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N Engl J Med. 2018 Sep 25. doi: 10.1056/NEJMoa1803484. [Epub ahead of print]

Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

Author information

1
From GlaxoSmithKline, Wavre, Belgium (O.V.D.M., M.-A.D., T.S., E.J.A., A.K.A., A.B., P.G.); South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology (M.H., T.J.S., M.T.), and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (R.J.W., F.T.), University of Cape Town, Task Applied Science (E.V.B., A.D.), Stellenbosch University (A.D.), and Aeras Global TB Vaccine Foundation (D.R.T.) Cape Town, Setshaba Research Centre, Pretoria (M. Malahleha), the Aurum Institute, Klerksdorp and Tembisa Research Centres (J.C.I.), and the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South African Medical Research Council Collaborating Centre for HIV/AIDS and TB, and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, University of the Witwatersrand (N.M.), Johannesburg, and Be Part Yoluntu Centre, Paarl (E.H.) - all in South Africa; Kenya Medical Research Institute, Nairobi (V.N.); Francis Crick Institute (R.J.W.), the Department of Medicine, Imperial College London (R.J.W.), and the London School of Hygiene and Tropical Medicine (H.M.A.) - all in London; Centre for Infectious Disease Research in Zambia (M. Muyoyeta, G.H.) and Zambart, University of Zambia (H.M.A.) - both in Lusaka, Zambia; the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and Aeras, Rockville (G.L.B., A.M.G., T.G.E.), and Johns Hopkins University Center for Tuberculosis Research, Baltimore (N.M.) - both in Maryland.

Abstract

BACKGROUND:

A vaccine to interrupt the transmission of tuberculosis is needed.

METHODS:

We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both.

RESULTS:

We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.

CONCLUSIONS:

M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

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