efficacy testing of the rvsv-zebov ebola vaccine in guinea, dr. gunnstein norheim

Efficacy testing of the rVSV-ZEBOV Ebola vaccine in Guinea

Gunnstein NorheimMScPharm PhD

Norwegian Institute of Public HealthMember of Study Steering Group

ESCAIDE November 13th 2015

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

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)

Menu of challenges in November 2014

• Study design• Study location• Implementation in Guinea• Choice of vaccine• Ethical and regulatory approval pathways• Community engagement• Financing

Study design: ring vaccination study

50% of rings randomized to immediate vaccination

Time (days)Compare incidence

50% of rings randomized to delayed vaccination

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

Major vaccine target: glycoprotein (GP)

Konstantinov et al. Visual Science 2011

Immunity against Ebola

Human natural immunityVaccine-induced immunityin non human primates

Becquart et al PLOSOne 2010:5:e9126Sullivan et al. Nature Reviews Microbiology 2009;7:393-400

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

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

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

Logistics, organisation and data management

Photo: Sean Hawkey

Community engagement

Photos: Sean Hawkey

Vaccination of contacts

Frontline workers study

Photo: MSF

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-vaccinationto document the potential occurrence of any serious adverse events

Comparability of rings

Interim results for 90 rings per 20th July 2015

Vaccine efficacy: 100%95% confidence interval: 74.7 – 100%

Immediate: 48 rings2014 vaccinated of 4123 contacts/cc

0 Ebola viral disease cases

Delayed: 42 rings1498 vaccinated of 3528 contacts/cc

16 Ebola viral disease cases

Henao-Restrepo et al. Lancet July 31st 2015

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

• Request from MoH, August 2015

• Declared free of EVD transmission on 7th Nov.

Extension of trial to Sierra Leone

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

The Guinea Trial: race against the clock

90 rings

www.cdc.gov

5th Nov 2014Country group formed

Vaccinationinitiated

Reached 90 rings

Last randomized ring

9 months

Publication 31st July 2015

5 months?

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

Partners and funders

Chair, Study steering group: John-Arne Røttingen, NIPHRegulatory sponsor representative: Marie-Paule Kieny, WHOPrincipal 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 KondéWHO: Marie-Paule Kieny, Ana Maria Henao-Restrepo, Godwin Enwere, Souleymane Kone, Ximena Riveros, Andrea Vicari University of Florida: Ira M Longini, Natalie E DeanLSTHM: W John Edmunds, Anton Camacho, Conall H WatsonUniversity of Bern: Matthias Egger, Stefanie Hossmann, Sven TrelleEMLab: Miles W Carroll, Sophie Duraffour, Eeva Kuisma, Stephan GuntherCVD Mali: Moussa Doumbia, Myron M LevineMSF/Epicentre: Bertrand Draguez, Aboubacar Soumah, Rebecca GraisPHE: Sema MandalNIPH: John-Arne Røttingen, Gunnstein Norheim, Bjørg D. Nilsson, Sara Watle

The future

• Licensing and access to rVSV vaccine

• Identify a correlate of protection

• Develop a pan-Ebola vaccine

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)