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M72/AS01E candidate vaccine development
Olivier Van Der Meeren, MDSenior Clinical R&D LeadGSK Vaccines
M72/AS01E : A fusion peptide and an adjuvant
Candidate vaccine
Skeiky et al, Inf and Immun 1999. Dillon et al, Inf and Immun 1999. Al-Attiyah et al, Clin Exp Immunol 2004. Garçon et al, Expert Rev Vaccines 2007.
Gey van Pittius et al, BMC Evol Biol 2006. Nair et al, J immunol 2009 and 2011. Lewinshon et al, Am J Respir 2002. J Immunol 2004;172(12):7618-28.
*QS-21: Quillaja saponaria Molina, fraction 21; Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., Lexington, MA, USA.
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Mtb32a C-term 192-323
(132aa)N-term C-term
Mtb32a N-term 1-195
(195aa)
Mtb39a full length
(391aa)
1 725
706Ser→Ala
MHH
EcoRI siteEF residues
EcoRV siteDI residues
138 528 53143 135
Mtb39A (PPE18, TbH9 , Rv1196) Mtb32A (PepA, Rv0125)
Membrane-associated protein Secreted protein
Putative evasion factor Putative Serine protease
Early expression Constitutive expression
Induces proliferation and production of IFN- by T cells
Expressed in BCG strains and M. tuberculosis
GSK Proprietary Adjuvant System : AS01E
Liposomes + MPL + QS-21* = Promotes Th1 response
(1) Von Eschen et al, 2009; (2) Leroux-Roels et al, 2010; (3) Spertini et al, 2012; (4) Leroux-Roels et al, 2012; (5) Montaya et al, 2013; (6) Day et al, 2013; (7) Tacher et al, 2014 ; (8) Penn-Nicholson et al , 2015; (9) Idoko et al, 2014; (10) Kumarasamy et al, 2016; (11) Gillard et al, 2016; (12) TB-019/NCT1669096.
Clinical phase 1/2 experience so far
Safety and immunogenicity assessed in a broad range of populations
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2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
MTB-001: Ph 1 FTIHAdults PPD-
USA(1)
TB-002: Ph I Adults PPD-Belgium(2)
TB-004: Ph I/IIAdults PPD+
Switzerland(3)
TB-010: PhIIAdults PPD +/-South Africa (6)
TB-005/008: Ph I/IIAdults PPD-Belgium (4)
TB-012: Ph II Adolescents
South Africa (8)
TB-013: Ph IIInfants (±EPI)The Gambia (9)
TB-019: Ph II Adults (BCG+ QFT-)
Belgium(12)
TB-014: Ph II Adults HIV+/- ±ART
India (10)
TB-009: Ph IIAdults PPD+ Philippines (5)
TB-011: Ph I/II Adults HIV+/ART+
Switzerland (7)
TB-017: Ph II Adults with TB disease Taiwan & Estonia (11)
Safe and well tolerated in the tested populations; more reactogenic in subjects with active TB disease
Induce a high-magnitude M72-specific CD4 polyfunctional response (IFNγ, IL2, TNFα, CD40L) that persists >1 year
3,500 adult male and female subjects
aged 18-50 years, who at baseline have:
o IGRA +
o HIV -
o Negative clinical screening questionnaire
o Negative sputum sample
Randomised 50/50 to receive, 2 intramuscular
injections one month apart of either:
o M72(10µg)/AS01E
o Placebo
Follow-up of 3 years for occurrence
of TB disease
With this sample size, assuming a
mean yearly attack rate of 0.55% in
the control group, the study has
80% power to detect vaccine
efficacy when 21 cases of
tuberculosis disease are accrued
Sub-cohort (n=450) provided blood
samples for immunogenicity, and
filled out diary cards for
reactogenicity
Proof of concept study TB-018 (NCT01755598)
A randomised, double-blind, placebo-control efficacy study
IGRA: Interferon Gamma Release Assay 4
Primary Outcome Measure
Incident cases of definite pulmonary TB disease not associated with HIV-infection meeting the
first case definition
Secondary Outcome Measures
Incident cases of TB disease meeting the secondary case definitions
Occurrence of SAEs, unsolicited AEs, solicited local and general AEs, and potential immune-
mediated diseases
Evaluation of CMI responses in terms of frequency of M72-specific CD4+/CD8+ T cells
expressing TNFα and/or IFNγ and/or IL-2 and/or CD40L after in vitro stimulation
Evaluation of humoral responses with respect to components of the study vaccine in terms of
M72-specific antibody titres and seropositivity rates
Occurrence of grade ≥ 2 haematological and biochemical levels
Study endpoints
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Case definitions
The primary endpoint will be analysed when 21 type-1 cases are accrued
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Case Definition Localisation Culture ResultGeneXpert
MTB/RifHIV status Other
1st Case Def.
