Gain-of-Function Experiments on H7N9
Since the end of March 2013, avian a
influenza viruses of the H7N9 subtype have caused more than 130 human
cases of infection
in China, many of which were severe, resulting in
43 fatalities. Although this A(H7N9) virus outbreak is now under
control,
the virus (or one with similar properties) could
reemerge as winter approaches. To better assess the pandemic threat
posed
by A(H7N9) viruses, NIAID/NIH Centers of Excellence
in Influenza Research and Surveillance (CEIRS) investigators and other
expert laboratories in China and elsewhere have
characterized the wild-type avian A(H7N9) viruses in terms of host
range,
virulence, and transmission, and are evaluating the
effectiveness of antiviral drugs and vaccine candidates. However, to
fully
assess the potential risk associated with these
novel viruses, there is a need for additional research including
experiments
that may be classified as “gain-of-function” (GOF).
Here, we outline the aspects of the current situation that most
urgently
require additional research, our proposed studies,
and risk-mitigation strategies.
The A(H7N9) virus hemagglutinin protein
has several motifs that are characteristic of mammalian-adapted and
human influenza
viruses, including mutations that confer human-type
receptor-binding and enhanced virus replication in mammals. The
pandemic
risk rises exponentially should these viruses
acquire the ability to transmit readily among humans.
Reports indicate that several A(H7N9)
viruses from patients who were undergoing antiviral treatment acquired
resistance to
the primary medical countermeasure—neuraminidase
inhibitors (such as oseltamivir, peramivir, and zanamivir). Acquisition
of
resistance to these inhibitors by A(H7N9) viruses
could increase the risk of serious outcomes of A(H7N9) virus infections.
The hemagglutinin proteins of A(H7N9)
viruses have a cleavage site consistent with a low-pathogenic phenotype
in birds; in
the past, highly pathogenic H7 variants (with basic
amino acid insertions at the cleavage site that enable the spread of
the
virus to internal organs) have emerged from
populations of low pathogenic strains circulating in domestic
gallinaceous poultry.
Normally, epidemiological studies and
characterization of viruses from field isolates are used to inform
policy decisions
regarding public health responses to a potential
pandemic. However, classical epidemiological tracking does not give
public
health authorities the time they need to mount an
effective response to mitigate the effects of a pandemic virus. To
provide
information that can assist surveillance
activities—thus enabling appropriate public health preparations to be
initiated before
a pandemic—experiments that may result in GOF are
critical.
Therefore, after review and approval, we propose to perform the following experiments that may result in GOF:
(i) Immunogenicity. To
develop more effective vaccines and determine whether genetic changes
that confer altered virulence, host range, or transmissibility
also change antigenicity.
(ii) Adaptation. To
assist with risk assessment of the pandemic potential of field strains
and evaluate the potential of A(H7N9) viruses to
become better adapted to mammals, including
determining the ability of these viruses to reassort with other
circulating influenza
strains.
(iii) Drug resistance.
To assess the potential for drug resistance to emerge in circulating
viruses, evaluate the genetic stability of the mutations
conferring drug resistance, evaluate the efficacy
of combination therapy with antiviral therapeutics, determine whether
the
A(H7N9) viruses could become resistant to available
antiviral drugs, and identify potential resistance mutations that
should
be monitored during antiviral treatment.
(iv) Transmission. To
assess the pandemic potential of circulating strains and perform
transmission studies to identify mutations and gene combinations
that confer enhanced transmissibility in mammalian
model systems (such as ferrets and/or guinea pigs).
(v) Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the hemagglutinin cleavage site, that
would enable circulating A(H7N9) viruses to become more pathogenic.
All experiments proposed by influenza
investigators are subject to review by institutional biosafety
committees. The committees
include experts in the fields of infectious
disease, immunology, biosafety, molecular biology, and public health;
also, members
of the lay public represent views from outside the
research community. Risk-mitigation plans for working with potentially
dangerous influenza viruses, including 1918 virus
and highly pathogenic avian H5N1 viruses, will be applied to conduct GOF
experiments with A(H7N9) viruses (see supplementary
text). Additional reviews may be required by the funding agencies for
proposed studies of A(H7N9) viruses (see
scim.ag/13BK5Hs).
The recent H5N1 virus transmission controversy focused on the balance of risks and benefits of conducting research that proved
the ability of the H5N1 virus to become transmissible in mammals (see
www.sciencemag.org/special/h5n1).
These findings demonstrated the pandemic potential of H5N1 viruses and
reinforced the need for continued optimization of
pandemic preparedness measures. Key mutations
associated with adaptation to mammals, included in an annotated
inventory for
mutations in H5N1 viruses developed by the U.S.
Centers for Disease Prevention and Control, were identified in human
isolates
of A(H7N9) viruses. Scientific evidence of the
pandemic threat posed by A(H7N9) viruses, based on H5N1 GOF studies,
factored
into risk assessments by the public health
officials in China, the United States, and other countries.
Since the H5N1 transmission papers were published, follow-up scientific studies have contributed to our understanding of host
adaptation by influenza viruses, the development of vaccines and therapeutics, and improved surveillance.
Finally, a benefit of the H5N1 virus
research controversy has been the increased dialogue regarding
laboratory biosafety and
dual-use research. The World Health Organization
issued laboratory biosafety guidelines for conducting research on H5N1
transmission
and, in the United States, additional oversight
policies and risk-mitigation practices have been put in place or
proposed.
Some journals now encourage authors to include
biosafety and biosecurity descriptions in their manuscripts, thereby
raising
the awareness of researchers intending to replicate
experiments.
The risk of a pandemic caused by an avian
influenza virus exists in nature. As members of the influenza research
community,
we believe that the avian A(H7N9) virus outbreak
requires focused fundamental and applied research conducted by
responsible
investigators with appropriate facilities and
risk-mitigation plans in place. To answer key questions important to
public
health, research that may result in GOF is
necessary and should be done.
- Ron A. M. Fouchier1,*,
- Yoshihiro Kawaoka2,*,
- Carol Cardona3,
- Richard W. Compans4,
- Adolfo García-Sastre5,
- Elena A. Govorkova6,
- Yi Guan7,
- Sander Herfst1,
- Walter A. Orenstein8,
- J. S. Malik Peiris9,
- Daniel R. Perez10,
- Juergen A. Richt11,
- Charles Russell6,
- Stacey L. Schultz-Cherry6,
- Derek J. Smith12,
- John Steel4,
- S. Mark Tompkins13,
- David J. Topham14,
- John J. Treanor15,
- Ralph A. Tripp13,
- Richard J. Webby6,
- Robert G. Webster6
-
1Department of Viroscience, Erasmus Medical Center, 3015GE, Rotterdam, Netherlands.
-
2Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711,
USA.
-
3Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
-
4Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
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5Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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6Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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7State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong SAR.
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8Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
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9Centre of Influenza Research, School of Public Health, The University of Hong Kong, Hong Kong SAR.
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10Department of Veterinary Medicine, University of Maryland, College Park, College Park, MD 20742, USA.
-
11College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
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12Department of Zoology, University of Cambridge, Cambridge, CB2 3EJ, UK.
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13Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
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14Department of Microbiology and Immunology, Center for Vaccine Biology and Immunology, University of Rochester Medical Center,
Rochester, NY 14642, USA.
-
15Infectious Diseases Division, University of Rochester Medical Center, Rochester, NY 14642, USA.
- ↵*Corresponding author. E-mail: r.fouchier@erasmusmc.nl (R.A.M.F.); kawaokay@svm.vetmed.wisc.edu (Y.K.)
http://www.sciencemag.org/content/early/2013/08/07/science.1243325.full