SARS-CoV-2 serosurvey among adults involved in healthcare and health research in Guinea-Bissau, West Africa.

OBJECTIVES: Many African countries have reported fewer COVID-19 cases than countries elsewhere. By the end of 2020, Guinea-Bissau, West Africa, had <2500 PCR-confirmed cases corresponding to 0.1% of the ∼1.8 million national population. We assessed the prevalence of SARS-CoV-2 antibodies in urban Guinea-Bissau to help guide the pandemic response in Guinea-Bissau. STUDY DESIGN: Cross-sectional assessment of SARS-CoV-2 antibody in a cohort of staff at the Bandim Health Project. METHODS: We measured IgG antibodies using point-of-care rapid tests among 140 staff and associates at a biometric research field station in Bissau, the capital of Guinea-Bissau, during November 2020. RESULTS: Of 140 participants, 25 (18%) were IgG-positive. Among IgG-positives, 12 (48%) reported an episode of illness since the onset of the pandemic. Twenty-five (18%) participants had been PCR-tested between May and September; 7 (28%) had been PCR-positive. Four of these seven tested IgG-negative in the present study. Five participants reported that somebody had died in their house, corresponding crudely to an annual death rate of 4.5/1000 people; no death was attributed to COVID-19. Outdoor workers had a lower prevalence of IgG-positivity. CONCLUSIONS: In spite of the low official number of COVID-19 cases, our serosurvey found a high prevalence of IgG-positivity. Most IgG-positives had not been ill. The official number of PCR-confirmed COVID-19 cases has thus grossly underestimated the prevalence of COVID-19 during the pandemic. The observed overall mortality rate in households of Bandim Health Project employees was not higher than the official Guinean mortality rate of 9.6/1000 people.

Systematic review and meta-analysis of the effect of pertussis vaccine in pregnancy on the risk of chorioamnionitis, non-pertussis infectious diseases and other adverse pregnancy outcomes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Parental Bacillus Calmette-Guérin vaccine scars decrease infant mortality in the first six weeks of life: A retrospective cohort study.

BACKGROUND: Live attenuated vaccines have been observed to have particularly beneficial effects for child survival when given in the presence of maternally transferred immunity (priming). We aimed to test this finding and furthermore explore the role of paternal priming. METHODS: In an exploratory, retrospective cohort study in 2017, parental Bacillus Calmette-Guérin (BCG) scars were assessed for infants from the Bandim Health Project (BHP) who had participated in a 2008-2013 trial of neonatal BCG vaccination. Parental scar effects on mortality were estimated from birth to 42 days, the age of the scheduled diphtheria-tetanus-pertussis (DTP) vaccination, in Cox proportional hazard models adjusted with Inverse Probability of Treatment Weighting. FINDINGS: For 66% (510/772) of main trial infants that were still registered in the BHP area, at least one parent was located. BCG scar prevalence was 77% (353/461) among mothers and 63% (137/219) among fathers. In the first six weeks of life, maternal scars were associated with a mortality reduction of 60% (95%CI, 4% to 83%) and paternal scars with 49% (-68% to 84%). The maternal scar association was most beneficial among infants that had received BCG vaccination at birth (73% (-1% to 93%)). Although priming was less evident for paternal scars, having two parents with scars reduced mortality by 89% (13% to 99%) compared with either one or none of the parents having a scar. INTERPRETATION: Parental BCG scars were associated with strongly increased early-life survival. These findings underline the importance of future studies into the subject of inherited non-specific immunity and parental priming. FUNDING: Danish National Research Foundation; European Research Council; Novo Nordisk Foundation; University of Southern Denmark.

BCG scarring and improved child survival: a combined analysis of studies of BCG scarring.

Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) is recommended at birth in TB-endemic areas. Currently, BCG vaccination programmes use "BCG vaccination coverage by 12 months of age" as the performance indicator. Previous studies suggest that BCG-vaccinated children, who develop a scar, have better overall survival compared with BCG-vaccinated children, who do not develop a scar. We summarized the available studies of BCG scarring and child survival. A structured literature search for studies with original data and analysis of BCG scarring and mortality were performed. Combined analyses on the effect of BCG scarring on overall mortality. We identified six studies covering seven cohorts, all from Guinea-Bissau, West Africa, with evaluation of BCG scarring amongst BCG-vaccinated children and follow-up for mortality. Determinants of BCG scarring were BCG strain, intradermal injection route, size of injection wheal, and co-administered vaccines and micronutrients. In a combined analysis, having a BCG scar vs. no BCG scar was associated with a mortality rate ratio (MRR) of 0.61 (95% CI: 0.51-0.74). The proportion with a BCG scar varied from 52 to 93%; the estimated effect of a BCG scar was not associated with the scar prevalence. The effect was strongest in the first (MRR = 0.48 (0.37-0.62)) and second (MRR = 0.63 (0.44-0.92)) year of life, and in children BCG-vaccinated in the neonatal period (MRR = 0.45 (0.36-0.55)). The effect was not explained by protection against TB. Confounding and genetic factors are unlikely to explain the strong association between BCG scarring and subsequent survival. Including "BCG scar prevalence" as a BCG vaccination programme performance indicator should be considered. The effect of revaccinating scar-negative children should be studied.

Is it time for South Africa to end the routine high-dose vitamin A supplementation programme?

In accordance with World Health Organization guidelines, South Africa (SA) introduced routine periodic high-dose vitamin A supplementation (VAS) in 2002. These guidelines were developed after research in the 1980s and 1990s showed the efficacy of VAS in reducing childhood mortality. However, two recent studies in low- to middle-income countries (2013 and 2014) have shown no effect of high-dose VAS on mortality. Additionally, there is no clear research evidence that 6-monthly doses of vitamin A result in a sustained shift in serum retinol levels or reduce subclinical vitamin A deficiency. These two points should encourage SA to re-examine the validity of these guidelines. A long-term view of what is in the best interests of the majority of the people is needed. The short-term intervention of administering vitamin A capsules not only fails to improve serum retinol levels but may create dependence on a 'technical fix' to address the fundamental problem of poor nutrition, which is ultimately underpinned by poverty. It may also cause harm. Although there are those, some with vested interests, who will argue for continuation of the routine high-dose VAS programmes, SA policymakers and scientists need to evaluate the facts and be prepared to rethink this policy. There is cause for optimism: SA's health policymakers have previously taken bold stands on the basis of evidence. The examples of regulation of tobacco products and taxation of sugar-sweetened beverages, ending the free distribution of formula milk for HIV-positive mothers and legislating against the marketing of breastmilk substitutes provide precedents. Here is a time yet again for decision-makers to make bold choices in the interests of the people of SA. While the cleanest choice would be national discontinuation of the routine VAS programme, there may be other possibilities, such as first stopping the programme in Northern Cape Province (where there is clear evidence of hypervitaminosis A), followed by the other provinces in time.

Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies.

BACKGROUND: Epidemiological and immunological studies are increasingly reporting non-specific effects (NSEs) of vaccines; i.e. vaccines may affect the risk and severity of non-targeted infections. We reviewed how epidemiological studies developed the concept of beneficial NSEs of live vaccines. SOURCES: This is a personal narrative of how we came to pursue the concept of NSEs in studies of measles vaccine (MV) from the late 1970s. We also searched Pubmed for epidemiological studies of nonspecific/non-specific effects (NSEs) of the most common human vaccines. CONTENT: When smallpox vaccine was introduced around 1800, bacillus Calmette-Guérin (BCG) against tuberculosis in the 1920s and oral polio vaccine (OPV) in the 1960s, there were suggestions that these live attenuated vaccines reduced mortality more than expected. However, scientific follow-up was limited and the concept of beneficial NSEs did not become mainstream. We observed beneficial NSEs after MV was introduced in low-income countries in the 1970s. Subsequent observational studies and randomized trials confirmed beneficial NSEs of smallpox vaccine, BCG and OPV. Recently, beneficial NSEs have been claimed for the non-live diphtheria-tetanus-pertussis and rabies vaccines. However, no non-live vaccine has yet been documented to produce beneficial NSEs. IMPLICATIONS: Observational and experimental research has shown beneficial NSEs of four live attenuated vaccines: smallpox vaccine, BCG, OPV and MV. With immunological evidence now supporting the epidemiological observations, it is urgent to take both the specific and NSEs into account in the planning of vaccination programmes.

