Publications by authors named "Peter Aaby"

388 Publications

Non-specific effects of maternal and offspring rabies vaccination on mortality and antibiotic use in a Danish pig herd: A randomized trial.

Vaccine 2021 Apr 9. Epub 2021 Apr 9.

Bandim Health Project, Department of Clinical Research, University of Southern Denmark, Copenhagen, Denmark; Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark.

Introduction: Human non-live vaccines have been associated with detrimental non-specific effects (NSE), particularly in females. A large trial found 2-fold increased overall mortality in girls receiving a new malaria vaccine compared to the rabies vaccine used as a coontrol; a beneficial NSE of the rabies vaccine was proposed. Conversely, in dogs increased mortality was seen in females but not males following rabies vaccination of puppies born to immunized mothers. We investigated NSE of non-live rabies vaccine in piglets and the potential modifying effect of maternal priming with rabies vaccine.

Methods: In a Danish herd of commercial rabies virus-free pigs, 575 pregnant sows (2-3 weeks before scheduled farrowing) and 5747 of their offspring (median 6-day-old) were allocated (1:1) to non-live rabies vaccine (Versiguard rabies vet) or no rabies vaccine. Outcomes were overall mortality and antibiotic treatment until departure from the nursery (approximately age 12 weeks/30 kgs).

Results: Until weaning, overall offspring mortality was 2.2% (127 piglets died, rabies vaccine: n = 69; control: n = 58), the proportion ratio (PR) being 1.19 (95% confidence interval: 0.84-1.68). Until end of follow-up, mortality was 4.1% (233, rabies vaccine: n = 115; control = 118, PR: 0.97 (0.76-1.25)). Prior sow rabies vaccination did not affect piglet mortality. For mortality as well as risk of antibiotic treatment before weaning, there was indication of a beneficial effect of rabies vaccine in female piglets, but a negative effect in (castrated) male piglets from rabies-naïve sows. Prior sow vaccination significantly modified the vaccine effect estimate in female piglets toward a detrimental effect of rabies vaccine on treatment risk. These effects had waned by 12 weeks of age.

Conclusion: The study did not support the hypothesized beneficial NSE of rabies vaccine. Although under-powered for subgroup analyses, the study indicated effect modification by sex and maternal vaccination. Results could be different in a herd with higher mortality and infectious burden.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.083DOI Listing
April 2021

Chronic Political Instability and the HIV/AIDS Response in Guinea-Bissau from 2000 to 2015: A Systematic Review.

Trop Med Infect Dis 2021 Mar 16;6(1). Epub 2021 Mar 16.

Institute of Global Health, University of Geneva, 1202 Geneva, Switzerland.

Guinea-Bissau suffers from political instability and an unusually high HIV/AIDS burden compared to other countries in the West Africa region. We conducted a systematic review on the HIV/AIDS epidemic in Guinea-Bissau during the Millennium Development Goals (MDGs) period (2000-2015), which dovetailed with a period of chronic political instability in the country's history. We searched published works on the HIV/AIDS epidemic in Guinea-Bissau for references to chronic political instability. Six databases and the grey literature were searched, informed by expert opinion and manual research through reference tracing. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The search yielded 122 articles about HIV/AIDS in Guinea-Bissau during the MDG years. Biomedical, clinical, or epidemiological research predominated public health research production on HIV/AIDS in Guinea-Bissau in this period. Six articles addressing themes related to chronic political instability, including how political instability has affected the HIV/AIDS disease response, were identified. The results suggest the importance of considering a broader political epidemiology that accounts for socio-political aspects such as governance, human rights, and community responses into which any national HIV/AIDS response is integrated.
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http://dx.doi.org/10.3390/tropicalmed6010036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005934PMC
March 2021

BCG: new life for a centenarian vaccine.

Lancet Infect Dis 2021 Feb 17. Epub 2021 Feb 17.

Bandim Health Project, Bissau, Guinea-Bissau; University of Southern Denmark, 5230 Odense M, Denmark.

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http://dx.doi.org/10.1016/S1473-3099(20)30714-3DOI Listing
February 2021

Letter to the Editor.

Risk Anal 2021 Feb;41(2):387-388

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1111/risa.13669DOI Listing
February 2021

Life expectancy of HIV-infected patients followed at the largest hospital in Guinea-Bissau is one-fourth of life expectancy of the background population.

Infection 2021 Feb 2. Epub 2021 Feb 2.

Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.

Purpose: To estimate the life expectancy (LE) of HIV-infected patients in the West African country Guinea-Bissau and compare it with the background population.

