The Effect of Smallpox and Bacillus Calmette-Guerin Vaccination on the Risk of Human Immunodeficiency Virus-1 Infection in Guinea-Bissau and Denmark.
ABSTRACT: The live smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with better adult survival in both Guinea-Bissau and Denmark. In Guinea-Bissau, human immunodeficiency virus (HIV)-1 became an important cause of death after smallpox vaccination was phased out globally in 1980. We hypothesised that smallpox and BCG vaccinations were associated with a lower prevalence of HIV-1 infection, and we tested this hypothesis in both Guinea-Bissau and Denmark.We conducted 2 studies: (1) a cross-sectional study of HIV infection and vaccination scars in Guinea-Bissau including 1751 individuals and (2) a case-base study with a background population of 46239 individuals in Denmark. In Guinea-Bissau, HIV-1 transmission was almost exclusively sexually transmitted. In Denmark, we excluded intravenous drug users. Data were analyzed using logistic regression.Bacillus Calmette-Guérin and/or smallpox vaccination compared with neither of these vaccines was associated with an adjusted odds ratio (aOR) for HIV-1 of 0.62 (95% confidence interval [CI], 0.36-1.07) in Guinea-Bissau and 0.70 (95% CI, 0.43-1.15) in Denmark. We combined the results from both settings in a meta-analysis (aOR = 0.66; 95% CI, 0.46-0.96). Data from Guinea-Bissau indicated a stronger effect of multiple smallpox vaccination scars (aOR = 0.27; 95% CI, 0.10-0.75) as follows: women, aOR = 0.18 (95% CI, 0.05-0.64); men, aOR = 0.52 (95% CI, 0.12-2.33); sex-differential effect, P = .29.The studies from Guinea-Bissau and Denmark, 2 very different settings, both suggest that the BCG and smallpox vaccines could be associated with a decreased risk of sexually transmitted HIV-1. It might be informative to pursue this observation and explore possible protective mechanisms as part of the search for an HIV-1 vaccine.
Project description:OBJECTIVE:In Guinea-Bissau, West Africa, we observed that having a smallpox vaccination scar was associated with lower HIV-1 prevalence, more strongly for women than men. If this represents a causal effect, the female/male HIV-1 prevalence ratio would increase for birth cohorts no longer receiving smallpox vaccination due to the phase-out of this vaccine. DESIGN:An ecological design using HIV surveys and information about smallpox vaccination coverage. SETTING:Urban and rural Guinea-Bissau. PARTICIPANTS:Participants in HIV surveys were grouped into an age group with decreasing smallpox vaccination coverage (15-34 years) and an age group with steady smallpox vaccination coverage (?35 years). INTERVENTIONS:The exposure of interest was the phase-out of the smallpox vaccine in Guinea-Bissau. PRIMARY AND SECONDARY OUTCOME MEASURES:HIV-1 prevalence. RESULTS:At both sites, the female/male HIV-1 prevalence ratio increased by calendar time for the age group with decreasing smallpox vaccination coverage; the combined female/male HIV-1 prevalence ratio among people aged 15-34 years was 1.00 (95% CI 0.17 to 5.99) in 1987-1990, 1.16 (95% CI 0.69 to 1.93) in 1996-1997, 2.32 (95% CI 1.51 to 3.56) in 2006-2007 (p value for no trend=0.04). There was no increase in the female-to-male HIV-1 prevalence ratio for the age group >35 years with steady smallpox vaccination coverage; 1.93 (95% CI 0.40 to 9.25) in 1987-1990, 1.32 (95% CI 0.83 to 2.10) in 1996-1997, 0.81 (95% CI 0.56 to 1.16) in 2006-2007 (p value for no trend=0.07). CONCLUSIONS:Thus, data was compatible with the deduction that the phase-out of smallpox vaccination may have increased the susceptibility to HIV-1 relatively more for women than men. Hence, phasing out smallpox vaccination may have contributed to the global increase in the female/male HIV-1 prevalence ratio among young individuals. Due to the potential fallacies of ecological studies, the results should be interpreted carefully, and this hypothesis needs further assessment. If the hypothesis is true, studies of smallpox vaccination could inform HIV-1 vaccine research.
