Session 3: Key Issues on GOF Benefits (Kawaoka)

8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)

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Yoshihiro Kawaoka, DVM, Ph

University of Wisconsin-Madiso

Influenza GO

Research


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Types of GOF research

3. Are more pathogenic/transmissible than the starting viruses in animalmodels, but do not appear to be a major public health concern

GOF research resulting in the generation of viruses that:

1. Do not exist in nature

2. Are more pathogenic/transmissible than the starting viruses, but stillcomparable to or less pathogenic/transmissible than those existing in na

Very few

Many

Many

GOF research of concern

e.g., Low-pathogenic H5N1 viruses with mutations found in naturalisolates that improve replication in mammalian cells

e.g., high-growth A/PR/8/34 virus with increased pathogenicity in mice

e.g., H5N1 viruses that are airborne-transmissible in ferrets


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In my presentation:

The benefits of GOF research

Why we need GOF research

- Specific examples- Conceptual justification


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Risks of GOF research of concern

Why are we concerned?

While the probability of an accidental or deliberate release of a huma

transmissible virus from a single lab is arguably small, but not zero,the more groups performing GOF virology, the greater the overall risk

The generation of viruses through GOF research in labs withlow-level containment facilities or scrutiny increases the risk of

accidental release.

the risks are finite and small, but of catastrophic proportions if ever

there was a breakdown of biosafety or biosecurity.Wain-Hobson, EMBO Mol Med 20

Wain-Hobson, Frontiers in Public Health 20


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1. Loss-of-function research

Alternatives to GOF research of concern

2. Use of low pathogenicity viruses

3. Phenotypic analyses

Lipsitch and Galvani, PLoS Med 2014

alternative scientific approaches are not only less risky, but

also more likely to generate results that can be readilytranslated into public health benefits.


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alternative scientific approaches are not only less risky, but

also more likely to generate results that can be readilytranslated into public health benefits.

Loss-of-function research does not always provide answers


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LOF research

An example in which loss-of-function research fell short

LOF mutations

Receptor specificity

Transmission

1918 virus

No transmission

1918 virusLOF mutant

Tumpey et al. Science, 2

X

HA-D190E


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GOF research of concern

GOF mutations

Receptor specificity

Growth inmammalian cells

HA-N224K, HA-Q226L, HA-N158D

PB2-E627K

Transmission

Virus withwild-type H5 HA

No transmission

GOF mutant

Imai et al. Nature, 20

HA stabilityHA-T317I

X

required for ferret transmission was identified by GOF

research, but not by LOF research.

HA-T317I

A new phenotype

HA stability


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Highly pathogenic

avian influenza virusesLow pathogenic

avian influenza viruses

109

107

105

103

101

d7d5d3604836302418129630

Infectious units/

g lung

Hours post-infection

H5N1 highly pathog

Seasonal H1N1

Highly pathogenic avian influenza viruses differ from low pathogenic virusein their kinetics of virus replication and tissue tropism.


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Highly pathogenic

avian influenza virusesLow pathogenic

avian influenza viruses

109

107

105

103

101

d7d5d3604836302418129630

Infectious units/

g lung

Hours post-infection

H5N1 highly pathog

Seasonal H1N1Data obtained with low pathogenic virusescan be misleading.

Alt ti t GOF h f


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Alternatives to GOF research of concern necessary


If, after careful examination, the attenuated viruses behave exactly

the same way as the wild-type highly pathogenic viruses, this would

be a promising approach.

Alt ti t GOF h f


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Alt ti t GOF h f


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Alternative approaches


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Safer approaches to studying human adaptation of influenza A viruses


Modeling

Receptor specificity, Fusion activity

Replication complex

Sequence comparison

Sequence and phenotypic comparison of natural isolates

Use of seasonal influenza viruses for transmission

Host factors



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Safer approaches to studying human adaptation of influenza A viruses


Alternative approaches alone do not provide answers to key

questions. For example, none of these alternative approaches

revealed the transmissibility of H5N1 viruses in ferrets.

The data obtained using alternative approaches do not alwayscorrelate with data obtained from GOF experiments.



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Phenotypically new traits and the molecular basis for those

traits have been identified by GOF research of concern but

not by alternative approaches.

We cannot rely solely on alternative approaches.

