Effect of distributing locally produced cloth facemasks on COVID-19-like illness and all-cause mortality-a cluster-randomised controlled trial in urban Guinea-Bissau.

Facemasks have been employed to mitigate the spread of SARS-CoV-2. The community effect of providing cloth facemasks on COVID-19 morbidity and mortality is unknown. In a cluster randomised trial in urban Bissau, Guinea-Bissau, clusters (geographical areas with an average of 19 houses), were randomised to an intervention or control arm using computer-generated random numbers. Between 20 July 2020 and 22 January 2021, trial participants (aged 10+ years) living in intervention clusters (n = 90) received two 2-layer cloth facemasks, while facemasks were only distributed later in control clusters (n = 91). All participants received information on COVID-19 prevention. Trial participants were followed through a telephone interview for COVID-19-like illness (3+ symptoms), care seeking, and mortality for 4 months. End-of-study home visits ensured full mortality information and distribution of facemasks to the control group. Individual level information on outcomes by trial arm was compared in logistic regression models with generalised estimating equation-based correction for cluster. Facemasks use was mandated. Facemask use in public areas was assessed by direct observation. We enrolled 39,574 trial participants among whom 95% reported exposure to groups of >20 persons and 99% reported facemasks use, with no difference between trial arms. Observed use was substantially lower (~40%) with a 3%, 95%CI: 0-6% absolute difference between control and intervention clusters. Half of those wearing a facemask wore it correctly. Few participants (532, 1.6%) reported COVID-19-like illness; proportions did not differ by trial arm: Odds Ratio (OR) = 0.81, 95%CI: 0.57-1.15. 177 (0.6%) participants reported consultations and COVID-19-like illness (OR = 0.83, 95%CI: 0.56-1.24); 89 participants (0.2%) died (OR = 1.34, 95%CI: 0.89-2.02). Hence, though trial participants were exposed to many people, facemasks were mostly not worn or not worn correctly. Providing facemasks and messages about correct use did not substantially increase their use and had limited impact on morbidity and mortality. Trial registration: clinicaltrials.gov: NCT04471766.

Protocol for a cluster randomised placebo-controlled trial of adjunctive ivermectin mass drug administration for malaria control on the Bijagós Archipelago of Guinea-Bissau: the MATAMAL trial.

INTRODUCTION: As malaria declines, innovative tools are required to further reduce transmission and achieve elimination. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) is capable of reducing malaria transmission where coverage of control interventions is already high, though the impact is short-lived. Combining ACT with ivermectin, an oral endectocide shown to reduce vector survival, may increase its impact, while also treating ivermectin-sensitive co-endemic diseases and minimising the potential impact of ACT resistance in this context. METHODS AND ANALYSIS: MATAMAL is a cluster-randomised placebo-controlled trial. The trial is being conducted in 24 clusters on the Bijagós Archipelago, Guinea-Bissau, where the peak prevalence of Plasmodium falciparum (Pf) parasitaemia is approximately 15%. Clusters have been randomly allocated to receive MDA with dihydroartemisinin-piperaquine and either ivermectin or placebo. The primary objective is to determine whether the addition of ivermectin MDA is more effective than dihydroartemisinin-piperaquine MDA alone in reducing the prevalence of P. falciparum parasitaemia, measured during peak transmission season after 2 years of seasonal MDA. Secondary objectives include assessing prevalence after 1 year of MDA; malaria incidence monitored through active and passive surveillance; age-adjusted prevalence of serological markers indicating exposure to P. falciparum and anopheline mosquitoes; vector parous rates, species composition, population density and sporozoite rates; prevalence of vector pyrethroid resistance; prevalence of artemisinin resistance in P. falciparum using genomic markers; ivermectin's impact on co-endemic diseases; coverage estimates; and the safety of combined MDA. ETHICS AND DISSEMINATION: The trial has been approved by the London School of Hygiene and Tropical Medicine's Ethics Committee (UK) (19156) and the Comite Nacional de Eticas de Saude (Guinea-Bissau) (084/CNES/INASA/2020). Results will be disseminated in peer-reviewed publications and in discussion with the Bissau-Guinean Ministry of Public Health and participating communities. TRIAL REGISTRATION NUMBER: NCT04844905.

