area of the building, is discharged to 
the outside, and is dispersed away from occupied areas and air intakes. 
Personnel shall verify that the direction of the airflow (into the 
laboratory) is proper. The exhaust air from the laboratory room may be 
discharged to the outside without being filtered or otherwise treated 
unless research is being conducted with mammalian-transmissible HPAI 
H5N1 virus. For research with mammalian-transmissible HPAI H5N1 virus, 
exhaust air must be HEPA filtered and there must be sealed ductwork 
from the containment barrier to the filter. In addition, the air 
handling system shall be designed such that under failure conditions, 
the airflow will not be reversed and periodic verification, with annual 
verification of the HEPA filters, shall be performed. Finally, backup 
power shall be available for critical controls and instrumentation 
necessary to maintain containment.

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

    (See Appendices G-II-C-2-n, G-II-C-2-r, and G-II-C-4-i for 
additional guidance for facilities, waste handling, and serum 
collection for research involving mammalian-transmissible HPAI H5N1 
virus.)

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 (disposable) are worn. For research with 
mammalian-transmissible HPAI H5N1 viruses, protective sleeves shall be 
worn over the gown while working in a biosafety cabinet.
    (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, with the exception 
that showers prior to exiting the laboratory are required for all 
research with mammalian-transmissible HPAI H5N1 virus, including care 
of animals infected with mammalian-transmissible HPAI H5N1 virus.
    (6) For research with mammalian-transmissible HPAI H5N1 virus, 
prior to leaving containment, personal protective equipment shall be 
sprayed or wiped down with a disinfectant that has activity against 
influenza viruses.
    (7) In order to promote adherence to proper practices, including 
proper removal of personal protective equipment, and reporting of any 
loss of containment or exposures, at least two individuals should be in 
the laboratory at all times when research with mammalian-transmissible 
HPAI H5N1 virus involves experimental procedures with animals or 
sharps, or when procedures are being conducted whereby the generation 
of aerosols is reasonably anticipated. Removal of personal protective 
equipment should be observed.

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, are required. For 
research with mammalian-transmissible HPAI H5N1 virus, laboratory 
workers shall be required to sign a document acknowledging their 
understanding of and intent to adhere to biosafety, biosecurity, and 
occupational health requirements. This document shall include a 
statement that the laboratory worker agrees to report any exposures or 
accidents, including those by other individuals in the lab.

[[Page 12082]]

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. If susceptibility to neuraminidase 
inhibitors or other effective antiviral agents is lost as a result of 
genetic modification or serial passage of a mammalian-transmissible 
HPAI H5N1 virus, then any research with this antiviral agent-resistant 
virus shall be stopped and research shall only proceed after review by 
the NIH (as outlined in Section III-A-1-a) or the appropriate federal 
regulatory agency.

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 shall include a description 
of the incident reporting system in place for incidents, which includes 
any loss of containment, spills, accidents, or potential exposures. The 
plan must specify that all incidents must be reported immediately to 
the appropriate institutional authorities, and no later than 24 hours 
to the appropriate public health authorities (e.g., the U.S. Department 
of Agriculture, the Centers for Disease Control and Prevention, NIH, 
local and state health authorities).

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., a severe egg allergy), annual seasonal influenza vaccination as 
a prerequisite for research to reduce the risk of influenza-like 
illness that would require isolation and testing to rule out infection 
with experimental viruses and raise the risk for possible co-infection 
with circulating influenza strains.
    (2) Virus-specific vaccination, if available, should be offered and 
if a licensed HPAI H5N1 vaccine is available, and there are no medical 
contraindications, laboratory workers performing research with 
mammalian-transmissible HPAI H5N1 virus should be vaccinated. A post-
vaccination serum sample shall be collected, assessed for immune 
response, and stored in accordance with institutional policy, at least 
for the time in which the laboratory worker continues to conduct HPAI 
H5N1 virus research.
    (3) Reporting of all respiratory symptoms and/or fever (i.e., 
influenza-like illnesses). For research involving mammalian-
transmissible HPAI H5N1 virus, laboratory workers shall be actively 
monitored for influenza-like illness (i.e., fever and respiratory 
symptoms).
    (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) assays should be used 
for virus detection and 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 or mammalian-transmissible HPAI 
H5N1 viruses, 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, human H2N2 (1957-1968), or HPAI H5N1) of 
appropriately timed specimens. Laboratory workers with a known 
laboratory exposure with high risk for infection during research with 
HPAI H5N1 virus strains that are not transmissible among mammals should 
be prepared to self-isolate (for example at home) until infection can 
be ruled out by testing (e.g., 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 an individual has entered (within ten days) a laboratory 
conducting research with influenza viruses containing the human H2N2 HA 
gene or any gene from the 1918 H1N1 or HPAI H5N1 viruses, or housing 
animals exposed to such viruses, and the individual demonstrates 
symptoms and/or signs of influenza infection (e.g., fever/chills, 
cough, myalgia, headache), then he/she shall report by phone to the 
supervisor/principal investigator and other individuals identified in 
the occupational health plan. If needed, the person with influenza-like 
illness shall be transported, under the appropriate isolation 
conditions, 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-(6)

    Antiviral agents for an exposure shall be provided only after 
medical evaluation. Home supplies shall not be provided in advance for 
research with 1918 H1N1, mammalian-transmissible HPAI H5N1 or influenza 
viruses containing the HA gene from human H2N2.

    Dated: February 14, 2013.
Lawrence A. Tabak,
Deputy Director, National Institutes of Health.
[FR Doc. 2013-03974 Filed 2-20-13; 8:45 am]
BILLING CODE 4140-01-P