[Federal Register Volume 77, Number 201 (Wednesday, October 17, 2012)]
[Proposed Rules]
[Pages 63783-63785]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-25377]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

42 CFR Part 73

[Docket: CDC-2012-0010]


Influenza Viruses Containing the Hemagglutinin from the Goose/
Guangdong/1/96 Lineage

AGENCY: Centers for Disease Control and Prevention (CDC), Department of 
Health and Human Services (HHS).

ACTION: Request for information and comment.

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SUMMARY: The Centers for Disease Control and Prevention (CDC) within 
the Department of Health and Human Services (HHS) announces the opening 
of a docket to obtain information and comments from the public to 
questions concerning highly pathogenic avian influenza (HPAI) H5N1 
viruses that contain a hemagglutinin (HA) from the Goose/Guangdong/1/96 
lineage, and their potential to pose a severe threat to public health 
and safety. This information will be considered in a determination of 
whether such viruses should be listed as HHS select agents, by revising 
the HHS Select Agent Regulations (42 CFR Part 73).

DATES: Electronic or written comments should be received on or before 
December 17, 2012.

ADDRESSES: You may submit comments identified by Docket Number CDC-
2012-0010, by any of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Mail: Division of Select Agents and Toxins, Centers for 
Disease Control and Prevention, 1600 Clifton Road NE., Mailstop A-46, 
Atlanta, Georgia 30333, Attn: Docket Number: CDC-2012-0010.
    Instructions: All submissions received must include the agency name 
and docket number (CDC-2012-0010) for this notice. All relevant 
comments received will be posted without change to www.regulations.gov, 
including any personal information provided. For access to the docket 
to read background documents or comments received, go to 
www.regulations.gov.

FOR FURTHER INFORMATION CONTACT: Dr. Robbin Weyant, Director, Division 
of Select Agents and Toxins, Centers for Disease Control and 
Prevention, 1600 Clifton Road NE., Mailstop A-46, Atlanta, Georgia 
30333. Telephone: (404) 718-2000.

SUPPLEMENTARY INFORMATION:

I. Background

    Since late 2003, the World Health Organization (WHO) has reported 
over 600 cases of human infection with highly pathogenic avian 
influenza (HPAI) H5N1 viruses with a mortality rate that exceeds 50 
percent in hospitalized patients (Ref 1). Current epidemiologic 
evidence indicates that, once transmitted into a human host, H5N1 
viruses may result in more severe disease in humans than other subtypes 
of influenza.
    One important factor that can account for some of the increased 
pathogenicity is the hemagglutinin (HA) molecule. Cleavage of the HA 
molecule by host proteases (chemicals that can break amino acid bonds) 
enables influenza viruses to productively infect cells (i.e., 
replicate). For human influenza viruses, replication is restricted to 
the respiratory tract. However, HPAI H5N1 viruses contain a polybasic 
amino acid sequence in the HA molecule that is not found in human 
influenza viruses. This feature allows the molecule to be cleaved by a 
wider variety of proteases throughout the body and consequently, HPAI 
H5N1 viruses can replicate systemically in avian species.
    Extrapulmonary dissemination of HPAI H5N1 virus has been documented 
among some fatal human HPAI H5N1 virus infections. The HA molecule 
mediates binding of the influenza virus to host cells in the 
respiratory tract. Human influenza viruses preferentially bind to 
different receptors than avian influenza viruses (Ref 2). While human 
influenza virus receptors are more prevalent in the upper respiratory 
tract, the receptors that bind avian viruses are present in the lower 
respiratory tract of humans. The ability of H5N1 viruses to bind and 
infect cells within the lung may contribute to the severity of H5N1 
induced viral pneumonia (Ref 3-5). Furthermore, a change from avian- to 
human-type receptor-binding specificity, as seen with the pandemic 
strains of 1918 (H1N1), 1957 (H2N2),