Tempo de exposição a telas em lactentes: comparação pré e durante a pandemia da COVID-19 / Infants' screen time exposure: a comparison before and during the COVID-19 pandemic

Comparar o tempo de exposição a telas de lactentes entre os períodos pré e durante a pandemia da COVID-19 e averiguar fatores relacionados a exposição de tela durante esse período. Responderam ao "Questionário tempo de exposição a telas", 63 responsáveis de lactentes, em dois períodos: pré e durante a pandemia COVID-19. Para a comparação entre os períodos, foi utilizado o teste de Wilcoxon Rank. Durante a pandemia da COVID-19, aumentou-se significativamente o tempo de telas, passando de mediana de 4 para 7 horas semanais, destacando-se a televisão como dispositivo mais utilizado. Observou-se a correlação entre idade do lactente e tempo de exposição a telas. Houve aumento do tempo de exposição a telas durante a pandemia da COVID-19 nos lactentes avaliados. O tempo total de telas apresentou uma correlação proporcional com a idade nos períodos avaliados, porém não se correlacionou com a realização de home-office dos responsáveis.

To compare the infants' time exposure to screens between pre- and during the COVID-19 pandemic and to investigate factors related to screen exposure during this period. The "Screen exposure time questionnaire" was answered by 63 caregivers of infants, in two periods: before and during the COVID-19 pandemic. For comparison between periods, the Wilcoxon Rank test was used. During the COVID-19 pandemic, infants' time exposure to screens increased significantly, from a median of 4 to 7 hours per week, with television being the most used device. A correlation was observed between infant age and time exposure to screens. There was an increase in infants' time exposure to screens during the COVID-19 pandemic. Total screen time showed a proportional correlation with age in the evaluated periods; however, it did not correlate with the home-office performance of those responsible.

Oral Polio Vaccine to Mitigate the Risk of Illness and Mortality During the Coronavirus Disease 2019 Pandemic: A Cluster-Randomized Trial in Guinea-Bissau.

Background: Oral polio vaccine (OPV) may improve resistance to non-polio-infections. We tested whether OPV reduced the risk of illness and mortality before coronavirus disease 2019 (COVID-19) vaccines were available. Methods: During the early COVID-19 pandemic, houses in urban Guinea-Bissau were randomized 1:1 to intervention or control. Residents aged 50+ years were invited to participate. Participants received bivalent OPV (single dose) or nothing. Rates of mortality, admissions, and consultation for infections (primary composite outcome) during 6 months of follow-up were compared in Cox proportional hazards models adjusted for age and residential area. Secondary outcomes included mortality, admissions, consultations, and symptoms of infection. Results: We followed 3726 participants (OPV, 1580; control, 2146) and registered 66 deaths, 97 admissions, and 298 consultations for infections. OPV did not reduce the risk of the composite outcome overall (hazard ratio [HR] = 0.97; 95% confidence interval [CI], .79-1.18). OPV reduced the risk in males (HR = 0.71; 95% CI, .51-.98) but not in females (HR = 1.18; 95% CI, .91-1.52) (P for same effect = .02). OPV also reduced the risk in Bacillus Calmette-Guérin scar-positive (HR = 0.70; 95% CI, .49-.99) but not in scar-negative participants (HR = 1.13; 95% CI, .89-1.45) (P = .03). OPV had no overall significant effect on mortality (HR = 0.96; 95% CI, .59-1.55), admissions (HR = 0.76; 95% CI, .49-1.17) or recorded consultations (HR = 0.99; 95% CI, .79-1.25), but the OPV group reported more episodes with symptoms of infection (6050 episodes; HR = 1.10 [95% CI, 1.03-1.17]). Conclusions: In line with previous studies, OPV had beneficial nonspecific effects in males.

Stopping Oral Polio Vaccine (OPV) After Defeating Poliomyelitis in Low- and Middle-Income Countries: Harmful Unintended Consequences? Review of the Nonspecific Effects of OPV.