Methods: Using data from the largest HIV outpatient clinic at the Hospital Nacional Simão Mendes in the capital Bissau, a retrospective observational cohort study was performed. The study included patients attending the clinic between June 2005 and January 2018. A total of 8958 HIV-infected patients were included. In the analysis of the background population, a total of 109,191 people were included. LE incorporating loss to follow-up (LTFU) was estimated via Kaplan-Meier estimators using observational data on adult HIV-infected patients and background population.

Results: The LE of 20-year-old HIV-infected patients was 9.8 years (95% CI 8.3-11.5), corresponding to 22.3% (95% CI 18.5-26.7%) of the LE of the background population. (LE for 20-year-olds in the background population was 44.0 years [95% CI 43.0-44.9].) Patients diagnosed with CD4 cell counts below 200 cells/µL had a LE of 5.7 years (95% CI 3.6-8.2). No increase in LE with later calendar period of diagnosis was observed.

Conclusions: LE was shown to be markedly lower among HIV-infected patients compared with the background population. While other settings have shown marked improvements in prognosis of HIV-infected patients in recent years, no improvement in Bissau was observed over time (9.8 years (95% CI 7.6-12.2) and 9.9 years (95% CI 7.6-12.1) for the periods 2005-2010 and 2014-2016, respectively).
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http://dx.doi.org/10.1007/s15010-020-01574-6DOI Listing
February 2021

Reduced Mortality After Oral Polio Vaccination and Increased Mortality After Diphtheria-tetanus-pertussis Vaccination in Children in a Low-income Setting.

Clin Ther 2021 Jan 2;43(1):172-184.e7. Epub 2020 Dec 2.

Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; Research Centre for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. Electronic address:

Purpose: The diphtheria-tetanus-pertussis vaccine (DTP) and oral polio vaccine (OPV) were introduced in children 3 of 5 months of age in 1981-1983 in Bandim, in the capital of Guinea-Bissau. Because DTP has been linked to deleterious nonspecific effects (NSEs) and OPV to beneficial NSEs, we followed up this cohort to 3 years of age and examined the effects of DTP with OPV on all-cause mortality and the interactions of DTP and OPV with the measles vaccine (MV).

Methods: DTP and OPV were offered at 3 monthly community weighing sessions. Vaccination groups were defined by the last vaccine received. We compared overall mortality for different groups in Cox proportional hazards regression models, reporting hazards ratios (HRs) with 95% CIs.

Findings: The study cohort included 1491 children born in Bandim from December 1980 to December 1983. From 3 to 35 months of age, with censoring for MV, children vaccinated with DTP and/or OPV had higher mortality than both unvaccinated children (HR = l.66; 95% CI, 1.03-2.69) and OPV-only vaccinated children (HR = 2.81; 95% CI, 1.02-7.69); DTP-only vaccinated children had higher mortality than OPV-only vaccinated children (HR = 3.38; 95% CI, 1.15--9.93). In the age group of 3-8 months, before MV is administered, DTP-only vaccination was associated with a higher mortality than DTP with OPV (HR = 3.38; 95% CI, 1.59-7.20). Between 9 and 35 months of age, when MV is given, DTP-vaccinated and MV-unvaccinated children had higher mortality (HR = 2.76; 95% CI, 1.36-5.59) than children who had received MV after DTP, and among children who received DTP with MV or after MV, DTP-only vaccination was associated with a higher mortality than DTP with OPV (HR = 6.25; 95% CI, 2.55-15.37).

Implications: Because the 2 vaccines had differential effects and the healthiest children were vaccinated first, selection biases are unlikely to explain the estimated impact on child survival. OPV had beneficial NSEs, and administration of OPV with DTP may have reduced the negative effects of DTP.
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http://dx.doi.org/10.1016/j.clinthera.2020.11.010DOI Listing
January 2021

Diphtheria-tetanus-pertussis (DTP) vaccine is associated with increased female-male mortality rate ratios. A meta-analysis of studies of DTP administered before and after measles vaccine.

J Infect Dis 2020 Oct 30. Epub 2020 Oct 30.

Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej, Copenhagen S, Denmark.

Background: The third dose of diphtheria-tetanus-pertussis (DTP3) is used to monitor immunization programs. DTP has been associated with higher female mortality.

Methods: We updated previous literature searches for DTP-studies of mortality by sex. We examined the female/male (F/M) mortality rate ratio (MRR) with increasing number of doses of DTP and for subsequent doses of measles vaccine (MV) after DTP and of DTP after MV.

