Can earlier BCG-Japan and OPV vaccination reduce early infant mortality? A cluster-randomised trial in Guinea-Bissau.

OBJECTIVE: To assess the effect of providing BCG and oral polio vaccine (OPV) at an early home visit after delivery. DESIGN: Cluster-randomised trial, randomising 92 geographically defined clusters 1:1 to intervention/control arms. SETTING: Bandim Health Project Health and Demographic Surveillance System, Guinea-Bissau. PARTICIPANTS: 2226 newborns enrolled between July 2016 and August 2019. INTERVENTIONS: In both arms, newborns received a home visit within 72 hours after birth. In intervention clusters (n=46), BCG and OPV were provided at the home visit. MAIN OUTCOME MEASURE: Rates of non-accidental mortality were compared in Cox proportional hazards models from (last of) day 1 or enrolment, until (first of) day 60 or registration of non-trial vaccines. RESULTS: A total of 35 deaths (intervention: 7, control: 28) were registered during the trial. Providing BCG and OPV reduced non-accidental early infant mortality by 59% (8-82%). The intervention also reduced non-accidental hospital admissions. The intervention had little impact on growth and BCG scarring and tended to increase the risk of consultations. CONCLUSIONS: The trial was stopped early due to lower-than-expected enrolment and event rates when 33% of the planned number of newborns had been enrolled. Despite the small size of the trial, the results support that early BCG and OPV vaccinations are beneficial and reduce early child mortality and morbidity. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02504203).

The mortality effects of disregarding the strategy to save doses of measles vaccine: a cluster-randomised trial in Guinea-Bissau.

INTRODUCTION: Measles vaccine (MV) may improve health beyond measles protection. To avoid wastage from multi-dose vials, children in Guinea-Bissau are only measles vaccinated when aged 9-11 months and when six or more children are present. We assessed health impacts of providing MV to all measles-unvaccinated children 9-35 months. METHODS: We cluster-randomised 182 village clusters under demographic surveillance in rural Guinea-Bissau to an 'MV-for-all-policy' arm where we offered MV regardless of age and number of children present at our bi-annual village visits, or a 'Restrictive-MV-policy' arm where we followed national policy. Measles-unvaccinated children aged 9-35 months were eligible for enrolment and followed to 5 years of age. In intention-to-treat analyses, we compared mortality using Cox regression analyses with age as underlying timescale. The primary analysis was for children aged 12-35 months at eligibility assessment. Interactions with several background factors were explored. RESULTS: Between 2011 and 2016, we followed 2778 children in the primary analysis. MV coverage by 3 years was 97% among children eligible for enrolment under the MV-for-all-policy, and 48% under the Restrictive-MV-policy. Mortality was 59% lower than anticipated and did not differ by trial arm (MV-for-all-policy: 45/1405: Restrictive-MV-policy: 44/1373; HR: 0.95 (95% CI 0.64 to 1.43)). The effect of MV-for-all changed over time: The HR was 0.53 (95% CI 0.27 to 1.07) during the first 1½ years of enrolment but 1.47 (95% CI 0.87 to 2.50) later (p=0.02, test of interaction). Explorative analyses indicated that the temporal change may be related to interactions with other childhood interventions. CONCLUSION: The MV-for-all-policy increased MV coverage but had no overall effect on overall mortality. TRIAL REGISTRATION NUMBER: NCT01306006.

Immediate Bacille Calmette-Guérin Vaccination to Neonates Requiring Perinatal Treatment at the Maternity Ward in Guinea-Bissau: A Randomized Controlled Trial.