Early BCG Vaccination, Hospitalizations, and Hospital Deaths: Analysis of a Secondary Outcome in 3 Randomized Trials from Guinea-Bissau.

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.

Long-term effects of smallpox vaccination on expression of the HIV-1 co-receptor CCR5 in women.

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.

Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial.

BACKGROUND: Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. METHODS: The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency or no Danish-speaking parent. Data were collected through telephone interviews and clinical examinations until 13 months. RESULTS: Clinical atopic dermatitis was diagnosed in 466/2,052 (22.7%) children in the BCG group and 495/1,952 (25.4%) children in the control group (RR = 0.90 [95% confidence intervals 0.80-1.00]). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74-0.95)) and children without atopic predisposition (RR 1.09 [0.88-1.37]) (test of no interaction, P = .04). CONCLUSION: Among children with atopic predisposition, the number-needed-to-treat with BCG to prevent one case of atopic dermatitis was 21 (12-76).

Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1ß, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

Campaigns with oral polio vaccine may lower mortality and create unexpected results.

Three studies from Guinea-Bissau found conflicting effects of OPV-at-birth (OPV0) on child survival. One study from 2004 suggested excess male mortality among children receiving OPV0 compared with children receiving NoOPV0 during a period of shortage of OPV. However, two subsequent studies showed beneficial effects of OPV0. In 2004, two national OPV-campaigns had been conducted in Guinea-Bissau. In a reanalysis of the 2004-study, in a survival analysis the age-adjusted mortality rate of study participants was 67% (95% CI=42-81%) lower after the OPV-campaigns than before the campaigns. In the OPV0 group only 22% (655/3031 person-years (pyrs)) of follow-up time was "after" the OPV-campaigns whereas 55% (473/859 pyrs) of the time in the NoOPV0 group was post-campaign (p<0.0001, Chi2). Censoring for OPV-campaigns in the original study removed excess male mortality and made the three studies more homogeneous. Overall, there is now considerable evidence that OPV, like other live vaccines, has important beneficial non-specific effects.

A general measles vaccination campaign in urban Guinea-Bissau: Comparing child mortality among participants and non-participants.

BACKGROUND: Measles vaccination campaigns targeting children aged 9-59months are conducted every three years in Guinea-Bissau. Studies have demonstrated beneficial non-specific effects of measles vaccine. We compared mortality one year after the December 2012 measles vaccination campaign in Bissau city for children who received campaign measles vaccine with children who did not receive campaign measles vaccine. METHODS: Field workers from Bandim Health Project registered all children living in the Bandim Health Project's study area who received measles vaccination at the campaign posts. Children not seen during the campaign were visited at home and campaign participation status was assessed. We compared mortality rates of participants vs. non-participants in Cox regression models. RESULTS: 5633 children aged 9-59months (85%) received campaign measles vaccination and 1006 (15%) did not. During the subsequent year 16 children died. Adjusted for background factors, the hazard ratio (HR) comparing measles vaccinated versus unvaccinated was 0.28 (95% CI: 0.10-0.77). The benefit was larger for girls (HR: 0.17 (0.05-0.59)) and for children who had received routine measles vaccine before the campaign (HR: 0.15 (0.04-0.63)). CONCLUSIONS: We found indications of strong beneficial non-specific effects of receiving measles vaccine during the 2012 campaign, especially for girls and children with previous routine measles vaccination. Measles vaccination campaigns may be an effective way of improving child survival.

Household experience and costs of seeking measles vaccination in rural Guinea-Bissau.

