Ebola: Progress with Vaccines
Pandemics and Emerging Infections
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
Human Vaccines Pipeline
Disease Area
Number
of GMP
Vaccines
Preclinical
Phase I
Phase IIa
Oxford
Malaria
17
TB
3
HCV
3
HIV
5
Pandemic Flu
2
Meningitis
1
RSV
3
Ebola
4
Prostate cancer
2
Phase Ib
Phase IIb
Phase III
Patient Group /Endemic Area
Staph aureus
The busiest pipeline of any non-profit vaccine institute
Licensure
Ebola in West Africa, 2014
• Epidemic in Guinea, Liberia, Sierra Leone
– international public health emergency declared in August 2014
– 28, 295 cases, 11, 295 deaths by September 2015
– No vaccines, no drugs licensed
• Two vaccines had shown single dose efficacy in
macaques
– Chimpanzee adenovirus vector
– Vesicular stomatitis virus vector
Adenovirus-Based Vaccine
against Ebola
This Ebola Vaccine, ChAd3 EBO Z, induces strong
immune responses in non-human primates
B cell response
Experimental design
1010 or 1011 vp ChAd3 (N=4)
Weeks 0
1000 pfu ZEBOV
4
Ad5 average
5
Plasma IgG ELISA
PBMC ICS
ChAd3 induced anti-GP IgG titers above the level that
predicts 100% protection for an Ad5 vaccine
T cell response
Ad5 average
Ad5 average
ChAd3 induces high levels of anti-Ebola GP CD4 and CD8 T cells
Stanley et al. Nat Med 2014
A Single Injection of 1010 vp ChAd3 EBO Z
Fully Protects Macaques from Ebolavirus
Ebolavirus
Ebolavirus
challenge
challenge
Vaccinate ChAd Ebola GP
n = 4 /group
0
1
2
3
4
5
One year
Acute protection
100
% Protection
Weeks:
Ebolavirus
challenge
80
60
40
20
0
Ad5
1010 vp
ChAd3
1010 vp
Stanley et al. Nat Med 2014
ChAd3-ZEBOV prime/MVA-ZEBOV boost induces
100% protection from EBOV at one year
0
1
2
3
4
5
One year
Acute protection
Durable protection
100
% Protection
Weeks:
Ebolavirus
challenge
Ebolavirus
Ebolavirus
challenge
challenge
Vaccinate ChAd Ebola GP
n = 4 /group
80
60
40
20
0
Ad5
ChAd3
ChAd3/MVA
Accelerated Ebola Vaccine
Development
• Chimpanzee adenovirus 3 vaccine chosen
• WHO / Oxford / Wellcome / GSK / Okairos / NIH plan
– Phase I in Oxford mid-September: 60 volunteers
– Phase I in Mali: 80 volunteers
– Parallel manufacturing of 20,000 doses of ChAd3 EBO Z
• Objectives
– Safety data in 140 volunteers, especially healthcare workers
– Immunogenicity comparable to protected macaques
• Decision on whether to deploy in phase III: December 2014
– Primary target population: healthcare workers
Oxford Ebola Vaccine Trial
• First vaccination 17 September 2014
• Three doses assessed in 60 vaccinees by 18 November
– Approval to immunise in West Africa given by Data Safety
Monitoring Board by 4 October 2014
Ebola Vaccine Trial Timeline
14 August
26 August
30 August
2 September
5 September
8 September
9 September
11 September
15 September
16 September
17 September
18 November
Grant application submitted
Award letter
Vaccine filled
Trial file submission to UK regulator
Ethics meeting
Ethical approval
Regulatory approval
Vaccine shipping
Vaccine labelled
Trial contract signed
1st vaccinee
60th vaccinee
First Volunteer in Bamako, Mali
CONFIDENTIAL
Oxford Trial Results: Safety
• The ChAd3 vaccine has been safe in 92
Oxford vaccinees
– and in many others
• 91 in Mali, 100 in Switzerland, 20 in USA
• Some arm soreness, rarely fevers, but well
tolerated
– Similar to other ChAd vectors and most other vaccines
EBOZ Antibody Immunogenicity
ADI ELISA
= response rate
Mean antibody level:
235
402
469
3700 was the correlate of protection in macaques
Rampling et al. NEJM January 2015
Viral Vector Vaccines
to Maximise Immunogenicity
8 weeks
Adenovirus Prime
MVA Boost
Malaria, HCV, HIV, influenza, TB, RSV, Ebola
Two MVA Products
• MVA-BN Filo
– Used in the first Oxford trial
– Glycoproteins of Zaire and Sudan strain of Ebolavirus
• Also nucleoprotein of Taï Forest strain of Ebolavirus
and Marburg virus glycoprotein
• MVA-EBOZ
– NIH doses manufactured by mid-2014 (n = 800)
– Large scale manufacture undertaken with Wellcome funding
• > 30,000 doses; filled in February
• Made on a cell line, not chick embryo fibroblasts
MVA EBO Boost Design
• 30 of the total of 60 ChAd3 EBO Z
vaccinees boosted with MVA
– at 3 – 10 weeks (mean of 6 weeks)
– 10 subjects from each ChAd3 dose level
– Dose either 1.5 x108 or 3 x 108 pfu
• MVA was well tolerated
– in Oxford and subsequently in Mali
Ebola Antibody Responses Increased by
20-fold using an MVA Booster Vaccine
>
No Correlation between ChAd-MVA
Dose Interval and Antibody Titre
Exceptional CD8+ T Cell Potency
with 1 Week Prime-Boost Interval
Further Vectored Ebola trial in Oxford
PI: Matthew Snape
• Prime boost study using
– Ad26 ZEBOV
– MVA-BN
– Johnson & Johnson-sponsored
• Ad26 - MVA and MVA - Ad26
– Four or eight week interval
– Excellent immunogenicity with both regimens
• 72 volunteers in total, started December 2014
ChAd3-MVA Progress
July 15 2015 Update
• 46 MVA-BN boosted subjects in Oxford
• 27 MVA-BN boosted subjects in Mali
• 21 vaccinated in Oxford MVA-EBOZ trial
• 35 vaccinated in Dakar MVA-EBOZ trial
Remarkable immunogenicity in UK and Africa
- with a satisfactory safety profile
Vesicular Stomatitis Virus Vector
another vaccine approach for Ebola
•
•
•
•
•
A rhabdovirus vector
Single dose efficacy in short term challenges in macaques
Replication competent!
