Ebola: Progress with Vaccines Pandemics and Emerging Infections Sarah Gilbert, Jenner Institute, University of Oxford

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Human Vaccines Pipeline Disease Area Number of GMP Vaccines Preclinical Phase IPhase IIaPhase IbPhase IIb Phase IIILicensure OxfordPatient Group /Endemic Area Malaria17 TB3 HCV3 HIV5 Pandemic Flu2 Meningitis 1 RSV3 Ebola 4 Prostate cancer 2 Staph aureus The busiest pipeline of any non-profit vaccine institute

Ebola in West Africa, 2014 Epidemic in Guinea, Liberia, Sierra Leone –international public health emergency declared in August 2014 –28, 295 cases, 11, 295 deaths by September 2015 –No vaccines, no drugs licensed Two vaccines had shown single dose efficacy in macaques –Chimpanzee adenovirus vector –Vesicular stomatitis virus vector

Adenovirus-Based Vaccine against Ebola

This Ebola Vaccine, ChAd3 EBO Z, induces strong immune responses in non-human primates Experimental design or vp ChAd3 (N=4) Weeks045 Plasma IgG ELISA PBMC ICS 1000 pfu ZEBOV ChAd3 induced anti-GP IgG titers above the level that predicts 100% protection for an Ad5 vaccine Ad5 average B cell response ChAd3 induces high levels of anti-Ebola GP CD4 and CD8 T cells T cell response Ad5 average Stanley et al. Nat Med 2014

% P r o t e c t io n Ad vp ChAd vp Acute protection A Single Injection of vp ChAd3 EBO Z Fully Protects Macaques from Ebolavirus Ebolavirus challenge Vaccinate ChAd Ebola GP n = 4 /group Weeks: One year Ebolavirus challenge Ebolavirus challenge Stanley et al. Nat Med 2014

% P r o t e c t io n Durable protection Ad5 ChAd3 Acute protection ChAd3/MVA ChAd3-ZEBOV prime/MVA-ZEBOV boost induces 100% protection from EBOV at one year Ebolavirus challenge Vaccinate ChAd Ebola GP n = 4 /group Weeks: One year Ebolavirus challenge Ebolavirus challenge

Accelerated Ebola Vaccine Development Chimpanzee adenovirus 3 vaccine chosen WHO / Oxford / Wellcome / GSK / Okairos / NIH plan –Phase I in Oxford mid-September: 60 volunteers –Phase I in Mali: 80 volunteers –Parallel manufacturing of 20,000 doses of ChAd3 EBO Z Objectives –Safety data in 140 volunteers, especially healthcare workers –Immunogenicity comparable to protected macaques Decision on whether to deploy in phase III: December 2014 –Primary target population: healthcare workers

Oxford Ebola Vaccine Trial First vaccination 17 September 2014 Three doses assessed in 60 vaccinees by 18 November –Approval to immunise in West Africa given by Data Safety Monitoring Board by 4 October 2014

Ebola Vaccine Trial Timeline 14 AugustGrant application submitted 26 August Award letter 30 AugustVaccine filled 2 SeptemberTrial file submission to UK regulator 5 SeptemberEthics meeting 8 SeptemberEthical approval 9 SeptemberRegulatory approval 11 SeptemberVaccine shipping 15 SeptemberVaccine labelled 16 September Trial contract signed 17 September1 st vaccinee 18 November60 th vaccinee

First Volunteer in Bamako, Mali CONFIDENTIAL

Oxford Trial Results: Safety The ChAd3 vaccine has been safe in 92 Oxford vaccinees –and in many others 91 in Mali, 100 in Switzerland, 20 in USA Some arm soreness, rarely fevers, but well tolerated –Similar to other ChAd vectors and most other vaccines

EBOZ Antibody Immunogenicity ADI ELISA Mean antibody level: = response rate 3700 was the correlate of protection in macaques Rampling et al. NEJM January 2015

Viral Vector Vaccines to Maximise Immunogenicity Adenovirus Prime MVA Boost 8 weeks - Malaria, HCV, HIV, influenza, TB, RSV, Ebola

Two MVA Products MVA-BN Filo –Used in the first Oxford trial –Glycoproteins of Zaire and Sudan strain of Ebolavirus Also nucleoprotein of Taï Forest strain of Ebolavirus and Marburg virus glycoprotein MVA-EBOZ –NIH doses manufactured by mid-2014 (n = 800) –Large scale manufacture undertaken with Wellcome funding > 30,000 doses; filled in February Made on a cell line, not chick embryo fibroblasts

MVA EBO Boost Design 30 of the total of 60 ChAd3 EBO Z vaccinees boosted with MVA –at 3 – 10 weeks (mean of 6 weeks) –10 subjects from each ChAd3 dose level –Dose either 1.5 x10 8 or 3 x 10 8 pfu MVA was well tolerated –in Oxford and subsequently in Mali

