Correlates in the real world
Hazel M Dockrell
London School of Hygiene & Tropical
Medicine
Improving health worldwide
www.lshtm.ac.uk
Usual exclusion criteria for studies of
TB immunology and correlates:
• Outside age range – too young or too old
• Already on TB treatment
• Pregnancy
• Diabetes
• HIV positive
• Other major co-morbidity or co-infection
(and we often don’t test for helminth infections,
control for seasonality etc)
Projected diabetes changes from 2015-2040
International Diabetes Federation Diabetes Atlas, 7th Edition, 2015
• Diabetes patients are
more susceptible to TB,
and harder to treat
• As many as 139 million
undiagnosed cases of
diabetes, 2/3 in Africa?
Concurrent Tuberculosis and Diabetes Mellitus
Unraveling the causal link, and improving care
Jackie Cliff, Clare Eckold, Dave Moore, Ulla Griffiths, Yoko Laurence
TB treatment response and prediction of TB relapse
after apparently successful cure:
will they be different in patients with TB and DM?
Diluted whole blood, stimulated
with M. tuberculosis for 6 days
weeks
668 genes
consistently
differentially
expressed
between relapse
and cured
patients in
ANOVA
Patients recruited at diagnosis of first
episode of TB, then followed up to see
who subsequently relapsed
Jackie Cliff J Infect Dis 2016; 213:485
Modulation of ex
vivo gene
expression with
TB treatment
(without
diabetes)
Cliff et al, J Infect.
Dis, 2013; 207:18
Serpin G1
BF
C2
C1QB
C1QA
C1QC
0
1
4
26
C1QBP
CD55
C3AR1
CD59
C5
CR1
CFD
C4BPB
CFH
C3
C4BPA
Prediction of relapse: 18
gene signature, based on
the most stringently
differentially expressed
genes in ANOVA, has high
predictive sensitivity and
specificity
Frequency CD4+FoxP3+
Frequency CD4+IFNγ+
Helminth infections decrease CD4 IFNg+ T cells and increase regulatory T cells
1.50
1.00
p = 0.0001
p = 0.0001
P = 0.01
0.50
0.00
10
Control Helminth
LTBI
Helminth -LTBI
p = 0.87
p = 0.124
p = 0.0001
p = 0.0001
8
6
4
2
0
Control Helminth
LTBI
Helminth -LTBI
Toulza, Tsang, Ottenhoff, Brown, Dockrell, Eur J Immunol 2016; 46:752
LTBI Latent TB infection; Hel helminth infection;
V1 pre treatment; V2 post treatment or same time point
Mycobacterial growth inhibition as an
unbiased measure of TB vaccine-induced
immunity
Straight to MGIT
reference tube
Sample A
Incubate diluted blood
and mycobacteria for
4 days
Sample B
Lyse cells, extract
remaining mycobacteria
and add to MGIT tube
Time to
positivity
(TTP) in
days
and
hours
Latent TB infection in mother: effect on infant response
to BCG vaccination
• LTBI in mother defined by positive TST and T-SpotTB test
• Transient effects but might still influence epigenetic changes
Mawa et al, Phil Trans Roy Soc B 2015; 370:20140137.
Biosignatures to identify progression to
disease:
Gates Grand Challenge GC6-74/GC6-2013
S. Kaufmann, MPIIB, G. Walzl, SUN/UCT
Signatures of early progression to disease can be identified; some of these
samples used to validate signatures from the Adolescent Cohort Study
(Hanekom , Scriba et al, Lancet in press)
Biosignatures can be developed that will work irrespective of setting
or HIV status
TB vs Other Diseases discrimination using 44 genes, in combined South African
and Malawian cohorts, HIV+ and HIV-ve: sensitivity 93%, specificity 88%,
positive predictive value 92%, negative predictive value 90%
Kaforou et al, Plos Med 2013: 10:e1001538
Some thoughts on correlates
and biosignatures
• Co-morbidity, co-infection and other factors including location and
seasonality will affect immune responses and gene expression
signatures
• Signatures can be developed that will work in different settings, with
different co-morbidities and co-infections
• In order to do this we need to collect the right sort of samples and
analyse the data in different ways
Thanks particularly to:
Jackie Cliff, Katharina Ronacher, Gerhard Walzl,
David Moore, Reinout van Crevel (TANDEM)
Shampa Anwar, Frederic Toulza, Ji-Sook Lee,
Jackie Cliff, Lilian Tsang, Christina Fernandez
Turienzo, Mike Brown (IDEA)
Patrice Mawa, Alison Elliott, Steve Cose
UVRI/MRC Entebbe (MRC/IDEA)
Mike Levin, Myrsini Kaforou, Victoria Wright,
(ILULU)
Funded by
EU FP7 TANDEM and IDEA (G.Pantaleo)
Gates Grand Challenge GC6-74/GC6-2013 (S.Kaufmann, G. Walzl)
EU FP7 ILULU (M.Levin)
MRC UK (A.Elliott)
Commonwealth Scholarships Commission