Background: The live vaccines bacille Calmette-Guérin (BCG) and measles vaccine have beneficial nonspecific effects (NSEs) reducing mortality, more than can be explained by prevention of tuberculosis or measles infection. Live oral polio vaccine (OPV) will be stopped after polio eradication; we therefore reviewed the potential NSEs of OPV. Methods: OPV has been provided in 3 contexts: (1) coadministration of OPV and diphtheria-tetanus-pertussis (DTP) vaccine at 6, 10, and 14 weeks of age; (2) at birth (OPV0) with BCG; and (3) in OPV campaigns (C-OPVs) initiated to eradicate polio infection. We searched PubMed and Embase for studies of OPV with mortality as an outcome. We used meta-analysis to obtain the combined relative risk (RR) of mortality associated with different uses of OPV. Results: First, in natural experiments when DTP was missing, OPV-only compared with DTP + OPV was associated with 3-fold lower mortality in community studies (RR, 0.33 [95% confidence interval {CI}, .14-.75]) and a hospital study (RR, 0.29 [95% CI, .11-.77]). Conversely, when OPV was missing, DTP-only was associated with 3-fold higher mortality than DTP + OPV (RR, 3.23 [95% CI, 1.27-8.21]). Second, in a randomized controlled trial, BCG + OPV0 vs BCG + no OPV0 was associated with 32% (95% CI, 0-55%) lower infant mortality. Beneficial NSEs were stronger with early use of OPV0. Third, in 5 population-based studies from Guinea-Bissau and Bangladesh, the mortality rate was 24% (95% CI, 17%-31%) lower after C-OPVs than before C-OPVs. Conclusions: There have been few clinical polio cases reported in this century, and no confounding factors or bias would explain all these patterns. The only consistent interpretation is that OPV has beneficial NSEs, reducing nonpolio child mortality.

Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%. Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355. Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028]. Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further. Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

Understanding the child mortality decline in Guinea-Bissau: the role of population-level nutritional status measured by mid-upper arm circumference.

BACKGROUND: Malnutrition is considered an important contributing factor to child mortality, and the mid-upper arm circumference (MUAC) is regarded as one of the better anthropometric predictors of child mortality. We explored whether the decline in child mortality over recent decades could be explained by changes in children's MUAC. METHODS: This prospective study analysed individual-level data from 47 731 children from the capital of Guinea-Bissau followed from 3 months until 36 months of age over 2003 to 2016. We used standardization to compare the mortality rate as if only the MUAC distribution had changed between an early period (2003-05) and a late period (2014-16). We adjusted the analyses for age, sex, socioeconomic-related possessions and maternal education. RESULTS: A total of 949 deaths were included in the analysis. The adjusted mortality rate was 18.9 [95% confidence interval (CI) 14.3-23.3] deaths per 1000 person-years (pyrs) in the early period and declined to 4.4 (95% CI 2.9-6.0) deaths per 1000 pyrs in the late period, a 77% (95% CI 71-83%) reduction in the mortality rate. At all calendar years, the MUAC distribution in the population was close to the WHO reference population. MUAC below -1 z-score was associated with increased child mortality. The change in MUAC distribution from the early period to the late period (in the early period mortality standardization) corresponded to 1.5 (95% CI 1.0-2.2) fewer deaths per 1000 pyrs, equivalent to 11% (95% CI 7-14%) of the observed change in child mortality. CONCLUSIONS: From 2003 to 2016, child mortality in urban Guinea-Bissau declined considerably but, though a low MUAC was associated with increased mortality, changes in the MUAC distribution in the population explained little of the decline. Understanding the driving factors of child mortality decline can help scope tomorrow's interventions.

Health effects of utilising hospital contacts to provide measles vaccination to children 9-59 months-a randomised controlled trial in Guinea-Bissau.