[[Page 63784]]

and 1968 (H3N2), is thought to be a critical step in the adaptation of 
avian influenza viruses to humans and the ability to transmit 
efficiently among humans (Ref 6-8). In two recent independent studies 
(Ref 9 and Ref 10), investigators have shown that laboratory modified 
HPAI H5N1 influenza viruses with certain mutations can be transmitted 
via the respiratory route between ferrets. Ferrets are widely 
considered to provide the best animal model for exploring these aspects 
of influenza virus pathogenicity as they might relate to human 
infection (Ref 11).
    We recognize that all HPAI H5N1 influenza virus clades found in 
humans to date have been derived from the Goose/Guangdong/1/96 lineage, 
and the HA molecule enables the virus to infect a host cell. Thus, we 
are interested in receiving information and comments on whether the 
influenza viruses that contain a hemagglutinin (HA) from the Goose/
Guangdong/1/96 lineage have the potential to pose a severe threat to 
public health and safety (Ref 12). Currently, all HPAI H5 subtype 
viruses are regulated by the U.S. Department of Agriculture (USDA) 
Animal and Plant Health Inspection Service (APHIS) whose oversight 
focuses on the threat to animal health and safety. Listing influenza 
viruses that contain an HA from the goose/Guangdong/1/96 lineage as an 
HHS select agent will ensure that the focus of regulation will also be 
on the potential impact of these viruses on human health as well as 
agriculture. While USDA sets biosafety measures that may also be more 
generally beneficial to public health, its focus with respect to select 
agent designation is primarily on risks to agricultural animals, rather 
than direct effects on human health. There is precedence (e.g., 
Bacillus anthracis) for including agents that have both human and 
agricultural impacts on both the HHS and USDA Select Agent Lists. 
Designating HPAI containing an HA from the Goose/Guangdong/1/96 lineage 
an HHS select agent, in addition to its status as a USDA select agent, 
may help to ensure that HPAI strains that have the greatest potential 
for major direct effects on human health will be regulated with a focus 
on protection of human health.
    The question of whether the influenza viruses that contain an HA 
from the Goose/Guangdong/1/96 lineage pose a severe threat to public 
health and safety was considered by HHS/CDC's Intragovernmental Select 
Agents and Toxins Technical Advisory Committee (ISATTAC). The ISATTAC 
is comprised of Federal government scientists from HHS/CDC, the 
Biomedical Advanced Research and Development Authority (BARDA) within 
the Office of the Assistant Secretary for Preparedness and Response 
(HHS/ASPR) in HHS, the National Institutes of Health (HHS/NIH), the 
Food and Drug Administration (HHS/FDA), USDA/APHIS, the USDA/
Agricultural Research Service, the USDA/Center for Veterinary 
Biologics, the Department of Homeland Security (DHS), and the 
Department of Defense (DOD). The criteria used by the ISATTAC in its 
review were the degree of pathogenicity, communicability, ease of 
dissemination, route of exposure, environmental stability, ease of 
production, ability to genetically manipulate or alter, long-term 
health effects, acute morbidity, acute mortality, available treatment, 
status of host immunity, vulnerability of special populations, and the 
burden or impact on the health care system. ISATTAC made the 
recommendation that the influenza viruses containing an HA from the 
Goose/Guangdong/1/96 lineage do have the potential to pose a severe 
threat to public health and safety. In making its recommendation to 
HHS/CDC, the ISATTAC considered both the historical data regarding the 
Goose/Guangdong/1/96 lineage and data from current in vitro and in vivo 
animal studies. The virulence of viruses of this lineage, the data 
showing transmissibility of genetically modified H5N1 viruses among 
ferrets, together with the fact that the level of immunity in the 
general population is low were all considered. Further, in its 
recommendation the ISATTAC voiced concern that an influenza pandemic 
caused by viruses containing an HA from the Goose/Guangdong/1/96 
lineage, could potentially overwhelm the health care system. The 
ISATTAC also recognized that the study of the Goose/Guangdong/1/96 
lineage-derived viruses could lead to significant public health 
benefits for understanding pandemic influenza, improved diagnostics, 
and the development of more effective countermeasures. Therefore, the 
risks posed by these viruses need to be weighed against any adverse 
impact that a regulation will have on legitimate research.
    On July 2, 2010, the President signed Executive Order 13546, 
``Optimizing the Security of Biological Select Agents and Toxins in the 
United States'' that directed the Secretaries of HHS and USDA to 
designate a subset of the select agents and toxins list (Tier 1) that 
presents the greatest risk of deliberate misuse with the most 
significant potential for mass casualties or devastating effects to the 
economy, critical infrastructure, or public confidence. The Executive 
Order 13546 also established the Federal Experts Security Advisory 
Panel (FESAP) to advise the HHS and USDA Secretaries on the designation 
of Tier 1 agents and toxins. In December of 2010, the FESAP provided 
the HHS and USDA Select Agent regulatory programs with recommendations 
on updating the HHS and USDA Select Agent and Toxin lists, including a 
subset of agents and toxins recommended for Tier 1 designation.
    On October 3, 2011, HHS/CDC published a notice of proposed 
rulemaking (76 FR 61206) in which we proposed a list of select agents 
and toxins that should be considered Tier 1 select agents and toxins. 
The proposed Tier 1 agents and toxins that were based on Executive 
Order 13546 and the recommendations from FESAP were scored against 20 
criteria by over 60 Subject Matter Experts representing the Federal 
life sciences, public health, law enforcement, security, and 
intelligence communities. The criteria included:
     The relative ease with which a particular select agent or 
toxin might be disseminated or transmitted from one human to another or 
into the environment where it could produce a deleterious effect upon 
human health;
     The potential for a high mortality rate;
     The potential for a major human health impact;
     Select agents or toxins whose misuse might result in 
public panic or other social or economic disruption; and
     Select agents or toxins whose use might require Federal, 
State, and/or local officials to take special action in planning for 
major human health disasters.
    We proposed that the following agents should be designated as Tier 
1 agents: Bacillus anthracis, Botulinum neurotoxin, Botulinum 
neurotoxin producing species of Clostridium, Burkholderia mallei, B. 
pseudomallei, Francisella tularensis, Marburg virus, Variola major 
virus, Variola minor virus, and Yersinia pestis. On the same day, USDA/
APHIS published a companion rule in the Federal Register proposing its 
list of select agents and toxins that should be considered Tier 1 
select agents and toxins. Although USDA/APHIS regulates HPAI viruses as 
select agents, they did not propose to designate HPAI viruses as Tier 1 
select agents. Given the above criteria used by the FESAP, we would 
welcome comment on whether HPAI H5N1 influenza viruses containing the 
HA from the Goose/Guangdong/1/96 lineage should be listed as a Tier 1 
select agent. The final determination of whether or not to designate 
this particular lineage

