Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial

Abstract

SummaryBackgroundBCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants.MethodsIn our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927FindingsBetween July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9).InterpretationMVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.FundingAeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).

Vaccine against tuberculosis: what’s new?

“…The vaccine was well tolerated and immunogenic, but it was poorly protective against TB infection [22]. Authors suggested that the immunologic response induced by the vaccine could not be related to protective effect against TB infection.…”

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

“…This antigen was selected on the basis of conservation among all mycobacterial species as a vaccine candidate, MVA85A (40). MVA85A recently was evaluated in phase II trials in which it was used to boost bCG vaccinees, but it failed to protect against MTB infection (41). Interestingly, response to this antigen has not yet been shown to be dominant following bCG vaccination in humans.…”

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

“…Immunological responses considered critical for long-term mycobacterial control have focused on conventional T cell responses directed at peptide antigens presented by major histocompatibility complex (MHC) I and II, ultimately leading to secretion of anti-microbial cytokines, including TNF-α and IFN-γ (3,4). A number of subunit vaccines based on immunogenic peptides have been developed, some of which have been evaluated in clinical trials, but results to date have not been encouraging (5)(6)(7).…”