Publications by authors named "Peter Aaby"

409 Publications

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

Open Forum Infect Dis 2022 Aug 27;9(8):ofac340. Epub 2022 Jul 27.

Odense Patient Data Explorative Network, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

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.
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http://dx.doi.org/10.1093/ofid/ofac340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348612PMC
August 2022

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.

EClinicalMedicine 2022 Jul 27;49:101467. Epub 2022 May 27.

Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau.

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[n=4,397; n=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: n=90; n=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n=21; n=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n=10/2,801; n=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: n=27/1,602; n=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: n=51/3,132; n=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.
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http://dx.doi.org/10.1016/j.eclinm.2022.101467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156892PMC
July 2022

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

Int J Epidemiol 2022 May 28. Epub 2022 May 28.

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

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.
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http://dx.doi.org/10.1093/ije/dyac113DOI Listing
May 2022

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

Trials 2022 Apr 23;23(1):349. Epub 2022 Apr 23.

Bandim Health Project, Indepth Network, 1004, Bissau, 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.
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http://dx.doi.org/10.1186/s13063-022-06291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034539PMC
April 2022

Mortality risk among frail neonates might be associated with maternal BCG scar status: Observational study from Guinea-Bissau.

J Infect Dis 2022 Apr 13. Epub 2022 Apr 13.

Bandim Health Project, INDEPTH Network, postal code 8611004, Bissau, Guinea-Bissau.

Background: Maternal priming with Bacille Calmette-Guérin (BCG) has been associated with reduced offspring mortality. We investigated this association in a cohort of frail neonates.

Methods: We performed an observational study within a randomized BCG trial conducted at the Neonatal Intensive Care Unit (NICU) in Guinea-Bissau from 2015-2017. At NICU admission and following informed consent, the maternal scar status was evaluated by visual inspection before neonates were randomized 1:1 to receive BCG + Oral Polio Vaccine (OPV) immediately versus BCG + OPV at hospital discharge. Stratified by maternal scar status, we assessed overall in-hospital and post-discharge mortality up to 42 days of age in Cox Proportional Hazards models providing adjusted Mortality Rate Ratios (aMRRs).

Results: 62% (903/1451) of mothers had a BCG scar. During NICU admission, the mortality risk was 1.7% (15/903) for neonates born to mothers with a scar vs 3.3% (18/548) for those born to mothers with no scar, the maternal scar/no scar aMRR = 0.53 (0.26-1.05); the aMRR was 0.39 (0.13-1.05) for unvaccinated neonates and 0.70 (0.26-1.87) for vaccinated neonates.

Conclusion: This small study indicates that maternal BCG might be associated with reduced all-cause NICU mortality. If confirmed elsewhere, this finding would have substantial ramifications for global health.
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http://dx.doi.org/10.1093/infdis/jiac140DOI Listing
April 2022

The effect of a second dose of measles vaccine at 18 months of age on non-accidental deaths and hospital admissions in Guinea-Bissau: interim analysis of a randomized controlled trial.

Clin Infect Dis 2022 Feb 26. Epub 2022 Feb 26.

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

Background: The world is set on the eradication of measles. Continuation of measles vaccine (MV) after eradication could still reduce morbidity, since MV has so-called beneficial non-specific effects (NSEs). We evaluated the effect of a 'booster' dose of MV on overall severe morbidity.

Methods: We conducted a randomized controlled trial among children aged 17.5-48 months in Guinea-Bissau, where MV is recommended only at 9 months of age. At the time of this interim analysis, 3,164 children had been allocated 1:1 to a second dose of measles vaccine (MV2) at 18 months of age or no vaccine. Severe morbidity (a composite outcome of non-accidental 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 non-accidental 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%CI, 0.38-1.38)). At 12 months of follow-up the number needed to treat (NNT) to prevent one severe morbidity event was 137 children. After OPV campaigns, the estimated effect of MV2 was reduced to 9% (SMRR: 0.91 (0.46-1.81)).

