Bandim Health Project

Diarrhoea is an important cause of death and illness among children in developing countries; however, it remains controversial as to whether diarrhoea leads to stunting. We conducted a pooled analysis of nine studies that collected daily diarrhoea morbidity and longitudinal anthropometry to determine the effects of the longitudinal history of diarrhoea prior to 24 months on stunting at age 24 months. Data covered a 20-year period and five countries. We used logistic regression to model the effect of diarrhoea on stunting. The prevalence of stunting at age 24 months varied by study (range 21-90%), as did the longitudinal history of diarrhoea prior to 24 months (incidence range 3.6-13.4 episodes per child-year, prevalence range 2.4-16.3%). The effect of diarrhoea on stunting, however, was similar across studies. The odds of stunting at age 24 months increased multiplicatively with each diarrhoeal episode and with each day of diarrhoea before 24 months (all P < 0.001). The adjusted odds of stunting increased by 1.13 for every five episodes (95% CI 1.07-1.19), and by 1.16 for every 5% unit increase in longitudinal prevalence (95% CI 1.07-1.25). In this assembled sample of 24-month-old children, the proportion of stunting attributed to >or=5 diarrhoeal episodes before 24 months was 25% (95% CI 8-38%) and that attributed to being ill with diarrhoea for >or=2% of the time before 24 months was 18% (95% CI 1-31%). These observations are consistent with the hypothesis that a higher cumulative burden of diarrhoea increases the risk of stunting.

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.

In 1999, the World Health Organization (WHO) estimated that one-third of the world's population had latent tuberculosis infection (LTBI), which was recently updated to one-fourth. However, this is still based on controversial assumptions in combination with tuberculin skin test (TST) surveys. Interferon-γ release assays (IGRAs) with a higher specificity than TST have since been widely implemented, but never used to estimate the global LTBI prevalence.We conducted a systematic review and meta-analysis of LTBI estimates based on both IGRA and TST results published between 2005 and 2018. Regional and global estimates of LTBI prevalence were calculated. Stratification was performed for low, intermediate and high TB incidence countries and a pooled estimate for each area was calculated using a random effects model.Among 3280 studies screened, we included 88 studies from 36 countries with 41 IGRA (n=67 167) and 67 TST estimates (n=284 644). The global prevalence of LTBI was 24.8% (95% CI 19.7-30.0%) and 21.2% (95% CI 17.9-24.4%), based on IGRA and a 10-mm TST cut-off, respectively. The prevalence estimates correlated well to WHO incidence rates (Rs=0.70, p<0.001).In the first study of the global prevalence of LTBI derived from both IGRA and TST surveys, we found that one-fourth of the world's population is infected. This is of relevance, as both tests, although imperfect, are used to identify individuals eligible for preventive therapy. Enhanced efforts are needed targeting the large pool of latently infected individuals, as this constitutes an enormous source of potential active tuberculosis.

OBJECTIVE: To examine the association between routine childhood vaccinations and survival among infants in Guinea-Bissau. DESIGN: Follow up study. PARTICIPANTS: 15 351 women and their children born during 1990 and 1996. SETTING: Rural Guinea-Bissau. MAIN OUTCOME MEASURES: Infant mortality over six months (between age 0-6 months and 7-13 months for BCG, diphtheria, tetanus, and pertussis, and polio vaccines and between 7-13 months and 14-20 months for measles vaccine). RESULTS: Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated, the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG was associated with significantly lower mortality (0.55 (0.36 to 0.85)). However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and pertussis). Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87). When deaths from measles were excluded from the analysis the mortality ratio was 0.51 (0.28 to 0.95). Estimates were unchanged by controls for background factors. CONCLUSIONS: These trends are unlikely to be explained exclusively by selection biases since different vaccines were associated with opposite tendencies. Measles and BCG vaccines may have beneficial effects in addition to protection against measles and tuberculosis.

Data obtained in animals indicate that neonatal immune responses are biased toward Th2. This could reduce the efficacy of vaccines against viral and mycobacterial diseases. The ability of human newborns to develop a Th1 immune response upon immunization has not been studied. Since the vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) triggers a Th1-type response in adults, we investigated whether it induces a similar response in newborns and whether age at vaccination influences immunogenicity. We found that BCG vaccination at birth induces a memory Th1-type response of similar magnitude to that when given later in life. This study demonstrates that human newborns can be immunized against pathogens controlled by a Th1 immune response.