Project description:BACKGROUND:Smallpox vaccinations were stopped globally in 1980. Recent studies have shown that in women, being smallpox vaccinated was associated with a reduced risk of HIV infection compared with not being smallpox vaccinated. At the initial infection, HIV-1 most often uses CCR5 as a co-receptor to infect the T-lymphocytes. We therefore investigated whether smallpox vaccination is associated with a down-regulation of CCR5 on the surface of peripheral T-lymphocytes in healthy women in Guinea-Bissau. METHODS:We included HIV seronegative women from Bissau, Guinea-Bissau, born before 1974, with and without a smallpox vaccination scar. Blood samples were stabilised in a TransFix buffer solution and stained for flow cytometry according to a T-cell maturation profile. RESULTS:Ninety-seven women were included in the study; 52 with a smallpox vaccination scar and 45 without a scar. No association between smallpox vaccination scar and CCR5 expression was found in any T-lymphocyte subtype. CONCLUSION:Among HIV seronegative women, being smallpox vaccinated more than 40 years ago was not associated with a down-regulation of CCR5 receptors on the surface of peripheral T-lymphocytes.
Project description:Live vaccines against measles (MV), tuberculosis (BCG), polio (OPV) and smallpox reduce mortality more than explained by target-disease prevention. The beneficial nonspecific effects (NSEs) of MV are strongest when MV is given in presence of maternal antibodies. We therefore hypothesised that revaccination in presence of prior immunity enhances beneficial NSEs.Literature search for studies of revaccination and mortality.In two randomised trials (RCTs), two doses versus one dose of MV reduced all-cause mortality by 63% (95% CI: 23-83%) from 9 to 18months of age. In a quasi-experimental study two doses before and after 9months compared with one dose of MV after 9months of age reduced mortality by 59% (25-81%). BCG-revaccination significantly enhanced BCG's effect against overall child mortality in two RCTs. In a natural experiment study of OPV campaigns over a 13-year-period in Guinea-Bissau, each additional dose of OPV was associated with a 13% (4-21%) reduction in mortality rate. The beneficial NSEs of smallpox vaccination for survival increased significantly with the number of smallpox vaccination scars.Revaccination with live vaccines led to substantial reductions in overall mortality. These findings challenge current understanding of vaccines and may explain the beneficial effects of campaigns with live vaccines.
Project description:To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates.Randomised, placebo controlled, two by two factorial trial.Bissau, Guinea-Bissau.1717 low birthweight neonates born at the national hospital.Neonates who weighed less than 2.5 kg were randomly 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.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.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 randomisation 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).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 ClinicalTrials.gov NCT00168610.
Project description:Background:BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods:In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results:Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months. Conclusion:Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration:NCT00625482.
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: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:Reducing vaccine wastage is important. Bacille Calmette-Guérin (BCG) vaccine is produced in vials of 20 infant doses. The reconstituted vaccine is discarded after 4-6 hours. Therefore, to reduce vaccine wastage, a 20-dose vial of BCG is often only opened if at least 10-12 infants are present, jeopardising BCG vaccination coverage and timely vaccination. We observed that nurses were not able to withdraw 20 doses from the vials and aimed to quantify how many doses could be obtained from these vials by experienced nurses under real-life circumstances.At the maternity ward of the national hospital in Guinea-Bissau, since 2002 the same two nurses have been vaccinating all eligible children with BCG before discharge. During a month in 2015, within a randomised trial comparing BCG-Denmark and BCG-Russia, we registered how many doses the nurses were able to withdraw from the two types of vaccine vials.The median number of doses which it was possible to withdraw from the vials was 13 (range 11-17): 13 (11-16) for BCG-Denmark (based on 39 vials) and 15 (12-17) for BCG-Russia (based on 29 vials).In real life, experienced nurses could only obtain 13-15 doses from the 20-dose vials. Thus, vaccine wastage is much lower than assumed. Adjusting practice to the real-life number of doses would immediately suggest vials should be opened if 7 rather than 10 infants are present. As other studies have indicated that BCG may have beneficial non-specific effects on overall mortality, the potential gain by opening a 20-dose vial even for one child may be considerable.