Results: Eight studies had information on both DTP1 and DTP3. The F/M MRR was 1.17 (0.88-1.57) after DTP1 and increased to 1.66 (1.32-2.09) after DTP3. Following receipt of MV the F/M MRR declined to 0.63 (0.42-0.96). In 11 studies the F/M MRR increased to 1.73 (1.33-2.27) when DTP-containing vaccine was administered after MV.

Conclusions: The F/M MRR increased with increasing doses of DTP. After MV, females had lower mortality than males. If DTP was provided after MV, mortality increased again for females relative to males. No bias can explain these changes in the F/M MRR. DTP does not improve male survival substantially in situations with herd immunity to pertussis and the higher F/M MRR after DTP may therefore reflects an absolute increase in female mortality.
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http://dx.doi.org/10.1093/infdis/jiaa684DOI Listing
October 2020

Timeliness of DTaP-IPV-Hib Vaccination and Development of Atopic Dermatitis Between 4 Months and 1 Year of Age-Register-Based Cohort Study.

J Allergy Clin Immunol Pract 2021 Apr 2;9(4):1520-1528.e8. Epub 2020 Oct 2.

Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen, Denmark; Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.

Background: An Australian study including 4433 children found that delayed Diphtheria-Tetanus-acellular Pertussis-containing vaccination was associated with reduced risk of developing atopic dermatitis (AD) before age 1 year.

Objective: We assessed whether delayed vaccination against diphtheria, tetanus, acellular pertussis, polio, and Haemophilus influenzae type b (Diphtheria, Tetanus, acellular Pertussis - Inactivated Polio vaccine - Haemophilus influenzae type b [DTaP]) was associated with a reduced risk of new cases of AD before age 1 year in Denmark.

Methods: We used nationwide registers to follow 883,160 children born in Denmark from 1997 to 2012. Binary regression models adjusting for potential confounding factors were applied to estimate relative risks (adjusted relative risks [aRRs]) of developing AD among children with delayed DTaP vaccination (defined as given 1 month or more after the recommended age) compared with timely vaccinated children.

Results: Among 143,429 children with a delayed first dose of DTaP, 4,847 (3.4%) developed AD between age 4 months and 1 year, compared with 27,628 (3.7%) among 739,731 children not having delayed DTaP (aRR 0.94; 95% CI, 0.91-0.97). The aRR was 0.94 (95% CI, 0.90-0.99) for children with a delayed second dose, and the aRR was 0.88 (95% CI, 0.82-0.93) when comparing children with delayed first and second doses with all timely vaccinated children.

Conclusions: The results support the hypothesis that delayed vaccination with DTaP is associated with reduced risk of developing new cases of AD after age 4 months. The dose-dependent relationship strengthens the evidence of a causal relationship. Some countries are introducing maternal pertussis vaccination and delaying the first dose of DTaP, providing a possibility for further testing the hypothesis.
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http://dx.doi.org/10.1016/j.jaip.2020.09.024DOI Listing
April 2021

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

BMJ Glob Health 2020 09;5(9)

Bandim Health Project, Institute of Clinical Research, Uni. Southern Denmark and Odense University Hospital, Odense, Denmark.

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.
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http://dx.doi.org/10.1136/bmjgh-2020-002993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520814PMC
September 2020

National immunisation campaigns with oral polio vaccine may reduce all-cause mortality: An analysis of 13 years of demographic surveillance data from an urban African area.

Clin Infect Dis 2020 Sep 19. Epub 2020 Sep 19.

Bandim Health Project, Indepth Network, Apartado, Bissau, Guinea-Bissau.

Background: Between 2002-2014, Guinea-Bissau had 17 national campaigns with oral polio vaccine (OPV) as well as campaigns with vitamin A supplementation (VAS), measles vaccine (MV), and H1N1-influenza vaccine. We examined the impact of these campaigns on child survival.

Methods: We examined the mortality rate between day 1 and 3 years of age of all children in the study area. We used Cox models with age as underlying time to calculate adjusted mortality rate ratios (MRR) between "after-campaign" mortality and "before-campaign" mortality, adjusted for temporal change in mortality and stratified for season at risk.

