Divergent mortality for male and female recipients of low-titer and high-titer measles vaccines in rural Senegal. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau Small Randomized Trial Among Low–birth-weight Children Receiving Bacillus Calmette-Guérin Vaccination at First Health Center Contact Non-specific effects of vaccination on child survival: prospective cohort study in Burkina Faso Measles Vaccination in the Presence or Absence of Maternal Measles Antibody: Impact on Child Survival Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? Non-specific and sex-differential effects of vaccinations on child survival in rural western India. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations? An analysis of surveillance data from Navrongo, Ghana. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Effects of the introduction of new vaccines in Guinea-Bissau on vaccine coverage, vaccine timeliness, and child survival: an observational study. Measles incidence, vaccine efficacy, and mortality in two urban African areas with high vaccination coverage. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. A comparison of vaccine efficacy and mortality during routine use of high-titre Edmonston-Zagreb and Schwarz standard measles vaccines in rural Senegal. Impact of measles vaccination on childhood mortality in rural Bangladesh. Co-administration of live measles and yellow fever vaccines and inactivated pentavalent vaccines is associated with increased mortality compared with measles and yellow fever vaccines only. An observational study from Guinea-Bissau. Sex Differential Effects of Routine Immunizations and Childhood Survival in Rural Malawi
The female/male mortality ratio among unimmunized children and children vaccinated with st and ard or high-titer measles vaccines  was examined for all children born in the period 1985 - 1991 in a rural area of Senegal . The female/male mortality ratio from 9 months to 5 years of age for unvaccinated children was 0.94 ( 95 % confidence interval ( CI ) 0.75 - 1.19 ) , significantly different from the ratio of 0.64 ( 95 % CI 0.48 - 0.85 ) for recipients of the Schwarz st and ard measles vaccine ( p = 0.040 ) . In the 4-year period , where high-titer measles vaccines were used in the study area , the female/male mortality ratio was 1.33 ( 95 % CI 1.00 - 1.78 ) for recipients of high-titer Edmonston-Zagreb or Schwarz vaccines compared with 0.67 ( 95 % CI 0.42 - 1.07 ) for recipients of the Schwarz st and ard vaccine ( p = 0.013 ) . Hence , the Schwarz st and ard and high-titer measles vaccines have divergent sex-specific effects on mortality throughout childhood . Further studies of the underlying mechanisms are needed Objective To determine whether BCG revaccination at 19 months of age reduces overall child mortality . Design R and omised trial , with follow-up to age 5 . Setting A health project in Bissau , Guinea-Bissau , which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants . Participants 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrolment . Intervention BCG vaccination or no vaccination ( control ) . Main outcome measure Hazard ratios for mortality . Results 77 children died during follow-up . Compared with controls , the BCG revaccinated children had a hazard ratio of 1.20 ( 95 % confidence interval 0.77 to 1.89 ) . Two hundred and fifty children were admitted to hospital for the first time between enrolment and the end of the study , with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 ( 0.81 to 1.33 ) . The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study . This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation ; the hazard ratio for BCG revaccinated children compared with controls was 2.69 ( 1.05 to 6.88 ) in the period after these campaigns . Throughout the trial , the effect of BCG revaccination on mortality was significantly different ( P=0.006 ) in children who had received diphtheria-tetanus-pertussis ( DTP ) booster vaccination before enrolment ( hazard ratio 0.36 , 0.13 to 0.99 ) and children who had not received the booster before enrolment ( 1.78 , 1.04 to 3.04 ) . Conclusions There was no overall beneficial effect of being revaccinated with BCG . The effect of BCG revaccination on mortality might depend on other health interventions . Trial registration Clinical Trials ICA4-CT-2002 - 10053-REVAC A total of 105 low – birth-weight children presenting for first vaccination were r and omized to receive bacillus Calmette-Guérin ( BCG ) immediately or later ( current practice ) . The mortality rate ratio for