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Though previous studies have suggested a non-specific beneficial effect of oral polio vaccine (OPV), there has been no evaluation of the mortality impact of national polio immunization days. On the other hand, studies examining the effect of OPV and diphtheria–tetanus–pertussis (DTP) vaccines, which are usually administered together in routine immunisation programmes in low-income countries, have found no beneficial or even a negative effect on infant survival. In 1998, we used the opportunity of two national immunisation days to examine the impact of OPV administered alone on survival for the 6103 children less than 5 years of age in the Bandim Health Project's study area in Guinea-Bissau. Survival was ascertained through regular surveillance from March 1998 until the beginning of the war on June 7, 1998, the end of 1998, or the end of 1999, respectively. The child register was linked with a register for the only paediatric ward in Bissau to determine the risk of hospitalisations. Among children under 5 years of age, 82% had received 1 or 2 doses of polio vaccines during the campaign. Though polio vaccination during the campaign was associated with slightly lower mortality, this difference was not significant for all children under 5 years of age (mortality ratio (MR) = 0.46 (0.18–1.15)). However, oral polio vaccination was associated with a beneficial effect for children under 6 months of age at the time of the campaign, the mortality ratio being 0.09 (95% CI 0.01–0.85) in the 3 months before the war controlling for significant background factors, including routine immunizations, antenatal consultations, and arm circumference. The polio-vaccinated children aged 0–5 months had fewer hospitalisations than children who had not been polio vaccinated (RR = 0.27 (0.10–0.76)). With longer follow-up to December 1998 or December 1999, the difference in mortality gradually disappeared, the MR for polio-vaccinated children being 0.61 (0.32–1.14) and 0.83 (0.51–1.34), respectively. Among children aged 6–59 months of age, measles vaccine was associated with a 56% reduction in mortality (MR = 0.44 (0.28–0.69)) and no effect of oral polio vaccine was measurable in this age group. The effect of polio vaccine among children less than 6 months of age could be due to selection bias but might also represent a non-specific beneficial immune stimulation and there is nothing to suggest that OPV might have a negative effect on infant survival. Studies of the possible non-specific effects of oral polio vaccine are warranted before OPV is withdrawn.

The live Bacillus Calmette-Guérin (BCG) vaccine has beneficial non-specific effects (NSEs) affecting susceptibility to other infections than tuberculosis. The non-live Pentavalent vaccine (Penta) may have negative NSEs on overall health, particularly for girls. We tested whether timing of BCG (scheduled at birth) and first Penta (Penta1) vaccination (scheduled from 6 weeks) were associated with weight-for-age z-score (WAZ) in children under 5 years of age. Bandim Health Project (BHP) monitors vaccination status of children under 5 years through a Health and Demographic Surveillance System in Guinea-Bissau. Between 2016 and 2020, BHP weighed children eligible for enrolment in two large cluster-randomized trials. We classified BCG as timely if given during the neonatal period and Penta1 as timely if given within 2 months of age. Using linear regression models, we quantified the association between WAZ and timing of vaccination, adjusted for background factors associated with vaccination timeliness. A total of 25,693 children were included in the BCG cohort and 24,400 in the Penta cohort: 46 % had received no neonatal BCG and 54 % no timely Penta1. Children with no neonatal BCG had lower WAZ (adjusted difference − 0.08 (95 % confidence interval (95 %CI) -0.12 to −0.04)). The adjusted difference in WAZ for each week of delay in BCG vaccination was −0.005 (95 %CI -0.007 to −0.003). Associations were similar for boys and girls. Overall estimates for no timely Penta1 were similar (adjusted difference − 0.08 (95 % CI -0.11 to −0.05)) but the difference tended to be larger in males (adjusted difference − 0.10 (95 %CI -0.14 to −0.06)) than in females (adjusted difference − 0.06 (95 %CI -0.11 to −0.02) (p = 0.27 for interaction with sex). Receiving no timely BCG or Penta1 (or none at all) was associated with lower WAZ though much of the difference is likely explained by confounding. Timely Penta1 vaccination seemed less beneficial for girls. •Half the children in rural Guinea-Bissau receive delayed BCG and/or Penta1 vaccines.•∼25,000 children under 5 years were weighed and had vaccination status assessed.•Delayed vaccination with BCG or Penta1 was associated with lower weight-for-age.•Associations tended to differ by sex for Penta1 but did not for BCG.