Benefits of GOF research of concern?


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Benefits of GOF research of concern?

vaccine makers consider there is little in this influenza GOFresearch that will help them develop more effective vaccines

(Butler, 2012; Malakoff, 2013).

Wain-Hobson, EMBO Mol Med 201

there is nothing in GOF virology that will help us predict apandemic or help us develop more effective vaccines.

the benefit of this work to public health is unclear...

Relman JID 201

Benefits of GOF research of concern


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Specific benefits differ depending on the GOF research of conce


What did we learn from the ferret transmission H5N1 GOF research


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Vaccine stockpile


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H5N1 Vaccine stockpiling in Japan


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Vietnam + Indonesia10 million people

Vietnam + Indonesia

Anhui

Anhui

Qinghai

10 million people

10 million people

10 million people

10 million people

2014 2015 2016 20172009 2011 2012 20132005 2006 2007 2008

Anhui

10 million peopleQinghai

10 million people

Vietnam + Indonesia10 million people

H5N1 Vaccine stockpiling in Japan

74 million US dollars

to produce each

H5N1 stockpile vaccine

for 10 million people

Expired anddiscarded



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Questioned the pandemic potential of H5N1 viruses

H5N1 vaccine stockpiles are needed (important for policy makers)

It has been 17 years since the emergence of H5N1 viruses,yet they have not caused a pandemic.

Vaccine stockpile




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It has been 17 years since the emergence of H5N1 viruses,yet they have not caused a pandemic.

Vaccine stockpile

Strain selection for stockpile vaccines


WHO H5N1 candidate vaccine viruses


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There are 26 H5N1 vaccine candidates.

How do we select one?

WHO H5N1 candidate vaccine viruses

*September, 2014

http://www.who.int/influenza/vaccines/

virus/characteristics_virus_vaccines/en/

A ti i ll diff t H5N1


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Antigenically different H5N1

viruses are circulating

We now know

which H5N1

viruses havepandemic

potential.

Useful information

for vaccine

candidate selectionTransmissible virus

Implications I t t f d i d


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Implications Important for pandemic preparedness



It has been 17 years since the emergence of H5N1 viruses,

yet they have not caused a pandemic.

Vaccine stockpile


Vaccines would ideally be produced by using a virus that isclosely related to viruses of high pandemic potential.

Policy makers, not vaccine companies, select vaccine strains.

Naturally, vaccine companies will say no when asked if GOFresearch of concern has helped vaccine production.

Implications I t t f d i d


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Risk assessment of circulating strains



Vaccine stockpile



N158DKawaokaFouchier


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T160A

G228S

Q226L

H110Y

N158D

N224K

Q226L

T318I

Kawaoka Fouchier

Imai et al. Nature, 2012 Herfst et al. Science, 20

Global incidence of the mutation


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Egypt

265/352

75% Vietnam33/130

25%

China

31/4963%

Japan40/40

100%

Other56/137

41%

among H5N1 isolates in 2009-2011

H5N1 viruses in Egypt


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Mutation(+

100%

Mutation(+)

70%

Mutation (-)30%

2009-2011 birds 2009-2011 humanNeumann et al., PLoS Pathogens, 2012



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Questioned H5N1 vaccine stockpile





Vaccine stockpile



Surveillance of H5N1 viruses may be limited.

But, this is changing, e.g., H5N8 viruses in wild birds across Europe anAsia.


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Neumann et al., PLoS Pathogens, 2012



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Questioned H5N1 vaccine stockpile





Vaccine stockpile



Important information!

Imai et al., 2012, Nature



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GOF research of concern allows us to obtain information that wecould not obtain by other methods unless it actually occurred innature.

Droplet-transmissible H5N1 and other avian viruses to which humans

lack immunity

Specific benefits differ depending on the GOF research of conce

If so, it also allows us to examine the mechanism(s) for such events.

GOF research of concern allows us to determine whether theseviruses could emerge.

The information obtained is essential for pandemic preparatio

What are the key issues on benefits that need to be


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addressed in the assessments the NIH will undertake?

1. Focus on GOF research of concern

2. Recognize that for some questions, only GOF research of

concern can provide accurate answers

3. Obtain consensus from the community to perform GOF

research of concern


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Documents

Session 3: Key Issues on GOF Benefits (Kawaoka)