BCG was 0.17 ( 95 % CI = 0.02–1.35 ) within 3 days of enrollment , 0.28 ( 0.06–1.37 ) in the first month , and 0.27 ( 0.07–0.98 ) after 2 months of age . The mortality rate ratio was 0.41 ( 0.14–1.18 ) ( P = 0.098 ) in infancy . Administration of BCG vaccine at first contact may contribute to lower mortality Abstract Objective To study the effect of vaccination on  mortality before 2 years of age in a developing country . Design Prospect i ve cohort study . Setting Rural communities in Burkina Faso . Participants 9085 children born in the study area between 1985 and 1993 . Main outcome measure Child death rate . Results Mortality before 2 years of age was lower in children who had been vaccinated : those vaccinated with BCG only had significantly lower mortality ( risk ratio for vaccinated v unvaccinated children 0.37 , 95 % confidence interval 0.29 to 0.48 ) as did those vaccinated with diphtheria , tetanus , and pertussis only ( 0.24 , 0.13 to 0.43 ) . The second dose of diphtheria , tetanus , and pertussis was not associated with lower mortality ( 0.80 , 0.58 to 1.12 ) . Conclusion Vaccination with diphtheria , tetanus , and pertussis as well as BCG is associated with better survival of children up to 2 years of age In 2-dose trials , early measles vaccination at 4–6 months in presence of maternal measles antibody was associated with significantly better survival to age 5 years than vaccination in absence of measles antibody . Confounding factors did not explain the effect BACKGROUND Observational studies have suggested that BCG may have nonspecific beneficial effects on survival .  Low-birth-weight ( LBW ) children are not given BCG at birth in Guinea-Bissau ; we conducted a r and omized trial of BCG at birth ( early BCG ) vs delayed BCG . METHODS In the period 2004 - 2008 we recruited 2320 LBW children in Bissau . The children were visited at home at 2 , 6 , and 12 months of age . With a pretrial infant mortality of 250 per 1000 , we hypothesized a 25 % reduction in infant mortality for LBW children . RESULTS Infant mortality was only 101 per 1000 during the trial . In the primary analysis , infant mortality was reduced insignificantly by 17 % ( mortality rate ratio [ MRR ] = .83 [ .63 - 1.08 ] ) . In secondary analyses , early BCG vaccine was safe with an MRR of .49 ( .21 - 1.15 ) after 3 days and .55 ( .34-.89 ) after 4 weeks . The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis , respiratory infection , and fever . The impact of early BCG on infant mortality was marked for children weighing < 1.5 kg ( MRR = .43 [ .21-.85 ] ) who had lower coverage for diphtheria-tetanus-pertussis vaccinations . CONCLUSIONS Though early BCG did not reduce infant mortality significantly , it may have a beneficial effect in the neonatal period . This could be important for public health because BCG is often delayed in low-income countries BACKGROUND Studies from Africa have suggested marked non-specific effects ( NSEs ) of routine vaccinations with effects on child survival . There have been few studies from Asia . We re-analyzed a study from Maharashtra , India , which had collected information on vaccinations during infancy and survival until 5 years of age . DESIGN 4138 children born between 1987 and 1989 were visited at home every three months to collect information on nutritional status and vaccinations . Since nutritional status was a determinant of time to vaccinations , we adjusted for nutritional status in the analyzes of the association between vaccinations and mortality . SETTING 45 contiguous villages in Shirur Administrative Block in Pune District . MAIN OUTCOME MEASURES Mortality rate ratios ( MRR ) for different vaccination status groups . RESULTS The study area has male preferential treatment , but the female-male mortality ratio varied between age groups with different pre-dominant vaccines ; it was high in the age group in which diphtheria-tetanus-pertussis ( DTP ) vaccine predominates and low in the age group in which measles vaccine ( MV ) is given . Children who followed the WHO recommended schedule of first BCG and then DTP vaccination were vaccinated earlier than other children ( p<0.01 ) . Two-thirds of the children had received BCG and DTP out-of-sequence , i.e. BCG and DTP simultaneously or BCG after DTP . Children who received BCG and DTP simultaneously or BCG as most recent vaccination had significantly lower mortality than children having DTP as the most recent vaccination , the mortality rate ratio being 0.15 ( 0.03 - 0.70 ) . CONCLUSIONS BCG out-of-sequence may be associated with lower mortality than DTP as the most recent vaccination . Given the public health implication s , this possibility should be tested in r and omized trials . Excess female mortality may also be related to vaccination policy 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 OBJECTIVES Studies from low-income countries have suggested that routine vaccinations may have non-specific effects on child mortality ;  measles vaccine ( MV ) is associated with lower mortality and diphtheria-tetanus-pertussis ( DTP ) with relatively higher mortality . We used data from Navrongo , Ghana , to examine the impact of vaccinations on  child mortality .  