Jules Millogo, MD, MSc Director, Public Health Partnerships Merck & Co, Inc. North Wales, PA, USA

WHO-MSD Collaboration to Bring an Ebola Vaccine to the Populations in Need

V920: rVSVΔG-ZEBOV-GP Vaccine

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• V920 is a recombinant, replication-competent, vesicular

stomatitis virus (VSV)-vectored-vaccine containing only

the GP protein of Ebola virus (no live 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

The International Partnerships Facilitating V920 Clinical Trial Evaluation

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Study Sponsors and Sites

N vaccinated with

V920

Phase I – Safety and Immunogenicity Trials Using

Varying Vaccine Dose Levels

U. Dalhousie – Halifax, Canada 30

WRAIR – Silver Spring, MD, USA 30

NIAID – Bethesda, MD, USA 30

NewLink – USA 422

WHO – Geneva, Switzerland 100

WHO – Hamburg, Germany 30

WHO – Kilifi, Kenya 40

WHO – Lambarene, Gabon 115 adults/40 pediatric

Phase II/III - Safety, Immunogenicity/Efficacy Trials

at the Selected Vaccine Dose Level of ≥ 2x107 pfu

WHO – Guinea Ring Trial (Ebola ça

Suffit) ~5800

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

• 13 trials (one conducted by MSD)

• ~18,000 total vaccinated for all doses

combined (~17,000 subjects vaccinated at ≥ 2x107 dose)

• Efficacy was demonstrated in WHO’s

Ring Vaccination Trial

V920 Overall Safety Conclusions to Date

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• Preliminary data in healthy, non-pregnant adults suggest an acceptable safety profile that in the context of demonstrated efficacy supports a positive benefit-risk ratio:

– V920 is generally well tolerated.

– Few vaccine-related SAEs reported to date

– Injection-site reactions very common; majority mild to moderate

– Common systemic AEs include headache, fatigue, myalgia, shivering/chills, subjective or objective fever, arthralgia, feeling unwell, nausea, influenza-like illness, and pain. Majority mild to moderate, short duration.

– Joint pain (arthralgia) has been seen in 5%-50% of participants, but joint swelling (arthritis) has been less common (<5% in most studies to 24% in one study).

– Majority of joint events were mild to moderate and resolved within several days (arthralgia) to weeks (arthritis); some subjects reported arthritis of prolonged duration, recurrence and/or sequelae for up to 2 years after vaccination, the longest duration of follow-up to date.

– Rash (with or without vesicles) and mouth ulcers have also been reported.

– Vaccine virus shedding is not frequent in adults and is more frequent in children; secondary transmission has not been demonstrated to date.

– Additional studies in children and HIV+ adults/adolescents have started but data from these studies are not yet available.

Summary of the V920 Product Profile (for Licensure)

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Description • Live, attenuated vesicular stomatitis (VSV) recombinant

vaccine expressing Ebola Zaire surface glycoprotein

• Generic: Ebola Zaire vaccine (rVSVΔG-ZEBOV-GP, live

attenuated)

Proposed

Indication

Prevention of Ebola-Zaire related disease

• Initial indication: Reactive use

• Eventual indication: General use prophylaxis

Regimen Single dose

Administration Intramuscular (IM) injection of 1mL

Image • Single-dose, liquid-frozen vial (1.2mL)

• Multi-dose available as pre-licensure emergency-use

doses only

Storage • 60oC storage, could be kept up to two weeks at 2-8oC

after thawing.

• Shelf life 3 years; (5 years data TBD)

Target

population

• Initial: ≥ 18 years of age (~2019)

• Eventual: ≥ 1 year of age (~2022)

Regulatory Strategy

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• Objective: Obtain approval in African countries, facilitated by WHO Prequalification after approval by a stringent regulatory authority (e.g., EMA and/or U.S. FDA).

• Indication: Active immunization of at-risk subjects ≥ 18 years of age to

protect against disease caused by Zaire ebolavirus.

U.S. Food and Drug Administration (FDA)

European Medicines Agency (EMA)

World Health Organization Pre-Qualification

Priority African countries (list being finalized)

Four top priorities

• Expanded Access Clinical Protocols

– Designed to allow use in advance of product licensure under strict protocols requiring informed consent, adherence to GCP, collection of safety data, etc.

• Emergency Use Assessment and Listing (EUAL)

– Mechanism introduced by WHO 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 -2018; application is currently under review and could be activated/approved if needed

Pre-licensure Deployment Mechanisms

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• Regular and transparent Consultations, including ad hoc

emergency meetings to address pressing issues

• Advance exchange of agenda and pending issues to

address

• Leveraging each other’s strengths- for instance WHO has

frequent interactions with African NRAs

• Common voice when approaching regulatory agencies and

associations: FDA, EMA, AVAREF

The Way We Work With WHO PQ Team

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• Shared Priorities

• Mutual trust that both sides have the best intentions

• Mutual understanding of partner’s constraints

• Willingness to adjust schedules in order to address priorities

• Defined roles and responsibilities and tacit commitment to

implement agreed upon activities in allotted time

Pillars of the Collaboration

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• Technical Skills: WHO PQ Team has proven to be very

knowledgeable in the regulatory area.

• Understanding of Manufacturing Environment: there is

visible effort to understand Industry’s compliance, legal and

business environment.

• Willingness to Address Challenges- by adopting a

common problem-solving attitude.

How WHO PQ Team Won MSD’s Trust

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Illustrative Examples of Results of Collaboration

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Addressing programmatic suitability challenges

(thermostability, label, etc.)

Developing a strategy to facilitate African country

registration

Bringing on board AVAREF

Liaison with countries

.

MSD-WHO Collaboration Challenges

• No clear demand size for Ebola vaccine

• Occasional lack of consistency of messages from WHO

• Continued need to overcome cultural barriers between

Industry and WHO

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