Results: Mortality was lower after OPV-only campaigns than before, the MRR for after-campaign vs. before-campaign being 0.75 (95% CI=0.67-0.85). Other campaigns did not have similar effects, the MRRs being 1.22 (1.04-1.44) for OPV+VAS campaigns, 1.39 (1.20-1.61) for VAS-only campaigns, 1.32 (1.09-1.60) for MV-with-VAS campaigns, and 1.13 (0.86-1.49) for the H1N1 campaign. Thus, all other campaigns differed significantly from the effect of OPV-only campaigns. Effects did not differ for trivalent, bivalent, or monovalent strains of OPV. With each additional campaign of OPV-only, the mortality rate declined further (MRR=0.86 (0.81-0.92) per campaign). With follow-up to 3 years of age, the number needed to treat (NNT) to save one life with campaign-OPV-only was 50 neonates.

Conclusion: OPV campaigns can have a much larger effect on child survival than otherwise assumed. Stopping OPV campaigns in low-income countries as part of the endgame for polio infection may increase child mortality.
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http://dx.doi.org/10.1093/cid/ciaa1351DOI Listing
September 2020

Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial in Denmark.

Trials 2020 Sep 17;21(1):799. Epub 2020 Sep 17.

Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.

Objectives: The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is associated with non- specific protective effects against other infections, and significant reductions in all-cause morbidity and mortality have been reported. We aim to test whether BCG vaccination may reduce susceptibility to and/or the severity of COVID-19 and other infectious diseases in health care workers (HCW) and thus prevent work absenteeism.The primary objective is to reduce absenteeism due to illness among HCW during the COVID-19 pandemic. The secondary objectives are to reduce the number of HCW that are infected with SARS-CoV-2, and to reduce the number of hospital admissions among HCW during the COVID-19 pandemic.

Hypothesis: BCG vaccination of HCW will reduce absenteeism by 20% over a period of 6 months.

Trial Design: Placebo-controlled, single-blinded, randomised controlled trial, recruiting study participants at several geographic locations. The BCG vaccine is used in this study on a different indication than the one it has been approved for by the Danish Medicines Agency, therefore this is classified as a phase III study.

Participants: The trial will recruit 1,500 HCW at Danish hospitals.To be eligible for participation, a subject must meet the following criteria: Adult (≥18 years); Hospital personnel working at a participating hospital for more than 22 hours per week.A potential subject who meets any of the following criteria will be excluded from participation in this study: Known allergy to components of the BCG vaccine or serious adverse events to prior BCG administration Known prior active or latent infection with Mycobacterium tuberculosis (M. tuberculosis) or other mycobacterial species Previous confirmed COVID-19 Fever (>38 C) within the past 24 hours Suspicion of active viral or bacterial infection Pregnancy Breastfeeding Vaccination with other live attenuated vaccine within the last 4 weeks Severely immunocompromised subjects. This exclusion category comprises: a) subjects with known infection by the human immunodeficiency virus (HIV-1) b) subjects with solid organ transplantation c) subjects with bone marrow transplantation d) subjects under chemotherapy e) subjects with primary immunodeficiency f) subjects under treatment with any anti-cytokine therapy within the last year g) subjects under treatment with oral or intravenous steroids defined as daily doses of 10 mg prednisone or equivalent for longer than 3 months h) Active solid or non-solid malignancy or lymphoma within the prior two years Direct involvement in the design or the execution of the BCG-DENMARK-COVID trial Intervention and comparator: Participants will be randomised to BCG vaccine (BCG-Denmark, AJ Vaccines, Copenhagen, Denmark) or placebo (saline). An adult dose of 0.1 ml of resuspended BCG vaccine (intervention) or 0.1 ml of sterile 0.9% NaCl solution (control) is administered intradermally in the upper deltoid area of the right arm. All participants will receive one injection at inclusion, and no further treatment of study participants will take place.

Main Outcomes: Main study endpoint: Days of unplanned absenteeism due to illness within 180 days of randomisation.Secondary study endpoints: The cumulative incidence of documented COVID-19 and the cumulative incidence of hospital admission for any reason within 180 days of randomisation.Randomisation: Randomisation will be done centrally using the REDCap tool with stratification by hospital, sex and age groups (+/- 45 years of age) in random blocks of 4 and 6. The allocation ratio is 1:1.Blinding (masking): Participants will be blinded to treatment. The participant will be asked to leave the room while the allocated treatment is prepared. Once ready for injection, vaccine and placebo will look similar, and the participant will not be able to tell the difference.The physicians administering the treatment are not blinded.Numbers to be randomised (sample size): Sample size: N=1,500. The 1,500 participants will be randomised 1:1 to BCG or placebo with 750 participants in each group.Trial Status: Current protocol version 5.1, from July 6, 2020.Recruitment of study participants started on May 18, 2020 and we anticipate having finished recruiting by the end of December 2020.

