Determinants of BCG scarification among children in rural Guinea-Bissau: A prospective cohort study.
ABSTRACT: BACKGROUND:Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination. METHODS:Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). RESULTS:From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52-5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal <3 mm were more likely to not develop a scar (RR = 9.05 (3.69-22.20) and RR = 4.74 (1.96-11.45), respectively). Nutritional status and socioeconomic status were not associated with scarification. CONCLUSION:Vaccination technique and vaccine strain were associated with BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.
Project description:The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar has been associated with lower mortality. We aimed to examine the impact of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size.This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence or absence of a BCG scar and the size the scar was measured at 13 months of age.Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7-3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG-vaccinated infants had a scar at 13 months of age. In infants with a wheal, the probability of developing a scar was 96%, declining to 87% in the case of a bulge, and to 56% in the case of no reaction (p for same probability = 0.03). Wheal size was positively correlated with the probability of getting a scar and scar size.Scarring after BCG vaccination has been associated with lower infant mortality. In a high-income setting, we found that correct injection technique is highly important for the development of a BCG scar and that registration of the category of BCG skin reaction (as wheal, bulge, or no reaction) may be used to identify infants at risk of scar failure. Finally, the wheal size was positively associated with both the probability of getting a scar and scar size.The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108 .
Project description:The WHO aims for 90% coverage of the Expanded Program on Immunization (EPI), which in Guinea-Bissau included BCG vaccine at birth, three doses of diphtheria-tetanus-pertussis vaccine (DTP) and oral polio vaccine (OPV) at 6, 10 and 14 weeks and measles vaccine (MV) at 9 months when this study was conducted. The WHO assesses coverage by 12 months of age. The sequence of vaccines may have an effect on child mortality, but is not considered in official statistics or assessments of programme performance. We assessed vaccination coverage and frequency of out-of-sequence vaccinations by 12 and 24 months of age.Observational cohort study.The Bandim Health Project's (BHP) rural Health and Demographic Surveillance site covers 258 randomly selected villages in all regions of Guinea-Bissau. Villages are visited biannually and vaccination cards inspected to ascertain vaccination status. Between 2003 and 2009 vaccination status by 12 months of age was assessed for 5806 children aged 12-23 months; vaccination status by 24 months of age was assessed for 3792 children aged 24-35 months.Coverage of EPI vaccinations and frequency of out-of-sequence vaccinations.Half of 12-month-old children and 65% of 24-month-old children had completed all EPI vaccinations. Many children received vaccines out of sequence: by 12 months of age 54% of BCG-vaccinated children had received DTP with or before BCG and 28% of measles-vaccinated children had received DTP with or after MV. By 24 months of age the proportion of out-of-sequence vaccinations was 58% and 35%, respectively, for BCG and MV.In rural Guinea-Bissau vaccination coverage by 12 months of age was low, but continued to increase beyond 12 months of age. More than half of all children received vaccinations out of sequence. This highlights the need to improve vaccination services.
Project description:Over the past four decades, the World Health Organization established the Expanded Programme on Immunization (EPI) to foster universal access to all relevant vaccines for all children at risk. The success of this program has been undeniable, but requires periodic monitoring to ensure that coverage rates remain high. The aim of this study was to measure the BCG vaccination coverage in Manhiça district, a high TB burden rural area of Southern Mozambique and to investigate factors that may be associated with BCG vaccination.We used data from the Health and Demographic Surveillance System (HDSS) run by the Manhiça Health Research Centre (CISM) in the district of Manhiça. A questionnaire was added in the annual HDSS round visits to retrospectively collect the vaccination history of children under the age of 3 years. Vaccinations are registered in the National Health Cards which are universally distributed at birth. This information was collected for children born from 2011 to 2014. Data on whether a child was vaccinated for BCG were collected from these National Health Cards and/or BCG scar assessment.A total of 10,875 number of children were eligible for the study and 7903 presented the health card. BCG coverage was 97.4% for children holding a health card. A BCG-compatible scar was observed in 99.0% of all children and in 99.6% of children with recorded BCG in the card. A total of 93.4% of children had been vaccinated with BCG within their first 28 days of life. None of the factors analysed were found to be associated with lack of BCG vaccination except for living in the municipality of Maluana compared to living in the municipality of Manhiça; (OR?=?1.89, 95% CI: 1.18-3.00). Coverage for other EPI vaccines during the first year of life was similarly high, but decreased for subsequent doses.BCG coverage is high and timely administered. Almost all vaccinated infants develop scar, which is a useful proxy for monitoring BCG vaccine implementation.
