Ebola Vaccine Development
Sarah Gilbert, Jenner Institute, University of Oxford
THE JENNER INSTITUTE
THE JENNER INSTITUTE
a partnership between Oxford University and
the Pirbright Institute
- Developing innovative vaccines
- Partnering with industry
- Driving the One Health agenda
The Jenner Institute
• Global Health
– vaccines that make a difference
• HIV, TB, malaria, dengue, pandemic
influenza
• Translational Research
– rapid early clinical testing
• 32 vaccines made for clinical trials
• One Health
– vaccines for humans and other
animals
Human Vaccines Pipeline
Disease Area
Number
of GMP
Vaccines
Preclinical
Phase I
Phase IIa
Oxford
Malaria
15
TB
3
HCV
3
HIV
5
Pandemic Flu
2
Meningitis
1
RSV
3
Ebola
1
Phase Ib
Phase IIb
Phase III
Patient Group /Endemic Area
Staph aureus
Prostate cancer
Rift Valley Fever
The busiest pipeline of any non-profit vaccine institute
Licensure
Ebola in West Africa, 2014
• Epidemic worsening in Guinea, Liberia, Sierra Leone
– international public health emergency
– >13 567 cases, >4 951 deaths (by 31st October)
– No vaccines, no drugs licensed
• Two vaccines show single dose efficacy in macaques
– Chimpanzee adenovirus
– Vesicular stomatitis virus
• Both vaccines encode the surface glycoprotein
– 5 major strains defined: Zaire and Sudan most common
– Guinea outbreak is the Zaire strain
Pre-clinical Ebola Vaccine Development
• Nancy Sullivan group NIH, vaccine development with Ebola
glycoprotein in non-human primates
• 2000: DNA prime, replication deficient Ad5 boost (1010 pfu)
– All vaccinated animals asymptomatic after challenge
• 2005 recombinant attenuated VSV (replication competent)
– Single dose 5 x 107 pfu was completely protective
• 2006 single dose Ad5, (1010 vp = approx 108 pfu)
– Complete protection 4 weeks after immunisation
Clinical Ebola Vaccine Development
• Nancy Sullivan group NIH, vaccine development with Ebola
glycoprotein in clinical studies (Zaire and Sudan together)
• 2006: DNA vaccine is safe and immunogenic
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3 doses of either 2, 4 or 8 mg DNA vaccine
Safety good
ELISA and CD4+ responses detected in 20/20 volunteers
CD8+ responses in 6/20 volunteers
• 2010 replication-deficient Ad5 vectored vaccine is safe and
immunogenic
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–
–
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2 x 109 or 2 x 1010 vp single intramuscular injection
Safety good
50% of volunteers developed antibody responses 4 weeks after immunisation
Roughly 50% of volunteers developed CD4+ responses
Those with pre-existing neutralising antibodies to Ad5 made less response
More Pre-clinical Ebola Vaccine
Development
• Nancy Sullivan group NIH, vaccine development with Ebola
glycoprotein in non-human primates
• Ad26 in NHPs with pre-existing immunity to Ad5
– Partial protection from Ad26
• No survival when 1010 vp used
• 50% survival when 1011 vp used
• 75% survival when 1012 vp used
– Complete protection when boosted by Ad35
• 1011 vp of each vaccine 4 weeks apart
• 100% survival after challenge
• ChAd3 completely protective at 1010 or 1011 vp
– Short term protection, challenge 5 weeks after vaccination
– When challenged 6 months after vaccination, 0 or 50% protection
– Boost with 1 x 108 pfu MVA after 8 weeks, complete protection when challenged
10 months later
Accelerated Ebola Vaccine Development
• Chimpanzee adenovirus 3 vaccine chosen
– Previously used for hepatitis C phase I trials
• WHO / Oxford / Wellcome / GSK / Okairos /
NIH plan
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Phase I in Oxford mid-September: 60 volunteers
Phase I in Mali: 80 volunteers
Phase I in Switzerland
Parallel manufacturing of 10,000 doses of ChAd3
EBO Z
• Objectives
– Safety data in 140 volunteers
– Immunogenicity comparable to protected
macaques
• Decision on whether to deploy: December
2014
– Primary target population: healthcare workers
Accelerated Ebola Vaccine Development
• Attenuated VSV, replication competent
• VSV-Zebov is based in part on a genetically engineered version of
vesicular stomatitis virus , which primarily affects rodents, cattle,
swine and horses.