= Primary ObjectivePulmonary Either or Both Positive Negative
Sputum sample taken
before treatment
2nd Case Def. Pulmonary Any Positive Negative
3rd Case Def. Pulmonary Either or Both Positive NegativeSputum sample taken
up to 4 week after
treatment start4th Case Def. Pulmonary Either or Both Positive Any
5th Case Def. Any Any Any AnyPhysician decided to
treat for Tuberculosis
Participating centres
A total of 11 sites across South Africa, Kenya and Zambia
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Kisumu (KEMRI)
Lusaka (ZAMBART)
Lusaka (CIDRZ)
Cape Town (TASK)
Khayalitsha (CIDRI)
Paarl (BePart)
Worcester (SATVI)
Soweto (PHRU)
Tembisa (AURUM)
Soshanguve (Setshaba)
Klerksdorp (AURUM)
8,336 subjects were screened and 3,573 were vaccinated between August 2014 and
October 2015
All subjects have now completed ≥15 months of follow-up
An independent safety review committee had regular unblinded access to safety data, and
allowed the study to continue unchanged
Accrual of clinical cases is ongoing, follow-up expected to end by 4Q2018
Primary analysis will be triggered earlier, as soon as 21 clinical endpoints have been
observed
Primary results are expected in the next few months
Study status
8
Collection of Biological Samples for Future Research to Evaluate Correlates of Tuberculosis
Ancillary biobank study C-041
9
Samples collected at regular intervals from subjects in TB-018 could provide valuable
information on the immune profiles of subjects who develop TB disease – correlates of
risk, and, if the vaccine is efficacious – correlates of protection.
Plasma, peripheral blood mononuclear cells (PBMCs) and blood for RNA transcriptomics
are collected and stored pre-vaccination, Day 37, Month 6 and Month 12 (not PBMCs).
Samples have been obtained from 99% of TB-018 participants.
Immune assays to be conducted are not pre-specified.
Once study is completed, these samples will be made available to the scientific community
under a peer review process after a request for proposals. These will be evaluated and
selected based on best scientific rationale and knowledge at the time.
Prevalence by region Prevalence by baseline characteristics
LTBI prevalence in the screened population
The study is ongoing and double-blind, but screening data shed light on epidemiology
Lau et al, TB2016 Conference, Durban, South Africa, Poster P34. 10
N=7,404 screened subjects with IGRA results available
%
TB-018 is a double-blind randomised controlled trial assessing the efficacy of M72/AS01E
at preventing the occurrence of TB disease in HIV negative IGRA+ adults
More than 3,500 subjects were vaccinated in South Africa, Kenya and Zambia
An independent safety review committee had regular access to safety data and allowed
the study to continue unchanged
Primary analysis will be triggered in the next few months, when 21 cases are accrued
Study follow-up is planned to complete by the end of 2018
An AERAS-sponsored ancillary biobank study is ongoing that could provide additional
information on correlates of protection and risks
Conclusions
11
Investigators and teams:
Andreas Diacon
Mark Hatherill
Nduba Videlis
Malahleha Mookho
Innes Craig
Elizabeth Hellstrom
Neil Martinson
Robert Wilkinson
German Henostroza
Helen Ayles
Acknowledgments
We deeply thank all study participants and their families, as well as:
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AERAS:
Dereck Tait
Maria Lempicki
Maureen Lambrick
Tom Evans
Cadwill Pillay
Gretta Blatner
GSK:
Paul Gillard
Marie-Ange Demoitié
Nadia Ouaked
Anne Bollaerts
Christina Caporaso
Pramod Dhoke
Neela Kumar
Erik Jongert
Hildegarde Lemaire
Jacqueline Akite
François Roman
IDMC Members:
Annanele Nel
Linda-Gail Bekker
Neil French
William Blackwelder
CRO and Lab partners:
Quintiles
BARC
KEMRI
CIDRZ