Case Study:
H5N1 avian influenza
Robert G. Webster, PhD, FRS
Rose Marie Thomas Endowed Chair
Division of Virology
Department of Infectious Diseases
St. Jude Children’s Research Hospital
H1
H2
Influenza A H3
Virus Host H4
Range H5
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15
H16
Migratory Bird Reservoirs of all
Influenza A Viruses
All 16 HA and 9 NA subtypes
Ecology of avian influenza in wild birds
AI viruses replicate primarily in the intestinal tract.
Limited overt disease signs (low path)
There can be a “cost”.
Only LPAI are perpetuated in wild birds
Including H5 and H7 subtypes
Has H5N1 changed this rule?
LPAI in wild birds are the reservoir of all
influenza A viruses in other species
The H5 and H7 subtypes are unique
Low pathogenic in wild bird reservoir
-Largely intestinal replication
Evolve rapidly after transmission to domestic
poultry
-Host response varies
-Generalized infection, systemic spread-poultry, tigers
-Replication and spread-ducks pigs horses
LETHAL INFECTION INAPPARENT INFECTION
A child dies in Hong Kong..
H5N1 – The Starting Point?
Culling of all poultry in Hong Kong
-No more human infections
½ OF NEW TIMELINE
Initial Spread of H5N1: 2004
Current status:
Poultry: +500 million Human Cases: 602 Human Deaths: 355
Continuing evolution of H5 hemagglutinin
Clade 1
Clade 2.1
Clade 2.2
Clade 2.3
Control Strategies
Stamping out-compensation- successful
Vaccination, reduces disease signs- fails to
eradicate
H5N1 Influenza 2012
Humans: 24 cases/15 deaths
Ongoing outbreaks of highly pathogenic H5N1 in domestic poultry &wild birds
Bangladesh Hong Kong Israel Nepal Egypt
Bhutan India Indonesia Myanmar Vietnam
China
62
34
24
15
2012
Pandemic
Preparedness
The Spread of Pandemic H1N1
April - November 2009
-At least 6,000 deaths.
-Modest severity except in young adults
-Decreased relevance of H5N1
Rationale for research on pathogenicity and transmissibility of H5N1
Reverse genetics for influenza viruses
-Luytjes....Palese Cell 1989
-Neumann…Kawaoka PNAS 1999
-Hoffmann et al PNAS 2000
Approval processes for a “typical” H5N1 transmission experiment
Approvals based on Approvals based on Approvals based on
“science” “facilities” “material transfer”
Select Agent
Peer review of registration
Requires
grant funding Importation permits
-Specific HPAI
Requires
enhancements to
-USDA permit
NIH Office of standard BSL3
-CDC permit
Biotechnology -USDA and/or CDC
-USDA facility inspections
Activities (for some registration paperwork
-Multiple inspections for
experiments)
facilities, security,
inventory, etc.
Institutional
-Renewed every three yrs Export permits
Biosafety
Requires
Committee Personnel requirements -Dept. of Commerce
-Dept. Justice personnel License
Institutional clearance
Animal Care and -Documented personnel
Use Committee training and proficiency
Biosecurity–
to prevent loss, theft, or misuse of microorganisms and biological material
Accomplished by limiting access to facilities, research materials, and information
All personnel undergo FBI Inventory and tracking of virus
Security Risk Assessment strains is strictly controlled
Access granted through Inventory is inspected/verified
biometric reader biannually by USDA
Biosafety
- to reduce or eliminate exposure of individuals and the environment
to potentially hazardous biological agents
Accomplished by four primary controls
1. PPE:
Powered-Air Respirator (PAPR), Scrub Suit,
Tyvek Coverall, Dedicated Shoes, Booties,
Disposable Gown, 2 Pair Nitrile Gloves
2. Work Place Practices:
Entry and Exit Process, Decontamination,
Emergency Procedures, Handling Sharps,
Working in Class II Biosafety Cabinets
3.Administrative:
Immunizations, Security Clearance, Training,
Supervision
4.Engineering:
Directional Air Flow, HEPA Filtration, BSCs,
Entry and Access Point Control
The Fouchier/Kawaoka reports
● Avian HP H5N1 viruses have the potential to become
mammalian transmitted
● Identification of specific markers in HA
● Receptor binding
● Stability
● Glycosylation
● Multiple strategies to become mammalian transmissible
● Confusing information provided to NSABB
The doomsday agent report
January 7, 2012
An Engineered Doomsday
Scientists have long worried that an influenza virus that has ravaged poultry
and wild birds in Asia might evolve to pose a threat to humans. Now
scientists financed by the National Institutes of Health have shown in a
laboratory how that could happen…
April 21, 2012
The Latest on the Doomsday Virus
We can worry less that a newly created bird flu virus
might kill tens or hundreds of millions of people if it
escaped from the laboratory. But there is still some
residual danger.…
Global influenza program
for influenza
WHO/Indonesia/Vietnam
Sharing of influenza viruses
and knowledge
H5N1:The continuing global threat
Indonesia Egypt
Humans:188 cases/156 deaths Humans: 167 cases/60 deaths
Endemic in poultry Endemic in poultry
Wild birds: Clade 2.3.2.1
Bangladesh
Whooper swan, Grebes, Tufted duck, passerines
Humans:6 cases/0 deaths China, Japan, Mongolia, Israel, Vietnam, South
Poultry-over 2 million dead Korea,
Nature is the greatest bioterrorist threat
Benefits
Public Health:
Knowledge that H5N1 virus can adapt to become efficiently
transmissible in mammals/ humans.