[[Page 63785]]

of H5N1 HPAI as Tier 1 would be a collaborative process between HHS and 
USDA. HHS and USDA would continue to work closely together whether or 
not both HHS and USDA designate these viruses as Tier 1 Select Agents.

II. Establishment of a Docket and Request for Specific Input on Certain 
Topics

    We are establishing a docket to provide an opportunity for 
interested persons to submit comments, research data, and other 
information that will better inform us about the risk posed by HPAI 
H5N1 influenza viruses containing the HA from the Goose/Guangdong/1/96 
lineage to public health and safety. In particular, we welcome comment 
on the following questions:
    (1) Do HPAI H5N1 influenza viruses containing the HA from the 
Goose/Guangdong/1/96 lineage pose a severe threat to public health and 
safety?
    (2) Are there other influenza strains containing HA from Goose/
Guangdong/1/96 lineage that would also pose a severe threat even if 
they were not fully of HPAI H5N1 origin?
    (3) Are there any other HPAI H5N1 influenza strains that have been 
identified to pose a severe threat to public health and safety?
    (4) Should these viruses be regulated as HHS select agents?
    (5) If these viruses should be regulated as HHS select agents, 
should these viruses be designated as Tier 1 select agents?
    (6) Should special precautions (i.e., safety and containment 
measures) be considered when working with diagnostic specimens 
suspected of containing HPAI H5N1 influenza viruses containing the HA 
from the Goose/Guangdong/1/96 lineage (i.e., any precautions versus 
none at all, precautions beyond those usual for clinical samples and/or 
laboratory microbes, etc.)? and
    (7) Should special precautions (i.e., safety and containment 
measures) be considered when working with strains of HPAI containing 
the HA from the Goose/Guangdong/1/96 lineage that have been shown to be 
transmissible between mammals beyond those recommended for non-
mammalian transmissible HPAI (Ref 13 and Ref 14)?

