Session 3: Key Issues on GOF Benefits (Kawaoka)
-
Upload
national-academies-of-science-engineering-and-medicine -
Category
Documents
-
view
225 -
download
0
Transcript of Session 3: Key Issues on GOF Benefits (Kawaoka)
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
1/38
Yoshihiro Kawaoka, DVM, Ph
University of Wisconsin-Madiso
Influenza GO
Research
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
2/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
3/38
In my presentation:
The benefits of GOF research
Why we need GOF research
- Specific examples- Conceptual justification
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
4/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
5/38
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.
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
6/38
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.
Loss-of-function research does not always provide answers
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
7/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
8/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
9/38
1. Loss-of-function research
Alternatives to GOF research of concern
2. Use of low pathogenicity viruses
3. Phenotypic analyses
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
10/38
1. Loss-of-function research
Alternatives to GOF research of concern
2. Use of low pathogenicity viruses
3. Phenotypic analyses
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
11/38
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.
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
12/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
13/38
1. Loss-of-function research
Alternatives to GOF research of concern necessary
2. Use of low pathogenicity viruses
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
14/38
1. Loss-of-function research
Alternatives to GOF research of concern
2. Use of low pathogenicity viruses
3. Phenotypic analyses
Alt ti t GOF h f
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
15/38
1. Loss-of-function research
Alternatives to GOF research of concern
2. Use of low pathogenicity viruses
3. Phenotypic analyses
Alternative approaches
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
16/38
Alternative approaches
Safer approaches to studying human adaptation of influenza A viruses
Lipsitch and Galvani, PLoS Med 2014
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
Alternative approaches
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
17/38
Alternative approaches
Safer approaches to studying human adaptation of influenza A viruses
Lipsitch and Galvani, PLoS Med 2014
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.
Alternatives to GOF research of concern
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
18/38
1. Loss-of-function research
Alternatives to GOF research of concern
2. Use of low pathogenicity viruses
3. Phenotypic analyses
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?
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
19/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
20/38
Specific benefits differ depending on the GOF research of conce
Benefits of GOF research of concern
What did we learn from the ferret transmission H5N1 GOF research
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
21/38
What did we learn from the ferret transmission H5N1 GOF research
Vaccine stockpile
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
22/38
H5N1 Vaccine stockpiling in Japan
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
23/38
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
What did we learn from the ferret transmission H5N1 GOF research
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
24/38
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
What did we learn from the ferret transmission H5N1 GOF research
What did we learn from the ferret transmission H5N1 GOF research
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
25/38
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
Strain selection for stockpile vaccines
What did we learn from the ferret transmission H5N1 GOF research
WHO H5N1 candidate vaccine viruses
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
26/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
27/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
28/38
Implications Important for pandemic preparedness
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
Strain selection for stockpile vaccines
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
29/38
Implications Important for pandemic preparedness
Questioned the pandemic potential of H5N1 viruses
H5N1 vaccine stockpiles are needed (important for policy makers)
Risk assessment of circulating strains
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
Vaccines would ideally be produced by using a virus that isclosely related to viruses of high pandemic potential.
N158DKawaokaFouchier
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
30/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
31/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
32/38
Mutation(+
100%
Mutation(+)
70%
Mutation (-)30%
2009-2011 birds 2009-2011 humanNeumann et al., PLoS Pathogens, 2012
Implications Important for pandemic preparedness
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
33/38
Implications Important for pandemic preparedness
Questioned H5N1 vaccine stockpile
H5N1 vaccine stockpiles are needed (important for policy makers)
Risk assessment of circulating strains
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
Vaccines would ideally be produced by using a virus that isclosely related to viruses of high pandemic potential.
Surveillance of H5N1 viruses may be limited.
But, this is changing, e.g., H5N8 viruses in wild birds across Europe anAsia.
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
34/38
Neumann et al., PLoS Pathogens, 2012
Implications Important for pandemic preparedness
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
35/38
Implications Important for pandemic preparedness
Questioned H5N1 vaccine stockpile
H5N1 vaccine stockpiles are needed (important for policy makers)
Risk assessment of circulating strains
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
Vaccines would ideally be produced by using a virus that isclosely related to viruses of high pandemic potential.
Important information!
Imai et al., 2012, Nature
Benefits of GOF research of concern
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
36/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
37/38
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
-
8/10/2019 Session 3: Key Issues on GOF Benefits (Kawaoka)
38/38