Conclusion: MV2 may reduce non-measles 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.
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http://dx.doi.org/10.1093/cid/ciac155DOI Listing
February 2022

Measles in the European past: outbreak of severe measles in an isolated German village, 1861.

J Infect 2022 05 16;84(5):668-674. Epub 2022 Feb 16.

Medical Faculty, University of Tübingen, Germany.

Objectives: We examined measles mortality in the European past in an outbreak in an isolated German village, Hagelloch, in 1861.

Methods: Pfeilsticker's contemporary thesis was used to describe the measles case fatality ratio (CFR) and complications. Data on onset of prodromes and rash was used to determine index cases and secondary cases of measles within the household. The church register provided information on survival in 1862.

Results: The epidemic affected nearly all children under 14 years of age. The overall CFR was 6.4%(12/187), and 10%(7/70) for children under five years of age; 44% of children were secondary cases (82/187). Secondary cases had higher CFR than index cases (RR = 3.03 (95% CI: 0.91-10.07). Boys had higher CFR than girls (RR = 4.46 (1.03-19.22)). Boys infected by a girl had higher CFR than boys infected by other boys (RR = 6.30 (1.18-85.64)). Children who survived measles virus infection in 1861, did not have higher mortality in the following year compared with those who had not had measles in 1861 (RR = 0.24 (0.07-0.82)).

Conclusions: Severe measles in the European past had determinants similar to those observed more recently in low-income countries.

Brief Summary: The measles case fatality was 6% in rural Germany in 1861. Mortality was highest for boys infected in the household by a girl. There was no excess mortality after the acute phase of measles infection.
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http://dx.doi.org/10.1016/j.jinf.2022.02.010DOI Listing
May 2022

Does Influenza Vaccination during Pregnancy Have Effects on Non-Influenza Infectious Morbidity? A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Vaccines (Basel) 2021 Dec 8;9(12). Epub 2021 Dec 8.

Bandim Health Project, OPEN, Department of Clinical Research, Odense University Hospital/University of Southern Denmark, Studiestræde 6, 1455 Copenhagen, Denmark.

The recommendation to provide inactivated influenza vaccine (IIV) to pregnant women is based on observed protection against influenza-related morbidity in mother and infant. Non-live vaccines may have non-specific effects (NSEs), increasing the risk of non-targeted infections in females. We reviewed the evidence from available randomised controlled trials (RCTs) of IIV to pregnant women, to assess whether IIV may have NSEs. Four RCTs, all conducted in low- and middle-income settings, were identified. We extracted information on all-cause and infectious mortality and adverse events in women and their infants. We conducted meta-analyses providing risk ratios (RR). The meta-analysis for maternal all-cause mortality provided a RR of 1.48 (95% CI = 0.52-4.16). The estimates for miscarriage/stillbirth and infant all-cause mortality up to 6 months of age were 1.06 (0.78-1.44) and 1.11 (0.87-1.41), respectively. IIV was associated with a higher risk of non-influenza infectious adverse events, with meta-estimates of 2.01 (1.15-3.50) in women and 1.36 (1.12-1.67) in infants up to 6 months of age. Thus, following a pattern seen for other non-live vaccines, IIV was associated with a higher risk of non-influenza infectious adverse events. To ensure that scarce resources are used well, and no harm is inflicted, further RCTs are warranted.
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http://dx.doi.org/10.3390/vaccines9121452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707251PMC
December 2021

Maternal BCG primes for enhanced health benefits in the newborn.

J Infect 2022 03 24;84(3):321-328. Epub 2021 Dec 24.

Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau; Bandim Health Project, OPEN, Institute of Clinical Research, Uni. Southern Denmark and Odense University Hospital, Odense, Denmark; Danish Institute of Advanced Science, Uni. Southern Denmark, Odense, Denmark. Electronic address:

Objectives: Bacille Calmette-Guérin (BCG) vaccination lowers the risk of severe infection; we tested whether effects are modulated by maternal BCG in a large cohort of BCG-vaccinated newborns from Guinea-Bissau.

