BACKGROUND: HIV-1 infection is associated with increased risk of tuberculosis 
and a safe and effective vaccine would assist control measures. We assessed the 
safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, 
modified 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 μL if they had never received antiretroviral therapy or greater than 
300 cells per μL (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 stratified 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 first 
vaccination. The primary study outcome was safety in all vaccinated participants 
(the safety analysis population). Safety was assessed throughout the trial as 
defined in the protocol. Secondary outcomes were immunogenicity and vaccine 
efficacy 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 μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts 
above 350 cells per μL 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 efficacy 
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 effect against 
disease. Potential reasons for the absence of detectable efficacy in this trial 
include insufficient induction of a vaccine-induced 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.