METHODS  Vaccination status was assessed at the initiation of a trial of vitamin A supplementation and after 12 and 24 months of follow-up . Within the placebo group , we compared the mortality over the first 4 months and the full 2 years of follow-up for different vaccination status groups with different likelihoods of additional vaccinations during follow-up . The frequency of additional vaccinations  was assessed among children whose vaccination card was seen at 12 and 24 months of follow-up . RESULTS Among children with a vaccination card , more than 75 % received missing DTP or MV  during the first 12 months of follow-up , whereas only 25 % received these vaccines among children with no vaccination card at enrollment . Children without a card at enrollment had a significant threefold higher mortality over the 2-year follow-up period than those fully vaccinated . The small group of children with DTP3 - 4 but no MV at enrollment had lower mortality than children without a card and had the same mortality as fully vaccinated children . In contrast , children with 1 - 2 DTP doses but no MV had a higher mortality during the first 4 months than children without a card [ MRR = 1.65 ( 0.95 , 2.87 ) ] ; compared with the fully vaccinated children , they had significantly higher mortality after 4 months [ MRR = 2.38 ( 1.07 , 5.30 ) ] and after 2 years [ MRR = 2.41 ( 1.41 , 4.15 ) ] . Children with 0 - 2 DTP doses at enrollment had higher mortality after 4 months ( MRR = 1.67 ( 0.82 , 3.43 ) and after 2 years [ MRR = 1.85 ( 1.16 , 2.95 ) ] than children who had all three doses of DTP at enrollment . CONCLUSIONS As hypothesised , DTP vaccination was associated with higher child mortality  than measles vaccination . To optimise vaccination policies , routine vaccinations need to be evaluated in r and omised trials measuring the impact on survival Background . Previous studies have suggested that st and ard measles vaccine may reduce mortality by more than the number of deaths thought to be caused by measles infection in areas with high mortality . However , these observations have not been based on r and omized trials . Methods . During the recent war in Guinea-Bissau , most children fled from the city of Bissau and immunization services in the country broke down for several months . We were performing a trial in which children were r and omized at 6 months of age to receive either measles vaccine or inactivated polio vaccine . Because of the war many children did not receive the dose of measles vaccine planned for 9 months of age . We were able to monitor mortality during the war and after . Results . Included in the study were 433 children 6 to 11 months of age . Fifteen children died ( 3.6 % ) during the first 3 months of the war before vaccination programs were resumed , 4 of 214 measles-vaccinated children and 11 of 219 children who had received inactivated polio vaccine . The effect of measles vaccine was marked for girls [ mortality rate ratio ( MR ) , 0.00 ; 95 % confidence limits , 0.0 to 0.37 ] , whereas there was no difference for boys ( MR = 1.02 ; 95 % confidence limits , 0.25 to 3.88 ) . In a combined analysis controlling for factors that differed between the two groups , the MR for measles-vaccinated children was 0.30 ( 95 % confidence limits , 0.08 to 0.87 ) . Prolonging the period of observation to the end of 1998 or including the prewar period did not modify the significant beneficial effect of measles vaccine for girls . Twenty-two of the children in the cohort were reported to have had measles , 8 cases occurring during the 3 months of the war . Exclusion of measles cases in the analysis did not change the results ; children who had received measles vaccine had a MR of 0.28 ( 95 % confidence limits , 0.06 to 0.89 ) during the first 3 months of the war . Conclusions . Consistent with previous observational studies , measles vaccination was associated with a