III. References

1. WHO, Cumulative number of confirmed human cases for avian 
influenza A(H5N1) reported to WHO, 2003-2011; http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/index.html.
2. Fukuyama S, Kawaoka Y. The pathogenesis of influenza virus 
infections: The contributions of virus and host factors. Curr Opin 
Immunol. 2011 Aug;23(4):481-6. Epub 2011 Aug 11.
3. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian 
flu: Influenza virus receptors in the human airway. Nature. 2006 Mar 
23;440(7083):435-6.
4. Nicholls JM, Chan MC, Chan WY, Wong HK, Cheung CY, Kwong DL, Wong 
MP, Chui WH, Poon LL, Tsao SW., Guan Y, Peiris JS. Tropism of avian 
influenza A (H5N1) in the upper and lower respiratory tract. Nat 
Med. 2007 Feb;13(2):147-9. Epub 2007 Jan 7.
5. Van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, 
Osterhaus AD, Kuiken T. H5N1 Virus Attachment to Lower Respiratory 
Tract. Science. 2006 Apr 21;312(5772):399. Epub 2006 Mar 23.
6. Matrosovich, M., et al. Early alterations of the receptor-binding 
properties of H1, H2, and H3 avian influenza virus hemagglutinins 
after their introduction into mammals. J Virol 74, 8502-8512 (2000).
7. Stevens, J., et al. Glycan microarray analysis of the 
hemagglutinins from modern and pandemic influenza viruses reveals 
different receptor specificities. J Mol Biol 355, 1143-1155 (2006).
8. Connor, R.J., Kawaoka, Y., Webster, R.G. & Paulson, J.C. Receptor 
specificity in human, avian, and equine H2 and H3 influenza virus 
isolates. Virology 205, 17-23 (1994).
9. Masaki Imai,1 Tokiko Watanabe,1, 2 Masato Hatta,1 Subash C. Das,1 
Makoto Ozawa,1, 3 Kyoko Shinya,4 Gongxun Zhong,1 Anthony Hanson,1 
Hiroaki Katsura,5 Shinji Watanabe,1, 2 Chengjun Li,1 Eiryo 
Kawakami,2 Shinya Yamada,5 Maki Kiso,5 Yasuo Suzuki,6 Eileen A. 
Maher,1 Gabriele Neumann1 & Yoshihiro Kawaoka. Experimental 
adaptation of an influenza H5 HA confers respiratory droplet 
transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. 
2012 May 2;486(7403):420-8.
10. Russell CA, Fonville JM, Brown AE, Burke DF, Smith DL, James SL, 
Herfst S, van Boheemen S, Linster M, Schrauwen EJ, Katzelnick L, 
Moster[iacute]n A, Kuiken T, Maher E, Neumann G, Osterhaus AD, 
Kawaoka Y, Fouchier RA, Smith DJ. The potential for respiratory 
droplet-transmissible A/H5N1 influenza virus to evolve in a 
mammalian host. Science. 2012 Jun 22; 336(6088):1541-7.
11. Belser JA, Szretter KJ, Katz JM, Tumpey TM. Use of animal models 
to understand the pandemic potential of highly pathogenic avian 
influenza viruses. Adv Virus Res. 2009;73:55-97.
12. WHO/OIE/FAO H5N1 Evolution Working Group. Continued evolution of 
highly pathogenic avian influenza A (H5N1): updated nomenclature. 
Influenza Other Respi Viruses. 2012 Jan; 6(1): 1-5. doi: 10.1111/
j.1750-2659.2011.00298.x. Epub 2011 Oct 29.
13. Guidelines for Avian Influenza Viruses (http://www.selectagents.gov/resources/Guidelines%20for%20Avian%20Influenza%20Viruses_2011-11-4.pdf).
14. Biosafety in Microbiological and Biomedical Laboratories (http://www.cdc.gov/biosafety/publications/bmbl5/index.htm).

    Dated: October 9, 2012.
Kathleen Sibelius,
Secretary.
[FR Doc. 2012-25377 Filed 10-16-12; 8:45 am]
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