Methods: Maternal BCG scar status were inspected at enrolment in a BCG trial conducted from 2014 to 17 in Bissau, Guinea-Bissau. We tested associations with background factors for potential confounding; maternal age affected effect estimates >5% and accordingly, all analyses were adjusted for maternal age. Hospitalization data was collected prospectively and assessed in Cox-models providing adjusted Incidence Rate Ratios (aIRRs). In-hospital risk of death (case-fatality) risk was assessed using binomial regression providing adjusted Risk Ratios (aRRs).

Results: 60% (6,309/10,598) of mothers had a scar. The maternal-scar/no-scar admission aIRR was 0.96 (0.81-1.14) from 0 to 6 weeks and 1.12 (0.97-1.28) for 6 weeks-3 years. The 6-week in-hospital case-fatality infection aRR was 0.59 (0.34-1.05); 0.40 (0.17-0.91) for males and 0.86 (0.38-1.94) for females. Protection was especially evident against sepsis, the overall 6-week aRR=0.49 (0.26-0.91); no effect was observed for non-infectious deaths or after 6 weeks of age. Effects were similar across BCG strains and multivariate models adjusted for socioeconomic status did not affect estimates.

Conclusion: Among BCG-vaccinated newborns, there was a trend for fewer in-hospital deaths from infection associated with maternal BCG priming, especially for males. Providing BCG to adults without a vaccination scar might enhance their offspring's capacity to handle severe infections. Brief 40-word summary: Within a trial comparing BCG strains for their overall effects on morbidity and mortality in Guinea-Bissau, vertical priming with BCG (represented by the maternal BCG scar) was associated with beneficial sex-differential effects on offspring survival.
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http://dx.doi.org/10.1016/j.jinf.2021.12.028DOI Listing
March 2022

Oral Polio Vaccine Campaigns May Reduce the Risk of Death from Respiratory Infections.

Vaccines (Basel) 2021 Oct 4;9(10). Epub 2021 Oct 4.

International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Health System and Population Studies Division, Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka 1212, Bangladesh.

Oral polio vaccine (OPV) campaigns, but not other campaigns, have been associated with major reductions in child mortality. Studies have shown that OPV reduces the risk of respiratory infections. We analysed the causes of death at 0-2 years of age in Chakaria, a health and demographic surveillance Systems in Bangladesh, in the period 2012-2019 where 13 national campaigns with combinations of OPV ( = 4), vitamin A supplementation ( = 9), measles vaccine (MV) ( = 2), and albendazole ( = 2) were implemented. OPV-only campaigns reduced overall mortality by 30% (95% confidence interval: -10-56%). Deaths from respiratory infections were reduced by 62% (20-82%, = 0.01) in the post-neonatal period (1-35 months), whereas there was as slight increase of 19% (-37-127%, = 0.54) for deaths from other causes. There was no benefit of other types of campaigns. Hence, the hypothesis that OPV may have beneficial non-specific effects, protecting particularly against respiratory infections, was confirmed.
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http://dx.doi.org/10.3390/vaccines9101133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537441PMC
October 2021

100 years of Mycobacterium bovis bacille Calmette-Guérin.

Lancet Infect Dis 2022 01 7;22(1):e2-e12. Epub 2021 Sep 7.

Global TB Program, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.
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http://dx.doi.org/10.1016/S1473-3099(21)00403-5DOI Listing
January 2022

Disregarding the restrictive vial-opening policy for BCG vaccine in Guinea-Bissau: impact and cost-effectiveness for tuberculosis mortality and all-cause mortality in children aged 0-4 years.

BMJ Glob Health 2021 08;6(8)

TB Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, London, UK.