reduction in mortality that can not be explained by the prevention of measles infection . This nonspecific beneficial effect was particularly strong for girls . Further studies are needed to examine the extent of nonspecific effects in setting s with high mortality Background Measles vaccines ( MV ) have sex-differential effects on mortality not explained by protection against measles infection . Objective The authors examined whether whole-cell diphtheria – tetanus – pertussis ( DTP ) vaccine has sex-differential and non-specific effects . Data sources and eligibility Following previous review s and a new search , the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospect i ve follow-up after ascertainment of vaccination status . Setting High-mortality countries in Africa and Asia . Methods The initial observation of negative effect of DTP generated six hypotheses , which were examined in all available studies and two r and omised trials reducing the time of exposure to DTP . Main outcome Consistency between studies . Results In the first study , DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV . This pattern was repeated in the six other studies available . Second , the two ‘ natural experiments ’ found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children . Third , the female – male mortality ratio was increased after DTP in all nine studies ; in contrast , the ratio was decreased after BCG and MV in all studies . Fourth , the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine . Fifth , in six r and omised trials of early MV , female but not male mortality was increased if DTP was likely to be given after MV . Sixth , the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV . The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine ( MV and BCG ) shortly after DTP . Both trials reduced child mortality . Conclusions These observations are incompatible with DTP merely protecting against the targeted diseases . With herd immunity to whooping cough , DTP is associated with higher mortality for girls . R and omised studies of DTP are warranted to measure the true impact on survival OBJECTIVE To examine whether the reduction in  childhood mortality  after immunization can be explained by the prevention of measles and its long-term effects . METHODS and Data We re-analysed an existing data set from Matlab , Bangladesh . During 1982 - 1985 , measles immunization was used from 9 months of age in half of the study area , and the other half was used as an unvaccinated control area . A total of 8134 immunized children had been matched by age with 8134 non-immunized children ; 578 children died during the follow-up period of 3 years . Using these data , we calculated the  vaccine effectiveness against death ( VED ) controlling for significant factors in a matched analysis . In the absence of measles , there should be no difference in mortality between immunized , uninfected children and non-immunized , uninfected children . We therefore calculated VED after the exclusion of all measles cases in the survival analysis . To assess the long-term effects of measles , we compared survival of unvaccinated children after measles disease with children who had not yet contracted measles . RESULTS Prior to immunization and again after 1985 ,  childhood mortality rates were 10 % lower in the area that had received immunization . Though measles deaths only constituted 12.4 % of the non-accidental deaths , the VED controlling for significant factors was 49 % ( 95 % CI : 38 - 58 % ) . The vaccine was protective against measles death throughout the study , but it also had a marked effect against other causes of death , particularly diarrhoea and oedema . This effect may have been particularly strong in the first 6 months after immunization ( VED = 74 , 95 % CI : 57 - 84 % ) . The VED was only reduced from 49 % to 43 % ( 95 % CI : 31 - 54 % ) when measles cases were excluded in the survival analysis . Controlling for background factors , mortality among measles cases was increased during the acute phase ( 0 - 45 days ) ( mortality ratio [ MR ] = 17.35 , 95 % CI : 11.9 - 25.3 ) and in the following 1(1/2 ) months ( MR = 2.35 , 95 % CI : 0.95 - 5.84 ) . However , post-measles cases had significantly lower mortality than uninfected , non-immunized children in the following 9 months ( MR = 0.40 , 95 % CI : 0.16 , 0.98 ) . CONCLUSIONS The non-r and omized character of the original study and the possibility of uncontrolled confounding between the two areas prevent a precise estimate of the effectiveness of measles