Project description:OBJECTIVES:To assess the association between neonatal BCG vaccination and mortality between 28 days and 3 years of age among tuberculosis (TB)-exposed and TB-unexposed children. DESIGN:Prospective cohort study. SETTING:Bandim Health Project runs an urban Health and Demographic Surveillance site in Guinea-Bissau with registration of mortality, vaccination status and TB cases. PARTICIPANTS:Children entered the analysis when their vaccination card was inspected after 28 days of age and remained under surveillance to 3 years of age. Children residing in the same house as a TB case were classified as TB-exposed from 3 months prior to case registration to the end of follow-up. METHODS:Using Cox-proportional hazards models with age as underlying time scale, we compared mortality of children with and without neonatal BCG between October 2003 and September 2017. MAIN OUTCOME MEASURE:HR for neonatal BCG compared with no neonatal BCG by TB-exposure status. RESULTS:Among the 39?421 children who entered the analyses, 3022 (8%) had observation time as TB-exposed. In total, 84% of children received neonatal BCG. Children with neonatal BCG had lower mortality both in TB-exposed (adjusted HR: 0.57 (0.26 to 1.27)) and in TB-unexposed children (HR: 0.57 (95% CI 0.47 to 0.69)) than children without neonatal BCG. Children exposed to TB had higher mortality than TB-unexposed children if they had not received neonatal BCG. CONCLUSION:Neonatal BCG vaccination was associated with lower mortality among both TB-exposed and TB-unexposed children, consistent with neonatal BCG vaccination having beneficial non-specific effects. Interventions to increase timely BCG vaccination are urgently warranted.
Project description:OBJECTIVE:The objective of this study is to assess the determinants of BCG vaccination in Ethiopia from 2016 Ethiopia Demographic and Health Survey (EDHS). SETTING:Since Ethiopia has nine regional states and two administrative cities, sample was taken from all the divisions. The population-based sample was intended to provide estimates of key indicators for the country. PARTICIPANT:The sampling frame used for the 2016 EDHS is the Ethiopia Population and Housing Census. From 15 683 women recorded in EDHS dataset, women with no child (n=10 379) were excluded from the study. Therefore, the total sample size for this study was 5304 women. The outcome variable was BCG immunisation status of children. RESULT:Out of the study participants (n=5304), the majority were in between 20 and 34 years of age (73.8%). The median age of the respondents was 28.4 (SD=±6.5) years old. Prevalence of BCG vaccination was 63.6% (n=3373) and BCG vaccination coverage in urban residents was higher (88%) than rural residents (57.3%). Mothers' age between 20 up to 34 (Adjusted odds ratio (AOR)=1.48; 95% CI: 1.13 to 1.93) and between 35 up to 49 (AOR=1.83; 95% CI: 1.35 to 2.46) were more likely to vaccinate their child's than those mothers' age less than 20. Mothers settled in urban areas were two times more likely to vaccinate their child's than those living in rural areas (AOR=1.94; 95% CI: 1.45 to 2.60). Mothers with greater antenatal visits show higher BCG vaccination, Antenatal Care (ANC) 4 and above (AOR=3.48; 95% CI: 2.91 to 4.15). BCG vaccination is higher for mothers delivered at non-governmental organisation health facility than home (AOR=2.9; 95% CI: 1.69 to 4.96). Maternal occupation and wealth index also had a significant association with BCG vaccination. CONCLUSION:BCG vaccination coverage, in this study, was lower and determinant factors for BCG vaccination were residence, mother's age, place of delivery, mother's antenatal visit, wealth index and mother's occupation.