Trial Registration: The trial was registered with EudraCT on April 16, 2020, EudraCT number: 2020-001888-90, and with ClinicalTrials.gov on May 1, 2020, registration number NCT04373291.Full protocol: The full protocol is attached as an additional file, accessible from the Trialswebsite (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04714-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495402PMC
September 2020

Reduction in Short-term Outpatient Consultations After a Campaign With Measles Vaccine in Children Aged 9-59 Months: Substudy Within a Cluster-Randomized Trial.

J Pediatric Infect Dis Soc 2020 Nov;9(5):535-543

OPEN, University of Southern Denmark, Odense, Denmark.

Background: We assessed a measles vaccination campaign's potential short-term adverse events.

Methods: In a cluster-randomized trial assessing a measles vaccination campaign's effect on all-cause mortality and hospital admission among children aged 9-59 months in Guinea-Bissau, children received a measles vaccination (intervention) or a health check-up (control). One month to 2 months later, we visited a subgroup of children to ask mothers/guardians about outpatient consultations since enrollment. In log-binomial models, we estimated the relative risk (RR) of nonaccidental outpatient consultations.

Results: Among 8319 children (4437 intervention/3882 control), 652 nonaccidental outpatient consultations occurred (322 intervention/330 control). The measles vaccination campaign tended to reduce nonaccidental outpatient consultations by 16% (RR, 0.84 [95% confidence interval {CI}, .65-1.11]), especially if caused by respiratory symptoms (RR, 0.68 [95% CI, .42-1.11]). The reduction tended to be larger in children who prior to trial enrollment had a pentavalent vaccination (diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b) as the most recent vaccination (RR, 0.61 [95% CI, .42-.89]) than in children who prior to trial enrollment had a routine measles vaccination as the most recent vaccination (RR, 0.93 [95% CI, .68-1.26]) (P = .04 for interaction).

Conclusions: In the short term, a measles vaccination campaign seems not to increase nonaccidental outpatient consultations but may reduce them.

Clinical Trials Registration: NCT03460002.
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http://dx.doi.org/10.1093/jpids/piaa091DOI Listing
November 2020

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

Cell Rep Med 2020 Aug 5;1(5):100073. Epub 2020 Aug 5.

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.xcrm.2020.100073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405881PMC
August 2020

The COVID-19 pandemic: diverse contexts; different epidemics-how and why?

BMJ Glob Health 2020 07;5(7)

School of Public Health, The University of Queensland, Brisbane, Queensland, Australia.

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.
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http://dx.doi.org/10.1136/bmjgh-2020-003098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392634PMC
July 2020

Vaccinology: time to change the paradigm?

Lancet Infect Dis 2020 10 6;20(10):e274-e283. Epub 2020 Jul 6.

Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; Bandim Health Project, Open Patient data Explorative Network, Institute of Clinical Research, Odense University Hospital, Odense, Denmark.

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.
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http://dx.doi.org/10.1016/S1473-3099(19)30742-XDOI Listing
October 2020

Penta is associated with an increased female-male mortality ratio: cohort study from Bangladesh.

Hum Vaccin Immunother 2021 Jan 23;17(1):197-204. Epub 2020 Jun 23.

Former Deputy Executive Director, icddr,b , Dhaka, Bangladesh.

Diphtheria-tetanus-pertussis (DTP) vaccine may be associated with excess female deaths. There are few studies of possible nonspecific effects of the DTP-containing vaccine Penta (DTP-hepatitis B- influenzae type . We therefore investigated whether Penta vaccinations were associated with excess female deaths in rural Bangladesh. Between June 29, 2011 and April 20, 2016, we examined the mortality rates of 7644 children followed between 6 weeks and 9 months of age. We analyzed mortality using crude mortality rate ratio (MRR) and age-adjusted MRR (aMRR) from a Cox proportional hazards model. Mortality was analyzed according to sex, number of doses of Penta, and the order in which BCG and Penta were administered. During follow-up, 43 children died. For children who were only BCG vaccinated (BCG-only), the adjusted F/M MRR was 0.47 (0.09-2.48). However, among children who had Penta as their most recent vaccination, the adjusted F/M MRR was 9.91 (1.16-84.44). Hence, the adjusted F/M MRR differed significantly for BCG-only and for Penta as the most recent administered vaccination. Although the mortality rate was low in rural Bangladesh, there was a marked difference between adjusted F/M MRR's for children vaccinated with BCG-only compared with children where Penta was the most recent administered vaccination. Although usually ascribed to differential treatment and access to care, DTP-containing vaccines may be part of the explanation for the excessive female mortality reported in some regions.
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http://dx.doi.org/10.1080/21645515.2020.1763084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872037PMC
January 2021

Can existing live vaccines prevent COVID-19?