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:PURPOSE:Bandim Health Project (BHP) monitors health and survival of women and children in a nationally representative rural Health and Demographic Surveillance System (HDSS) in Guinea-Bissau. The HDSS was set up in 1989-1990 to collect data on health interventions and child mortality. PARTICIPANTS:The HDSS covers 182 randomly selected clusters across the whole country. The cohort is open, and women and children enter the cohort, when they move into the selected clusters, and leave the cohort, when they move out or die, or when children reach 5 years of age. Data are collected through biannual or more frequent household visits. At all village visits, information on pregnancies, vital status, vaccination status, arm circumference, use of bed nets and other basic information is collected for women and children. Today, more than 25?000 women and 23?000 children below the age of 5 years are under surveillance. FINDINGS TO DATE:Research from the BHP has given rise to the hypothesis that vaccines, in addition to their targeted effects, have important non-specific effects altering the susceptibility to other infections. Initially, it was observed that mortality among children vaccinated with the live BCG or measles vaccines was much lower than the mortality among unvaccinated children, a difference, which could not be explained by prevention of tuberculosis and measles infections. In contrast, mortality tended to be higher for children who had received the non-live Diphtheria-Tetanus-Pertussis vaccine compared with children who had not received this vaccine. Since the effect differed for the different vaccines, no bias explained the contrasting findings. FUTURE PLANS:New health interventions are introduced with little assessment of real-life effects. Through the HDSS, we can describe both the implementation of interventions (eg, the vaccination programme) and their effects. Furthermore, the intensive follow-up allows the implementation of randomised trials testing potential better vaccination programmes.
Project description:Introduction:The aim of this study was to explore the effectiveness of BCG vaccination on the severity of clinical symptoms of pulmonary tuberculosis symptoms (PTb) in patients from the northwest and west of Iran. Materials and methods:In a cross sectional study of 358 patients with a diagnosis of PTb, 11 clinical symptoms, including cough, chest pain, dyspnea, sputum, fever, hemoptysis, weight loss, loss of appetite, wheezing, weakness, and fatigue were checked and patients with a score of six or more were placed in the severe clinical symptoms group. BCG vaccination scar and clinical symptoms were examined and recorded. Results:Of the subjects included in this study, 264 cases (73.7%) had no BCG vaccination scar. Comparison of the severity of clinical symptoms of PTb in patients with BCG vaccine history to those lacking vaccination history revealed lower symptom severity in patients who had been vaccinated (vaccine effectiveness = 95.5%; p < 0.00001). Conclusion:The results of this study may imply that Adjusting for age sex and smoking status, BCG vaccination decreases the severity of clinical symptoms in patients with PTb. We suggest performing a retrospective cohort study on a larger population.
Project description:Bacille Calmette-Guérin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humans in vivo during experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG (n = 10) or placebo (n = 10) and received 1?ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess the in vivo immune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assess ex vivo immune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither this in vivo immune response, nor ex vivo leukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered with NCT02085590.
Project description:Intradermal bacille Calmette-Guérin (BCG) vaccination by needle-free, disposable-syringe jet injectors (DSJI) is an alternative to the Mantoux method using needle and syringe (NS). We compared the safety and immunogenicity of BCG administration via the DSJI and NS techniques in adults and newborn infants at the South African Tuberculosis Vaccine Initiative (SATVI) research site in South Africa.Thirty adults and 66 newborn infants were randomized 1:1 to receive intradermal BCG vaccine (0.1 mL in adults; 0.05 mL in infants) via DSJI or NS. Wheal diameter (mm) and skin fluid deposition at the site of injection (SOI) were measured immediately post-vaccination. Adverse events and SOI reactogenicity data were collected 30 min and 1, 2, 4, and 12 weeks after vaccination for adults and at 30 min and 4, 10, and 14 weeks for infants. Blood was collected in infants at 10 and 14 weeks to assess BCG-specific T-cell immune responses.More infant BCG vaccinations by DSJI deposited >5 ?L fluid on the skin surface, compared to NS (49% versus 9%, p=0.001). However, all 12 infant vaccinations that did not produce any SOI wheal occurred in the NS group (36%, p<0.001). Median wheal diameter, in participants for which an SOI wheal formed, did not differ significantly between groups in infants (combined 3.0mm IQR 2.0 to 4.0, p=0.59) or in adults (combined 9.0mm IQR 7.0 to 10.0, p=0.13). Adverse events were similar between study arms. Proportion of participants with BCG scars after three months did not differ in adults (combined 97%, p=0.67) or infants (combined 62%, p=0.13). Frequencies of BCG-specific clusters of differentiation 4 (CD4) and clusters of differentiation 8 (CD8) T-cells co-expressing IFN-?, TNF-?, IL-2, and/or IL-17 were not different in the DSJI and NS groups.BCG vaccination of newborn infants via DSJI was more likely to deliver an appropriate intradermal wheal at the SOI as compared to NS, despite leaving more fluid on the surface of the skin. Safety, reactogenicity, and antigen-specific T-cell immune responses did not differ between DSJI and NS techniques.
