This document summarizes the efficacy testing of the rVSV-ZEBOV Ebola vaccine in Guinea during the 2014-2015 outbreak. It describes the challenges of conducting vaccine trials during an epidemic, the ring vaccination study design that was implemented, and the interim results showing 100% efficacy of the vaccine. It also reviews the community engagement efforts, logistical challenges, partnerships involved, and lessons learned from this pivotal vaccine trial.

1. Efficacy testing of the
rVSV-ZEBOV Ebola vaccine in Guinea
Gunnstein Norheim
MScPharm PhD
Norwegian Institute of Public Health
Member of Study Steering Group
ESCAIDE November 13th 2015

2. Challenges for testing vaccine
efficacy in epidemics
-Ethical aspects and community engagement
-Study designs for efficacy testing
-Race against the clock
Foto: Daniel Berehulak, The New York Times

3. Setting and purpose of the Guinea vaccine trial
• Limitation of classical tools to stop outbreak
• Potential of vaccines to limit the outbreak
• Provide complementary data to trials in Sierra
Leone (stepped wedge) and Liberia (RCT)

4. Menu of challenges in November 2014
• Study design
• Study location
• Implementation in Guinea
• Choice of vaccine
• Ethical and regulatory approval pathways
• Community engagement
• Financing

5. Study design: ring vaccination study
50% of rings randomized
to immediate vaccination
Time (days)Compare incidence
50% of rings randomized
to delayed vaccination

6. Frontline-workers study
• 1200 frontline workers
• Immunogenicity
• Adverse events
• Samples drawn at days 0, 7, 28,
84 and 180 after vaccination
• Samples to be analysed in US,
Germany, UK and Norway
• Capacity building in Guinea

7. Major vaccine target: glycoprotein (GP)
Konstantinov et al. Visual Science 2011

8. Immunity against Ebola
Human natural immunityVaccine-induced immunity
in non human primates
Becquart et al PLOSOne 2010:5:e9126Sullivan et al. Nature Reviews Microbiology 2009;7:393-400

9. Structures of Ebola Vaccine Candidates rVSV (Panel A) and cAd3 (Panel B).
Two vaccine candidates fulfilled requirements
Kanapathipillai R et al, NEJM Dec 11, 2014. CDC 1981. Graham Beards.
1. 100% protection in non-human primates (NHP)
2. GMP product available
rVSV vaccine
chAd3 vaccine

10. Choice of study area: case variability and labs
Conakry: 85 beds
Gueckedou: 85 beds
Macenta: 60 beds
(transfer)
Nzerekore: 40 beds
WHO situation report 10.12.2014

11. The process leading to the trial
• Protocol development, consent, SOPs
• Ethics approvals: Norway, WHO and Guinea
• Regulatory approval in Guinea
• Monitoring for GCP adherence
• Logistics, organisation
• Data management: University of Bern

12. Logistics, organisation and data management
Photo: Sean Hawkey

13. Community engagement
Photos: Sean Hawkey
Vaccination of contacts

14. Frontline workers study
Photo: MSF

15. Interim results for 90 rings per 20th July 2015
Henao-Restrepo et al. Lancet July 31st 2015 WHO, August 9th 2015
Each ring visited at days 0, 3, 14, 21, 42, 63, and 84 post-vaccination
to document the potential occurrence of any serious adverse events

16. Comparability of rings

17. Interim results for 90 rings per 20th July 2015
Vaccine efficacy: 100%
95% confidence interval: 74.7 – 100%
Immediate: 48 rings
2014 vaccinated of 4123 contacts/cc
0 Ebola viral disease cases
Delayed: 42 rings
1498 vaccinated of 3528 contacts/cc
16 Ebola viral disease cases
Henao-Restrepo et al. Lancet July 31st 2015

18. No new cases of Ebola virus disease
were diagnosed in vaccinees
from 6 days post-vaccination

19. • Request from MoH, August 2015
• Declared free of EVD transmission on 7th Nov.
Extension of trial to Sierra Leone

20. Latest developments in Guinea
• Ring vaccination trial continues
• 4 new cases last 21d (Nov 7th). 0 cases last week
• 69 contacts followed, completes 21d Nov 14th
WHO Ebola Situation report per 7th November 2015

21. The Guinea Trial: race against the clock
90 rings
www.cdc.gov
5th Nov 2014
Country group formed
Vaccination
initiated
Reached
90 rings
Last randomized ring
9 months
Publication 31st July 2015
5 months?

22. Lessons learned
• Broad and open collaboration key to success
• Clear leadership: «command and control»
• Peer-review: study design, vaccine choice
• Expertise diversity, pragmatism and speed
• Community engagement, local study team
Photos: Sean Hawkey

23. Partners and funders
Chair, Study steering group: John-Arne Røttingen, NIPH
Regulatory sponsor representative: Marie-Paule Kieny, WHO
Principal investigators: Mandy K. Konde, Moussa Doumbia, Aboubacar Soumah
Funding
• Wellcome Trust
• Research Council of Norway
• Institute Development
Research Centre, Canada
• WHO
• Medecins Sans Frontieres
Republic of Guinea: Sakoba Kéïta, Mandy Kader Kondé
WHO: Marie-Paule Kieny, Ana Maria Henao-Restrepo, Godwin Enwere, Souleymane Kone, Ximena Riveros, Andrea
Vicari
University of Florida: Ira M Longini, Natalie E Dean
LSTHM: W John Edmunds, Anton Camacho, Conall H Watson
University of Bern: Matthias Egger, Stefanie Hossmann, Sven Trelle
EMLab: Miles W Carroll, Sophie Duraffour, Eeva Kuisma, Stephan Gunther
CVD Mali: Moussa Doumbia, Myron M Levine
MSF/Epicentre: Bertrand Draguez, Aboubacar Soumah, Rebecca Grais
PHE: Sema Mandal
NIPH: John-Arne Røttingen, Gunnstein Norheim, Bjørg D. Nilsson, Sara Watle

24. The future
• Licensing and access to rVSV vaccine
• Identify a correlate of protection
• Develop a pan-Ebola vaccine

26. Choice of dose level – rVSV-ZEBOV vaccine
Huttner et al, Lancet Oct 2015
n=51 received rVSV-ZEBOV 5x105
n=35 received rVSV-ZEBOV 1x107
n=16 received rVSV-ZEBOV 5x107
n=13 received placebo (saline)
IgG against GP protein Neutralisation (pseudovirion)