Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development: Results from the Danish Calmette Study - A Randomised Clinical Trial.
ABSTRACT: OBJECTIVES:To assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development. DESIGN:This is a pre-specified secondary outcome from a randomised, clinical trial. SETTING:Maternity units and paediatric wards at three university hospitals in Denmark. PARTICIPANTS:Children born at gestational age (GA) 32 weeks and above. All women planning to give birth at the three sites were invited during the recruitment period. Out of 4262 randomised children, 144 were premature (GA < 37 weeks). There were 2129 children (71 premature) randomised to BCG and 2133 randomised (73 premature) to the control group. INTERVENTIONS:BCG vaccination 0.05 ml was given intradermally in the upper left arm at the hospital within seven days of birth. Children in the control group did not receive any intervention. Parents were not blinded to allocation. MAIN OUTCOME MEASURES:Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age < 37 weeks) completed an ASQ at 6 and 22 months. Developmental assessment was available for 3453/4262 (81%). RESULTS:The mean difference in ASQ score at 12 months adjusted for age and prematurity was -0.7 points (BCG vs. control, 95% confidence interval; -3.7 to 2.4), p = 0.67, corresponding to an effect size of Cohen's d = -0.015 (-0.082 to 0.052). The mean difference in ASQ score for premature children at 22 months was -7.8 points (-20.6 to 5.0, p = 0.23), d = -0.23 (-0.62 to 0.15). CONCLUSIONS:A negative non-specific effect of BCG vaccination at birth on psychomotor development was excluded in term children. TRIAL REGISTRATION:ClinicalTrials.gov NCT01694108.
Project description:The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting.Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7?days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses.4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15?months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics.BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15?months of age in this Danish study population.NCT01694108, results.
Project description:WHO recommends BCG at birth and diphtheria-tetanus-pertussis (DTP)-containing vaccine at 6, 10 and 14weeks of age. However, BCG and DTP are often co-administered in low-income countries. The health implications have not been examined.We reanalysed data from Matlab, Bangladesh, to examine the influence of co-administration on mortality; 37,894 children born 1986-1999 were followed with registration of vaccinations and survival.Using Cox models, survival was analysed from 6weeks to 9months of age when measles vaccine is given; 712 children died in this age group. We calculated mortality rate ratios (MRR) for children starting the vaccination schedule with BCG-first, BCG+DTP1-first or DTP1-first.Only 17% followed the WHO-schedule with BCG-first. Mortality was 16/1000 person-years for children who initiated the vaccination schedule with BCG+DTP1 but 32/1000 and 20/1000 for children who received BCG-first or DTP-first, respectively. Compared with BCG+DTP1-first and adjusting for background factors, the BCG-first-schedule was associated with 2-fold higher mortality (MRR=1.94 (1.42-2.63)). DTP1 administered after BCG-first was associated with higher mortality than receiving DTP1 with BCG (MRR=1.78 (1.03-3.03)).Co-administration of BCG and DTP may further reduce mortality. Since all observational studies support this trend, co-administration of BCG and DTP should be tested in randomised trials.
Project description:BCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination ("restricted vial-opening policy"). BCG coverage is usually reported as 12-month coverage, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau.Bandim Health Project (BHP) runs a health and demographic surveillance system covering women and their children in 182 randomly selected village clusters in rural Guinea-Bissau. BCG coverage was assessed for children born in 2010, when the restricted vial-opening policy was universally implemented, and in 2012-2013, where BHP provided BCG to all children at monthly visits in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log-binomial regression models providing prevalence ratios.Among 3951 children born in 2010, vaccination status was assessed for 84%. BCG coverage by 1 week of age was 11%, 38% by 1 month, and 92% by 12 months. If BCG had been given at first contact with the health system, 1-week coverage would have been 35% and 1-month coverage 54%. When monthly visits were introduced in intervention regions, 1-month coverage was higher in intervention regions (88%) than in control regions (51%), the prevalence ratio being 1.74 (1.53-2.00). Several factors, including socioeconomic factors, were associated with delayed BCG vaccination in the 2010-birth cohort. When BCG was available at monthly visits these factors were no longer associated with delayed BCG vaccination, only region of residence was associated with delayed BCG vaccination.BCG coverage during the first months of life is low in Guinea-Bissau. Providing BCG at monthly vaccination visits removes the risk factors associated with delayed BCG vaccination.