vaccine , but it is likely to have been substantial . Though there may have been some underreporting of cases of measles , the prevention of measles infection can only explain a limited part of the observed impact of measles immunization in Bangladesh . Furthermore , mortality may be reduced after the acute phase of measles infection . The observations from Bangladesh are consistent with recent research from Africa suggesting that measles immunization may have non-specific beneficial effects on survival Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation  to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies Objective To examine in a r and omised trial whether a 25 % difference in mortality exists between 4.5 months and 3 years of age for children given two st and ard doses of  Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age ( current policy ) . Design R and omised controlled trial . Setting The B and i m Health Project , Guinea-Bissau , which maintains a health and demographic surveillance system in an urban area . Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment . A large proportion of the children ( 80 % ) had previously taken part in r and omised trials of neonatal vitamin A supplementation . Intervention Children were r and omised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age ( group A ) , no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age ( group B ) , or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age ( group C ) . Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group , in girls , and in the dry season , but the study was not powered to test whether effects differed significantly between subgroups . Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 ( 95 % confidence interval 0.59 to 1.05 ) . In the analyses of secondary outcomes , the intention to treat mortality rate ratio was 0.67 ( 0.38 to 1.19 ) between 4.5 and 9 months and 0.83 ( 0.83 to 1.16 ) between 9 and 36 months of age . The effect on mortality between 4.5 and 36 months of age was significant for girls ( intention to treat mortality rate ratio 0.64 ( 0.42 to 0.98 ) ) , although this was not significantly different from the effect in boys ( 0.95 ( 0.64 to 1.42 ) ) ( interaction test , P=0.18 ) . The effect did not differ between the dry season and the rainy season . As neonatal vitamin A supplementation is not WHO policy , the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children , the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age ( intention to treat mortality rate ratio 0.59 ( 0.39 to 0.89 ) ) . The effect was again significant for girls but not statistically significant from the effect in boys . When measles cases were censored , the intention to treat mortality rate ratio was 0.65 ( 0.43 to 0.99 ) . Conclusions Although the overall effect did not reach statistical significance , the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children ’s survival , particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations . Trial registration Clinical trials NCT00168558 Previous studies have suggested that the bacille Calmette-Guérin ( BCG ) vaccine may have a non-specific beneficial effect on childhood survival in areas with high mortality . We examined whether  BCG-vaccinated children with a BCG scar or a positive tuberculin reaction had better survival than children without such reactions . As part of an ongoing two-dose measles vaccine trial for which children were recruited at 6 months of age , we examined 1813 children for BCG scar at 6 months of age and 813 BCG-vaccinated children were skin-tested for delayed hypersensitivity to tuberculin , tetanus and diphtheria . We found that BCG-vaccinated children with a BCG scar had significantly lower mortality compared with BCG scar-negative children , the mortality ratio in the first 12 months of follow-up being 0.41 ( 0.25 - 0.67 ) . BCG-vaccinated children with a positive tuberculin test had a mortality ratio of 0.45 ( 0.24 - 0.85 ) compared with tuberculin negative children . These results were unchanged by control for potential confounders or using different cut-off points for a tuberculin-positive response . Exclusion of dead children who had HIV antibodies did not modify the estimate ( mortality rate (MR)=0.46 ( 0.23 - 0.94 ) ) . After censoring for tuberculosis ( TB ) exposure at home , the mortality ratios for having a scar and being tuberculin-positive were 0.46 ( 0.27 - 0.79 ) or 0.42 ( 0.21 - 0.84 ) , respectively . Children positive to tetanus or diphtheria in the skin test had the same mortality