BACKGROUND: Measles vaccination coverage in Guinea-Bissau is low; fewer than 80% of children are currently measles vaccinated before 12 months of age. The low coverage hampers control of measles. Furthermore, accumulating evidence indicates that measles vaccine has beneficial non-specific effects, strengthening the resistance towards other infections. Thus, even if children are not exposed to measles virus, measles-unvaccinated children may be worse off. To increase vaccination coverage, WHO recommends that contacts with the health system for mild illness are utilised to vaccinate. Currently, in Guinea-Bissau, curative health system contacts are not utilised. METHODS: Bandim Health Project registers out-patient consultations and admissions at the paediatric ward of the National Hospital in Guinea-Bissau. Measles-unvaccinated children aged 9-59 months consulting for milder illness or being discharged from the paediatric ward will be invited to participate in a randomised trial. Among 5400 children, randomised 1:1 to receive standard measles vaccine or a saline placebo, we will test the hypothesis that providing a measles vaccine at discharge lowers the risk of admission/mortality (composite outcome) during the subsequent 6 months by 25%. All enrolled children are followed through the Bandim Health Project registration system and through telephone follow-up. The first 1000 enrolled children are furthermore followed through interviews on days 2, 4, 7 and 14 after enrolment. DISCUSSION: Utilising missed vaccination opportunities can increase vaccination coverage and may improve child health. However, without further evidence for the safety and potential benefits of measles vaccination, these curative contacts are unlikely to be used for vaccination in Guinea-Bissau. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT04220671 . Registered on 5 January 2020.

The Effect of a Second Dose of Measles Vaccine at 18 Months of Age on Nonaccidental Deaths and Hospital Admissions in Guinea-Bissau: Interim Analysis of a Randomized Controlled Trial.

BACKGROUND: The world is set on the eradication of measles. Continuation of the measles vaccine (MV) after eradication could still reduce morbidity because the MV has so-called beneficial nonspecific effects. We evaluated the effect of a "booster" dose of the MV on overall severe morbidity. METHODS: We conducted a randomized controlled trial among children aged 17.5 to 48 months in Guinea-Bissau, where the MV is recommended only at 9 months of age. At the time of this interim analysis, 3164 children had been allocated 1:1 to a second dose of measles vaccine (MV2) at 18 months of age or to no vaccine. Severe morbidity (a composite outcome of nonaccidental deaths and hospital admissions) rate ratios (SMRRs) were calculated by Cox regression analysis censored for national oral polio vaccine (OPV) campaigns. RESULTS: There were no measles cases during the trial period. There were 43 nonaccidental deaths or hospital admissions during follow-up. Severe morbidity was 2.6 per 100 person-years in the MV2 group and 3.6 per 100 person-years among controls; hence, the estimated effect of MV2 on severe morbidity was 28% (SMRR, 0.72; 95% confidence interval [CI], .38-1.38). At 12 months of follow-up, the number needed to treat to prevent 1 severe morbidity event was 137 children. After OPV campaigns, the estimated effect of MV2 was reduced to 9% (SMRR, 0.91; 95% CI, .46-1.81). CONCLUSIONS: MV2 may reduce nonmeasles severe morbidity by 28% (-38% to 62%), although this did not achieve statistical significance in this study. If significant in higher powered studies, this has major implications for child health, even after measles eradication. CLINICAL TRIALS REGISTRATION: NCT02943681.

Measles Vaccination in Presence of Measles Antibody May Enhance Child Survival.

Background: In trials of early two-dose measles vaccination (MV), with the first dose being given before 9 months of age, vaccination in the presence of maternal antibody reduced mortality 2- to 3-fold compared with MV in the presence of no measles antibody. We tested this finding in two historical studies in which the children had received one dose of MV. Methods: We used data from a surveillance study of seroconversion after standard-titer MV (Schwarz strain) (Study 1) and a trial of early medium-titer MV (Edmonston-Zagreb strain) in which a pre-vaccination blood sample had been collected (Study 2). Both studies had control children, who were enrolled under similar conditions, but did not receive effective MV. Study 1 was a natural experiment where all children measles vaccinated during 1 month did not seroconvert and had therefore received an ineffective vaccine. In Study 2, the controls were randomized to an inactivated polio vaccine (IPV). We compared mortality for children with undetectable levels of measles antibody (<31.25 mIU) at baseline with children with detectable levels (≥31.25 mIU). Results: In both studies, children who were measles vaccinated in the presence of measles antibody had lower mortality compared with children who were measles vaccinated in presence of no measles antibody, the combined mortality rate ratio (MRR) being 0.51 (0.27-0.96). In the control groups, a detectable level of measles antibody vs. an undetectable level was not associated with lower mortality, the MRR being 1.40 (0.31-6.38). Conclusion: The results supported previous findings: measles vaccination in the presence of measles antibody had beneficial effects on child survival. Since maternal antibody levels are declining, it may be time to consider giving MV earlier and/or to provide MV to adolescent girls to boost antibody levels.