Project description:OBJECTIVE:Delayed vaccination increases the susceptibility window for vaccine preventable diseases. Our analysis estimates the proportion of children between 10 and 23?months of age with delayed vaccination in India and the associated socio-demographic, maternal and child related factors. METHODS:We used individual level data from the National Family and Health Survey 4, conducted in 2015-2016. The primary outcome of the study was delayed vaccination for BCG, DPT- 1st dose and Measles. Delayed vaccination for each vaccine was defined as administration of the vaccine dose after 28?days of the minimum recommended age, as per the national immunization schedule in India. We estimated the proportion of children with delayed vaccination for each vaccine and used multivariable logistic regression to explore associated factors. FINDINGS:In the current analysis, 23.1%, 29.3% and 34.8% of children aged 10 to 23?months had delayed vaccination for BCG, DPT-1st dose and Measles respectively. Children from Muslim families (aOR 1.36 for BCG; aOR 1.45 for DPT-1; aOR 1.26 for Measles); birth weight?<?2000?g (aOR 2.33 for BCG; aOR 1.53 for DPT-1; aOR 1.36 for Measles) had higher odds of delayed vaccination. Lower maternal education and belonging to a family from lower wealth quintile had higher odds of delayed vaccination. Children of mothers who had tetanus toxoid immunization during pregnancy had lower odds of delayed vaccination (aOR 0.69 for BCG; aOR 0.76 for DPT-1; aOR 0.78 for Measles). CONCLUSION:The proportion of children with delayed vaccination is high in India. Vaccine timeliness should be a core indicator of the immunization program with greater focus on groups with higher chances of delayed vaccination i.e. home birth, low birth weight new-borns, poorer households, children of mothers with lower education and children from Muslim families.
Project description:BCG vaccination prevents disseminated tuberculosis in children, but it is contraindicated for persons with human immunodeficiency virus (HIV) infection because it can result in severe disease in this population. In tuberculosis-endemic regions, BCG vaccine is administered soon after birth, before in utero and peripartum HIV infection is excluded. We therefore assessed the immunogenicity of BCG vaccine in HIV-exposed infants who received BCG at birth or at 8 weeks of age.HIV-exposed, uninfected infants were randomly assigned to receive BCG vaccination at birth (the early vaccination arm) or 8 weeks of age (the delayed vaccination arm). BCG-specific proliferative and intracellular cytokine responses were assessed in 28 infants per arm at 6, 8, and 14 weeks of life.There was no difference in BCG-specific T-cell proliferation between the study arms 6 weeks after vaccination. However, at 14 weeks of age, the frequency of interferon γ-expressing CD4(+) T cells and multifunctional BCG-specific responses in the delayed vaccinated arm were significantly higher than those in the early vaccination arm (P = .021 and P = .011, respectively).The immunogenicity of BCG vaccination in HIV-exposed, uninfected infants is not compromised when delayed until 8 weeks of age and results in robust BCG-specific T-cell responses at 14 weeks of age. These findings support further evaluation of this modified BCG vaccination strategy for HIV-exposed infants.NCT02062580.
