session 5: potential benefits of gof (coronavirus vaccines)
DESCRIPTION
Ralph Baric's presentation regarding the potential benefits of GOF research in creating vaccines that target coronaviruses.TRANSCRIPT
Ralph S. Baric, PhD Professor: Epidemiology
University of North Carolina at Chapel Hill
No Approved Vaccines or Therapeutics for SARS-CoV or MERS-CoV Midst of an ongoing MERS-CoV Outbreak (950+ cases/40% mortality)
Theme • Impact of GOF Restrictions
– Emerging Coronavirus Vaccine/Therapeutic Research
• Focus: Two Stories
Restrictions will reduce public health preparedness to respond to future SARS-CoV-like outbreaks
Restrictions on animal model development increases the risk of vaccine induced immune pathology and mortality in human populations
• Debunk: Concept
That ethical and safe alternative experimental approaches exist that provide equivalent information as GOF studies
Demonstrate complexity of defining GOF research
Impact: Public Health Preparedness
SARS-CoV
Epidemic
Strains
SARS-CoV Epidemic 2002-2004; ~8,000 cases/~10% mortality Originated pool of related Bat CoV (5-30% sequence variation)
Since 2005, no new cases
Vaccines/Therapeutics: Target SARS-like prepandemic strains
Civet/Raccoon dog
SARS-like Viruses
Group 2b Coronaviruses Original
Vaccine Target
Sheahan T, J Virol 2011
Impact: Public Health Preparedness
SARS-CoV
Epidemic
Strains
SARS-CoV Epidemic 2002-2004 Originated pool of related Bat CoV (5-30% sequence variation)
Since 2004: no new reported cases (extinct?)
Recognition: Vaccines must target SARS-like pre-pandemic strains
Civet/Raccoon dog
SARS-like Viruses
CENTRAL QUESTIONS
Do any other bat SARS-like CoV have pre-
pandemic potential?
YES? Will existing SARS-CoV vaccines
and drugs work
Impact: Public Health Preparedness
SARS-CoV
Epidemic
Strains
SARS-CoV Epidemic 2002-2004 Originated pool of related Bat CoV (5-30% sequence variation)
Since 2004, no new reported cases
Recognition: vaccines must target SARS-like pre-pandemic strains
Civet/Raccoon dog
SARS-like Viruses
CENTRAL QUESTIONS: PREPAREDNESS
Do other bat SARS-like CoV have
pandemic potential?
YES? Will existing SARS-CoV vaccines
and drugs work?
Synthesized spike genes in red Ge et al., Nature 2013, Becker, PNAS 2008, Menachery, unpublished)
SARS MA
WIV-1 S
SHC014-S
HKU3-S
BtCoV 279-S
hACE2-
Expressing
Cells
Pseudotype
INFECT
YES (5/5)
YES (3/5)
NO (0/5)
NO (1/5)
NO (1/5)
hACE2-
Expressing
Cells
Chimeric
INFECT
YES (5/5)
YES (3/5)
YES (0/5)
NO (1/5)
NO (1/5)
Recombinant
Virus
Lethal
ND
ND
Attenuated
Attenuated
Mouse
Virulence
Cross-Neut
SARS hmAB
4/4
2/4
0/4
ND
ND
SARS
Vaccines
Protect
Aged
YES
No
No
No*
No*
Potential
Threats SHC014 and WIV-1 have
same growth phenotype
as wildtype SARS-CoV
PSEUDOTYPES + STRUCTURE-
BASED PREDICTIONS FAILED
TO IDENTIFY SHC014
Different S Pseudotype
CoV S
Conserved virus-ACE2 receptor
contact interface residues Ge et al., Nature 2013 Menachery, unpublished
“Ethical
Alternative”
SARS MA
WIV-1 S
SHC014-S
HKU3-S
BtCoV 279-S
hACE2-
Expressing
Cells
Pseudotype
INFECT
YES
YES
NO
NO
NO
hACE2-
Expressing
Cells
Chimeric
INFECT
YES
YES
YES
NO
NO
Recombinant
Virus
Lethal
Attenuated
Attenuated
Mouse
Virulence
Cross-Neut
SARS hmAB
4/4
2/4
0/4
SARS
Vaccines
Protect
Aged
YES
No
No
Loss of
Virulence
Function
Vaccines
fail in 1 yr
aged mice
hmAB
therapy
fails
Pseudotype
CoV S
Group 2b Coronaviruses
Greatest Pandemic
Threat Potential
No Vaccines or hmAB!
