Ebola: Progress with VaccinesPandemics and Emerging Infections

Sarah Gilbert, Jenner Institute, University of Oxford

THE JENNER INSTITUTEa partnership between Oxford University and

the Pirbright Institute

- Developing innovative vaccines

- Partnering with industry

- Driving the One Health agenda

THE JENNER INSTITUTE

Human Vaccines Pipeline

Disease AreaNumber of GMP Vaccines

PreclinicalPhase I Phase IIa Phase Ib Phase IIb

Phase III Licensure

Oxford Patient Group /Endemic Area

Malaria 17  

     

 

 

TB 3    

   

 

 

HCV 3  

     

 

 

HIV 5    

 

 

   

Pandemic Flu 2  

 

 

   

Meningitis  1   

     

RSV 3

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 primatesExperimental design

1010 or 1011 vp ChAd3 (N=4)

Weeks 0 4 5

Plasma IgG ELISAPBMC 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

Ad5 average

Stanley et al. Nat Med 2014

% P

rote

ctio

n  

100

80

60

40

20

0

Ad51010 vp

ChAd31010 vp

Acute protection

A Single Injection of 1010 vp ChAd3 EBO Z Fully Protects Macaques from Ebolavirus

 

Ebolavirus challenge 

Vaccinate ChAd Ebola GP n = 4 /group 

Weeks:  0 1 2 3 4 5  One year

 

Ebolaviruschallenge

 

Ebolavirus challenge 

Stanley et al. Nat Med 2014

% P

rote

ctio

n  

Durable protection

100

80

60

40

20

0

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:  0 1 2 3 4 5  One year

 

Ebolaviruschallenge

 

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 August Grant application submitted

26 August Award letter

30 August Vaccine filled

2 September Trial file submission to UK regulator

5 September Ethics meeting

8 September Ethical approval

9 September Regulatory approval

11 September Vaccine shipping

15 September Vaccine labelled

16 September Trial contract signed

17 September 1st vaccinee

18 November 60th vaccinee

CONFIDENTIAL

First Volunteer in Bamako, Mali

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 ImmunogenicityADI ELISA

Mean antibody level: 235 402 469

= 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 x108 or 3 x 108 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 Potencywith 1 Week Prime-Boost Interval

Further Vectored Ebola trial in OxfordPI: 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 ProgressJuly 15 2015 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 Vectoranother 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 groupno 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 clustersVaccine 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 ImmunogenicityEwer et al. manuscript submitted

Assays performed byThomas Strecker Stefan Becker

Institut für VirologieUniversity 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 Forwardfor 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, Bamako Birahim Ndiaye Georgie BowyerSamba Sow Souleymane Mboup Rachel RobertsMyron Levine Tommy Rampling

Emergent Biosolutions Alison LawrieMarburg University Eric Balsley Babatunde ImoukhuedeThomas Strecker Rick Welsh Katie EwerStephan Becker Eleanor Berrie

WHO Bavarian Nordic GSK Vaccines Marie-Paule Kieny Paul Chaplin Ripley Ballou

Vasee Moorthy Ariane Volkmann François Roman