Pandemic preparedness for H5 is needed: viruses persistently endemic in poultry in
many countries, such as China, Indonesia, Egypt and Vietnam.
Continued monitoring of H5N1 antigenic changes in the field.
Control measures for blocking transmission from avian species to mammalian
species (such as swine) to prevent further adaptation. (> 500 millions pigs in China)
Provide the knowledge to determine which of the multitude of
influenza viruses have pandemic potential – risk assessment
Which clade of H5N1 is acquiring the necessary mutations for transmissibility?
Vaccine seed stock preparation - need to keep updating the vaccine seed.
Stamping out – with international assistance .
Science:
Look for the mutations that would confer such functionality (they may
already exist!!!):
Need for increased surveillance and rapid sequencing and sharing.
Importance of deep sequencing of all human H5N1 original isolates.
More Science to be addressed…
Is there a required sequence of events for the transmission
to occur; i.e. are the receptor binding mutations a critical
first step during the adaptation?
Does the virulence of transmissible H5N1 increase or
decrease for mammals (as a result of tissue tropism
change)?
Do the changes in the receptor binding domain alter the
antigenicity and immunogenicity of H5N1 viruses?
Does the transmissible H5N1 possess the capacity to
spread in wild birds or in swine?
Do the transmissible H5N1 viruses have a higher
propensity to reassort with the circulating pandemic
H1N1? (it most likely occurs in China, Thailand, Vietnam)
Risks
High lethality in humans?
Laboratory escape: intentional or accidental
Development of bioterrorist agent – possible but less likely
H5N1 continues to evolve and spread, including in
countries with high terrorist threat.
• Shutting down research in US will not necessarily be
followed globally.
Pandemic influenza will definitely emerge again. Will it be
H5? (Nature poses the greatest bioterrorist threat.)
Life is not risk free.
The future… Risk management
“The cat is out of the bag.” Things cannot be undone.
Managing the risk instead of avoiding the risks
Managing the risk instead of thinking that stopping US
research will make the risk disappear
Are the risks manageable?
Assess the risk of research projects and receive pre-
approval
Dual Use Research of Concern (DURC)
Inspections, inspections…
“Real-time” communication between principle
investigators with funding agency; avoid surprises…
Can the questions be addressed using low-path viruses?
Yes partially but not the high pathogenic aspects
Education of the scientists and younger generations.
“Risk free?”
Acknowledgements
Support: HHSN266200700005C, NIAID, ALSAC
St. Jude Children’s Research Hospital
Richard Webby, Charlie Russell, Elena Govorkova, Stacey Schultz-Cherry,
Paul Thomas, Elena Govorkova, Subrata Barman, Scott Krauss
Yi Guan, Malik Peiris, Leo Poon
Hong Kong University Canadian Wildlife Services, Environment Canada
Mohammed Mostafa Feeroz Kathy Magor, Megan Barber
Jahangirnagar University, University of Alberta, Canada
Savar, Dhaka, Bangladesh
WHO Collaborating Centers and
Ghazi Kayali , Mohamed Ali CEIRS Collaborators
NRI Research Center, Cairo Egypt