Objective: BCG vaccination is frequently delayed in low-income countries. Restrictive vial-opening policies, where a vial of BCG vaccine is not opened for few children, are a major reason for delay. During delays, children are unprotected against tuberculosis (TB) and deprived of non-specific effects of BCG. We assessed the potential effect and cost-effectiveness of disregarding the restrictive vial-opening policy, on TB and all-cause mortality, in children aged 0-4 years in Guinea-Bissau.

Methods: Using static mathematical models, we estimated the absolute and percentage change in TB and all-cause deaths, in children aged 0-4 years, between the current BCG vaccine restrictive-opening policy scenario, and a non-restrictive policy scenario where all children were vaccinated in the first health-facility contact. Incremental cost-effectiveness was estimated by integration of vaccine and treatment costs.

Findings: Disregarding the restrictive BCG vial-opening policy was estimated to reduce TB deaths by 11.0% (95% uncertainty range (UR):0.5%-28.8%), corresponding to 4 (UR:0-15) TB deaths averted per birth cohort in Guinea-Bissau, resulting in incremental cost-effectiveness of US$ 911 per discounted life-year gained (LYG) (UR:145-9142). For all-cause deaths, the estimated reduction was 8.1% (UR: 3.3%-12.7%) corresponding to 392 (UR:158-624) fewer all-cause deaths and an incremental cost-effectiveness of US$ 9 (UR:5-23) per discounted LYG.

Conclusions: Disregarding the restrictive BCG vial-opening policy was associated with reductions in TB deaths and all-cause deaths and low cost-effectiveness ratios. Our results suggest that it would be cost-effective to disregard the restrictive vial-opening policy. Other settings with similar practice are also likely to gain from disregarding this policy.
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http://dx.doi.org/10.1136/bmjgh-2021-006127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336130PMC
August 2021

The genomic epidemiology of multi-drug resistant invasive non-typhoidal in selected sub-Saharan African countries.

BMJ Glob Health 2021 08;6(8)

University of Antananarivo, Antananarivo, Madagascar.

Background: Invasive non-typhoidal (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. We aimed to provide a better understanding of the genetic characteristics and transmission patterns associated with multi-drug resistant (MDR) iNTS serovars across the continent.

Methods: A total of 166 iNTS isolates collected from a multi-centre surveillance in 10 African countries (2010-2014) and a fever study in Ghana (2007-2009) were genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes-genotypes. Phylogenetic analyses were conducted in the context of the existing genomic frameworks for various iNTS serovars. Population-based incidence of MDR-iNTS disease was estimated in each study site.

Results: Typhimurium sequence-type (ST) 313 and Enteritidis ST11 were predominant, and both exhibited high frequencies of MDR; Dublin ST10 was identified in West Africa only. Mutations in the gene (fluoroquinolone resistance) were identified in . Enteritidis and . Typhimurium in Ghana; an ST313 isolate carrying was found in Kenya. International transmission of MDR ST313 (lineage II) and MDR ST11 (West African clade) was observed between Ghana and neighbouring West African countries. The incidence of MDR-iNTS disease exceeded 100/100 000 person-years-of-observation in children aged <5 years in several West African countries.

Conclusions: We identified the circulation of multiple MDR iNTS serovar STs in the sampled sub-Saharan African countries. Investment in the development and deployment of iNTS vaccines coupled with intensified antimicrobial resistance surveillance are essential to limit the impact of these pathogens in Africa.
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http://dx.doi.org/10.1136/bmjgh-2021-005659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330565PMC
August 2021

Neonatal Bacille Calmette-Guérin vaccination and tuberculin skin test reactions at 2- and 6-months: Effects on mortality up to 1 year of age.

Vaccine 2021 12 3;39(50):7286-7294. Epub 2021 Jul 3.

Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau; Bandim Health Project, OPEN, Department of Clinical Research, Uni. Southern Denmark and Odense University Hospital, Odense, Denmark; Danish Institute of Advanced Science, Uni. Southern Denmark, Odense, Denmark.