Secondary analysis of 3 randomized controlled trials of BCG vaccine administered shortly after birth versus delayed vaccination in infants weighing <2500g showed that early vaccination did not affect admission rates but protected against in-hospital death, particularly deaths due to sepsis. Study protocols were approved by the Guinean Ministry of Health’s Research Coordination Committee and the Central Danish Ethical Committee gave its consultative approval. The trials were conducted in accordance with the Helsinki Declaration ethical standards. Abstract Background This study was performed to examine the effects of early BCG vaccination on the risk, cause, and severity of infant hospitalizations. The analysis included 3 trials randomizing low-weight neonates to early BCG vaccination (intervention) versus no BCG vaccination (usual practice in low-weight neonates, control), with hospitalizations as secondary outcome. Methods Hospitalization data were collected at the pediatric ward of the National Hospital. Effects of BCG vaccination on hospitalization risk were assessed in Cox models providing overall and major disease-group incidence rate ratios (IRRs). Severity was assessed by means of in-hospital case-fatality rates and compared by group as cohort study risk ratios (RRs). Results Among 6583 infants (3297 in BCG group, 3286 controls), there were 908 infant hospitalizations (450 BCG, 458 controls) and 135 in-hospital deaths (56 BCG, 79 controls). The neonatal (28 days), 6-week, and infant (1-year) BCG versus control hospitalization IRRs were 0.97 (95% confidence interval [CI], .72–1.31), 0.95 (.73–1.24), and 0.96 (.84–1.10). Corresponding BCG versus control case-fatality rate RRs were 0.58 (95% CI, .35–.94), 0.56 (.35–.90), and 0.72 (.53–.99). BCG vaccination tended to reduce neonatal and infant sepsis hospitalization rates (IRR, 0.75 [95% CI, .50–1.13] and 0.78 [.55–1.11], respectively), and it reduced the neonatal in-hospital sepsis mortality rate (RR, 0.46; 95% CI, .22–.98). There were no confirmed hospitalizations for tuberculosis. Conclusions BCG vaccination did not affect hospitalization rates but reduced in-hospital mortality rates significantly, primarily by preventing fatal cases of sepsis. The observed beneficial effects of BCG on the in-hospital mortality rate were entirely nonspecific. Clinical Trials Registration NCT00146302, NCT00168610, and NCT00625482.

•MMR vaccinated children had lower rates of antibiotic treatments than children with no MMR.•Bias may explain at least some of the observed association.•Limited non-specific effects of MMR vaccine on infections treated out-of-hospital. Previous studies have shown that vaccination against measles, mumps, and rubella (MMR) may have beneficial non-specific effects, reducing the risk of infections not targeted by the vaccine. We investigated if MMR vaccine given after the third dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP3), was associated with reduced rates of antibiotic treatments. Register-based cohort study following children from the age of recommended MMR vaccination until age 2 years. We included 831,287 children born in Denmark, Finland, Norway, and Sweden who had received DTaP3 but not yet MMR vaccine. Cox proportional hazards regression with age as the underlying timescale and vaccination status as a time-varying exposure was used to estimate covariate-adjusted Hazard Ratios (aHRs) and inverse probability of treatment weighted (IPTW) HRs of antibiotic treatments. Summary estimates were calculated using random-effects meta-analysis. Compared with only having received DTaP3, receipt of MMR vaccine after DTaP3 was associated with reduced rates of antibiotic treatments in all countries: the aHR was 0.92 (0.91–0.93) in Denmark, 0.92 (0.90–0.94) in Finland, 0.84 (0.82–0.85) in Norway, and 0.87 (0.85–0.90) in Sweden, yielding a summary estimate of 0.89 (0.85–0.93). A stronger beneficial association was seen in a negative control exposure analysis comparing children vaccinated with DTaP3 vs two doses of DTaP. Across the Nordic countries, receipt of MMR vaccine after DTaP3 was associated with an 11% lower rate of antibiotic treatments. The negative control analysis suggests that the findings are affected by residual confounding. Findings suggest that potential non-specific effects of MMR vaccine are of limited clinical and public health importance for the milder infections treated out-of-hospital in the Nordic setting.