• Human VSV infections are rare and generally produce three to four
days of mild illness
• Has been given post exposure to two accidentally infected lab workers
– 5 x 107 pfu, resulted in fever
• Otherwise no experience with the vector in clinical trials
– Virus shedding, extent of replication and persistence unknown
• Long term protection in rodents 12-18 months after single dose of 2 x
105 pfu
• Trials will test 106 to 108 pfu
– 800 vials delivered to WHO
– One or two doses to be tested in US
– More trials in Switzerland, Germany, Gabon, Kenya
Process Development Challenges
mitigated by using platform technologies
•
Which vaccine?
– ChAd3, VSV, Ad26, MVA
– Virus-like particles
•
What dose?
– ChAd3 (1 x1010 vp), 2.5 x1010 vp 5 x1010 vp
– VSV 106 to 108 pfu
•
How many doses per person?
– One or two
•
How many vaccines?
– Ad prime MVA boost
•
How many people?
– Front line workers
– Population in isolated areas where new outbreaks occur
Expected numbers of doses
•
VSV, depends on dose
– between 120,000 and 12 million doses available next year
•
ChAd3
– Original batch size of 10,000 doses, can expand capacity
•
MVA
– Process for thousands of doses exists
•
Sterile filling capacity will be needed in all cases
•
WHO asking for 500,000 doses by mid 2015, plus another 500,000 by end
2015
Testing Efficacy and Defining Correlates of
Protection
•
Can and should efficacy be tested?
•
Has implications for outbreak control, defining CoP, defining optimum
dose/regimen, best use of available funds
•
Stepped wedge or randomised placebo controlled trial
•
CoP
– Total IgG
– Neutralising antibodies
– T cell response
•
Duration of immunity
– Requirements depend on intended use
Does it Have to Be This Way?
“Well, that’s another fine mess…!”
Rapid Response versus Outbreak Preparedness
Some Outbreak Pathogens
• Rift valley fever virus
• Ebola virus
• Chikungunya virus
• Marburg virus
• MERS coronavirus
• Pandemic influenza
• Crimean-Congo
hemorrhagic fever virus
• Enterovirus 71
• Hendra virus
• Lassa virus
• Monkeypox virus
• Nipah virus
• SARS coronavirus
• Venezuelan equine
encephalitis virus
• West Nile virus
Figure S1: Vaccine design and confirmation of transgene expression
A
Vaccine design using ChAdOx1 and HAdV5
Human tissue plasminogen
activator leader sequence
V5 tag
MP-12 RVF virus GnGc
Human cytomegalovirus
major immediate early
promoter
ChAdOx1 or HAdV5 genome
Pb9 tag
BGH poly (A) tail
ChAdOx1 or HAdV5 genome
B
75KDa
Anti-Gn antibody
50KDa
75KDa
Anti-Gc antibody
50KDa
Warimwe et al. Virol J. 2013;10:349.
Immunogenicity and efficacy against RVF viral
challenge in mice 8 weeks post-vaccination
1000
VNT50
**
**
100
 100% protective efficacy by all
regimens in BALB/c mice
 ChAdOx1-GnGc +/- Matrix-Q™
selected for ruminant trials
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Warimwe et al. Virol J. 2013;10:349.
Evaluation of ChAdOx1-GnGc in ruminants
• Species: Sheep, cattle, goats (locally available breeds)
• Regimen: Single dose (109 infectious units) intramuscularly
• RVF viral challenge: 4 weeks post-vaccination
• Efficacy endpoints: Fever, viraemia, monitored over 2 weeks
A Suggested Way Forward
for Outbreak Pathogens
• Vaccine development to phase II trials for all of
these pathogens
– Safety and immunogenicity as for Ebola
– Largely public funding
– Preferably a common manufacturing platform
• Vaccine stockpiles held in affected regions
– 10,000 to 50,000 doses
– Emergency use approvals and efficacy evaluation
– Learn from existing stockpiling strategies