as children not responding to these vaccine-related antigens . Thus , BCG scar and a positive tuberculin reaction were associated with better survival in early childhood in an area with high mortality . Since nothing similar was found for responders to diphtheria-tetanus-pertussis ( DTP ) vaccine , and the effect could not be explained by protection against tuberculosis , the effect of BCG vaccination could be due to non-specific immune-stimulation protecting against other infections BACKGROUND In 2008 , the GAVI Alliance funded the introduction of new vaccines ( including pentavalent diphtheria-tetanus-pertussis [ DTP ] plus hepatitis B and Haemophilus influenzae type b antigens ) in Guinea-Bissau . The introduction was accompanied by increased vaccination outreach services and a more restrictive wastage policy , including only vaccinating children younger than 12 months . We assessed coverage of all vaccines in the Exp and ed Program on Immunizations before and after the new vaccines ' introduction , and the implication s on child survival . METHODS This observational cohort study used data from the B and i m Health Project , which has monitored vaccination status and mortality in r and omly selected village clusters in Guinea-Bissau since 1990 . We assessed the change in vaccination coverage using cohort data from children born in 2007 and 2009 ; analysed the proportion of children who received measles vaccine after 12 months of age using data from 1999 - 2006 ; and compared child mortality after age 12 months in children who had received measles vaccine and those who had not using data from 1999 to 2006 . FINDINGS The proportion of children who were fully vaccinated by 12 months of age was 53 % ( 468 of 878 ) in the 2007 cohort and 53 % ( 467 of 879 ) in the 2009 cohort ( relative risk [ RR ] 1·00 , 95 % CI 0·89 - 1·11 ) . Coverage of DTP-3 and pentavalent-3  increased from 73 % ( 644 of 878 ) in 2007 to 81 % ( 712 of 879 ) in 2009 ( RR 1·10 , 95 % CI 1·04 -1·17 ) ; by contrast , the coverage of measles vaccination declined from 71 % ( 620 of 878 ) to 66 % ( 577 of 879 ; RR 0·93 , 0·85 - 1·01 ) . The effect of the changes was significantly different for DTP-3 coverage compared with measles vaccine coverage ( p=0·002 ) . After 12 months of age , the adjusted mortality rate ratio was 0·71 ( 95 % CI 0·56 - 0·90 ) for children who had received measles vaccine compared with those who had not ( 0·59 [ 0·43 - 0·80 ] for girls and 0·87 [ 0·62 - 1·23 ] for boys ) . INTERPRETATION The introduction of the new vaccination programme in 2008 was associated with increased coverage of DTP  , but decreased coverage of measles vaccine  . In 1999 - 2006 , child mortality was higher in children who had not received measles vaccine than in those who had . FUNDING DANIDA , European Research Council , the Danish Independent Research Council , European Union FP7 via OPTIMUNISE , and Danish National Research Foundation Measles incidence , vaccine efficacy , and mortality were examined prospect ively in two districts in Bissau where vaccine coverage for children aged 12 - 23 months was 81 % ( B and i m 1 ) and 61 % ( B and i m 2 ) . There was little difference in cumulative measles incidence before 9 months of age ( 6.1 % and 7.6 % , respectively ) . Between 9 months and 2 years of age , however , 6.1 % contracted measles in B and i m 1 and 13.7 % in B and i m 2 . Even adjusting for vaccination status , incidence was significantly higher in B and i m 2 ( relative risk 1.6 , P = .04 ) . Even though 95 % of the children had measles antibodies after vaccination , vaccine efficacy was not more than 68 % ( 95 % confidence interval [ CI ] 39%-84 % ) and was unrelated to age at vaccination . Unvaccinated children had a mortality hazard ratio of 3.0 compared with vaccinated children ( P = .002 ) , indicating a protective efficacy against death of 66 % ( CI 32%-83 % ) of measles vaccination . These data suggest that it will be necessary to vaccinate before age 9 months to control measles in hyperendemic urban African areas Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates . Design R and omised , placebo controlled , two by two factorial trial . Setting Bissau , Guinea-Bissau . Participants 1717 low birthweight neonates born at the national hospital . Intervention Neonates who weighed less than 2.5 kg were r and omly assigned to 25 000 IU vitamin A or placebo , as well as to early BCG vaccine or the usual late BCG vaccine , and were followed until age 12 months . Main outcome measure Mortality , calculated as mortality rate ratios ( MRRs ) , after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo . Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation ( P=0.73 ) . Vitamin A supplementation at birth was not significantly associated with mortality : the MRR of vitamin A supplementation compared with placebo , controlled for r and omisation to “ early BCG ” versus “ no early BCG ” was 1.08 ( 95 % CI 0.79 to 1.47 ) . Stratification by sex revealed a significant interaction between vitamin A supplementation and sex ( P=0.046 ) , the MRR of vitamin A supplementation being 0.74 ( 95 % CI 0.45 to 1.22 ) in boys and 1.42 ( 95 % CI 0.94 to 2.15 ) in girls . When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau , the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 ( 95 % CI 0.87 to 1.33 ) ; 0.80 ( 95 % CI 0.58 to 1.10 ) in boys and 1.41 ( 95 % CI 1.04 to 1.90 ) in girls ( P=0.01 for interaction between neonatal vitamin A and sex ) . Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that , overall , it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau . Worryingly , the trials show that vitamin A supplementation at birth can be harmful in girls . Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects . Trial registration Clinical Trials.gov NCT00168610 OBJECTIVE The aim of this study was to assess the relationship between receipt of routine childhood immunizations and infant mortality before 6 months of age . METHODS This was an observational study of 10,274 infants , in a r and omized trial of vitamin A supplementation , who received the study dose and survived to at least 1 week of age . The primary outcome was mortality before 6 months of age , analysed in Cox regression models as a function of vaccine receipt and gender . RESULTS Receipt of Bacille Calmette Guerin ( BCG ) or diphtheria , tetanus , polio ( DTP ) vaccine was associated with significant reductions of one-half to two-thirds of mortality hazards ;  among girls , those who received both BCG and DTP experienced higher mortality than those who received only one of the two vaccines ( hazards ratio 2.4 ; 95 % confidence interval 1.2 - 5.0 ) . CONCLUSION The reduced mortality rate associated with receipt of BCG or DTP may be due to both biological and selection factors ; the analyses regarding the combined effect of these vaccines and gender need to be replicated in other setting Vaccine efficacy and mortality in successive cohorts of children who routinely received either Edmonston-Zagreb high-titre ( EZ-HT ) or Schwarz st and ard ( SW-STD ) measles vaccines  have been examined in a rural area of Senegal . The 2 vaccines were equally protective against measles infection ( vaccination efficacy : EZ-HT 94 % ; SW-STD 93 % ) . Children who did not attend a scheduled session to receive measles vaccine  had a higher mortality rate between 9 months and 2 years of age than did children receiving either EZ-HT  ( mortality ratio [ MR ] = 1.81 , 95 % confidence interval [ CI ] 1.06 - 3.08 ) or SW-STD measles vaccine ( MR = 1.74 , 95 % CI 0.95 - 3.21 ) . Children of either sex vaccinated with EZ-HT had lower mortality than their equivalents who had not received any measles vaccine . There was no difference in overall mortality between recipients of EZ-HT and SW-STD ( MR = 0.96 , 95 % CI 0.70 - 1.30 ) . Using a Cox regression analysis to adjust for sex , age and significant background factors ( season and death of mother ) , mortality rates tended to be lower for male recipients of EZ-HT than for boys receiving SW-STD ( MR = 0.73 , 95 % CI 0.50 - 1.11 ) and higher for girls receiving EZ-HT than for girls receiving SW-STD ( MR = 1.30 , 95 % CI 0.81 - 2.09 ) ( test of interaction between sex and vaccine , P = 0.067 ) . The tendency to reduced survival benefit for girls following receipt of high-titre measles vaccines substantiated observations from r and omized trials in Guinea-Bissau , Senegal and Haiti . Existing data provide little support for the notion that high-titre vaccine is deleterious but it may not have the same beneficial effects as st and ard-titre measles vaccine This study examines the impact of measles vaccination on  childhood mortality  , based on longitudinal data from the Matlab maternal and child health/family planning programme in rural Bangladesh . It analyses the mortality experience of 8135 vaccinated and 8135 r and omly matched nonvaccinated children aged 9 - 60 months , who were observed from March 1982 to October 1985 . The results indicate that measles vaccination had a pronounced impact on both short- and long-term survival -- the mortality