Immune Correlates of Risk of TB Disease
in BCG Vaccinated infants
Helen Fletcher
Senior Lecturer, Infection & Immunology Department
Director, LSHTM TB Centre
BCG efficacy by age and previous exposure to mycobacteria
infant
•
•
•
First given in 1921
0-80% efficacy
Reasons for variability?
– Variations in BCG
strain
– Geographical
location
– exposure to
mycobacteria
Skin test negative children 
Skin test positive children X
Skin test negative adult X
Skin test positive adult X
Punam Mangtani et al. Clin Infect Dis. 2014;58:470-480
Transcriptional profiling identified 2 major immune response clusters in BCG
vaccinated infants from South Africa
Cluster 1
Cluster 2
CD4+ T Cell Cytokine (%)
p = 0.0323
0.0112
0.0028
0.0085
1.5
1.0
0.5
Fletcher, Nemes, Filali submitted
TN
IF
N
Fα
γ+
+
IL
2+
TN
Fα
+
+
IL
2
IF
N
γ+
0.0
Monocyte to T cell ratio
AMPK
Oxidative phosphorylation
0.0214
30
CD14+monocytes(%of CD45+cells)
60
40
20
20
10
C
a
se
s
C
a
se
s
C
T
R
C
a
se
s
C
a
se
s
0
M1
•
Translation
M1
Differences in CD14+ and CD3+ frequency
between clusters
•
Differences in monocyte phenotype
•
Differences in the effectiveness of a
booster TB Vaccine?
Treg
Fletcher, Nemes, Filali submitted
0.1068
0.0224
0
Cluster 2 cases Cluster 1 cases
0.0365
80
CD3+Tcells(%of CD45+cells)
M2
0.6552
0.0412
C
T
R
Platelets
Birth
BCG
16-24 weeks
MVA85A or placebo
ADAPTIVE IMMUNITY
PBMC stored from ~2700 infants
Before immunisation and +28 days
• 71 infants developed TB in next 3 years (cases)
• 213 matched controls (controls)
1-3 years
Infants separate into distinct clusters – differences in monocyte genes
SFC/million PBMC
1100
600
100
50
E.
B
E. CG
B 1
C
E. G
PP 2
E. D
P 1
E. PD
10 2
E. 34
10 1
E. 34
E 2
E. BV
E 1
E. BV
C 2
E. MV
C 1
M
E. V
FL 2
E. U
FL 1
U
2
0
Frequency of live cells
30
p=0.007
20
p=0.024
10
MVA85A immunogenicity and efficacy by cluster?
Muller, Fletcher in preparation
Cluster 1
Cluster 2
N
.M
O
C
C
.M
O
N
1
N
I.M
O
I.M
O
N
1
0
T-cell activation and BCG IFN-g ELISPOT are immune
correlates in BCG-vaccinated infants
HLA-DR+ CD4+ T-cells
BCG-IFN- ELISPOT
400
OR 1.828, p = 0.002
10
OR 0.502, p = 0.013
300
SFC/million PBMC
log frequency of live cells
100
200
150
100
50
1
control
control
case
case
0
control
case
Result significant if Conditional Logistic Regression P<0.05 and FDR<2
Shaded bar indicates medium third of immune response level
Measured in healthy infants up to 3 years before disease develops
Fletcher HA et al Nature Communications, In Press
CD4 T cell activation also associated with risk of disease in adolescents
progressor
control
Time to TB diagnosis
Any
OR
95% CI
P value
1.387
1.068, 1.801
0.014
< 18 months
1.402
1.067, 1.843
0.015
< 12 months
1.537
1.106, 2.135
0.01
s < 6 months
1.501
1.047, 2.152
0.027
Fletcher et at Nature Communications in press; Zak et al Lancet in press
Also Type I IFN
associated
transcriptomic
signature
Type 1 IFN transcriptomic signature
associated with risk of disease
1500
1000
SFC/million PBMC
500
Strong
responses
to CMV in
~25% of
infants
100
80
60
40
20
se
ca
FL
U
V
M
tr
ca
se
e
C
EB
V
cn
U
FL
ca
s
l
l
cn
V
C
M
EB
V
cn
tr
tr
l
0
Controls
Cases
CMV-
152
44
CMV+
33
15
fisher one sided p = 0.138
Muller J et al,
unpublished data
Summary
• T cell activation associated with increased risk in infants and adolescents
• Type I Interferon signalling associated with increased risk in infants and
adolescents
• CMV associated with T-cell activation
• The challenge for TB vaccines is the co-factors impacting host immune response
BCG efficacy good
Mangtani et al
Pre exposure
vaccine
Environmental exposure/LTBI/viral infection/T cell activation
BCG efficacy poor
Mangtani et al
Helen McShane
University of Oxford
SATVI
Elisa Nemes
Michele Tameris
Mark Hatherill
Tom Scriba
Greg Hussey
Adam Penn-Nicholson
Hassan Mahomed
Willem Hanekom
Rafick-Pierre Sekaly
Ali Filali
AERAS
Bernard Landry
Peggy Snowden
Bruce McClain
Tom Evans
MVA85A Study team
All the mothers and babies