RATIONALE: Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis. OBJECTIVES: To test whether vitamin D supplementation of patients with tuberculosis (TB) improved clinical outcome and reduced mortality. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in TB clinics at a demographic surveillance site in Guinea-Bissau. We included 365 adult patients with TB starting antituberculosis treatment; 281 completed the 12-month follow-up. The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment. MEASUREMENTS AND MAIN RESULTS: The primary outcome was reduction in a clinical severity score (TBscore) for all patients with pulmonary TB. The secondary outcome was 12-month mortality. No serious adverse effects were reported; mild hypercalcemia was rare and present in both arms. Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo. Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58-1.95]). HIV infection was seen in 36% (131 of 359): 21% (76 of 359) HIV-1, 10% (36 of 359) HIV-2, and 5% (19 of 357) HIV-1+2. CONCLUSIONS: Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN35212132).

BACKGROUND: Available incidence data for invasive salmonella disease in sub-Saharan Africa are scarce. Standardised, multicountry data are required to better understand the nature and burden of disease in Africa. We aimed to measure the adjusted incidence estimates of typhoid fever and invasive non-typhoidal salmonella (iNTS) disease in sub-Saharan Africa, and the antimicrobial susceptibility profiles of the causative agents. METHODS: We established a systematic, standardised surveillance of blood culture-based febrile illness in 13 African sentinel sites with previous reports of typhoid fever: Burkina Faso (two sites), Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar (two sites), Senegal, South Africa, Sudan, and Tanzania (two sites). We used census data and health-care records to define study catchment areas and populations. Eligible participants were either inpatients or outpatients who resided within the catchment area and presented with tympanic (≥38·0°C) or axillary temperature (≥37·5°C). Inpatients with a reported history of fever for 72 h or longer were excluded. We also implemented a health-care utilisation survey in a sample of households randomly selected from each study area to investigate health-seeking behaviour in cases of self-reported fever lasting less than 3 days. Typhoid fever and iNTS disease incidences were corrected for health-care-seeking behaviour and recruitment. FINDINGS: Between March 1, 2010, and Jan 31, 2014, 135 Salmonella enterica serotype Typhi (S Typhi) and 94 iNTS isolates were cultured from the blood of 13 431 febrile patients. Salmonella spp accounted for 33% or more of all bacterial pathogens at nine sites. The adjusted incidence rate (AIR) of S Typhi per 100 000 person-years of observation ranged from 0 (95% CI 0-0) in Sudan to 383 (274-535) at one site in Burkina Faso; the AIR of iNTS ranged from 0 in Sudan, Ethiopia, Madagascar (Isotry site), and South Africa to 237 (178-316) at the second site in Burkina Faso. The AIR of iNTS and typhoid fever in individuals younger than 15 years old was typically higher than in those aged 15 years or older. Multidrug-resistant S Typhi was isolated in Ghana, Kenya, and Tanzania (both sites combined), and multidrug-resistant iNTS was isolated in Burkina Faso (both sites combined), Ghana, Kenya, and Guinea-Bissau. INTERPRETATION: Typhoid fever and iNTS disease are major causes of invasive bacterial febrile illness in the sampled locations, most commonly affecting children in both low and high population density settings. The development of iNTS vaccines and the introduction of S Typhi conjugate vaccines should be considered for high-incidence settings, such as those identified in this study. FUNDING: Bill & Melinda Gates Foundation.

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 (&lt;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.

OBJECTIVE: To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy). DESIGN: Randomised controlled trial. SETTING: The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area. PARTICIPANTS: 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation. INTERVENTION: Children were randomised 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 of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C). Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups. RESULTS: In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99). CONCLUSIONS: Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children's survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations. TRIAL REGISTRATION: Clinical trials NCT00168558.

Abstract Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic 1,2 . Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches 1 , while maintaining proven prevention measures using a vaccines-plus approach 2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities 3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with &gt;5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

A total of 105 low-birth-weight children presenting for first vaccination were randomized to receive bacillus Calmette-Guérin (BCG) immediately or later (current practice). The mortality rate ratio for BCG was 0.17 (95% CI = 0.02-1.35) within 3 days of enrollment, 0.28 (0.06-1.37) in the first month, and 0.27 (0.07-0.98) after 2 months of age. The mortality rate ratio was 0.41 (0.14-1.18) (P = 0.098) in infancy. Administration of BCG vaccine at first contact may contribute to lower mortality.