Ebola Antibody Responses Increased by 20-fold using an MVA Booster Vaccine >

No Correlation between ChAd-MVA Dose Interval and Antibody Titre

Exceptional CD8+ T Cell Potency with 1 Week Prime-Boost Interval

Further Vectored Ebola trial in Oxford PI: Matthew Snape Prime boost study using –Ad26 ZEBOV –MVA-BN –Johnson & Johnson-sponsored Ad26 - MVA and MVA - Ad26 –Four or eight week interval –Excellent immunogenicity with both regimens 72 volunteers in total, started December 2014

ChAd3-MVA Progress July Update 46 MVA-BN boosted subjects in Oxford 27 MVA-BN boosted subjects in Mali 21 vaccinated in Oxford MVA-EBOZ trial 35 vaccinated in Dakar MVA-EBOZ trial Remarkable immunogenicity in UK and Africa - with a satisfactory safety profile

Vesicular Stomatitis Virus Vector another vaccine approach for Ebola A rhabdovirus vector Single dose efficacy in short term challenges in macaques Replication competent! Previously used only in two lab workers New Link Genetics & Public Health Agency of Canada - WHO - Merck

VSV Ebola Vaccine Progress: Safety Trials from 5 sites reported in April 2015 –170 subjects in total 51 in Geneva, Switzerland 40 in Maryland, USA 39 in Lambarane, Gabon 20 in Kilifi, Kenya 20 in Hamburg, Germany Viraemia in 94% of subjects Fever in 35% Arthritis in 11/51 vaccinees in Geneva –Fewer at other sites Three doses compared Agnandji et al., Regules et al. NEJM April 2015

Field Trials in West Africa 1.27,000 subjects in Liberia –ChAd3 and VSV single dose regimes 2.8,000 healthcare workers in Sierra Leone –VSV 3.9,000 ring vaccinated subjects in Guinea –i) VSV and ii) ChAd3 +/- MVA 4.>40,000 subjects in Sierra Leone –Ad26 - MVA

Declining Case Incidence

Initial Efficacy Data April to July, 2015, Guinea, Ebola ça Suffit trial 90 clusters, total population of 7651 people included in the planned interim analysis. 48 of these clusters were randomly assigned to immediate vaccination with rVSV- ZEBOV, and 42 clusters randomly assigned to delayed vaccination with rVSV-ZEBOV. Immediate vaccination group no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, Delayed vaccination group 16 cases of Ebola virus disease from seven clusters Vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing Henao-Restrepo et al., Lancet, 2015

Comparing Immunogenicity Ewer et al. manuscript submitted Assays performed by Thomas Strecker Stefan Becker Institut für Virologie University of Marburg

Some Outbreak Pathogens “The Known Knowns” Ebola virus Chikungunya virus Marburg virus Rift valley fever virus MERS coronavirus Pandemic influenza SARS coronavirus Lassa virus Crimean-Congo hemorrhagic fever virus Enterovirus 71 Hendra virus Monkeypox virus Nipah virus Venezuelan equine encephalitis virus West Nile virus No licensed human vaccine for any of these!

Will There Be More Major Outbreaks? Almost certainly! –More people, especially in Africa –Bigger cities –More long distance travel –Many viruses lurking –And new viruses like SARS

An Alternative Route for Licensure of Vaccines against Outbreak Pathogens Demonstrate efficacy in a suitable animal model Identify immunological correlates of efficacy Demonstrate in clinical trials that these immune responses can be achieved safely Develop an adequate safety database –In thousands of subjects –In diverse populations Have plans in place to test the vaccines if an outbreak occurs

A Suggested Way Forward for Outbreak Pathogens Vaccine development to phase II trials for all of these pathogens –Safety and immunogenicity as for Ebola –Largely public funding –Preferably a common manufacturing platform Vaccine stockpiles held in affected regions –10,000 to 50,000 doses –Emergency use approvals and efficacy evaluation –Learn from existing stockpiling strategies

PM to pledge £20m to tackle future pandemic threat 7 June 2015

Conclusions Rapid clinical trial responses to outbreak pathogens are possible –the Ebola response speed has been unprecedented –but there is room for improvement Many viral threats exist against which we have no human vaccines –a new strategy is required to develop these vaccines, for which the business case is weak

Acknowledgements Jenner Pre-Clinical NIAID, NIH UK Clinical Trials Alison Turner Barney Graham Adrian Hill Alex Spencer Rick Koup Ruth Payne Tess Lambe Nancy Sullivan Felicity Hartnell Nick Edwards Navin Venkatraman University of Dakar Danny Wright CVD Mali, BamakoBirahim Ndiaye Georgie Bowyer Samba Sow Souleymane Mboup Rachel Roberts Myron Levine Tommy Rampling Emergent Biosolutions Alison Lawrie Marburg University Eric Balsley Babatunde Imoukhuede Thomas Strecker Rick Welsh Katie Ewer Stephan Becker Eleanor Berrie WHO Bavarian Nordic GSK Vaccines Marie-Paule KienyPaul Chaplin Ripley Ballou Vasee MoorthyAriane Volkmann François Roman