mechanisms of attenuation and protection of...
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MECHANISMS OF ATTENUATION AND PROTECTION OF MTBVAC:
a live attenuated TB vaccine moving to clinical efficacy trials in endemic countries
Carlos Martín, Nacho Aguilo, Jesús Gonzalo Asensio, Dessi Marinova (UNIZAR) Eugenia Puentes, Juana Doce, Ingrid Murillo (BIOFABRI)
Breakout Session 3: Novel Vaccine Concepts and Preclinical Research Thursday, 22 February 2018
Breaking Transmission with Vaccines: The Case for Tuberculosis
Individuals with LTBI had 79% lower risk of Progressive TB after reinfection than uninfected individual Andrews et al CID 2012
Lytic cycle of lambda phage, similar to active TB disease Lysogenic cycle of lambda phage, resembles LTBI
RD1 (ESAT6/CFP10)
TB INFECTION only 5-10% will develop TB disease!
Gonzalo et al Microbiology Spectrum 2017
Ag85B early expressed during infection
ESTA-6 constantly expressed during all infection
M. tuberculosis Vaccine Antigens, Ag85B and ESTA-6, are differentially expressed during infection
Moguche A., M. Musvosvi, A. Penn, C. Plumlee, H. Mearns!!!! W. Hanekom, M. Hatherill, P. Andersen, T. Scriba, K. Urdahl
2017
It is difficult to overcome the response induced by M. tuberculosis infection
Clinical Trial H1 IC31: Ag85B + Esat6
Ag85B!
TNF-
a+IL
-2+
CD4
T c
ells
.!
"#$%!&'!
Trial H1 IC31: Ag85B + Esat6
H1:IC31 vaccination is safe and induces long-lived TNF-a+IL-2+CD4 T cell responses in MTB infected and uninfected adolescents. Mearns H., H. Geldenhuys, B. M. Kagina , M. Musvosvi , F. Little, F. Ratangee , H. Mahomed , W A. Hanekom , S T. Hoff,M. Ruhwald , I. Kromann , P. Bang, M. Hatherill, P. Andersen, T. J. Scriba, the THYB04 study group Vaccine 2017
Esat6
ESAT6 response was too low in majority of QFT- individuals
RATIONALE FOR DEVELOPING MTBVAC Following Pasteur’s postulates for attenuated vaccines. Learning from BCG
!! ATTENUATE A PATHOGEN FROM HUMAN ORIGIN
!! SELECTE A WORLWIDE DISTRIBUTED M. tuberculosis CLINICAL ISOLATE
!! WHICH GENE(S) TO INACTIVATE? phoP !!!!fadD26
!! AVOID LABORATORY SUBCULTURE: INDUSTRIAL PARTNER
PRECLINICAL & PROOF-OF-CONCEPT STUDIES (2001-2012)
ATTENUATION, PROTECTION & IMMUNOGENICITY
INDUSTRIAL DEVELOPMENT FREEZE-DRIED MTBVAC (2008-2011)
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Eugenia Puentes
MTB GENETIC TOOLS 1987-1992 WHO 1992-2000 EU EU FP3/FP4
Brigitte Gicquel
Douglas Young “road map”
MTBVAC
MTBVAC
vs. H37Rv
~ 4.4 Mb
phoP fadD26
CDT: Clinical Development Team TBVI PDT: Product Development Team TBVI
Jelle Thole
Esteban Rodriguez
FIRST GENEVA CONSENSUS CRITERIA: CONSTRUCTION OF MTBVAC NO ANTIBIOTIC RESISTANCE MARKERS
TWO STABLE INDEPENDENT MUTATIONS
9E1"FG!!HEFE/0!1"F9EF9I9J!Criteria for further Clinical Development Phase 1 to 3!
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Gonzalo-Asensio et al. PLoS ONE 2008
Transcription factor PhoP plays an essential role in MTB virulence ~2-4% ORFS MTB genome under PhoP control (microarrays) :
mainly genes implicated in virulence or inmunomodulation
(! (!
-
PhoP Frigui et al. PLoS Path 2008
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Frigui et al. PLoS Path 2008
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Gonzalo Asensio et al. JBC 2006
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Gonzalo Asensio et al. JBC 2006
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Marcel Behr
Roland Brosh
MECHANISMS OF ATTENUATION OF MTBVAC:
Jesus Gonzalo
Brigitte Gicquel
Stewart Cole
M. tuberculosis MTBVAC
PhoP phoP
mutant
mcr7
P P
mcr7
Mg2+, Cl-, pH ?
Modified from Broset et al mBio. 2015 Solans et al. PLoS Pathogen 2014 Gonzalo et al Plos One 2008
P P P P
pks2
pks3
P P
P P
pks2
pks3
SL
DAT
PAT
tatC translation inhibition
TAT
Ag85A and C
TAT TAT TAT TAT
espA
P P
ESAT-6 espA
ESAT-6
PhoR P P
PhoR LAM
CONSEQUENCE OF fadD26 DELETION: loss of major virulence factor PDIM
PDIM + PDIM-
MECHANISMS OF ATTENUATION AND PROTECTION OF MTBVAC:
CONSEQUENCE OF phoP DELETION: loss of SL, PAT, DAT; impaired ESAT6 SECRETION and increased secretion of MTB antigens
M. canettii
Lineage 7 Lineage 1
Lineage 2 Lineage 3 Lineage 4 M. africanum Lineage 5
M. africanum Lineage 6
M. mungi
M. orygis
M. pinnipedii
M. microti
M. caprae
M. bovis
MRCA RD9
RD7 RD8
RD10
RD4
RD5
RD6
RD12 RD13
Hum
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mal
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mungimungi
orygismicroti
pinnipedii
caprae
M. t
uber
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BCG
D6!8V$+<V8*!