The effect of early measles vaccination on morbidity and growth: A randomised trial from Guinea-Bissau.

BACKGROUND: Measles vaccine (MV) has beneficial non-specific effects protecting against non-measles infections in some situations. Within a trial of the effect of MV on mortality, we assessed effects of early MV on the secondary outcomes consultations and growth, overall, and by sex and exposure to campaigns with oral polio vaccine (OPV). MATERIALS AND METHODS: Children were randomly assigned to MV at 4.5 + 9 months or MV at 9 months as recommended. At enrolment and 9 months children had their mid-upper-arm-circumference (MUAC) and weight measured. Consultations (out/inpatient) were registered at monthly home visits. Weight-for-age and MUAC-for-age Z-scores were obtained using the WHO growth reference and compared by group in linear regression models. Consultation rates between enrolment and 9 months were compared in Cox proportional hazards models, providing consultation Hazard Ratios (HRs) for early MV versus no early MV. We tested whether the effect of early MV was modified by OPV campaigns by splitting observation time at exposure to OPV campaigns. RESULTS: Among 3548 children enrolled between 2012 and 2015, early MV had no effect on MUAC-for-age (mean difference comparing early MV vs. no MV -0.01, 95% CI -0.06-0.04), weight-for-age (mean difference -0.03, 95% CI -0.07-0.02) or rates of consultations (HR = 1.03, 95% CI 0.92-1.16). The rate of consultations for children enrolled was lower after exposure to OPV campaigns (HR = 0.81, 95% CI 0.71-0.92). The effect of MV differed before exposure to OPV campaigns (HR = 1.12, 95% CI 0.98-1.29) and after OPV campaigns (HR = 0.83, 95% CI 0.67-1.03) (test for interaction: p = 0.03). Associations did not differ by sex. CONCLUSION: Early MV had no overall effect on consultation rates and growth between enrolment and 9 months of age. However, early MV tended to have beneficial effects for children subsequently exposed to OPV campaigns. As beneficial effects were observed in subgroups, the results should be interpreted with caution. CLINICAL TRIALS REGISTRATION: NCT01644721.

Maternal Priming: Bacillus Calmette-Guérin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar.

BACKGROUND AND HYPOTHESIS: Maternal priming might enhance the beneficial nonspecific effects (NSEs) of live measles vaccination (MV). Children with a bacillus Calmette-Guérin (BCG) vaccine scar have a lower mortality rate than those without a scar that is not explained by protection against tuberculosis. We examined the hypothesis that BCG scarring would have a stronger effect on a child if the mother also had a BCG scar. METHODS: In a randomized controlled trial (RCT) of early MV in children aged 4.5 months, the BCG-scar status of the children and their mother were registered at enrollment at 4.5 months of age. The children were followed up until they were 36 months of age. Using a Cox proportional hazards model, we compared mortality rate ratios according to maternal and child BCG-scar status after adjusting for where the BCG vaccine was given (the national hospital or elsewhere). We censored for other interventions that have immunomodulating effects on child survival, including neonatal vitamin A supplementation and early MV. RESULTS: A total of 2213 children had not received neonatal vitamin A supplementation and early MV; 83% of these children and 44% of the mothers had a BCG scar. Children whose mother had a BCG scar were not more likely to have a BCG scar than those whose mother did not have a BCG scar (risk ratio, 1.01 [95% confidence interval (CI), 0.98-1.05]). Among the children, having a BCG scar was associated with a 41% (95% CI, 5%-64%) lower mortality between the ages of 4.5 and 36 months. The reduction in mortality was 66% (95% CI, 33%-83%) if the mother also had a BCG scar but only 8% (95% CI, -83% to 53%) if the mother had no BCG scar (test of interaction, P = .04). CONCLUSIONS: Maternal BCG priming might be important for the effect of BCG vaccination on child survival. Ensuring better BCG vaccine scarring among mothers and children could have a considerable effect on child mortality levels.