Previously used only in two lab workers
New Link Genetics & Public Health Agency of Canada - WHO - Merck
VSV Ebola Vaccine Progress: Safety
• Trials from 5 sites reported in April 2015
– 170 subjects in total
•
•
•
•
•
51 in Geneva, Switzerland
40 in Maryland, USA
39 in Lambarane, Gabon
20 in Kilifi, Kenya
20 in Hamburg, Germany
• Viraemia in 94% of subjects
• Fever in 35%
• Arthritis in 11/51 vaccinees in Geneva
– Fewer at other sites
• Three doses compared
Agnandji et al., Regules et al. NEJM April 2015
Field Trials in West Africa
1. 27,000 subjects in Liberia
– ChAd3 and VSV single dose regimes
2. 8,000 healthcare workers in Sierra Leone
– VSV
3. 9,000 ring vaccinated subjects in Guinea
– i) VSV and ii) ChAd3 +/- MVA
4. >40,000 subjects in Sierra Leone
– Ad26 - MVA
Declining Case Incidence
Initial Efficacy Data
April to July, 2015, Guinea, Ebola ça Suffit trial
90 clusters, total population of 7651 people included in the planned interim analysis.
48 of these clusters were randomly assigned to immediate vaccination with rVSVZEBOV, and 42 clusters randomly assigned to delayed vaccination with rVSV-ZEBOV.
Immediate vaccination group
no cases of Ebola virus disease with symptom onset at least 10 days after randomisation,
Delayed vaccination group
16 cases of Ebola virus disease from seven clusters
Vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036).
43 serious adverse events were reported; one serious adverse event was judged to be causally
related to vaccination (a febrile episode in a vaccinated participant, which resolved without
sequelae). Assessment of serious adverse events is ongoing
Henao-Restrepo et al., Lancet, 2015
Comparing Immunogenicity
Ewer et al.
manuscript submitted
Assays performed by
Thomas Strecker
Stefan Becker
Institut für Virologie
University of
Marburg
Some Outbreak Pathogens
“The Known Knowns”
• Ebola virus
• Chikungunya virus
• Marburg virus
• Rift valley fever virus
• MERS coronavirus
• Crimean-Congo
hemorrhagic fever virus
• Enterovirus 71
• Hendra virus
• Monkeypox virus
• SARS coronavirus
• Nipah virus
• Venezuelan equine
encephalitis virus
•
• West Nile virus
• Pandemic influenza
Lassa virus
No licensed human vaccine for any of these!
Will There Be More Major
Outbreaks?
• Almost certainly!
– More people, especially in Africa
– Bigger cities
– More long distance travel
– Many viruses lurking
– And new viruses like SARS
An Alternative Route for Licensure of
Vaccines against Outbreak Pathogens
• Demonstrate efficacy in a suitable animal
model
• Identify immunological correlates of efficacy
• Demonstrate in clinical trials that these
immune responses can be achieved safely
• Develop an adequate safety database
– In thousands of subjects
– In diverse populations
• Have plans in place to test the vaccines if an
outbreak occurs
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
7 June 2015
PM to pledge £20m to tackle future pandemic threat
Conclusions
• Rapid clinical trial responses to outbreak
pathogens are possible
– the Ebola response speed has been unprecedented
– but there is room for improvement
• Many viral threats exist against which we have
no human vaccines
– a new strategy is required to develop these
vaccines, for which the business case is weak
Acknowledgements
Jenner Pre-Clinical
Alison Turner
Alex Spencer
Tess Lambe
Nick Edwards
CVD Mali, Bamako
Samba Sow
Myron Levine
Marburg University
Thomas Strecker
Stephan Becker
WHO
Marie-Paule Kieny
Vasee Moorthy
NIAID, NIH
Barney Graham
Rick Koup
Nancy Sullivan
University of Dakar
Birahim Ndiaye
Souleymane Mboup
Emergent Biosolutions
Eric Balsley
Rick Welsh
Bavarian Nordic
Paul Chaplin
Ariane Volkmann
UK Clinical Trials
Adrian Hill
Ruth Payne
Felicity Hartnell
Navin Venkatraman
Danny Wright
Georgie Bowyer
Rachel Roberts
Tommy Rampling
Alison Lawrie
Babatunde Imoukhuede
Katie Ewer
Eleanor Berrie
GSK Vaccines
Ripley Ballou
François Roman