We are Vulnerable!
Emerging CoV Pandemic Preparedness
Low Risk
High Risk
Many Chimeric Viruses: the definition implied in GOF is much too broad and must be redefined
GOF: Public Health Implications SARS Extinct? No
• Unequivocally established that some natural SARS-
like CoV bat strains:
– Pre-pandemic potential
• Results are generalizable to other zoonotic viruses
– Like Bat MERS-like CoV
– Framework: to establish risk and prioritize basic and
applied research
• Information to policy makers:
– SARS-like outbreaks are likely in the future
– Existing therapeutics and vaccines may fail (unprepared)
– Reagents exist to devise effective interventions
Importance of Animal Model Development
to Vaccine Development SARS-CoV replicates poorly in mice (~106)
No weight loss or clinical disease
Little if any pathology
Every vaccine developed works in the model
Development of Mouse Adapted Strains: 6-10 changes
Poor engagement
of mouse ACE2
receptor
More S Gene Mutations More in vivo
passages mACE2 usage
Captures many SARS human disease phenotypes
ARDS
2 logs increased titer
Phenocopy human in vivo tropism
Age-related disease severity
Theme: In vivo correlates of protection vary depending on model Frieman M, J Virol 2012; Roberts, A., Plos Pathogens 2007
Importance of Animal Model Development
to Vaccine Development SARS-CoV replicates poorly in mice (~106)
No weight loss or clinical disease
Little if any pathology
Every vaccine developed works in the model
Development of Mouse Adapted Strains: 6-10 changes
Poor engagement
of mouse ACE2
receptor
More S Gene Mutations More in vivo
passages mACE2 usage
Captures many SARS human disease phenotypes
ARDS
2 logs increased titer
Phenocopy human in vivo tropisms
Age-related disease severity
Insights into pathogenic mechanisms
Theme: In vivo correlates of protection vary depending on model
DIV SARS Vaccine
Protects in young mice inoculated with wildtype SARS-CoV
(replication model)
What happens after SARS MA Challenge?
Vaccine fails to protect, especially in elderly
Induces a Th2 Immune Pathology: BAD
Eosinophils
Deming, Plos Med 2006; Yasui, J. Immunol 2008; Bolles, J Virol. 2011; Tseng, Plos One 2012
DIV Performs: Models of Outbred Humans
Collaborative Cross Mice (musculus, castaneous, domesticus)
8 Founder Lines→64 F1 diallel combinations
Age: 1 year, vaccinate half with DIV, challenge with virus (~1860 mice)
Mock-vaccinated controls co-housed with challenged animals
No evidence of
transmission In
vulnerable inbred and
outbred populations
Models of Outbred Human Populations
Collaborative Cross Mouse Resource 8 Founder Lines→64 F1 diallel combinations
Age: 1 year, vaccinate half with DIV, challenge with virus (~1860 mice)
Mock-vaccinated controls co-housed with challenged animals
No evidence of
transmission In
vulnerable inbred and
outbred populations
SARS DIV
Seen with other vaccine formulations
Other CoV → Vaccine Complications
Robust animal models are essential
for vaccine/drug development, safety
testing and performance outcomes
Schaefer et al., unpublished
MERS-CoV Animal Model Development
MERS-CoV does not replicate in mice/small animals!
In vivo passage also fails
Transgenic mice developed: hDPP4 receptor
Replication model, very limited clinical disease
Passage is required to isolate mouse adapted strains that
reproduce human disease phenotypes
HALTED: In the midst of an ongoing epidemic!
Public Health vaccine development has been
compromised! No robust small animal models exist: testing of vaccines/drugs--delayed
Critical: MERS-CoV restrictions be lifted immediately
Summary Dangerous Times:
Human populations are being sampled by four
highly pathogenic viruses
H5N1, H7N9, MERS-CoV, Ebola Virus
International Travel: Allows for immediate worldwide dissemination of
newly emerged viruses
Only going to get faster--more frequent
Response Times: Compressed Strategies exist to develop broadly effective
interventions prior to future disease outbreaks
GOF is a crucial tool for public health
preparedness