OBJECTIVES: Children younger than 12 months of age are eligible for childhood vaccines through the public health system in Guinea-Bissau. To limit open vial wastage, a restrictive vial opening policy has been implemented; 10-dose measles vaccine vials are only opened if six or more children aged 9-11 months are present at the vaccination post. Consequently, mothers who bring their child for measles vaccination can be told to return another day. We aimed to describe the household experience and estimate household costs of seeking measles vaccination in rural Guinea-Bissau. METHODS: Within a national sample of village clusters under demographic surveillance, we interviewed mothers of children aged 9-21 months about their experience with seeking measles vaccination. From information about time and money spent, we calculated household costs of seeking measles vaccination. RESULTS: We interviewed mothers of 1308 children of whom 1043 (80%) had sought measles vaccination at least once. Measles vaccination coverage was 70% (910/1308). Coverage decreased with increasing distance to the health centre. On average, mothers who had taken their child for vaccination took their child 1.4 times. Mean costs of achieving 70% coverage were 2.04 USD (SD 3.86) per child taken for vaccination. Half of the mothers spent more than 2 h seeking vaccination and 11% spent money on transportation. CONCLUSIONS: We found several indications of missed opportunities for measles vaccination resulting in suboptimal coverage. The household costs comprised 3.3% of the average monthly income and should be taken into account when assessing the costs of delivering vaccinations.

The effect of early measles vaccination at 4.5 months of age on growth at 9 and 24 months of age in a randomized trial in Guinea-Bissau.

BACKGROUND: Providing an early, additional measles vaccine (MV) at 4.5 months of age has been shown to reduce child mortality in low-income countries. We studied the effects on growth at 9 and 24 months of age. METHODS: A randomized controlled trial was conducted in Guinea-Bissau from 2003-2007 including 6,648 children. Children were randomized 1:1:1 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 (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months (group C) Data on anthropometrics were obtained at enrolment at 4.5 months of age and again at 9 and 24 months of age. Analyses were stratified by sex, season of enrolment, and neonatal vitamin A supplementation (NVAS) status, as all these factors have been shown to modify the effect of early MV on mortality. RESULTS: Overall there was no effect of early MV on anthropometry at 9 months. At 24 months children who had received early MV had a significantly larger mid-upper-arm-circumference (MUAC/in cm) (Difference = 0.08; 95% CI (0.02;0.14)) compared with children in the control group; this effect was most pronounced among girls (0.12 (0.03;0.20)). The effect of early MV on MUAC remained significant in the dry season and in girls who received placebo rather than NVAS. CONCLUSION: Early MV was associated with a larger MUAC particularly in girls. These results indicate that a two-dose measles vaccination schedule might not only reduce child mortality but also improve growth. TRIAL REGISTRATION: ClinicalTrials.gov NCT00168558 . Registered September 9, 2005, retrospectively registered.

Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau.

BACKGROUND: Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. METHODS: During 2011-2013, infants in the Bandim Health Project's urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests. RESULTS: Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25-1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74-2.11)), p=0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06-1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain. CONCLUSION: BCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost.

Neonatal vitamin A supplementation associated with increased atopy in girls.

BACKGROUND: Neonatal vitamin A supplementation (NVAS) is currently being considered as policy in countries at risk of deficiency. A previous study suggested that NVAS may be associated with increased atopy. We examined the effect of NVAS on atopy by conducting long-term follow-up of a previous randomized controlled trial in Guinea-Bissau. METHODS: In 2002-2004, we randomized 4345 normal birthweight neonates to NVAS (50 000 IU retinyl palmitate) or placebo together with their Bacillus Calmette-Guérin vaccination. In 2013, we visited the 1692 (39%) children now aged 8-10 years who were still living in the study area, and 1478 (87%) were found at home. Provided consent, a skin prick test was performed, and history of allergic symptoms was recorded. Associations of NVAS and atopy (defined as skin prick test reaction of ≥3 mm) were analysed using binomial regression. RESULTS: Of the 1430 children with a valid skin prick test, 228 (16%) were positive (more boys (20%) than girls (12%), P-value < 0.0001). NVAS did not increase the overall risk of atopy (RR 1.10 [95% CI 0.87-1.40]). However, NVAS was associated with significantly increased risk among females (RR 1.78 [1.17-2.72]) but not among males (0.86 [0.64-1.15], P-value for interaction between NVAS and gender = 0.005). Furthermore, NVAS was associated with increased risk of wheezing among females (RR 1.80 [1.03-3.17], but not among males, P-value for interaction = 0.05). CONCLUSION: The study corroborated previous observations; NVAS was associated with increased risk of atopy and wheezing, in this study only among females. Further studies on NVAS and atopy are warranted.