rates for vaccinated children were as much as 46 % less than those for nonvaccinated children . Immunization of children aged up to 3 years with measles vaccine appears to improve significantly their subsequent chances of survival . The findings underscore the need to give greater priority to measles vaccination within primary health care programmes in setting s such as rural Bangladesh BACKGROUND Studies from low-income countries indicate that co-administration of inactivated diphtheria-tetanus-pertussis ( DTP ) vaccine and live attenuated measles vaccine ( MV ) is associated with increased mortality compared with receiving MV only . Pentavalent ( DTP-H. Influenza type B-Hepatitis B ) vaccine is replacing DTP in many low-income countries and yellow fever vaccine ( YF ) has been introduced to be given together with MV . Pentavalent and YF vaccines were introduced in Guinea-Bissau in 2008 . We investigated whether co-administration of pentavalent vaccine with MV and yellow fever vaccine has similar negative effects . METHODS In 2007 - 2011 , we conducted a r and omised placebo-controlled trial of vitamin A at routine vaccination contacts among children aged 6 - 23 months in urban and rural Guinea-Bissau . In the present study , we included 2331 children r and omised to placebo who received live vaccines only ( MV or MV+YF ) or a combination of live and inactivated vaccines ( MV+DTP or MV+YF+pentavalent ) . Mortality was compared in Cox proportional hazards models stratified for urban/rural enrolment adjusted for age and unevenly distributed baseline factors . RESULTS While DTP was still used 685 children received MV only and 358 MV+DTP ; following the change in programme , 940 received MV+YF only and 348 MV+YF+pentavalent . During 6 months of follow-up , the adjusted mortality rate ratio ( MRR ) for co-administered live and inactivated vaccines compared with live vaccines only was 3.24 ( 1.20 - 8.73 ) . For MV+YF+pentavalent compared with MV+YF only , the adjusted MRR was 7.73 ( 1.79 - 33.4 ) . CONCLUSION In line with previous studies of DTP , the present results indicate that pentavalent vaccine co-administered with MV and YF is associated with increased mortality Background : Recent studies from West Africa suggest that routine vaccinations may have sex differential nontargeted effects . To answer whether these patterns are found elsewhere , we reanalyzed data about vaccinations and mortality in a Malawian cohort . Methods : Children were followed from birth with monthly home visits until 18 months of age .  Anthropometric measurements and vaccination information were obtained at these visits . We investigated survival in relation to vaccination status using 2 different methods . First , we included all children updating vaccination information retrospectively . Second , we included only those present at monthly home visits for whom prospect i ve vaccination information was likely to be most complete . Subjects : This study included 751 children surviving the first week of life . Main Outcome Measures : Main outcome measures consisted of mortality rate ratios ( MR ) for BCG , diphtheria – tetanus – pertussis ( DTP ) and measles-vaccinated children compared with children who had not received these vaccines and female – male MRs among children who had received the same vaccine . Results : In all analyses , BCG and MV were associated with lower mortality .  Children with better nutritional status received DTP1 significantly earlier ( P = 0.02 ) . However , DTP1-vaccinated children did not have lower mortality , the MR being 0.99 ( 0.45–2.19 ) and 3.19 ( 0.80–12.8 ) , respectively , using the 2 analyses with retrospective updating or with prospect i ve determination of vaccination status . The female – male MR varied significantly with age , being increased at 3 to 8 months of age , the age of DTP vaccination , and reduced between 9 and 17 months of age , the age of measles vaccination ( MV ) . Using prospect i ve vaccination information , the MR for girls declined after BCG vaccination of unvaccinated girls but increased after DTP1 ( P = 0.10 ) and declined after MV ( P = 0.01 ) . Children who received DTP and MV simultaneously had a MR of 5.27 ( 1.11–25.0 ) compared with children who received MV only . Conclusion : The female – male mortality ratio varied with age . The mode of analysis was important . Using prospect i ve vaccination information like in previous studies from West Africa , BCG , DTP1 and MV had differential effects for girls and boys
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