Safety, immunogenicity and efficacy of the candidate tuberculosis vaccine MVA85A in healthy HIV-1-infected adults: A randomized, placebo-controlled phase 2 trial.
Background HIV-1 infection is associated with increased risk of tuberculosis and a safe and eff ective vaccine would assist control measures. We assessed the safety, immunogenicity, and effi cacy of a candidate tuberculosis vaccine, modif ed vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.
Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per ?L if they had never received antiretroviral therapy or greater than 300 cells per ?L (and with undetectable viral load before
randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo.
Randomisation was stratifi ed by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the fi rst vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defi ned in the protocol. Secondary outcomes were immunogenicity and vaccine effi cacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.
Findings Between Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per ?L and were receiving
antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per ?L and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of
participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI –41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine effi cacy of 32·8% (95% CI –111·5 to 80·3).
Interpretation MVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an eff ect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccineinduced immune response or the wrong type of vaccine-induced immune response, or both.
Funding European & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.
Auteur(s) : Ndiaye BP, Thienemann F, Ota M, Landry BS, Camara M, Dièye S, Dieye TN, Esmail H, Goliath R, , Huygen K, January V, Ndiaye I, Oni T, Raine M, Romano M
Pages : 190-200.
Année de publication : 2015
Revue : Lancet Respir Med
N° de volume : 03
Type : Article
Mise en ligne par : CAMARA Makhtar