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

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

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

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;15:825-32. 3 Parpia AS, et al. Impact of the 2014-2015 Ebola Outbreak on Malaria, HIV, and Tuberculosis in West Africa. Emerging Infectious Diseases. 2016; 22:433-41.

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 1http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/cost-of-ebola.html Photo: https://www.soschildrensvillages.ca/supporting-children-and-families-facing-ebola-930

1http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/cost-of-ebola.html

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  http://www.cdc.gov/vhf/ebola/resources/virus-ecology.html

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

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

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

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 (V920-012): 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

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

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 (V920-012) ~1060 Total vaccinated for all doses combined ~18,000; ~17,000 subjects vaccinated at dose ≥2x107 pfu nominal dose

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

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.

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

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

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 2014-2016 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

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 HHS010020150002C and HHSO10020160031C; and DTRA HDTRA1-15-C-0058