Project description:Vitamin A supplementation (VAS) may amplify the effect of vaccines. We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin (BCG) vaccine to low-birth-weight (LBW) neonates had an effect on growth in the first year of life. We hypothesised that VAS would be particularly beneficial when provided with BCG.We conducted a randomised two-by-two factorial trial in Guinea-Bissau; 1,717 LBW neonates were randomly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination. Anthropometric measurements were obtained at 2, 6, and 12 months after inclusion.Overall there was no effect of neonatal VAS on growth in the first year of life. By 2 months, VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG (interaction: weight-for-age p?=?0.07 and head circumference-for-age: p?=?0.06). By 6 months, there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion (weight: 0.18 (0.00; 0.36) and head circumference 0.27 (0.06; 0.48)), but no beneficial effect among those who had received DTP.The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary. They also show that the effect may differ by vaccination status, being beneficial when given with BCG at birth and when DTP is delayed.www.ClinicalTrials.gov (NCT00168610).
Project description:Randomised trials have shown that early Bacille Calmette-Guérin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants.Two-thousand three hundred forty-three LBW infants were randomly allocated 1:1 to "early BCG" (intervention group) or "late BCG" (current practice). Furthermore, a subgroup (N = 1717) were included in a two-by-two randomised trial in which they were additionally randomised 1:1 to vitamin A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment.Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p?= 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion.Though BCG vaccination is not recommended to be given to LBW infants at birth in Guinea-Bissau, early BCG had no negative effect on infant growth and may have had a beneficial effect for girls.ClinicalTrials.gov (NCT00146302).
Project description:BACKGROUND:Bacillus Calmette-Guérin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is fraught with controversy, BCG vaccination at birth may protect infants in high-mortality populations against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy may modify immune responses to non-TB antigens and potentially enhance immunity, potentially also against tuberculosis (TB). It is unclear whether BCG vaccination very early in life offers adequate protection against TB and other infections among HIV-1-exposed children because even those who remain uninfected with HIV-1 show signs of impaired immunocompetence early in infancy. This study will compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV-1-exposed infants. METHODS:This is an individually randomized controlled trial in 2200 HIV-1-exposed infants. The intervention is BCG vaccination within 24 h of birth while the comparator is BCG given at 14 weeks of age. The study co-primary outcomes are severe illness in the first 14 weeks of life, and production of tumor necrosis factor, interleukin (IL)-1?, IL-6 and interferon-? in response to mycobacterial and nonmycobacterial antigens. The study is being conducted in three health centers in Uganda. DISCUSSION:A well-timed BCG vaccination could have important nonspecific effects in HIV-1-exposed infants. This trial could inform the development of appropriate timing of BCG vaccination for HIV-1-exposed infants. TRIAL REGISTRATION:ClinicalTrials.gov, identifier: NCT02606526 . Registered on 12 November 2015.
Project description:The objective of the present observational study was to investigate if the docosahexaenoic acid (DHA) status assessed in infant erythrocytes (RBC) at 9 months was associated with the age when the infants reach developmental milestones and their psychomotor function at 3 years of age. Three hundred eleven healthy Danish children were followed from 9 months to 3 years of age (the SKOT cohort). RBC fatty acid composition was analysed by gas chromatography in 272 of the children. Milestone age was collected by questionnaires at 9 and 18 months and psychomotor development at 3 years of age was assessed by the parents using third edition of the Ages and Stages Questionnaire (ASQ-3). RBC DHA levels ranged from 2.2% to 12.6% of the RBC fatty acids. The age of reaching milestones correlated with psychomotor development, particularly with gross motor function at 3 years. An association between milestones and later personal and social skills was also observed, but only for girls. In girls, RBC-DHA was found to be inversely correlated with communication at 3 years of age (odds ratio = 0.69, 95% confidence interval: 0.56-0.86, P = 0.001), but no other associations with psychomotor development or milestones were found. The results from study indicate that DHA status at 9 months may not have a pronounced beneficial effect on psychomotor development in early childhood and that communicative skills at 3 years of age may even be inversely associated with early RBC-DHA levels in girls.
Project description:Bacille Calmette-Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, in utero or perinatal HIV infection is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants.Infants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-?) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens.Delaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p=0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p=0.032 and p=0.0035, respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age.Delaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants.NCT02062580.