Background: In randomized trials, Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced all-cause mortality. BCG-induced Tuberculin Skin Test (TST) reactions have also been associated with reduced all-cause mortality. We aimed to assess the association between TST responses and subsequent mortality in three birth cohorts and conducted a meta-analysis of existing studies.

Methods: Observational study within three Guinea-Bissau BCG trial birth cohorts (conducted 2002-04, 2009-2013 and 2014-18) that encompassed children who were BCG-vaccinated within 28 days with TSTs performed at 2- (n = 1389) and 6-months (n = 2635) of age. We evaluated TST reaction determinants by binomial regression and assessed the association between TSTs > 1 mm (reactors) vs. ≤ 1 mm (non-reactors) and subsequent mortality risk up to age 12 months in Cox-models providing Mortality Rate Ratios (MRRs). We searched PubMed for studies to calculate meta-estimates of the association between TST reactivity by age 2- and 6-months and all-cause mortality.

Results: Large post-vaccination wheal size was associated with 6-month TST positivity and so was receiving BCG-Denmark or BCG-Japan, compared with BCG-Russia. By age 2 months, 22% (302/1389) of infants were TST reactors with a 2-12-month mortality risk of 1.7% (5/302) vs. 3.3% (36/1087) for non-reactors, the corresponding reactor/non-reactor MRR = 0.49 (0.19-1.26). By age 6 months, 44% (1149/2635) of infants were reactors and the 6-12-month mortality risk was 0.4% (4/1149) vs. 0.6% (9/1486) for non-reactors, the MRR = 0.87 (0.27-2.86). The literature search provided 3 studies. The meta-analysis revealed a uniform pattern of reduced mortality associated with TST reactivity, a TST response by 2 months being associated with an MRR of 0.59 (0.39-0.90); for 6-month TST responses the MRR was 0.65 (0.43-1.00).

Conclusion: Among BCG-vaccinated infants, TST reactions were associated with markedly reduced mortality. Improved vaccination technique and using certain BCG strains could lead to a higher TST reaction prevalence, which would enhance BCG's beneficial non-specific effects.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.077DOI Listing
December 2021

Retesting the hypothesis that early Diphtheria-Tetanus-Pertussis vaccination increases female mortality: An observational study within a randomised trial.

Vaccine 2022 03 30;40(11):1606-1616. Epub 2021 Jun 30.

Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau; Bandim Health Project, Institute of Clinical Research, Uni. Southern Denmark and Odense University Hospital, Odense, Denmark; Danish Institute of Advanced Science, Uni. Southern Denmark, Odense, Denmark. Electronic address:

Background: There are worrying indications that diphtheria-tetanus-pertussis (DTP) vaccine has negative non-specific effects for females. We previously found, in a trial of early-Bacillus Calmette-Guérin (BCG) to low weight (LW) neonates, that receiving early-DTP (before 2 months of age), was associated with increased female mortality compared with no-DTP/delayed-DTP. Within a subsequent LW trial, we aimed to retest this observation.

Methods: Between 2010 and 2014, in Guinea-Bissau, 2,398 infants were randomised 1:1 to early-BCG (intervention) or delayed-BCG (standard practice for LW neonates) and visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. DTP is recommended at 6 weeks of age. We examined the effect of having "early-DTP" versus "no-DTP" at the time of the 2-month visit on all-cause mortality between the 2- and 6-month visits in Cox models stratified by sex and adjusted for BCG-group and 2-month-weight-for-age (z-scores) providing adjusted mortality rate ratios (aMRRs). We analysed to which extent conditions varied between the present and the previous LW trials and how that might have affected the overall result of comparing the early-DTP and the no-DTP groups.

