Remarkable durability of Ag85A-specific
CD4 T cell memory responses up to 6
years after MVA85A vaccination
Thomas J. Scriba
Institute of Infectious Disease and Molecular Medicine
University of Cape Town
Immune response
Analysis of vaccine-induced immunity
Why do we focus on the early response?
• Kinetics of response
• Magnitude of peak response
• Character of induced response
• Practical
Time (months)
Vaccine
What is the character of the immune response
induced by MVA85A?
Infants, aged 5-12 months
What is the character of the immune response
induced by MVA85A?
Infants, n = 18 per dose
5 X 107 pfu of MVA85A
New TB vaccines induce T cells of
distinct patterns
MVA85A
A402
M72
HyVac4
Dominant CD4 T
cells
IFN-γ+IL-2+TNF
No dominance
IFN-γ+IL-2+TNF;
IFN-γ alone
IL-2+TNF
CD4 IL-17
induction?
IL-17+IFN-γ+IL2+TNF
None
IL-17 alone
Very few
CD8 T cell
induction?
None
Potent
Some
None
Viral vectored
Subunit + Th1 adjuvants
Nazma Manoor, Erica Smit, Cheryl Day, Brian Abel, Willem Hanekom, many
others at SATVI; whole blood incubated with peptide pool of vaccine
antigen for 12 hours.
Immune response
What happens later?
Time (years)
Vaccine
Long-term
follow-up
of MVA85A
vaccine recipients
Time between
screening
and long-term
follow-up visit
2250
6
1750
1500
4
1250
3
1000
750
2
500
Years post-screening
5
TB
01
1
s
nt
fa
In
re
n
ld
hi
le
do
A
C
sc
du
en
l ts
ts
1
A
Days post-screening
2000
Hawkridge et al., JID 2008
Scriba et al., EJI 2010
Scriba et al., JID 2011
TB
01
01
01
TB
TB
TB
01
01
01
01
1
1
1
1
A
A
A
A
nt
nt
G
G
G
G
4
3
2
1
(1
(1
(1
(1
2)
2)
2)
2)
6)
6)
6)
6)
(3
(3
(3
(3
4)
24
l ts
l ts
l ts
l ts
3
2
1
bo
G
G
G
(2
2)
4)
(1
(2
Number
27
du
du
du
du
s
re
n
ac
e
fa
fa
Pl
In
In
nt
4
4
ld
nt
hi
ts
en
t
du
l
sc
A
fa
C
le
8
In
4
4
01
do
00
In
fa
TB
4
TB
TB
TB
TB
A
TB
00
8
01
TB
Analysis
of vaccine-induced immunity
Number of participants at long-term follow-up visits
Not M.tb infected
M.tb infected
21
18
15
12
9
6
3
0
How durable are MVA85A-induced T cell responses?
Infants vaccinated with 2.5 X 107 pfu MVA85A
How durable are MVA85A-induced T cell responses?
Infant responses >3 years after MVA85A vaccination
Vaccine dose
Character of the MVA85A-induced
CD4 T cell response?
Infants Ag85A Th1 Cytok
Cytokine+ CD4 T cells (%)
0.12
Group 1 (2.5 X 107 pfu)
Group 2 (5 X 107 pfu)
Group 3 (1 X 108 pfu)
Placebo
0.09
0.06
0.03
0.00
IL-2
IFNg
TNFa
+
+
+
+
+
-
+
+
+
+
+
-
+
-
+
Character of the MVA85A-induced CD4 T cell response?
1.0
400
r = 0.629
p = 0.0004
200
100
0.6
0.4
0.2
SFC per million PBMC (day 84)
8
200
16
150
84
100
28
50
7
0.0
0
0
0
p > 0.05
p < 0.05
p < 0.01
0.8
300
Spearman r
SFC per million PBMC (day >1000)
Can we predict the durability of T cell responses?
Days post-vaccination
Can we predict the durability of T cell responses?
5 X 107 pfu
0.8
0.4
Days post-vaccination
Vaccine dose
0
8
16
84
28
16
Days post-vaccination
7
0.0
0
0.0
8
0.0
84
0.2
28
0.2
7
0.2
8
0.4
0.6
16
0.6
84
Spearman r
Spearman r
0.8
0.4
1.0
p > 0.05
p < 0.05
p < 0.01
28
1.0
0.6
0
Spearman r
1.0 p > 0.05
p < 0.05
0.8 p < 0.01
1 X 108 pfu
7
2.5 X 107 pfu
Days post-vaccination
What can we learn?
• The early response does not necessarily
predict long-term immunity
• Magnitude
• Pattern of cytokine expression
• Durability of the response
Michele Tameris
Erica Smit
Yolanda Brown
Lebohang Makhethe
Alana Keyser
Jane Hughes
Wendy Whatney
Many others!
Ashley Veldsman
Hennie Geldenhuys
Mzwandile Erasmus
Marwou de Kock
Mark Hatherill
Linda van der Merwe
Hassan Mahomed
Willem Hanekom
Helen McShane
Nathaniel Brittain
Alison Lawrie
Adrian Hill
Others
EuropeAID