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/AS01Es efficacy against bacteriologically-confirmed pulmonary TB disease in HIV-seronegative (HIV) adults aged 1850 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 (D029) 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 (D0month 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
O. Van Der Meeren,
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. Demoitié, 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 .