The MVA85A Phase IIb study in South African

infants- what can we learn from this

TB vaccine efficacy trial?

Helen Fletcher, PhD Senior Lecturer in Immunology, London School of Hygiene and Tropical Medicine

Rappuloi and Aderem, Nature 2012

Why is TB vaccine development so difficult?

TB vaccines - BCG

• Live attenuated M.bovis

• First given in 1921

• Administered at birth in endemic countries

• 0-80% efficacy

• Reasons for variability?

– Variations in BCG strain

– Geographical location and exposure to environmental non-tuberculous mycobacteria

– Nutrition

• BUT protects against disseminated TB, TB meningitis in children, and leprosy

• Safety issues in immunosuppressed individuals

Modified vaccinia Ankara (MVA) Poxvirus

No replication in mammalian tissues

Good T cell boosting vector

Excellent safety record

M.tb antigen 85A Mycolyl transferase

Major target antigen

Protective in small animals

In all environmental mycobacteria

Doesn’t interfere with new diagnostic tests

MVA85A

BCG Prime – MVA85A Boost

Vaccines encoding the same antigen, are given several weeks apart

Highly effective at inducing high levels of antigen specific T cells

BCG prime

boost

Time

T c

ell

resp

onse

Scr

een

W1

W2

W4

W8

W12

W24

1

10

100

1000

10000

log

SF

C m

illio

n

Scr

een

W1

W2

W4

W12

W24

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UK high dose (1 x 108 pfu)

Immune responses in UK Adults

MVA85A can improve BCG induced protection

in preclinical animal models

Vordermeier M et al, I&I 2009

CATTLE

NHP

Verreck et al, PLoS ONE 2009

GUINEA

PIGS

Williams et al, I&I 2005

Goonetilleke et al, JI 2003

MICE

www.thelancet.com Published online February 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60177-4

• The first efficacy trial with a new TB vaccine in infants since BCG • BCG last tested in infants in 1968 • The first efficacy trial of a subunit TB vaccine

Trial design

• Infants randomised to MVA85A (1 x 108pfu) or placebo (candin)

• All infants followed up 3 monthly after enrolment until study completed

• Any child with TB exposure/symptoms admitted to CV ward for investigation – 507 (36%) of BCG-MVA85A group – 510 (37%) of BCG alone group

• Trial powered on TB disease to see 60% improvement over

BCG alone (with 90% power) – Follow up extended to reach target endpoint accrual

• M.tb infection endpoint using QFT conversion

Reasons for screening failure in TB20 Trial

• Changed protocol to recruit from home rather than at clinic • Trained phlebotomy staff • Recruited more nurses and field workers

TB020 – SAE’s (Serious adverse events)

• During trial we expected to see

– 300 SAEs

– 60 deaths

• We saw

– 618 SAEs and 417 (64%) were lower respiratory tract infection or gastroenteritis

– 37 deaths

– 25 deaths were prior to vaccination

– 7 in the MVA85A group (2 x kwashiorkor, 2 x meningitis, 1 gastroenteritis, 1 drowning, 1 sudden death)

– 4 in the placebo group (2 x gastroenteritis, 1 x lower respiratory tract infection, 1 x encephali)

Efficacy

TB Endpoint Definition

1. Isolation of M tuberculosis from any site

2. Identification of M tuberculosis by an approved molecular diagnostic test

One of each of the following:

Evidence of mycobacterial infection

AND

radiographic findings compatible with tuberculosis

AND

clinical manifestations compatible with tuberculosis

MVA85A vaccine efficacy

Placebo

(n=1395)

MVA85A

(n=1399)

Vaccine Efficacy %

(95% CI)

Endpoint #1 (Primary) 39 ( 2·8) 32 ( 2·3) 17·3%

(-31·9 to 48·2)

QFT Conversion 177 178 -3.8%

(-28.1-15.9)

Tameris et al 2013

Immunogenicity

0 7 0 70

100

200

300

400400

1200

2000 PlaceboMVA85A

Days post-vaccination

SF

C p

er

millio

n P

BM

C

Ag85A-specific T cell responses:

IFN-g ELISpot, 7 days post-vaccination

Tameris M et al, Lancet 2013

Median 136 spm

0.00

0.02

0.04

0.06

0.08

0.10

0.15

0.20

0.25 PlaceboMVA85A

IFN-g

TNF-a

IL-2

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ine

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0.015

0.020

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IL-1

7+ C

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T c

ells

(%

)

Ag85A-specific T cell responses:

Whole blood ICS, 28 days post-vaccination

Tameris M et al, Lancet 2013

Discussion

• Immunogenicity ‘modest’

– Significantly lower (up to 10 fold) than in UK adults

– Immature immune system?

• Immune response not sufficient to boost efficacy?

• Need more or something different?

Impact of length of follow up

• All follow up (median 24.6 months, IQR 19.2-28.1) – VE 17.3% (CI -31.9 to 48.2)

• Follow up truncated at 24 months – VE 23.9% (CI -27.9 to 54.7)

• Follow up truncated at 12 months – VE 37.7% (CI -37.2 to 72.8)

• No significant efficacy at any time point

• Not possible to detect early effect with current design of efficacy trials

Tameris M et al, Lancet 2013

Assays for immune correlates of risk analysis

Transcriptional analysis •Illumina HT12 arrays •RNA Seq •Fluidigm/qPCR for biomarkers identified in BCG infant study* Functional Assays •Growth inhibition assays with BCG and MTB Immune Assays •IFN-γ ELISPOT assays (UNS, PHA, BCG, 85A) •Antibodies on serum samples •Luminex on supernatants from above assays*

Cellular phenotyping •Cell surface flow cytometry for lymphoid and myeloid cells •Markers of acitvation, exhaustion, T cell regulation* •ICS flow cytometry for IFN-g, TNFα, IL2, IL17*

*Secondary assays to be performed on stored supernatant

Mycobacterial growth

inhibition assays

BCG Pasteur

WB/PBMC/Splenocytes

CFU counts

• Measures the summative ability to control mycobacterial growth • No knowledge of underlying immune mechanism required

Mycobacterial growth correlates with flow HLA-DR+CD14+CD16- classical monocytes

(Day -7)

Cases and controls from MVA85A efficacy trial

Blinded samples MVA85A vaccinated cases and controls and placebo cases and controls

IFN-γ ELISPOT Responses (n=189-289)

• No efficacy with MVA85A

• Stronger immune responses needed or different type? • Immune correlates of risk analysis should provide

some further insight

Summary

MVA85A Acknowledgements

Michele Tameris Mark Hatherill Tom Scriba Greg Hussey Hassan Mahomed Willem Hanekom

Bernard Landry Peggy Snowden Bruce McClain Tom Evans

Oxford Emergent Tuberculosis Consortium Jacqui Shea Steve Lockhart

MVA85A Study team All the mothers and babies

Helen McShane