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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
1
10
100
1000
10000
log
SF
C m
illio
n
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
+++
++-
-++
--+
-+-
+--
+-+
Cy
tok
ine
+ C
D4
T c
ells
(%
)
0.000
0.005
0.010
0.015
0.020
0.025
IL-1
7+ C
D4
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