Infant twin mortality and hospitalisations after the perinatal period - a prospective cohort study from Guinea-Bissau.

OBJECTIVE: To examine mortality and hospitalisations among infant twins and singletons after the perinatal period in Guinea-Bissau. METHODS: The study was conducted from September 2009 to November 2012 by the Bandim Health Project (BHP). Newborn twins and unmatched singleton controls were included at the National Hospital Simão Mendes in the capital Bissau. Children were examined clinically at enrolment. Maternal, pregnancy and obstetric information was collected and HIV testing offered at birth. Follow-up occurred at home at 2, 6 and 12 months and through linkage with the paediatric admission register at the National Hospital. RESULTS: About 495 twins and 333 singletons were alive on day 7 after birth. In total, 36 twins and 12 singletons died during follow-up, the post-perinatal infant mortality rate being 91/1000 person-years for twins and 42/1000 for singletons (HR = 2.11, 95% CI: 1.09-4.07). In a multivariable analysis among twins only, birth weight <2000 g [3.32, (1.36-8.07)], death of the cotwin perinatally [2.54, (1.16-5.57)] and severe maternal illness during pregnancy [2.35, (1.00-5.51)] were significant risk factors for twin death. In the subgroup with available HIV status, maternal HIV infection was strongly associated with twin mortality [3.16, (1.24-8.05)]. Death occurred at home for 60% of twins and 67% of singletons. During follow-up, 90 first-time hospital admissions were registered, with similar rates observed for twins (139/1000) and singletons (143/1000) [0.97, (0.61-1.52)]. CONCLUSION: The post-perinatal infant mortality rate of twins was double that of singletons. No excess in twin hospitalisations was observed, possibly implying obstacles to hospital admission for twins in case of severe illness.

Vitamin A supplementation and BCG vaccination at birth may affect atopy in childhood: long-term follow-up of a randomized controlled trial.

BACKGROUND: Recent evidence suggests that immunogenic interventions such as vaccines and micronutrients may affect atopic sensitization and atopic disease. We aimed to determine whether neonatal BCG vaccination, vitamin A supplementation and other vaccinations affect atopy in childhood. METHODS: In Guinea-Bissau, low-birthweight infants were randomized to early (intervention) or delayed (usual policy) BCG. A subgroup was also randomly assigned vitamin A supplementation or placebo in a two-by-two factorial design. Participants were followed up at age 3-9 years. The main outcome was atopy defined as skin prick test reaction ≥3 mm. Secondary outcomes were symptoms of eczema, asthma and food allergy. RESULTS: Two hundred eighty-one children had valid skin prick tests performed, and 14% (39/281) were atopic. There was no significant difference in atopy between the early and delayed BCG groups (OR, 0.71; 95% CI, 0.34-1.47). Atopy was significantly reduced in children who had responded to BCG with a scar (OR, 0.42; 0.19-0.94). Vitamin A supplementation was associated with increased atopy (OR, 2.88; 1.26-6.58), especially in those who received simultaneous BCG (5.99; 1.99-18.1, P = 0.09 for interaction between vitamin A supplementation and BCG). Early vs delayed BCG was not associated with symptoms of atopic disease, but vitamin A supplementation increased odds of wheeze within the past 12 months (OR, 2.45; 1.20-4.96). CONCLUSIONS: There were no statistically significant effects of early vs delayed BCG on atopy or symptoms of atopic disease. Having a BCG scar was associated with reduced atopy, whereas neonatal vitamin A supplementation was associated with increased atopy. STUDY REGISTRATION: Clinicaltrials.gov NCT 01420705.