Science 2020 06;368(6496):1187-1188

Global Virus Network, Baltimore, MD, USA.

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http://dx.doi.org/10.1126/science.abc4262DOI Listing
June 2020

The non-specific and sex-differential effects of vaccines.

Nat Rev Immunol 2020 08 27;20(8):464-470. Epub 2020 May 27.

Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

The textbook view of vaccination is that it functions to induce immune memory of the specific pathogen components of the vaccine, leading to a quantitatively and qualitatively better response if the host is exposed to infection with the same pathogen. However, evidence accumulated over the past few decades increasingly suggests that vaccines can also have non-specific effects on unrelated infections and diseases, with important implications for childhood mortality particularly in low-income settings. Furthermore, many of these non-specific effects, as well as the pathogen-specific effects, of vaccines show differences between the sexes. Here, members of the Optimmunize consortium discuss the evidence for and potential mechanisms of non-specific and sex-differential effects of vaccines, as well as their potential policy implications. Given that the non-specific effects of some vaccines are now being tested for their ability to protect against COVID-19, the authors also comment on the broader implications of these trials.
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http://dx.doi.org/10.1038/s41577-020-0338-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252419PMC
August 2020

Complete and on-time routine childhood immunisation: determinants and association with severe morbidity in urban informal settlements, Nairobi, Kenya.

Ann Hum Biol 2020 Mar;47(2):132-141

Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.

Completion of the full series of childhood vaccines on-time is crucial to ensuring greater protection against vaccine-preventable diseases. To examine determinants of complete and on-time vaccination and evaluate the relationship between vaccination patterns and severe morbidity outcomes. Vaccination information from infants in Nairobi Urban Health and Demographic Surveillance System was used to evaluate full and on-time vaccination coverage of routine immunisation. Logistic regression was used to identify determinants of full and on-time vaccination coverage. Cox regression model was used to evaluate the relationship between vaccination status and subsequent severe morbidity. A shared frailty cox model was fitted to account for the heterogeneity in hospitalisation episodes. Maternal age, post-natal care, parity, ethnicity, and residence place were identified as determinants of vaccination completion. Institutional deliveries and residence place were identified as the determinants of on-time vaccination. A significant 58% (confidence interval [CI]: 15-79%) ( = .017) lower mortality was observed among fully immunised children compared with not fully immunised. Lower mortality was observed among on-time immunised children, 64% (CI: 20-84%) compared to those with delays. Improving vaccination timeliness and completion schedule is critical for protection against vaccine preventable diseases and may potentially provide protection beyond these targets.
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http://dx.doi.org/10.1080/03014460.2020.1725121DOI Listing
March 2020

BCG vaccination-induced emergency granulopoiesis provides rapid protection from neonatal sepsis.

Sci Transl Med 2020 05;12(542)

Department of Experimental Medicine, University of British Columbia, 2775 Laurel Street, 10th Floor, Room 10117, Vancouver, BC V5Z 1M9, Canada.

Death from sepsis in the neonatal period remains a serious threat for millions. Within 3 days of administration, bacille Calmette-Guérin (BCG) vaccination can reduce mortality from neonatal sepsis in human newborns, but the underlying mechanism for this rapid protection is unknown. We found that BCG was also protective in a mouse model of neonatal polymicrobial sepsis, where it induced granulocyte colony-stimulating factor (G-CSF) within hours of administration. This was necessary and sufficient to drive emergency granulopoiesis (EG), resulting in a marked increase in neutrophils. This increase in neutrophils was directly and quantitatively responsible for protection from sepsis. Rapid induction of EG after BCG administration also occurred in three independent cohorts of human neonates.
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http://dx.doi.org/10.1126/scitranslmed.aax4517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008103PMC
May 2020

Seasonal variation in the non-specific effects of BCG vaccination on neonatal mortality: three randomised controlled trials in Guinea-Bissau.

BMJ Glob Health 2020 5;5(3):e001873. Epub 2020 Mar 5.

Bandim Health Project, University of Southern Denmark, Copenhagen, Denmark.

