Ebola: Progress with Vaccines - PowerPoint Presentation

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Ebola: Progress with Vaccines

Pandemics and Emerging Infections

Sarah Gilbert, Jenner Institute, University of OxfordSlide3

THE JENNER INSTITUTE

a partnership between Oxford University and

the Pirbright

Institute

- Developing innovative vaccines- Partnering with industry

- Driving the One Health agenda

THE

JENNER INSTITUTE Slide4

Human

Vaccines Pipeline

Disease Area

Number

of GMP

Vaccines

Preclinical

Phase

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     RSV3Ebola 4    Prostate cancer  2       Staph aureus

The busiest pipeline of any non-profit vaccine instituteSlide5

Ebola in West Africa, 2014

Epidemic in Guinea, Liberia, Sierra Leoneinternational public health emergency declared in August 2014

28, 295 cases, 11, 295 deaths by September 2015No vaccines, no drugs licensedTwo vaccines had shown single dose efficacy in macaquesChimpanzee adenovirus vector

Vesicular stomatitis virus vectorSlide6

Adenovirus-Based Vaccine against EbolaSlide7

This Ebola Vaccine, ChAd3 EBO Z, induces strong

immune responses in non-human primates

Experimental design

10

10

or 10

11

vp

ChAd3 (N=4)

Weeks

0

4

5

Plasma

IgG

ELISA

PBMC ICS

1000

pfu

ZEBOVChAd3 induced anti-GP IgG titers above the level that predicts 100% protection for an Ad5 vaccineAd5 averageB cell response ChAd3 induces high levels of anti-Ebola GP CD4 and CD8 T cellsT cell responseAd5 averageAd5 averageStanley et al. Nat Med 2014Slide8

%

P

r

o

t

e

c

t

io

n

100

80

60

40

20 0 Ad51010 vpChAd31010 vpAcute protectionA Single Injection of 1010 vp ChAd3 EBO Z Fully Protects Macaques from Ebolavirus Ebolavirus challenge Vaccinate

ChAd

Ebo

l

a

G

P

n =

4

/

g

r

oup

W

ee

k

s

:

0

1

2

3

4

5

One year

Ebolavirus

challenge

Ebo

l

a

v

ir

us

ch

all

en

g

e

Stanley et al.

Nat Med

2014Slide9

%

P

r

o

t

e

c

t

io

n

Durable protection

100

80

60

40 20 0 Ad5 ChAd3Acute protectionChAd3/MVA ChAd3-ZEBOV prime/MVA-ZEBOV boost induces 100% protection from EBOV at one yearEbolavirus challenge Vacci

n

a

t

e

ChAd

Ebo

l

a

G

P

n =

4

/

g

r

oup

W

ee

k

s

:

0

1

2

3

4

5

One year

Ebolavirus

challenge

Ebo

l

a

v

ir

us

ch

all

en

g

e

Slide10

Accelerated Ebola Vaccine Development

Chimpanzee adenovirus 3 vaccine chosen

WHO / Oxford / Wellcome / GSK / Okairos / NIH planPhase I in Oxford mid-September: 60 volunteersPhase I in Mali: 80 volunteersParallel manufacturing of 20,000 doses of ChAd3 EBO Z

ObjectivesSafety data in 140 volunteers, especially healthcare workersImmunogenicity comparable to protected macaquesDecision on whether to deploy in phase III: December 2014

Primary target population: healthcare workersSlide11

Oxford Ebola Vaccine Trial

First vaccination 17 September 2014Three doses assessed in 60 vaccinees by 18 NovemberApproval to immunise in West Africa given by Data Safety Monitoring Board by 4 October 2014Slide12

Ebola Vaccine Trial Timeline

14 August Grant application submitted26 August Award letter

30 August Vaccine filled2 September Trial file submission to UK regulator5 September Ethics meeting8 September Ethical approval9 September Regulatory approval

11 September Vaccine shipping15 September Vaccine labelled16 September Trial contract signed17 September 1st vaccinee

18 November 60th vaccineeSlide13

First Volunteer in Bamako, Mali

CONFIDENTIALSlide14

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 USASome arm soreness, rarely fevers, but well toleratedSimilar to other ChAd vectors and most other vaccinesSlide15

