120. A Randomized Double-blind Trial Assessing the Efficacy of M72/AS01E Vaccine against Pulmonary Tuberculosis Disease in Adults with Latent Mycobacterium tuberculosis Infection
Session: Oral Abstract Session: Tuberculosis and other Mycobacterial Infections
Thursday, October 4, 2018: 9:00 AM
Room: W 2002

                    

Background: An effective tuberculosis (TB) vaccine is urgently needed to support the End TB Strategy to reduce the number of new TB cases by 80% by 2030. M72/AS01E candidate vaccine is an adjuvanted recombinant fusion protein derived from Mycobacterium tuberculosis Mtb32A and Mtb39A proteins.

Methods: We conducted a randomized, double-blind, placebo-controlled phase 2b trial (NCT01755598) in Southern and Eastern Africa to assess M72/AS01E’s efficacy  against bacteriologically-confirmed pulmonary TB disease in HIV-seronegative (HIV–) adults aged 18–50 years infected with Mtb (defined by a positive IFN-γ release assay). Participants were randomized 1:1 to receive M72/AS01E or placebo at day D0 and D30. Reactogenicity, safety, immunogenicity were assessed, and incident TB disease measured from D30 post-dose 2 up to ≥24 months for this analysis (follow-up ongoing up to 37 months). Efficacy against various TB disease case definitions (Figure 1) was estimated. Primary objective: efficacy against culture- or PCR-confirmed pulmonary TB disease in HIV– adults (case definition 1; success criterion: lower limit of 90% 2-sided CI >0%, power: 80%).

Results: Demographic characteristics were similar between M72/AS01E (1786) and placebo (1787) recipients. Efficacy against pulmonary TB disease case definition 1 was 54.0% (90% CI: 13.9, 75.4; p=0.042); efficacy against other case definitions and a sensitivity analysis are shown in Figure 1. Leading solicited symptoms were pain, fatigue and headache (Figure 2). In all recipients, unsolicited symptoms (D0–29) were more frequent after M72/AS01E (67.4%) than placebo (45.4%), mainly attributable to increased injection site reactions and flu-like symptoms. Serious adverse events (D0–month 7) incidences were similar between groups (M72/AS01E: 1.6%; placebo: 1.8%). During the study, 24 adults died (14 due to traumatic events); all deaths were unrelated to the trial.

Conclusion: M72/AS01E presents a clinically acceptable safety profile and significantly reduces bacteriologically-confirmed pulmonary TB disease incidence in HIV– adults with latent Mtb infection.

Funding: BMGF; Aeras; DFID UK; DGIS; AusAID; GlaxoSmithKline Biologicals SA

 

Olivier Van Der Meeren, MD1, Mark Hatherill, MD2, Videlis Nduba, MBChB, MPH3, Robert J. Wilkinson, FMedSci4, Monde Muyoyeta, MBChB, PhD5, Elana Van Brakel, MBChB, MSc6, Helen M. Ayles, MBBS, PhD7,8, German Henostroza, MD5,9, Friedrich Thienemann, MD, MScIH, DTMPH4, Thomas J. Scriba, PhD2, Andreas Diacon, MD, PhD6,10, Gretta L. Blatner, MS, MPH11,12, Marie-Ange DemoitiƩ, MSc1, Michele Tameris, MBChB2, Mookho Malahleha, MD, MPH13, James C. Innes, MBChB, MSc14,15, Elizabeth Hellstrom, MBChB16, Neil Martinson, MBChB, MD, MPH17, Tina Singh, MD1, Elaine J. Akite, MSc1, Aisha K. Azam, MBBS1, Anne Bollaerts, MSc1, Ann M. Ginsberg, MD, PhD11, Thomas G. Evans, MD11,18, Paul Gillard, MD1 and Dereck R. Tait, FRCPath19, (1)GSK, Wavre and Rixensart, Belgium, (2)South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa, (3)Kenya Medical Research Institute (KEMRI), Nairobi, Kenya, (4)Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa, (5)Centre for Infectious Diseases Research in Zambia (CIDRZ), Lusaka, Zambia, (6)Task Applied Science, Cape Town, South Africa, (7)Zambia AIDS Related Tuberculosis (ZAMBART), Lusaka, Zambia, (8)London School of Hygiene and Tropical Medicine, London, United Kingdom, (9)University of Alabama at Birmingham, Birmingham, AL, (10)University of Stellenbosch, Cape Town, South Africa, (11)AERAS, Rockville, MD, (12)Biomedical Advanced Research and Development Authority, The Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services, Washington, DC, (13)Setshaba Research Centre, Pretoria, Gauteng, South Africa, (14)The Aurum Klerksdorp Clinical Research Site, Klerksdorp, South Africa, (15)The Aurum Tembisa Clinical Research Site, Tembisa, South Africa, (16)Be Part Yoluntu Centre (Be Part), Paarl, South Africa, (17)Perinatal HIV Research Unit (PHRU), SAMRC Soweto Matlosana Collaborating Centre for HIV/AIDS and TB, University of the Witwatersrand, Soweto, South Africa, (18)Vaccitech Ltd, Oxford, United Kingdom, (19)AERAS, Cape Town, South Africa

Disclosures:

O. Van Der Meeren, GSK: Employee and Shareholder , Salary .

M. Hatherill, Aeras: Investigator , Research grant .

V. Nduba, None

R. J. Wilkinson, GSK: Grant Investigator , indirect funding .

M. Muyoyeta, None

E. Van Brakel, None

H. M. Ayles, GSK: Grant Investigator , Research grant .

G. Henostroza, Aeras: Investigator , Grant recipient .

F. Thienemann, None

T. J. Scriba, None

A. Diacon, None

G. L. Blatner, None

M. A. DemoitiƩ, GSK: owns stocks and is named inventor on patent applications relating to certain uses of M72/AS01E , Salary .

M. Tameris, None

M. Malahleha, None

J. C. Innes, None

E. Hellstrom, None

N. Martinson, None

T. Singh, GSK: Employee and Shareholder , Salary .

E. J. Akite, GSK: Employee , Salary .

A. K. Azam, GSK: Employee , Salary .

A. Bollaerts, GSK: Employee , Salary .

A. M. Ginsberg, GSK: Collaborator , Research support . BMGF: Grant Investigator , Grant recipient . UK DFID: Grant Investigator , Grant recipient .

T. G. Evans, None

P. Gillard, GSK: Employee and Shareholder , Salary and stock .

D. R. Tait, Aeras: Employee , Salary . GSK: Shareholder , Salary .

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