The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. B.C.G. and Vole Bacillus Vaccines in the Prevention of Tuberculosis in Adolescents
Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Summary Background BCG vaccination provides incomplete protection against tuberculosis in infants . A new vaccine , modified Vaccinia Ankara virus expressing antigen 85A ( MVA85A ) , was design ed to enhance the protective efficacy of BCG . We aim ed to assess safety , immunogenicity , and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants . Methods In our double-blind , r and omised , placebo-controlled phase 2b trial , we enrolled healthy infants ( aged 4–6 months ) without HIV infection who had previously received BCG vaccination . We r and omly 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 C and ida 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 Clinical Trials.gov on July 31 , 2009 , number NCT00953927 Findings 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 ) . Interpretation 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 . Funding Aeras , Wellcome Trust , and Oxford-Emergent Tuberculosis Consortium ( OETC ) The Medical Research Council 's trial of BCG and vole bacillus vaccines in the prevention of  tuberculosis in Great Britain has ended after 20 years ' follow-up of the 54 239 participants , who were aged 14 to 15 years when the entered the trial in 1950 - 2 . Participants who were tuberculin positive on entry were left unvaccinated ; those who were tuberculin negative were allocated at r and om to an unvaccinated or to a vaccinated group . The protective efficacy of each of the two vaccines , among those initially tuberculin negative , was 84 % during the first five years , and gradually decreased , averaging 77 % for each vaccine over the whole period . The incidence of tuberculosis decreased substantially in all groups during the trial , however , and of the total of 610 cases of tuberculosis only 27 developed between 15 and 20 years . Thus we can not make a reliable assessment of efficacy during this final period . The prevalence and incidence of tuberculosis in Great Britain have decreased radically since this trial began . The expected benefit from large-scale BCG-vaccination of children is now far less , and may decrease further if the incidence of tuberculosis continues to decline A clinical trial of B.C.G. and vole bacillus vaccines , directed by the Tuberculosis Vaccines Clinical Trials Committee of the Medical Research Council ( M.R.C. ) , was begun in Engl and in 1950 , and is still in progress . The effect of the vaccines is being studied during adolescence and early adult life in groups with no special risk of exposure to tuberculous infection , and initially free both from active tuberculosis and from known contact with the disease at home . There are more than 50,000 participants of both sexes in the investigation , all aged 14 to 152 years on entry , and now aged between 21 and 23 years . Those with negative reactions to tuberculin on entry were vaccinated with B.C.G. or vole bacillus vaccine or left unvaccinated , according to a method of r and om allocation . All the participants , including those with a positive reaction to tuberculin initially , have now ( January , 1959 ) been followed intensively for more than six years . The first report of this investigation ( M.R.C. , 1956 ; see also Hart , Pollock , and Sutherl and , 1957 ) presented complete results after each participant had been in the trial for two and a half years . The present report gives corresponding results for the period of five years since entry to the trial , together with preliminary incomplete information for the period between five and seven and a half years after entry . The work described was carried out by the Council 's Tuberculosis Research Unit , with the assistance of many statutory and voluntary organizations ( see Acknowledgments )
BACKGROUND R and omized trials assessing BCG vaccine protection against tuberculosis have widely varying results , for reasons that are not well understood .