BACKGROUND: Randomized controlled trials (RCTs) indicate that bacille Calmette-Guérin (BCG) vaccination provides broad beneficial "nonspecific" protection against infections. We investigated the effect on in-hospital mortality of providing BCG immediately upon admission to a neonatal intensive care unit (NICU), rather than BCG-at-discharge. The pretrial NICU mortality was 13% and we hypothesized that BCG would reduce mortality by 40%. METHODS: Parallel-group, open-label RCT was initiated in 2013 in Guinea-Bissau. Neonatal intensive care unit-admitted neonates were randomized 1:1 to BCG + oral polio vaccine (OPV) immediately (intervention) versus BCG + OPV at hospital discharge (control; usual practice). The trial was discontinued due to decreasing in-hospital mortality and major NICU restructuring. We assessed overall and disease-specific mortality by randomization allocation in cox proportional hazards models providing mortality rate ratios (MRRs). RESULTS: We recruited 3353 neonates, and the overall mortality was 3.1% (52 of 1676) for BCG-vaccinated neonates versus 3.3% (55 of 1677) for controls (MRR = 0.94; 0.64-1.36). For noninfectious causes of death, the MRR was 1.20 (0.70-2.07), and there tended to be fewer deaths from infections in the BCG group (N = 14) than among controls (N = 21) (MRR = 0.65; 0.33-1.28). CONCLUSIONS: Providing BCG + OPV to frail neonates was safe and might protect against fatal infection in the immediate newborn period. Deaths due to prematurity and perinatal complications were unaffected by BCG.

BCG skin reactions by 2 months of age are associated with better survival in infancy: a prospective observational study from Guinea-Bissau.

INTRODUCTION: Receiving Bacille Calmette-Guérin (BCG)-Denmark vaccine at birth has been associated with ~40% reductions in all-cause neonatal mortality. We evaluated determinants of BCG skin reaction characteristics by age 2 months and tested the association with subsequent mortality. METHODS: Prospective observational study amalgamating five trials providing BCG-at-birth that were conducted between 2002 and 2018 in Guinea-Bissau. The reaction status and size were evaluated at home-visits by 2 months of age among 6012 neonates; mortality from 2 to 12 months was assessed at subsequent visits. Reaction determinants were evaluated by binomial regression providing risk ratios (RRs). In Cox-models providing adjusted mortality rate ratios (aMRRs), we assessed the association between (1) having a 2-month reaction (yes/no) and (2) reaction size tertiles and subsequent all-cause mortality risk. A subgroup had their BCG reaction evaluated and were bled at age 4 weeks; their samples underwent in vitro analysis for specific and non-specific cytokine responses. RESULTS: The BCG strain was the main determinant for developing a 2-month reaction and the reaction size: the BCG-Russia/BCG-Denmark RR for large-reaction was 0.38 (0.30-0.47) and the BCG-Russia/BCG-Japan RR was 0.61 (0.51-0.72). 5804 infants (96.5%) were reactors by age 2 months; 208 (3.5%) were non-reactors. The 2-12 months mortality risk was 4.8% (10/208) for non-reactors, 2.9% (64/2213) for small reactors, 1.8% (30/1710) for medium reactors and 0.8% (15/1881) for large reactors. The reactor/non-reactor aMRR was 0.49 (0.26-0.95) and there was a linear trend of decreasing mortality with increasing reaction size (p for trend <0.001). BCG reactors had higher 4-week specific and non-specific cytokine responses, responses that were highest among those with large reactions. CONCLUSION: Among BCG-vaccinated infants, having a BCG skin reaction by age 2 months was associated with markedly better survival, as was the reaction size. Our findings thus support that BCG has substantial effects on all-cause mortality. Emphasising at-birth vaccination with immunogenic BCG strains and revaccinating non-reactors and small reactors could have major public health benefits. TRIAL REGISTRATION NUMBERS: NCT00146302, NCT00168610, NCT00625482, NCT01989026 and NCT02447536.

Safety and COVID-19 Symptoms in Individuals Recently Vaccinated with BCG: a Retrospective Cohort Study.

Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.

Defining trained immunity and its role in health and disease.

Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.

Correction: Stillbirths in urban Guinea-Bissau: A hospital- and community-based study.

[This corrects the article DOI: 10.1371/journal.pone.0197680.].

Outcomes of controlled human malaria infection after BCG vaccination.

Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed 'trained immunity'. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.

Maternal Measles Antibodies and Their Influence on All-cause Mortality Following Measles Vaccination: An Alternative to Measure Very Low Maternal Antibody Levels.

It was previously shown by hemagglutination inhibition that measles vaccination in the presence of maternal measles antibodies was associated with reduced all-cause mortality. We confirmed this serological association using a multiplexed immunoassay as a sensitive alternative and estimated a threshold concentration (28.7 mIU/mL) that correlates with lower all-cause mortality (P = .02).

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.