Results: At the time of the 2-month visit, 75% (1,795/2,398) had received DTP. Those vaccinated had better anthropometric indices than no-DTP infants at birth and by 2 months of age. Between the 2- and 6-month visits, 29 deaths occurred. The early-DTP/no-DTP aMRR was 1.09 (95% CI: 0.44-2.69); 1.19 (0.45-3.15) for females and 0.77 (0.14-4.19) for males. Compared to the previous study, the present study cohort had 56% (30-72%) lower overall mortality, fewer no-DTP infants, higher BCG vaccination coverage and several more oral polio vaccine campaigns.

Conclusion: We did not find that early-DTP was associated with increased female mortality as found in a previous study; differences in results may partly be due to a decline in overall mortality and changes in vaccination practices.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.008DOI Listing
March 2022

The introduction of BCG vaccination to neonates in Northern Sweden, 1927-31: Re-analysis of historical data to understand the lower mortality among BCG-vaccinated children.

Vaccine 2022 03 13;40(11):1516-1524. Epub 2021 Jun 13.

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

Background: Following the introduction of oral Bacille Calmette-Guérin (BCG) a century ago, Albert Calmette suggested that BCG both provided protection against death from tuberculosis (TB) and other causes. The findings were not pursued. Today, there is considerable evidence that intradermal BCG have beneficial non-specific effects (NSEs). We re-analyzed data from BCG's introduction 1927-1931 in Sweden hypothesizing that BCG reduced infectious deaths.

Methods: In three papers published by Dr Carl Näslund, the progress of oral neonatal BCG rollout provided free-of-charge and the effects on child mortality in the highly TB-prevalent region Norrbotten was sequentially updated. We analyzed cause-specific post-neonatal mortality by vaccination status excluding deaths from congenital conditions. Due to apparent differences in effects during study years, effects were assessed overall and separately in two periods (1927-1929, 1930-1931).

Results: According to Näslund, TB households were slightly more likely to accept vaccination; fewer newborns that were sick or had congenital problems were vaccinated. BCG coverage was 28.3% (5659/20,012); 8.7% (1746/20,012) died. The BCG/unvaccinated Risk Ratio (RR) of post-neonatal childhood death was 0.53 (0.45-0.62). BCG was associated with 80% (49-92%) reduced mortality from TB. From 1927 to 29, BCG appeared to protect strongly against deaths from all diseases, including the non-infectious, RR = 0.09 (0.02-0.36), presumably reflecting selection bias. From 1930 to 1931, there was no protection against non-infectious deaths, RR = 0.92 (0.49-1.70) indicating less bias (p = 0.004 for same effect). During 1930-1931, BCG was associated with reductions in non-TB infectious deaths (RR = 0.75 (0.58-0.97)); 2/3 were caused by respiratory infections, against which the BCG/unvaccinated RR was 0.61 (0.43-0.84). Other causes of death were less frequent and provided no clear pattern, except that BCG was associated with more meningitis deaths, RR = 6.85 (2.20-21.4).

Conclusion: Healthy vaccinee bias, particularly in 1927-1929, resulted in strongly beneficial overall BCG effects. However, the 1930-1931 data provided some support that BCG both protected against TB deaths and deaths from respiratory infections.
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March 2022

National immunisation campaigns with oral polio vaccine may reduce all-cause mortality: Analysis of 2004-2019 demographic surveillance data in rural Bangladesh.

EClinicalMedicine 2021 Jun 24;36:100886. Epub 2021 May 24.

Health System and Population Studies Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka, BD 1212, Bangladesh.

Background: West African studies have suggested that national immunisation campaigns with oral polio vaccine (C-OPV) may non-specifically reduce all-cause child mortality rate by 15-25%. We investigated whether C-OPVs had similar non-specific effects in rural Bangladesh from 2004 to 2019.

Methods: Chakaria, is a health and demographic surveillance system (HDSS) in Southern Bangladesh. From 2004-2011 the HDSS covered a random sample of households; from 2012 to 2019 it covered a random sample of villages. Using Cox proportional hazards models, we calculated hazard ratios (HR) comparing mortality for children under 3 years of age after C-OPV versus before C-OPV to assess the effect of receiving a C-OPV. We allowed for different baseline hazard function in the two periods (2004-2011, 2012-2019), with separate models for each period.