W!8V$+<V8*!
RD1 : 311 epitopes (PPE68/ESAT6/CFP10)
RD1
RD3
Marinova et al Expert Rev Vaccines 2017
MTBVAC " 1603 epitopes
MTBVAC, 519 MORE EPITOPES THAN BCG
BCG " 1084 epitopes
Gonzalo-Asensio et al Frontiers in Immunology 2017
MECHANISMS OF PROTECTION OF MTBVAC:
Improved protection of MTBVAC 67!89:;6<=>!?9!1@A!B7!67798B6?=>!!CB?D!/E8=FF!:=>B6?=>!<=7;9G7=!?9!@H+'#I.30/J
Aguilo et al 2017 Nature Communications
Nacho Aguilo
ESAT6 (RD1) A Double Edged Sword
Host immune system / Mycobacterium tuberculosis
RD1 (ESAT6/CFP10)
RD1 : 31FP10) 1 epitopes (PPE68/ESAT6/C
AFTER 100 YEARS OF BCG FIRST EFFICACY TRIAL OF A TB VACCINE!!
Tameris et al Lancet. 2013
TODAY STILL LEARNING FROM THIS CLINICAL TRIAL !
NF/E9-NH0-E!-KE!AE;0-N"F!.E-=EEF!X?-!1"F/EA9N"F!NF?P"!/0;IE9!0FG!AN9S!"?!-.!
Andrews et al Lancet Repiratory Medicine 2017
Andrews et al Lancet Respir Med 2017
QFT >4#00 IU/ml !
QFT 0#35 - 4#00 IU/ml!
QFT <0#35 IU/ml!
Percentage TB –free survival from day 336 study visit, stratified by quantitative QTF!
QFT - <0#35 IU/ml, QFT + 0#35-4#00 IU/ml NO ICREASED RISK OF DISEASE !
QFT + >4#00 IU/ml associated with substantially increased disease incidence
QFT conversion at interferon-" values between 0#35–4#00 IU/ml did not have significantly increased risk of TB disease
64DD! 64D6! 64DY! 64DZ!64D4!
CLINICAL DEVELOPMENT MTBVAC
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Long-term, real time stability studies
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PHASE Ib in NEWBORNS With a safety arm in adults (BCG+, PPD-, HIV-)
Spertini et al Lancet Respiratory Medicine 2015
ClinicalTrials.gov NCT02729571
ClinicalTrials.gov: NCT02013245
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CFP10 Elispot
ESAT6 Elispot
CFP10 and ESAT6-specific responses in MTBVAC-vaccinated humans
Positive cut-off for TB infection
Positive cut-off for TB infection
MTBVAC Phase 1a ADULTS Clinical Trial
Aguilo et al 2017 Nat Comm Vaccination with MTBVAC induces a CFP10-specific immune response in humans
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Michele Tameris Tom Scriba
Mark Hatherill
Helen Mearns
ClinicalTrials.gov NCT02729571
PHASE 1B DOSE-ESCALATION SAFETY AND IMMUNOGENICITY OF MTBVAC IN NEWBORNS (with a Safety Arm in Adults (MTBVAC-Ph1b))
MTBVAC VACCINATION
AT BIRTH ADULTS/ ADOLESCENTS
INFANT ADOLESCENT ADULT ELDERLY
Burden of TB
Transmission of TB
ROLE OF ADULTS/ ADOLESCENTS IN THE TRANSMISSION OF TB AND TB VACCINE STRATEGIES
EFFICACY EVALUATION OF A NEW TB VACCINE: IN NEWBORNS: A PRE-EXPOSURE VACCINES COULD ALLOW FOR RELIABLE EFFICACY DETERMINATION
IN ADULTS/ADOLESCENTS MORE IMPACT, BUT PREVIOUS SENSITIZATION TO BCG, MTB OR NTM COULD
HAVE POTENTIAL MASKING / BLOCKING EFFECTS
VACCINATION AT BIRTH (NEONATES): PHASE 2A Dose-Defining Safety and Immunogenicity Study and Capacity Building to Support Vaccine Efficacy Trials in TB-Endemic Regions of Sub-Saharan Africa.
PI. DR. MICHELE TAMERIS (SATVI) Expected trial initiation date: / 3rd Quarter 2018
Ingrid Murillo COORDINATOR
!!
! ! !!
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ClinicalTrials.gov Identifier: NCT02933281
RE-VACCINATION IN ADOLESCENTS / ADULTS: PHASE 2A
Randomized, Double-blind, Active-controlled, Safety, Immunogenicity, and Dose-escalation Study in Adults with and without Latent Tuberculosis Infection in South Africa.
PI !0FHE;NXIE!S0FL!S0FL!;I0.EL0!(SATVI)
Expected trial initiation date: 2rd Quarter 2018
Ann Ginsberg COORDINATOR
Dessi Marinova
A New TUBERCULOSIS VACCINE: LIVE VACCINES (Huge experience in the production, distribution and use of BCG)
Safer / Better than BCG
-
A New TUBERCULOSIS VACCINE:
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