title: Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial.
abstract: BACKGROUND
  BCG 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.
  
  
  METHODS
  In 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 NCT00953927.
  
  
  RESULTS
  Between 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).
  
  
  CONCLUSIONS
  MVA85A 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.
  
  
  BACKGROUND
  Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).
authors: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. michele.tameris@uct.ac.za
authors: Michele D
authors: MD
authors: Tameris
authors: Mark
authors: M
authors: Hatherill
authors: Bernard S
authors: BS
authors: Landry
authors: Thomas J
authors: TJ
authors: Scriba
authors: Margaret Ann
authors: MA
authors: Snowden
authors: Stephen
authors: S
authors: Lockhart
authors: Jacqueline E
authors: JE
authors: Shea
authors: J Bruce
authors: JB
authors: McClain
authors: Gregory D
authors: GD
authors: Hussey
authors: Willem A
authors: WA
authors: Hanekom
authors: Hassan
authors: H
authors: Mahomed
authors: Helen
authors: H
authors: McShane
mesh_terms: D000942:Antigens, Bacterial / Q000097:blood / Q000276:immunology; D001500:BCG Vaccine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007223:Infant; D007271:Injections, Intradermal; D008297:Male; D009169:Mycobacterium tuberculosis; D016896:Treatment Outcome; D014374:Tuberculin Test; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D019444:Vaccines, DNA; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; C549320:MVA 85A; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D014765:Viral Vaccines
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