Findings: There were 768 deaths (2.1%) amongst 36,176 children. The HR after C-OPV was 0.69 (95% confidence interval: 0.52-0.90). National campaigns providing vitamin A or measles vaccine did not have similar effects. Each additional dose of C-OPV was associated with a reduction in the mortality rate by 6% (-2 to 13%). The number needed to treat with C-OPV to save one life between 0 and 35 months of age was 88 (81-96).

Interpretation: This is the fourth study to show that C-OPV has beneficial non-specific effects on child survival. All studies have shown a beneficial effect of C-OPV on child health. Stopping OPV as planned after polio eradication without any mitigation plan could have detrimental effects for overall child health in low-income countries.

Funding: The Chakaria HDSS was funded by international sponsors. No sponsor had any influence on the preparation of the article.
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http://dx.doi.org/10.1016/j.eclinm.2021.100886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144662PMC
June 2021

Chronic political instability and HIV/AIDS response in Guinea-Bissau: a qualitative study.

Infect Dis Poverty 2021 May 11;10(1):68. Epub 2021 May 11.

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

Background: The Republic of Guinea-Bissau in West Africa has a high HIV/AIDS disease burden and has experienced political instability in the recent past. Our study used qualitative methods to better understand key stakeholders' perceptions of the effects of chronic political instability on the HIV/AIDS response in Guinea-Bissau from 2000 to 2015 and lessons learned for overcoming them.

Methods: Seventeen semi-structured in-depth key informant interviews were conducted in Bissau, Guinea-Bissau in 2018. Interviews were recorded and transcribed verbatim, coded thematically, and analyzed inductively.

Results: Four themes emerged: (1) constantly start over; (2) the effects of instability rippling from central level throughout the health pyramid; (3) vulnerable populations becoming more vulnerable; and (4) coping mechanisms.

Conclusions: Stakeholders from government, civil society, and donor organizations have recognized instability's effects as a barrier to mounting an effective local response to HIV/AIDS in Guinea-Bissau. To mitigate the effects of the country's political instability on the health sector, concerted efforts should be made to strengthen the capacities of health officials within the Ministry of Health to shield them from the effects of the country's political instability.
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http://dx.doi.org/10.1186/s40249-021-00854-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112002PMC
May 2021

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

BMJ Glob Health 2021 05;6(5)

Bandim Health Project, INDEPTH Network, Bissau, 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.
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http://dx.doi.org/10.1136/bmjgh-2020-004328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098964PMC
May 2021

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

J Infect Dis 2021 12;224(11):1935-1944

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

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.
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http://dx.doi.org/10.1093/infdis/jiab220DOI Listing
December 2021

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

Vaccine 2022 03 9;40(11):1665-1673. 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
March 2022

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 07 17;21(7):897-898. 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
July 2021

Letter to the Editor.

Risk Anal 2021 02;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 Aug 2;49(4):631-643. 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
August 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 01 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. Studies of DTP administered before and after measles vaccine.

J Infect Dis 2021 06;223(11):1984-1991

Research Centre for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark.

Background: The third dose of diphtheria-tetanus-pertussis vaccine (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 (95% confidence interval [CI], .88-1.57) after DTP1 and increased to 1.66 (95% CI, 1.32-2.09) after DTP3. Following receipt of MV, the F/M MRR declined to 0.63 (95% CI, .42-.96). In 11 studies the F/M MRR increased to 1.73 (95% CI, 1.33-2.27) when DTP-containing vaccine was administered after MV.

Conclusions: F/M MRR increased with increasing doses of DTP. After MV, girls had lower mortality than boys. With DTP after MV, mortality increased again for girls relative to boys. No bias can explain these changes in F/M MRR. DTP does not improve male survival substantially in situations with herd immunity to pertussis and 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
June 2021

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 04 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
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