OBJECTIVES: To determine whether early infectious diseases could explain the association between number of siblings and other markers of microbial exposure and the development of atopic dermatitis before the age of 18 months. DESIGN: Cohort study. Information on atopic dermatitis, infectious diseases occurring before 6 months of age, number of siblings, early day care, pet keeping, farm residence, and background factors was collected in telephone interviews. SETTING: Danish national birth cohort. PARTICIPANTS: 24,341 mother-child pairs. MAIN OUTCOME MEASURES: Incidence rate ratios of atopic dermatitis. RESULTS: 13,070 children (54%) had at least one clinically apparent infectious disease before 6 months of age. At age 18 months, 2638 (10.8%) of the children had had atopic dermatitis. The risk of atopic dermatitis increased with each infectious disease before 6 months of age (incidence rate ratio 1.08, 95% confidence interval 1.04 to 1.13). The risk of atopic dermatitis decreased with each additional exposure to three or more siblings, day care, pet ownership, and farm residence (0.86, 0.81 to 0.93). CONCLUSIONS: Early infections do not seem to protect against allergic diseases. The protective effect of number of siblings, day care, pet ownership, and farm residence remained after adjustment for clinically apparent infectious diseases, suggesting that the effect is established independently early in life.

BACKGROUND: It has been proposed that certain viral and bacterial infections in early childhood may prevent allergic sensitization, by inducing Th1-type immune responses. This has led to speculation that mycobacterial vaccines might, through their Th1-stimulating properties, also protect against atopy. OBJECTIVE: To investigate whether the prevalence of atopy is lower in children who have been vaccinated with BCG in infancy than in children who have not been vaccinated. METHODS: We measured skin test reactivity to three allergens (Dermatophagoides pteronyssinus, D. farinae and cockroach) in 400 children, aged 3-14 years, as part of a follow-up study to examine the immune sequelae of measles in an urban area of Bissau, the capital of Guinea-Bissau in west Africa. Information on childhood vaccinations, including BCG in infancy, was available from child records. Of these children, 271 had been vaccinated with BCG (according to records) and 53 had not been vaccinated (no record and no BCG scar). Atopy was defined in two ways, according to the presence of any allergen reaction > or = 2 mm and any reaction > or = 3 mm. RESULTS: Of the children who had received BCG vaccine, 57 (21%) were atopic (any reaction > or = 2 mm), compared with 21 (40%) of the unvaccinated children [odds ratio, after controlling for potential confounding factors, 0.19 (95% CI 0.06-0.59)]. When atopy was defined using the 3-mm criterion, the reduction in atopy associated with BCG was greater the earlier the age at vaccination, and the largest reduction was seen in children vaccinated in the first week of life. CONCLUSION: BCG vaccination given early in infancy may prevent the development of atopy in African children.

Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1-19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.

It is very exceptional that a new disease becomes a true pandemic. Since its emergence in Wuhan, China, in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, has spread to nearly all countries of the world in only a few months. However, in different countries, the COVID-19 epidemic takes variable shapes and forms in how it affects communities. Until now, the insights gained on COVID-19 have been largely dominated by the COVID-19 epidemics and the lockdowns in China, Europe and the USA. But this variety of global trajectories is little described, analysed or understood. In only a few months, an enormous amount of scientific evidence on SARS-CoV-2 and COVID-19 has been uncovered (knowns). But important knowledge gaps remain (unknowns). Learning from the variety of ways the COVID-19 epidemic is unfolding across the globe can potentially contribute to solving the COVID-19 puzzle. This paper tries to make sense of this variability-by exploring the important role that context plays in these different COVID-19 epidemics; by comparing COVID-19 epidemics with other respiratory diseases, including other coronaviruses that circulate continuously; and by highlighting the critical unknowns and uncertainties that remain. These unknowns and uncertainties require a deeper understanding of the variable trajectories of COVID-19. Unravelling them will be important for discerning potential future scenarios, such as the first wave in virgin territories still untouched by COVID-19 and for future waves elsewhere.

BACKGROUND: Recent studies have suggested that Bacille Calmette-Guerin (BCG) vaccination may have a non-specific beneficial effect on infant survival and that a BCG scar may be associated with lower child mortality. No study has previously examined the influence of BCG vaccination on cause of death. METHODS: Two cohorts (A and B) were used to describe the mortality pattern for children with and without BCG scar and to determine specific causes of death. In cohort A (n = 1813), BCG scar was assessed at 6 months of age and as previously described children with a BCG scar had lower mortality over the next 12 months than children with no BCG scar. In cohort B, 1617 children aged 3 months to 5 years of age had their BCG scar status assessed in a household-based survey and mortality was assessed during a 12-month period. Causes of death were determined by verbal autopsy (VA) and related to BCG scar status in a cause-specific hazard function. RESULTS: Controlling for background factors associated with mortality, there was lower mortality for children with a BCG scar than without in cohort B, the mortality ratio (MR) being 0.45 (95% CI 0.21-0.96). Exclusion of children exposed to TB did not have any impact on the result. In a combined analysis of cohorts A and B, the MR was 0.43 (95% CI 0.28-0.65) controlling for background factors. There were no large differences in distribution of the five major causes of death (malaria, pneumonia, acute diarrhoea, chronic diarrhoea, and meningitis/encephalitis) according to BCG scar status in the two cohorts. Having a BCG scar significantly reduced the risk of death from malaria [MR 0.32 (95% CI 0.13-0.76)]. CONCLUSIONS: A BCG scar is a marker of better survival among children in countries with high child mortality. BCG vaccination may affect the response to several major infections including malaria.

