1. Development of an Ebola Vaccine in the Midst of an Unprecedented Epidemic
Beth-Ann G. Coller, Ph.D.
Uppsala Health Summit
October 10, 2017

2. Emerging Infectious Diseases (EIDs)
Infections that have recently appeared within a population or those whose incidence or geographic range is rapidly increasing or threatens to increase in the near future. 2

3. 2014–2016 Ebola Virus Outbreak
Declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) in Aug 2014
First case identified in Guinea, March 2014, peaked in Aug–Oct 2014
Caused by Zaire ebolavirus species
Cumulatively 28,000+ cases and 11,000+ deaths by March 2016
>10 times more cases during the most recent epidemic than in all previous outbreaks combined
Countries most affected: Guinea, Liberia, Sierra Leone
A few cases in Nigeria, Mali, Senegal, Spain, US, UK, Italy
An end of the PHEIC was declared by WHO in March 2016
Flare-ups occurred in Guinea and Liberia
Guinea and Liberia declared the end of the most recent outbreak on 1 and 9 June 2016, respectively

4. Direct and Indirect Costs of the 2014-2016 Ebola Outbreak were Vast
United Nations Development Group, a consortium of U.N. agencies predicted worst-case scenario losses of up to $4.9 billion per year over three years, with the bulk of the impact felt by the three worst affected countries (March 2015).
World Bank Group estimated that Liberia, Guinea and Sierra Leone will lose at least US$2.2 billion in forgone economic growth in 2015 as a result of the epidemic (April 2015).
881 HCW infected and 513 died
Increases in maternal and infant mortality secondary to losses in trained doctors, nurses and midwives1
Severely limited provision of health care services for HIV and tuberculosis1
Increases in malaria morbidity and mortality2
An estimated additional 10,600 lives lost to HIV, tuberculosis, and malaria during the epidemic based on a the assumption of an approximate 50% reduction in healthcare services in three affected countries3
1 Evans D, et al. Health-care worker mortality and the legacy of the Ebola epidemic. Lancet. 2015; 3:439–e440.
2 Walker PGT. et al. Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis. Lancet. 2015;15:
3 Parpia AS, et al. Impact of the Ebola Outbreak on Malaria, HIV, and Tuberculosis in West Africa.
Emerging Infectious Diseases ; 22:

5. Societal Cost of the Outbreak
Children1
20% of cases children <15 years of age
More than 17,000 children lost one or both parents
>30 weeks of school were missed in affected countries
Lost opportunity for routine health care
Vaccination coverage declined 30%
Families
Disruption of families due to travel restrictions and isolation/quarantine
Increase in responsibilities for remaining caregivers
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7. Transmission of Ebola Virus
Zoonotic virus – bats the most likely reservoir, although species unknown
Spillover event from infected wild animals (e.g., fruit bats, monkey, duiker) to humans, followed by human-human transmission  

8. Ebola Presents a Major Risk to Great Apes
Ebola Outbreak Killed 5000 Gorillas
Magdalena Bermejo, José Domingo Rodríguez-Teijeiro, Germán Illera, Alex Barroso, Carles Vilà, Peter D. Walsh
Science  08 Dec 2006: Vol. 314, Issue 5805, pp. 1564
FINBARR O'REILLY/REUTERS
GREAT APES
Ebola Is Wiping Out the World’s Gorillas
In just four decades, Ebola has wiped out one third of the world’s chimp and gorilla populations. If it continues, the results will be devastating.
Ebola has wiped out a third of the world’s chimpanzee and gorilla populations since the 1990s, conservationists warn
The Telegraph 22 Jan 2015
Ebola represents a major threat not only to humans, but also to the Great Ape populations in Africa
Highlights the need for a One Health Approach for EIDs
Evaluation of various vaccine candidates in gorillas being contemplated, spearheaded by University of Plymouth