The BCG vaccine protects non-specifically against other diseases than tuberculosis. Three randomised controlled trials of early BCG in Guinea-Bissau found a 38% reduction in all-cause neonatal mortality. Little is known about the underlying mechanisms. In Guinea-Bissau, prevalent infectious diseases display distinct seasonality. Revisiting the three trials (>6500 infants) comparing early BCG versus no early BCG in low weight infants on all-cause neonatal mortality over 12 consecutive years, we explored the seasonal variation in BCG's effect on mortality. In a subgroup of participants, adaptive and innate cytokine responses were measured 4 weeks after randomisation. Consistently over the course of the three trials and 12 years, the effect of BCG on all-cause neonatal mortality was particularly beneficial when administered in November to January, coincident with peaking malaria infections. During these months, BCG was also associated with stronger proinflammatory responses to heterologous challenge. Recent studies have suggested a protective effect of BCG against malaria. BCG may also ameliorate immune-compromising fatal effects of placental malaria in the newborn.
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http://dx.doi.org/10.1136/bmjgh-2019-001873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059430PMC
March 2020

Out-of-sequence vaccinations with measles vaccine and diphtheria-tetanus-pertussis vaccine. A re-analysis of demographic surveillance data from rural Bangladesh.

Clin Infect Dis 2020 Mar 18. Epub 2020 Mar 18.

International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.

Background: Due to delays in vaccinations, diphtheria-tetanus-whole-cell-pertussis (DTP) is often given with or after measles vaccine (MV) - out of sequence. We reanalysed data from Matlab, Bangladesh, to examine how administration of MV and DTP out-of-sequence was associated with child survival.

Methods: 36,650 children born between 1986 and 1999 were followed with registration of vaccinations and survival. Controlling for background factors using Cox proportional hazards models, survival was analysed between 9 and 24 months of age. We measured the mortality rate ratio (MRR) to compare vaccination groups. Oral polio vaccine (OPV) campaigns, which started in 1995, reduced the mortality rate and reduced the difference between vaccination groups. In the main analysis, we therefore censored for OPV campaigns; there were 151 non-accidents deaths before the OPV campaigns.

Results: Compared with MV administered alone (MV-only), DTP administered with or after MV had MRR 2.20 (1.31-3.70), and DTP-only had MRR 1.78 (1.01-3.11). Compared with MV-only, DTP administered with MV had a female-male MRR 0.56 (0.13-2.38), significantly different to DTP administered after MV which had MRR 14.83 (1.88-117.1), test of interaction p=0.011. Compared with having DTP (no MV) as most recent vaccination, MV-only had a non-accident MRR of 0.56 (0.32-0.99).

Conclusion: The negative effects of non-live DTP with or after live MV are not explained merely by selection bias. These observations support a live-vaccine-last policy where DTP should not be given with or after MV.
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http://dx.doi.org/10.1093/cid/ciaa291DOI Listing
March 2020

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

Front Pediatr 2020 7;8:20. Epub 2020 Feb 7.

Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau.

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. 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). 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). 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.
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http://dx.doi.org/10.3389/fped.2020.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020693PMC
February 2020

Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study.

BMJ Open 2020 02 28;10(2):e035595. Epub 2020 Feb 28.

Bandim Health Project, Bissau, Guinea-Bissau.

Objectives: To assess the association between neonatal BCG vaccination and mortality between 28 days and 3 years of age among tuberculosis (TB)-exposed and TB-unexposed children.

Design: Prospective cohort study.

Setting: Bandim Health Project runs an urban Health and Demographic Surveillance site in Guinea-Bissau with registration of mortality, vaccination status and TB cases.

Participants: Children entered the analysis when their vaccination card was inspected after 28 days of age and remained under surveillance to 3 years of age. Children residing in the same house as a TB case were classified as TB-exposed from 3 months prior to case registration to the end of follow-up.

Methods: Using Cox-proportional hazards models with age as underlying time scale, we compared mortality of children with and without neonatal BCG between October 2003 and September 2017.

Main Outcome Measure: HR for neonatal BCG compared with no neonatal BCG by TB-exposure status.

Results: Among the 39 421 children who entered the analyses, 3022 (8%) had observation time as TB-exposed. In total, 84% of children received neonatal BCG. Children with neonatal BCG had lower mortality both in TB-exposed (adjusted HR: 0.57 (0.26 to 1.27)) and in TB-unexposed children (HR: 0.57 (95% CI 0.47 to 0.69)) than children without neonatal BCG. Children exposed to TB had higher mortality than TB-unexposed children if they had not received neonatal BCG.

Conclusion: Neonatal BCG vaccination was associated with lower mortality among both TB-exposed and TB-unexposed children, consistent with neonatal BCG vaccination having beneficial non-specific effects. Interventions to increase timely BCG vaccination are urgently warranted.
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http://dx.doi.org/10.1136/bmjopen-2019-035595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050365PMC
February 2020

Differential effects of BCG vaccine on immune responses induced by vi polysaccharide typhoid fever vaccination: an explorative randomized trial.