•BCG vaccinations are given with delay not evident in current coverage estimates.•1 of 5 children in Guinea-Bissau received the BCG vaccine timely from 2013 to 2019.•Missed opportunities for BCG vaccination are common in Guinea-Bissau.•BCG coverage could be 45% instead of 19% if missed BCG opportunities were utilized.•Children should get BCG vaccinated at first contact with the health system. The Bacillus Calmette-Guérin (BCG) vaccine is recommended at birth in Guinea-Bissau but often given with delay. Delays are not evident in routine coverage estimates since coverage is measured by 12 months of age. Studies show that BCG protects against other infections than tuberculosis and lowers neonatal mortality. Hence, the timing of BCG is important since the children should benefit from these non-specific effects as early as possible. Using data from a nationally representative health and demographic surveillance system in Guinea-Bissau, we assessed BCG coverage at birth (within the first 3 days of life), 1 month, and 12 months for children born in 2013–19. We measured the proportion of children who had a documented health system contact within the first 3 days of life, thus an opportunity for BCG at birth, and whether the opportunities were utilized. In binomial regression models, we investigated factors associated with missed opportunities for vaccination. Among the 22,178 children only 19 % were vaccinated at birth. By 1 month and 12 months, BCG coverages were 64 % and 93 %. The timeliness of BCG improved over time, with coverage at birth increasing from 16 % in 2013 to 25 % in 2019 and 1-month coverage from 63 % in 2013 to 75 % in 2019. If all vaccination opportunities had been utilized, the BCG coverage at birth could have reached 45 % (in the 1-month cohort) instead of the actual coverage of 19 %, as only 40 % of the vaccination opportunities were utilized. Region of residence was associated with having a missed opportunity for vaccination. The high coverage estimates at 12 months falsely imply that the vaccine is being administered according to the recommended schedule. Our findings suggest that early coverage could be markedly improved by ensuring that children are vaccinated at their first contact with the health system.

Nigeria contributes a substantial number of under-5 deaths and ‘zero dose’ children (i.e. children with no routine vaccinations) to the global burden each year. Vaccines are a lifesaving intervention proven to reduce child mortality from specific diseases. Non-specific effects of vaccines may further affect all-cause child mortality. This analysis explores the association between vaccination status and child survival for children 12–59 months of age, using data from the INSPIRING trial in Jigawa, Nigeria (registration: ISRCTN39213655). Descriptive analysis and logistic regression were used, with multivariate models adjusting for the study design and child age, sex, malnutrition, maternal education, maternal age, compound size and wealth quintile. Interaction effects for child sex were explored given evidence for non-specific effects of vaccines. We found all groups of vaccinated children to have reduced mortality compared to unvaccinated children. Children that completed the Nigerian vaccination schedule, i.e. received the second measles vaccine dose, had the lowest odds of death, with a 70 % reduction in mortality compared to an unvaccinated child (AOR: 0.30, CI: 0.18, 0.49, p-value <0.001). A child that had basic antigens and the 1st measles dose had 30 % lower odds of death than an unvaccinated child (AOR: 0.70, CI: 0.49, 0.98, p-value 0.038). This study supports evidence that vaccines have non-specific effects on all-cause child mortality. Unvaccinated children had the highest odds of death between 12 and 59 months of age and must be reached through vaccination to improve their chances of survival. In this setting, receiving a second measles vaccine was associated with a large reduction in child mortality, and may be an effective focus for outreach campaigns in Northern Nigeria.