Project description:Bacillus Calmette-Guérin (BCG) vaccination possesses effects on health beyond its target disease, the so called "non-specific effects". We evaluate these effects, as well as the effect of timing of BCG and other vaccinations, on stunting in Sub-Saharan African (SSA) children under five.We use a Big Data design, including cross-sectional data for 368,450 children from 33 SSA countries. Logistic regression analysis is used with control factors at child, mother, household and context level.Overall, BCG vaccination did not affect stunting in SSA children (OR 1.00 [0.98-1.03]). Timing of BCG vaccination was of importance (?time=0.067 [0.061-0.073]): compared to unvaccinated children, BCG was associated with lower odds on stunting for children vaccinated early in life (OR 0.92 [0.89-0.94]) and higher odds for children vaccinated later in infancy (OR 1.64 [1.53-1.76]). Similar findings were done for diphtheria-tetanus-pertussis (DTP)1 and measles vaccination, and when hemoglobin concentration was used as outcome variable.We found a general time-dependent pattern of non-specific effects of vaccination, with positive associations for vaccinations given early in life and negative associations for vaccinations given later in infancy. If confirmed in further research, our findings may provide a new perspective on the non-specific effects of vaccination.
Project description:Importance:Bacillus Calmette-Guérin (BCG) vaccination is commonly delayed in infants who are preterm and have low birth weights (LBW) despite the association of early vaccination with better vaccination coverage and potentially nonspecific benefits for survival. Objective:To determine the safety, immunogenicity, and protective efficacy against tuberculosis (TB) of BCG vaccination given at or before 7 days after birth vs vaccination more than 7 days after birth among infants who are preterm and/or had LBW. Data Sources:Searches of Medline, Embase, and Global Health databases were conducted from inception until August 8, 2017. Study Selection:Clinical trials, cohort studies, and case-control studies that included infants who were preterm and/or had LBW and reported safety, mortality, immunogenicity, proxies of vaccine take, and/or efficacy against TB. Data Extraction and Synthesis:Two authors independently extracted data and assessed the quality of the studies. Data extracted included demographics, covariates, sources of bias, and effect estimates. Meta-analysis was performed using a random-effects model. Main Outcomes and Measures:Safety, mortality, immunogenicity, or other proxies of vaccine take, such as tuberculin skin test (TST) conversion and efficacy against tuberculosis. Results:Forty studies were included in a qualitative synthesis; infants who were preterm (born at 26-37 weeks' gestational age) and/or had LBW (0.69-2.5 kg at birth) were included. The BCG vaccine was administered at or before 7 days to 10 568 clinically stable infants who were preterm and/or had LBW; vaccination was administered to 4310 infants at varying times between 8 days and 12 months after birth. Twenty-one studies reporting safety found no cases of BCG-associated death or systemic disease in 8243 infants. Four studies reported no increase in all-cause mortality for infants who had LBW and who received early BCG vaccination compared with infants who had LBW with later vaccination or BCG-vaccinated infants of normal birth weight. Four studies reported lymphadenitis incidence; combined, these reported 0% to 2.9% incidence of vaccination within 7 days and 0% to 4.2% of vaccination after 7 days. Meta-analysis of 7 studies revealed no differences between early and delayed BCG vaccination for scar formation (n = 515; relative risk [RR], 1.01 [95% CI, 0.95-1.07]) or TST conversion (n = 397; RR, 0.97 [95% CI, 0.84-1.13]). Published data were insufficient to assess immunogenicity or protective efficacy against TB disease. Conclusions and Relevance:Early BCG vaccination in healthy infants who are preterm and/or had LBW has a similar safety profile, reactogenicity, and TST conversion rate as delayed vaccination. Based on current evidence, early BCG vaccination in stable infants who are preterm and/or have LBW to optimize uptake is warranted.