9. MSD Engagement in Ebola Vaccine R&D
In November 2014, MSD and NewLink Genetics Corp. entered into an exclusive worldwide license agreement wherein MSD assumed responsibility to research, develop, manufacture, and distribute the investigational Ebola vaccine candidate (rVSV∆G-ZEBOV-GP, referred to as V920)
MSD and a global network of partners have collaborated in unprecedented ways with the singular focus of speeding the research, development, and deployment of a well tolerated and effective Ebola vaccine
The efforts of all of our partners, in the midst of the largest Ebola epidemic in history, highlight what we in the public health community can accomplish if we work together

10. V920: rVSVΔG-ZEBOV-GP Vaccine
V920 is a recombinant, replication-competent, vesicular stomatitis virus (VSV)-vectored-vaccine containing the glycoprotein of Zaire Ebola virus
The Zaire Ebola virus (ZEBOV) glycoprotein (GP) antigen is displayed in native conformation on the surface of VSV
VSV WT
VSVΔG/ZEBOV-GP
Glycoproteins switched

11. Partnerships and Alliances to Develop V920
Public Health Agency of Canada (PHAC)
NewLink Genetics (Bio-Protection Systems Corporation)
II/III
Phase I studies I
Phase II/III studies
Liberia (PREVAIL): Liberia – NIH Partnership (NIAID) Sierra Leone (STRIVE): CDC/Sierra Leone Medical School/BARDA Guinea (Ebola ça suffit): WHO/Norwegian Institute of Public Health/MSF/HealthCanada US/Canada/Spain (V ): MSD/BARDA Additional funding and support: US Department of Health and Human Services (BARDA) US Department of Defense (DTRA, JVAP), Gavi
WHO Clinical Consortium/ VEBCON
Switzerland: University Hospitals of Geneva
Germany: University Medical Center Hamburg/Clinical Trial Center North
Gabon: Centre de Recherches Medicales de Lambarene/University of Tuebingen
Kenya: Kenya Medical Research Institute Marburg Laboratory
CCV – Halifax, Canada
US Department of Defense (WRAIR, JVAP, USAMRIID, DTRA)
NIAID/NIH
NewLink Genetics
BARDA
Ministries of Health and Regulators from all countries involved in the trials provided critical support

12. Liberia-NIH Partnership
The International Partnership Facilitating V920 Clinical Trial Evaluation
WRAIR
Silver Springs, MD, USA
CCV
Halifax, Nova Scotia, Canada
NewLink 8 Cities in USA
NIH
Bethesda, MD, USA
University Medical Center Hamburg + Clinical Trial Center North Hamburg, Germany
HUG Geneva, Switzerland
KEMRI Kilifi, Kenya
CDC + Sierra Leone Medical School Sierra Leone
Liberia-NIH Partnership
Liberia
WHO + Norwegian Institute of Public Health + Health Canada + MSF Guinea
CERMEL + University of Tuebingen Lambarene, Gabon I Ib II
III
MSD
Multiple sites in the USA, Canada, Spain II

13. Total Enrollment in Clinical Trials Proposed to Support Initial Licensure
Study Sponsors and Sites
N vaccinated with V920
Nominal Dose levels (pfu)
Phase I
University of Dalhousie – Halifax, Canada 30
1x105, 5x105, 3x106 (each, n=10), Placebo (n=10)
WRAIR – Silver Spring, MD, USA
3x106, 2x107, 1x108 (each, n=10), or Placebo (n=9)
NIAID – Bethesda, MD, USA
NewLink Genetics – multiple sites USA
422
3x103, 3x104, 3x105 (each, n=64), 3x106 (n=84), 9x106, 2x107 (each, n=47), 1x108 (n=48), Placebo (n=94)
WHO – Geneva, Switzerland
100
3x105 (n=51), 1x107 (n=35), 5x107 (n=16), Placebo (n=13)
WHO – Hamburg, Germany
3x105, 3x106, 2x107 (each, n=10)
WHO – Kilifi, Kenya 40
3x106, 1x107 (each, n=20)
WHO – Lambarene, Gabon
115 adults/40 pediatric
3x103 (n=20), 3x104 (n=20), 3x105 (n=20), 3x106 (n=39), 2x107 (n=16), 2x107 (n=40 pediatric subjects)
Phase II/III
WHO – Guinea Ring Trial (Ebola ça Suffit)
~5800
≥ 2x107
WHO/MSF – Guinea FrontLine Workers
~1800
CDC/COMAHS – Sierra Leone (STRIVE)
~8000
NIH/Liberian Partnership – Liberia (PREVAIL I)
~500
MSD – US / Canada / Europe (V )
~1060
Total vaccinated for all doses combined ~18,000;
~17,000 subjects vaccinated at dose ≥2x107 pfu nominal dose