•Three doses of diphtheria, tetanus and pertussis (DTP) vaccine are recommended from 6 weeks of age.•We assessed in-hospital case fatality among children aged 6 weeks to 8 months by DTP-vaccination status and sex.•Female case fatality was 23% (3–46%) higher than male case fatality among DTP-vaccinated children.•Among DTP-unvaccinated children, there was no sex-difference in mortality.•The data is consistent with the hypothesis that DTP negatively affects survival of girls. In spite of protection against the targeted infections, a large volume of observational data indicates that diphtheria-tetanus-pertussis (DTP) vaccine may have a negative impact on overall childhood mortality in low-income countries, especially in girls. In an observational study using data from Bandim Health Project’s continuous registration of all admissions to the paediatric ward at the National Hospital Simão Mendes in Bissau, we investigated whether DTP was associated with higher female than male in-hospital mortality (female/male case fatality ratio (F/M CFR)) and whether the CFR comparing DTP-vaccinated and DTP-unvaccinated children differed by sex. We included children aged 6 weeks to 8 months (274 days) admitted to the paediatric ward with a vaccination card seen during admission. From May 2001 to January 2008, 4230 children aged 6 weeks to 8 months were admitted and 3450 (82%; 1997 boys, 1453 girls) presented a vaccination card. The proportion presenting a vaccination card and DTP coverage did not differ by sex. During admission, 16% (200/1250) of the girls and 13% (220/1694) of the boys who had received DTP died. The F/M CFR among the 2944 DTP-vaccinated children was 1.23 (1.03–1.46); while it was 0.95 (0.66–1.38) among the 506 children who had not received DTP. DTP-vaccinated children were older and had better socioeconomic status. Adjusted for age, BCG-vaccination, residence, and maternal education the CFR comparing DTP-vaccinated boys with DTP-unvaccinated boys was 0.84 (0.63–1.11), while the CFR comparing DTP-vaccinated girls with DTP-unvaccinated girls was 1.28 (0.90–1.83) (p = .07 for same effect in boys and girls). Among DTP-vaccinated children, female in-hospital mortality was higher than male in-hospital mortality and DTP-vaccination tended to be associated with higher mortality in girls. The data are consistent with DTP having negative effects on mortality for girls. Further studies are necessary to design the optimal vaccination programme for both sexes.

•Healthier infants were more likely to receive early-DTP before 2 months of age.•Receiving early-DTP had no effects on all-cause mortality in the present study.•Receiving early-DTP after BCG-at-birth tended to increase female mortality.•Co-administration of BCG and DTP tended to reduce all-cause mortality.•Routine vaccinations and campaigns may affect the non-specific effects of vaccines. There are worrying indications that diphtheria-tetanus-pertussis (DTP) vaccine has negative non-specific effects for females. We previously found, in a trial of early-Bacillus Calmette-Guérin (BCG) to low weight (LW) neonates, that receiving early-DTP (before 2 months of age), was associated with increased female mortality compared with no-DTP/delayed-DTP. Within a subsequent LW trial, we aimed to retest this observation. Between 2010 and 2014, in Guinea-Bissau, 2,398 infants were randomised 1:1 to early-BCG (intervention) or delayed-BCG (standard practice for LW neonates) and visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. DTP is recommended at 6 weeks of age. We examined the effect of having “early-DTP” versus “no-DTP” at the time of the 2-month visit on all-cause mortality between the 2- and 6-month visits in Cox models stratified by sex and adjusted for BCG-group and 2-month-weight-for-age (z-scores) providing adjusted mortality rate ratios (aMRRs). We analysed to which extent conditions varied between the present and the previous LW trials and how that might have affected the overall result of comparing the early-DTP and the no-DTP groups. At the time of the 2-month visit, 75% (1,795/2,398) had received DTP. Those vaccinated had better anthropometric indices than no-DTP infants at birth and by 2 months of age. Between the 2- and 6-month visits, 29 deaths occurred. The early-DTP/no-DTP aMRR was 1.09 (95% CI: 0.44–2.69); 1.19 (0.45–3.15) for females and 0.77 (0.14–4.19) for males. Compared to the previous study, the present study cohort had 56% (30–72%) lower overall mortality, fewer no-DTP infants, higher BCG vaccination coverage and several more oral polio vaccine campaigns. We did not find that early-DTP was associated with increased female mortality as found in a previous study; differences in results may partly be due to a decline in overall mortality and changes in vaccination practices.