Correction: Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau.

[This corrects the article DOI: 10.1371/journal.pone.0177547.].

Impact of H1N1 Influenza Vaccination on Child Morbidity in Guinea-Bissau.

BACKGROUND: In addition to vaccines' specific effects, vaccines may have non-specific effects (NSEs) altering the susceptibility to unrelated infections. Non-live vaccines have been associated with negative NSEs. In 2010, a campaign with the non-live H1N1-influenza vaccine targeted children 6-59 months in Guinea-Bissau. METHODS: Bandim Health Project runs a health and demographic surveillance system site in Guinea-Bissau. Using a Cox proportional hazards model, we compared all-cause consultation rates after vs. before the campaign, stratified by participation status. RESULTS: Among 10 290 children eligible for the campaign, 60% had participated, 18% had not and for 22% no information was obtained. After the H1N1 campaign, the consultation rates tended to decline less for participants [HR = 0.80 (95% confidence interval, CI: 0.75; 0.85)] than for non-participants [HR = 0.68 (95% CI: 0.58; 0.79)], p = 0.06 for same effect. CONCLUSION: The decline in the vaccinated group may have been smaller than the decline in the non-vaccinated group consistent with H1N1-vaccine increasing susceptibility to unrelated infections.

Is early measles vaccination associated with stronger survival benefits than later measles vaccination?

BACKGROUND: Measles vaccine (MV) may protect against non-measles mortality. We tested whether survival depended on age of measles vaccination. METHODS: Bandim Health Project follows children under 5 years of age through a Health and Demographic Surveillance System in rural Guinea-Bissau. Children aged 6-36 months with a vaccination card inspected were followed to the next visit or for a maximum of 6 months. In Cox proportional-hazards models adjusted for age and village cluster, we compared the survival of children vaccinated with MV early (< 9 months), as recommended (9-11 months) or late (> 12+ months) with the survival of measles-unvaccinated children. Among measles-vaccinated children, we modelled the effect of age at measles vaccination linearly to assess mortality changes per month increase in vaccination age. RESULTS: From 1999 to 2006, 14,813 children (31,725 observations) were included. Children vaccinated with MV had a Hazard Ratio (HR) of 0.76 (95% CI: 0.63-0.91) compared with measles-unvaccinated children; censoring measles deaths did not change the results (HR = 0.79 (0.65-0.95)). For early MV the HR was 0.68 (0.53-0.87), for MV as recommended the HR was 0.77 (0.62-0.96) and for late MV the HR was 0.86 (0.67-1.11). Limiting the analysis to measles-vaccinated children, age at measles vaccination was associated with a 2.6% (0.4-5.1%) increase in mortality per month increase in vaccination age. CONCLUSION: Early MV was associated with a large survival advantage. The current policy to increase vaccination age, when measles control improves, may not optimize the impact of MV on child survival.

Admission and mortality at the main neonatal intensive care unit in Guinea-Bissau.

Background: The authors assessed the risk of admission and mortality at the main neonatal intensive care unit (NICU) at the National Hospital Simão Mendes (NHSM) in Guinea-Bissau. Methods: The Bandim Health Project (BHP) maintains a health and demographic surveillance system (HDSS) in the capital Bissau, including at the NHSM. Data from January 2008 to August 2013 was used to assess NICU incubator admissions and mortality. Results: The overall NICU admission rate was 4.8% (1575/33,005); the lowest rate in 2012 (4.0% (214/5293)) and the highest rate in 2009 (6.0% (369/6134)). The overall mortality among admitted children was 19.6% (289/1476), declining from 26.7% (68/255) in 2008 to 13.0% (16/123) in 2013. Birth weight <1500 g (OR=353, (95% CI: 244-510) compared with normal birth weight 2500 g-4000 g), Apgar score≤3 (OR=13.2 (9.72-18.0) compared with Apgar score 7-10) and single motherhood (OR=1.44 (1.20-1.74)) were associated with NICU admission. Low Apgar score was a risk factor for NICU mortality (OR=6.21 (2.05-18.81)) and females (OR=0.55 (0.38-0.79) had a lower mortality than males. Conclusion: Approximately 5% of the hospital-born children were admitted to an incubator and among those almost 20% died, although mortality did decline. Male sex, very low birth weight and low Apgar score were strongly associated with NICU admissions and mortality.