The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.

BACKGROUND: Routine vaccines may have nonspecific effects on mortality. An observational study found that OPV given at birth (OPV0) was associated with increased male infant mortality. We investigated the effect of OPV0 on infant mortality in a randomized trial in Guinea-Bissau. METHODS: A total of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven national OPV campaigns were also conducted during the trial period. Children were followed to age 12 months. We used Cox regression to calculate hazard ratios (HRs) for mortality. RESULTS: The trial contradicted the original hypothesis about OPV0 increasing male infant mortality. Within 12 months, 73 children in the BCG + OPV group and 87 children in the BCG-only group died, all from infectious diseases. Comparing BCG + OPV0 vs BCG only, the HR was 0.83 (95% confidence interval [CI], .61-1.13): 0.72 (95% CI, .47-1.10) in boys and 0.97 (95% CI, .61-1.54) in girls. For children enrolled within the first 2 days of life, the HR for BCG + OPV0 vs BCG only was 0.58 (95% CI, .38-.90). From enrollment until the time of OPV campaigns, the HR was 0.68 (95% CI, .45-1.00), the beneficial effect being separately significant for males (0.55 [95% CI, .32-.95]). CONCLUSIONS: This is the only randomized trial of the effect of OPV0 on mortality. OPV0 may be associated with nonspecific protection against infectious disease mortality, particularly when given early in life. There are reasons to monitor mortality when OPV is being phased out. CLINICAL TRIALS REGISTRATION: NCT00710983.

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.

IMPORTANCE: In low-income countries, live measles vaccine reduces mortality from causes other than measles infection. Such nonspecific effects of vaccines might also be important for the health of children in high-income settings. OBJECTIVE: To examine whether the live vaccine against measles, mumps, and rubella (MMR) is associated with lower rates of hospital admissions for infections among children in Denmark. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of Danish children born 1997-2006 and followed up from ages 11 months to 2 years (last follow-up, August 31, 2008). Nationwide Danish registers provided data on vaccinations and hospital admissions. The recommended vaccination schedule was inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) administered at ages 3, 5, and 12 months and MMR at age 15 months. MAIN OUTCOMES AND MEASURES: Incidence rate ratios (IRRs) of hospital admissions for any infection, comparing receipt of MMR vs DTaP-IPV-Hib as the most recent vaccine. Risks, risk difference, and number needed to vaccinate were calculated for receiving MMR on time. RESULTS: The study included 495,987 children contributing with 56,889 hospital admissions for any type of infection during 509,427 person-years (rate, 11.2 per 100 person-years). For the 456,043 children who followed the recommended schedule and received MMR after the third dose of DTaP-IPV-Hib, MMR (rate, 8.9 per 100 person-years) vs the third dose of DTaP-IPV-Hib (rate, 12.4 per 100 person-years) as the most recent vaccine was associated with an adjusted IRR of 0.86 (95% CI, 0.84-0.88) for any admission for infection. There were 19,219 children immunized out of sequence. The adjusted IRR was 0.87 (95% CI, 0.80-0.95) for those receiving MMR (rate, 9.9 per 100 person-years) after the second dose of DTaP-IPV-Hib (rate, 15.1 per 100 person-years). However, in the 1981 children who subsequently received the third dose of DTaP-IPV-Hib (rate, 12.8 per 100 person-years) after MMR, the IRR for hospital admissions for infection was significantly greater (adjusted IRR, 1.62 [95% CI, 1.28-2.05]). The risk of admission for an infection between ages 16 months and 24 months was 4.6% (95% CI, 4.5%-4.7%) for receiving MMR on time and 5.1% (95% CI, 5.0%-5.2%) for not receiving MMR on time. The risk difference was 0.5 percentage point (95% CI, 0.4-0.6), and the number needed to vaccinate with MMR before age 16 months to prevent 1 admission for any infection was 201 (95% CI, 159-272). CONCLUSIONS AND RELEVANCE: In a cohort of Danish children, receipt of live MMR vs inactivated DTaP-IPV-Hib as the most recent vaccine was associated with a lower rate of hospital admissions for any infections. These findings require replication in other high-income populations.