Eur J Clin Microbiol Infect Dis 2020 Jun 17;39(6):1177-1184. Epub 2020 Feb 17.

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6526, GA, Nijmegen, The Netherlands.

The Vi polysaccharide typhoid fever vaccine (TFV) provides incomplete protection against typhoid fever. BCG, the vaccine against tuberculosis, can potentiate immune responses to other vaccines through induction of trained innate immunity and heterologous adaptive immunity. We performed an explorative, randomized, noncontrolled open trial to investigate whether BCG vaccination increases humoral and cellular response to TFV and whether BCG and TFV modulate nonspecific immune responses. Thirty volunteers were randomized to receive either TFV alone or BCG followed by TFV after 2 weeks. Ex vivo leukocyte responses and anti-Vi IgG antibody titers were measured 2 weeks and 3 months after TFV. BCG administration prior to TFV vaccination did not increase specific humoral or cellular immune responses to Salmonella typhi. TFV vaccination decreased pro-inflammatory responses to non-related stimuli. This effect was counteracted by prior BCG administration, which also led to decreased IL-10 and increased IL-22 responses to non-related stimuli. In an in vitro model of trained immunity TFV led to immunotolerance, which was partially reversed by BCG-induced trained immunity. BCG does not modulate adaptive immune responses to TFV but partially prevents inhibition of innate immune responses induced by TFV. Nonspecific effects of vaccines to unrelated microbial stimuli must be considered in the evaluation of their biological effects (ClinicalTrials.gov NCT02175420).
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http://dx.doi.org/10.1007/s10096-020-03813-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225183PMC
June 2020

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

Vaccine 2020 03 13;38(11):2487-2494. Epub 2020 Feb 13.

Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau; Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen S, Denmark; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense C, Denmark. Electronic address:

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.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.096DOI Listing
March 2020

WHO's rollout of malaria vaccine in Africa: can safety questions be answered after only 24 months?

BMJ 2020 01 24;368:l6920. Epub 2020 Jan 24.

Bandim Health Project, INDEPTH Network, Apartado 861, Bissau, Guinea-Bissau

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http://dx.doi.org/10.1136/bmj.l6920DOI Listing
January 2020

BCG vaccination is associated with reduced malaria prevalence in children under the age of 5 years in sub-Saharan Africa.

BMJ Glob Health 2019 14;4(6):e001862. Epub 2019 Nov 14.

Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Introduction: Malaria continues to be a major cause of morbidity and mortality in sub-Saharan Africa (SSA) without effective interventions. Bacillus Calmette-Guérin (BCG) vaccine possesses protective non-specific effects, which extend beyond protection against tuberculosis. This study explores whether BCG is associated with protection against malaria in children under the age of 5 years in SSA.

Methods: We used data from the Demographic Health Survey programme, including 34 206 children from 13 SSA countries. BCG status was taken from vaccination cards when present; if not, mother's recall was used. Presence of malaria was defined as a positive rapid diagnostic test. Maternally reported presence or absence of fever in the previous 2 weeks defined symptomatic status. Multilevel logistic regression was used to account for the two-stage cluster sampling method.

Results: Of the 34 206 children, 12 325 (36.0%) children were malaria positive and 29 766 (87.0%) were BCG vaccinated. After correction for relevant child, maternal and household factors, BCG vaccination was associated with a lower malaria prevalence (adjusted OR (aOR)=0.94, 95% CI 0.90 to 0.98), especially among children of whom BCG information was retrieved from a vaccination card (aOR=0.88, 95% CI 0.82 to 0.94). Restricting the analysis to children from regions with suboptimal BCG coverage increased the association (aOR=0.81, 95% CI 0.73 to 0.89). We observed an increasingly beneficial association with each month of age of the child (aOR=0.996, 95% CI 0.993 to 0.999). BCG associations were similar for asymptomatic (aOR=0.86, 95% CI 0.81 to 0.92) and symptomatic (aOR=0.89, 95% CI 0.78 to 1.01) malaria.

Conclusions: BCG vaccination is associated with protection against malaria. This protection is highest in regions with suboptimal BCG coverage. These results indicate a possible role for timely BCG vaccination in the protection of malaria and its elimination by reducing the transmission reservoir. If confirmed in further research, our findings have substantial implications for global efforts to reduce malaria burden.
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http://dx.doi.org/10.1136/bmjgh-2019-001862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861070PMC
November 2019