•Maternal pertussis vaccination increases the risk of chorioamnionitis by 27%, CI 95%: 1.14–1.42.•Pertussis vaccination in pregnancy was not associated with other adverse events.•This study adds to the growing evidence on negative non-specific effects of non-live vaccines.•The findings indicate a need for further investigation with RCTs. Several countries have introduced maternal immunisation with pertussis vaccine to provide protection against pertussis in early infancy. There is increasing interest in non-specific effects of vaccines including that non-live vaccines may enhance susceptibility to non-targeted infections in females. Some studies have shown increased risk of chorioamnionitis among women receiving pertussis vaccine during pregnancy. We aimed to conduct a systematic review and meta-analysis of the effect of maternal pertussis immunisation on the risk of chorioamnionitis, as well as the secondary outcomes of non-pertussis infections in women, non-pertussis infections in infants, spontaneous abortion or stillbirth, maternal death and infant death. We searched PubMed and Embase for articles published until January 14, 2021. We screened articles for eligibility and extracted data using Covidence. Quality was assessed using Cochrane RoB tool and Newcastle-Ottawa Scale. Data were imported into RevMan for pooling and conduction of a meta-analysis stratified by study type. Outcomes are presented as risk ratios. We identified 13 observational studies and six randomized controlled trials eligible for inclusion. We pooled data on chorioamnionitis from six observational studies and found maternal pertussis vaccine (mostly compared with other maternal immunizations with non-live vaccines) to be associated with an increased risk among the pertussis vaccinated women, RR = 1.27 [CI 95%: 1.14–1.42]. We found no difference in the analysis of our secondary outcomes of non-pertussis infections, spontaneous abortion or stillbirth and death. We found an increased risk of chorioamnionitis among women who received pertussis vaccine in pregnancy. The large number of women receiving pertussis vaccine during pregnancy, as well as the growing evidence of non-live vaccines causing increased susceptibility to infections, indicates a need for further randomised trials to assess potential adverse effects of maternal immunisation with pertussis-containing vaccines.

•Vaccines have sex-differential non-specific effects affecting mortality.•The transition from DTP to measles vaccine lowers female/male mortality ratio.•Penta recently replaced DTP and yellow fever vaccine is now given with measles vaccine.•Pentavalent vaccine is associated with 73% higher female than male mortality.•Yellow fever and measles vaccine are associated with lower female mortality. In addition to protection against the target diseases, vaccines may have non-specific effects (NSEs). Measles vaccine (MV) has beneficial NSEs, providing protection against non-measles deaths, most so for girls. By contrast, though protecting against diphtheria, tetanus and pertussis, DTP vaccine is associated with increased female mortality relative to male mortality. In 2008, Guinea-Bissau replaced DTP with the DTP-containing pentavalent vaccine (Penta; DTP-H. influenza type B-Hepatitis B) at 6, 10 and 14weeks and yellow fever vaccine (YF) was to be given with MV. We investigated possible sex-differential mortality rates following Penta and MV+YF vaccination. Bandim Health Project (BHP) registers vaccines given by the three government health centres in the study area and vital status through demographic surveillance. We assessed the association between sex and mortality by vaccination status in Cox proportional hazards models with age as underlying timescale. Follow-up was censored at a subsequent vaccination contact or after 6months of follow-up. Between September 2008 and April 2011, we registered 23,448 vaccination contacts for children aged 42–365days; 17,313 were for Penta and 3028 for MV (2907 co-administered with YF). During follow-up 112 children died. The female/male mortality rate ratio was 1.73 (1.11–2.70) following Penta and 0.38 (0.12–1.19) after MV (p=0.02 for same effect). Adjusting for maternal education or weight-for-age at the time of vaccination did not change the estimates. Penta appears to have the same negative effects on mortality as those seen for DTP. Assessing post-vaccination mortality for boys and girls is necessary to improve the vaccination programme.