Sofie Biering-Sørensen

Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?

BACKGROUND Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. CONCLUSIONS Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

Background. Bacillus Calmette–Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia. Methods. Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD). Results. Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ. Conclusion. Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality.

The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial

Neonates were randomized to oral polio vaccine (OPV) and followed for mortality. Among those enrolled within the first 2 days, OPV was associated with a 42% (10%–62%) reduction in infant infectious disease mortality. OPV at birth may provide nonspecific protection against infections.

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

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.

Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau

Objective Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%. Previous studies indicate that the effect of VAS may vary with vaccination status. The authors evaluated the effect of VAS provided in campaigns on child survival overall and by sex and vaccination status at the time of supplementation. Design Observational cohort study. Setting and participants The study was conducted in the urban study area of the Bandim Health Project in Guinea-Bissau. The authors documented participation or non-participation in two national vitamin A campaigns in December 2007 and July 2008 for children between 6 and 35 months of age. Vaccination status was ascertained by inspection of vaccination cards. All children were followed prospectively. Outcome measures Mortality rates for supplemented and non-supplemented children were compared in Cox models providing mortality rate ratios (MRRs). Results The authors obtained information from 93% of 5567 children in 2007 and 90% of 5799 children in 2008. The VAS coverage was 58% in 2007 and 68% in 2008. Mortality in the supplemented group was 1.5% (44 deaths/2873 person-years) and 1.6% (20 deaths/1260 person-years) in the non-supplemented group (adjusted MRR=0.78 (0.46; 1.34)). The effect was similar in boys and girls. Vaccination cards were seen for 86% in 2007 and 84% in 2008. The effect of VAS in children who had measles vaccine as their last vaccine (2814 children, adjusted MRR=0.34 (0.14; 0.85)) differed from the effect in children who had diphtheria–tetanus–pertussis vaccine as their last vaccine (3680 children, adjusted MRR=1.29 (0.52; 3.22), p=0.04 for interaction). Conclusion The effect of VAS differed by most recent vaccination, being beneficial after measles vaccine but not after diphtheria–tetanus–pertussis vaccine.

Time trends in socio-economic factors and risk of hospitalisation with infectious diseases in pre-school children 1985-2004: a Danish register-based study.

The purpose of this study was to examine socio-economic differences in the risk of hospitalisation among children aged 0-5 years in Denmark from 1985 to 2004. All children born between 1985 and 2004 (n=1,278,286) were followed for hospital admissions for infectious diseases from the 29th day of life until the children reached the age of 6 years or the end of 2004, whichever came first. Information on parental socio-economic position (education, labour market attachment and household income) was gathered through record linkage with administrative registries. Infections were grouped into upper respiratory, lower respiratory, gastrointestinal, ear and fever infections. The data were analysed using Cox regression. Children of parents on sick leave or early retirement had an increased risk of being hospitalised with an infection compared with children of employed parents. A clear inverse educational gradient in risk of offspring hospitalisation was also found. From 1985 to 2004 the inverse associations between parental education and risk of hospitalisation grew stronger, whereas the comparatively weaker association between household income and risk of offspring hospitalisation decreased in magnitude. The association between socio-economic status and hospitalisation was strongest for lower respiratory, gastrointestinal and ear infections. This study documented a socially patterned hospitalisation of pre-school children in Denmark. Future studies should investigate possible explanations for the increased risk among children from families with low socio-economic status.

Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

Summary We conducted the present trial to test whether early BCG-Denmark reduces mortality rate in low-weight (LW) neonates. We found that early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate.

Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial

INTRODUCTION Bacille Calmette-Guérin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual delayed BCG, the manufacturer of the BCG vaccine experienced a period with relatively slow growth rate of the BCG. We investigated the association between growth rate of BCG when manufacturing the vaccine and its capability to induce immune responses in vivo and in vitro. METHODS 1633 neonates were randomised to BCG at birth and examined for scar at 12 months; a subgroup was tested for PPD response at 2 and 6 months. The BCG batches from the Slow growth period were compared with the precedent and subsequent Normal growth batches with regard to prevalence and size of BCG scar and PPD response. We also tested the effect of batches on in vitro cytokine responses. RESULTS At 12 months, the Slow growth batches were associated with higher BCG scar prevalence (98.2%) than the precedent batches (92.3%, p=0.01) but the prevalence remained high after return to normal growth (98.8%, p=0.52). The Slow growth batches were associated with larger scar size (5.0mm) than precedent (4.4mm, p<0.01) and subsequent batches (4.8mm, p=0.03). Compared with Normal growth batches, the Slow growth batches were associated with a higher prevalence of positive PPD responses, and among PPD positive children, a larger PPD reaction (geometric mean ratio: 1.40 (1.20-1.63)) at 2 months. In response to secondary heterologous stimulation, monocytes primed with Slow growth batches induced higher IL-6 (p=0.03) and TNF-α responses (p=0.03) compared with Normal growth batches. CONCLUSION The study indicates that variations in the production of BCG vaccine may influence important immunological effects of the vaccine. TRIAL REGISTRATION clinicaltrials.gov (NCT00625482).

Factors associated with thymic size at birth among low and normal birth-weight infants

OBJECTIVE To study the effect of gestational and perinatal exposures on thymic size in 366 normal birth weight and 426 low birth weight (LBW) neonates in Guinea-Bissau in West Africa. STUDY DESIGN In a cross-sectional study, thymic size was measured at birth by the use of ultrasound. Information on possible determinants was collected from pregnancy cards, hospital records, and interviews with the mother. We used the log-transformed thymic index and thymus/weight index as outcome measures. Data were analyzed with adjusted linear regression models providing geometric mean ratios (GMRs) with 95% CI. RESULTS Determinants of thymic size among normal birth weight infants were pathologic amniotic fluid (adjusted GMR for thymic index: 0.84 [0.74-0.96]) and male sex (GMR: 1.13 [1.06-1.22]). Among LBW infants, birth season (1.11 [1.01-1.22]), maternal body temperature (0.89 [0.79-0.98]), antibiotic treatment at the time of labor (0.84 [0.70-1.00]), number of pregnancy consultations (1.03 [1.00-1.05]), maternal age (0.91 [0.84-0.98]), Apgar score (1.06 [1.03-1.10]), and infant convulsions (0.44 [0.29-0.65]) were all independent determinants of thymic index but not all were determinants of thymus/weight index. Pathologic amniotic fluid and cesarean delivery were associated with thymus/weight index among LBW infants (0.85 [0.75-0.95] and 0.80 [0.67-0.96]) but were only borderline significant for thymic index. CONCLUSION Exposures mainly related to stress and infections were associated with a smaller thymus, mainly in LBW infants.

National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials

Background A recent WHO review concluded that live BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs) reducing mortality from non-targeted diseases. NSEs of oral polio vaccine (OPV) were not examined. If OPV vaccination campaigns reduce the mortality rate, it would suggest beneficial NSEs. Setting Between 2002 and 2014, Guinea-Bissau had 15 general OPV campaigns and other campaigns with OPV plus vitamin A supplementation (VAS), VAS-only, MV, and H1N1 vaccine. In this period, we conducted seven randomized controlled trials (RCTs) with mortality as main outcome. Methods Within these RCTs, we assessed whether the mortality rate was lower after-campaign than before-campaign. We used Cox models with age as underlying time and further adjusted for low birth-weight, season and time trend in mortality. We calculated the adjusted mortality rate ratio (MRR) for after-campaign vs before-campaign. Results The mortality rate was lower after OPV-only campaigns than before, the MRR being 0.81 (95% CI = 0.68–0.95). With each additional dose of campaign-OPV the mortality rate declined further (MRR = 0.87 (95% CI: 0.79–0.96) per dose) (test for trend, p = 0.005). No other type of campaign had similar beneficial effects. Depending on initial age and with follow-up to 3 years of age, the number needed to treat with campaign-OPV-only to save one life was between 68 and 230 children. Conclusion Bissau had no case of polio infection so the results suggest that campaign-OPV has beneficial NSEs. Discontinuation of OPV-campaigns in low-income countries may affect general child mortality levels negatively.