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.

Determinants of BCG scarification among children in rural Guinea-Bissau: A prospective cohort study.

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination. METHODS: Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). RESULTS: From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52-5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal <3 mm were more likely to not develop a scar (RR = 9.05 (3.69-22.20) and RR = 4.74 (1.96-11.45), respectively). Nutritional status and socioeconomic status were not associated with scarification. CONCLUSION: Vaccination technique and vaccine strain were associated with BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.

Randomized Trial of 2 Versus 1 Dose of Measles Vaccine: Effect on Hospital Admission of Children After 9 Months of Age.

BACKGROUND: Two doses of measles vaccine (MV) might reduce the nonmeasles mortality rate more than 1 dose of MV does. The effect of 2 versus 1 dose on morbidity has not been examined. Within a randomized trial of the effect of 2 doses versus 1 dose of MV on mortality in Guinea-Bissau, we investigated the effect on hospital admissions. METHODS: Children were randomly assigned 1:2 to receive MV at 4.5 and 9 months of age or the currently recommended dose at 9 months. We compared hospital admission rates among children between 9 and 18 months of age in a Cox regression model with age as the underlying time scale. Half of the children had received neonatal vitamin A supplementation (NVAS) in another trial. The beneficial effect of MV at 4.5 and 9 months on mortality was limited to children who had not received NVAS; therefore, we investigated the interaction of MV with NVAS on admission rates. RESULTS: Among 5626 children (2 doses of MV, 1960 children; 1 dose of MV, 3666), we identified 311 hospital admissions of children between 9 and 18 months of age. Overall, compared to 1 dose of MV, 2 doses reduced the risk of hospital admission for children who had not received NVAS (hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.47-0.93]), but we found no effect among NVAS recipients (HR, 1.16 [95% CI, 0.82-1.63]) (P = .02 for interaction). CONCLUSIONS: The benefit of 2 doses of MV was limited to children who had not received NVAS. NVAS is not generally recommended; hence, an early 2-dose measles vaccination policy might reduce hospital admissions more than the current policy of providing the first MV at 9 months of age. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00168558.

A Two-Center Randomized Trial of an Additional Early Dose of Measles Vaccine: Effects on Mortality and Measles Antibody Levels.

Background: In addition to protecting against measles, measles vaccine (MV) may have beneficial nonspecific effects. We tested the effect of an additional early MV on mortality and measles antibody levels. Methods: Children aged 4-7 months at rural health and demographic surveillance sites in Burkina Faso and Guinea-Bissau were randomized 1:1 to an extra early standard dose of MV (Edmonston-Zagreb strain) or no extra MV 4 weeks after the third diphtheria-tetanus-pertussis-hepatitis B-Haemophilus influenzae type b vaccine. All children received routine MV at 9 months. We assessed mortality through home visits and compared mortality from enrollment to age 3 years using Cox proportional hazards models, censoring for subsequent nontrial MV. Subgroups of participants had blood sampled to assess measles antibody levels. Results: Among 8309 children enrolled from 18 July 2012 to 3 December 2015, we registered 145 deaths (mortality rate: 16/1000 person-years). The mortality was lower than anticipated and did not differ by randomization group (hazard ratio, 1.05; 95% confidence interval, 0.75-1.46). At enrollment, 4% (16/447) of children in Burkina Faso and 21% (90/422) in Guinea-Bissau had protective measles antibody levels. By age 9 months, no measles-unvaccinated/-unexposed child had protective levels, while 92% (306/333) of early MV recipients had protective levels. At final follow-up, 98% (186/189) in the early MV group and 97% (196/202) in the control group had protective levels. Conclusions: Early MV did not reduce all-cause mortality. Most children were susceptible to measles infection at age 4-7 months and responded with high antibody levels to early MV. Clinical Trials Registration: NCT01644721.