EBOZ Antibody Immunogenicity

ADI ELISA

Mean antibody level: 235 402 469

= response rate

3700 was the correlate of protection in macaques

Rampling et al. NEJM January 2015Slide16

Viral Vector Vaccines

to Maximise Immunogenicity

Adenovirus Prime

MVA Boost

8 weeks

-

Malaria, HCV, HIV, influenza, TB, RSV, Ebola Slide17

Two MVA

ProductsMVA-BN FiloUsed in

the first Oxford trialGlycoproteins of Zaire and Sudan strain of EbolavirusAlso 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 fibroblastsSlide18

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 levelDose either 1.5 x108 or 3 x 108 pfuMVA was well tolerated

in Oxford and subsequently in MaliSlide19

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

>Slide20

No Correlation between

ChAd

-MVA

Dose Interval and Antibody TitreSlide21

Exceptional CD8+ T Cell Potency

with 1 Week Prime-Boost IntervalSlide22

Further Vectored Ebola trial in Oxford

PI: Matthew Snape Prime boost study using

Ad26 ZEBOV MVA-BN Johnson & Johnson-sponsoredAd26 - MVA and MVA - Ad26Four or eight week intervalExcellent immunogenicity with both regimens

72 volunteers in total, started December 2014Slide23

ChAd3-MVA Progress

July 15 2015 Update46 MVA-BN boosted subjects in Oxford

27 MVA-BN boosted subjects in Mali21 vaccinated in Oxford MVA-EBOZ trial35 vaccinated in Dakar MVA-EBOZ trialRemarkable immunogenicity in UK and Africa - with a satisfactory safety profile

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Vesicular Stomatitis Virus Vector

another vaccine approach for Ebola

A

rhabdovirus

vectorSingle dose efficacy in short term challenges in macaques

Replication competent!Previously used only in two lab workersNew Link Genetics & Public Health Agency of Canada - WHO - MerckSlide25

VSV Ebola Vaccine Progress: Safety

Trials from 5 sites reported in April 2015170 subjects in total

51 in Geneva, Switzerland40 in Maryland, USA39 in Lambarane, Gabon20 in Kilifi, Kenya

20 in Hamburg, GermanyViraemia in 94% of subjectsFever in 35%Arthritis in 11/51 vaccinees in GenevaFewer at other sites

Three doses compared

Agnandji et al., Regules et al. NEJM April 2015Slide26

Field Trials in West Africa

27,000 subjects in Liberia

ChAd3 and VSV single dose regimes8,000 healthcare workers in Sierra LeoneVSV

9,000 ring vaccinated subjects in Guineai) VSV and ii) ChAd3 +/- MVA>

40,000 subjects in Sierra LeoneAd26 - MVASlide27

Declining

Case IncidenceSlide28

Initial Efficacy Data

April to July,

2015, Guinea, Ebola ça Suffit

trial90 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, 2015Slide29

Comparing Immunogenicity

Ewer et al. manuscript submitted

Assays performed by

Thomas

Strecker Stefan BeckerInstitut für

VirologieUniversity of MarburgSlide30

Some Outbreak Pathogens

“The Known Knowns”

Ebola virusChikungunya

virusMarburg virus

Rift valley fever virusMERS coronavirusPandemic 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!Slide31

Will There Be More Major Outbreaks?

Almost certainly!

More people, especially in AfricaBigger citiesMore long distance travelMany viruses lurkingAnd new viruses like SARSSlide32

An Alternative Route for

Licensure of Vaccines against Outbreak PathogensDemonstrate efficacy in a suitable animal model

Identify immunological correlates of efficacyDemonstrate in clinical trials that these immune responses can be achieved safelyDevelop an adequate safety database In thousands of subjects In diverse populationsHave plans in place to test the vaccines if an outbreak occursSlide33

A Suggested Way Forward

for Outbreak Pathogens

Vaccine development to phase II trials for all of these pathogensSafety and immunogenicity as for EbolaLargely public fundingPreferably a common manufacturing platformV

accine stockpiles held in affected regions10,000 to 50,000 dosesEmergency use approvals and efficacy evaluationLearn from existing stockpiling strategiesSlide34

PM to pledge £20m to tackle future pandemic threat

7 June 2015 Slide35

Conclusions

Rapid clinical trial responses to outbreak pathogens are possiblet

he Ebola response speed has been unprecedentedbut there is room for improvementMany 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 weakSlide36

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 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 Kieny Paul Chaplin Ripley Ballou Vasee Moorthy Ariane Volkmann François Roman