14. WHO’s Ring Vaccination Trial in Guinea
A cluster-randomized trial design
Defined a cluster or “ring” around a confirmed Ebola case
Clusters were the units for randomization
Index case
Immediate Vaccination
Randomization
Contacts
Contacts of contacts
Delayed Vaccination

15. WHO’s Ring Vaccination Trial Final Results Dec 2016
Demonstrated efficacy in human subjects
Reference: 1Henao-Restrepo AM, et al. Lancet. 2016; final results published online 22-Dec-2016.

16. Ongoing Efforts in Advance of Product Licensure
Additional Clinical Trials to expand understanding of safety and immunogenicity in pediatric and HIV+ subjects
Expanded Access Clinical Protocols
V920 is an investigational product so an approved regulatory framework is required to support use in advance of product licensure. Requires informed consent, adherence to GCP, collection of safety data, etc.
Expanded access clinical protocols are one such framework. MSD working with various partners across Africa to put approved clinical protocols in place in advance of an outbreak to support rapid deployment of vaccine should the affected country(ies) so desire
Emergency Use Assessment and Listing (EUAL)
Mechanism introduced by the World Health Organization to allow deployment of a vaccine outside of clinical trials prior to licensure in the context of Public Health Emergency of International Concern
MSD filed an EUAL application for V920 with WHO in December 2015, with amendments submitted in 2016 and 2017; application is currently under review

17. V920 Vaccine Milestones: 2014–present
Accelerated timeline to develop the V920 Ebola vaccine
31 July 2015 Phase III ring vaccination trial in Guinea; interim results demonstrate vaccine efficacy
25 Jan 2015
Dose selection decision for efficacy trials
Jan-Mar 2016
Manufacturing of additional clinical supplies
Ongoing 2017
Technology transfer to commercial manufacturing site
III
2014
2015
2016
2017
OCT
NOV
DEC
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT I
II/III
13 Oct 2014
Start of Phase I trials
Feb–Aug 2015
Start of Phase II/III studies:
02 Feb: NIH PREVAIL in Liberia
23 Mar: WHO study in Guinea
09 Apr: CDC STRIVE in Sierra Leone
17 Aug: MSD lot consistency in US, EU, and Canada
22 Dec 2015
WHO agrees to review an Emergency Use Assessment and Listing submission
Jun 2016
23 Jun: Granted PRIME eligibility by EMA
29 Jun: Granted Breakthrough Therapy Designation by FDA

18. Summary
Emerging Infectious Diseases represent a major threat to both human and animal species and a One Health Approach is appropriate and required to maximize preparedness and responses.
MSD, working in collaboration with a large number of partners, has moved the V920 vaccine candidate forward at an unprecedented pace
V920 was demonstrated to be highly efficacious in a Ring Vaccination Trial conducted by the WHO in Guinea during the outbreak
The data from 13 clinical trials is expected to provide a solid body of evidence supporting the licensure of V920. The vaccine has been granted PRIME (EU) and Breakthrough Therapy (US) Designation.
MSD is committed to ensure vaccine availability for at-risk populations in advance of product licensure

19. Acknowledgements and Sincere Thanks
Study volunteers and study investigators
MSD-NewLink Joint Steering Committee; V920 product development team and all sub- teams
Our many external partners, collaborators, and funding organizations
This project has been partly funded under the following contracts: BARDA HHS C and HHSO C; and DTRA HDTRA1-15-C-0058