Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau.

BACKGROUND: The beneficial effects of Bacillus Calmette-Guérin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries. METHODS: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1ß, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327). FINDINGS: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53-9·96]) and increased release of the pro-inflammatory innate cytokines IL-1ß, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98-2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline. INTERPRETATION: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.

Evaluating the effect of BCG vaccination for non-specific protection from infection in senior citizens during the COVID-19 pandemic: A randomised clinical trial.

OBJECTIVES: The Bacillus Calmette-Guérin (BCG) vaccine may induce non-specific protection against unrelated infections. We tested the effect of BCG on the risk of infections among Danish senior citizens. METHODS: Single-blinded randomised controlled trial including 1676 volunteers >65 years. Participants were randomised 1:1 to BCG or placebo and followed for 12 months. The primary outcome was acute infection leading to medical contact. Secondary outcomes were verified SARS-CoV-2 infection, self-reported respiratory symptoms, and all-cause hospitalisation. Data was analysed using Cox regression models, estimating hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The incidence of acute infection was 52.1 and 58.2 per 100 person-years for BCG and placebo, respectively (HR=0.89, 95% CI=0.78-1.02). There was no effect of BCG on SARS-CoV-2 infections (0.97, 0.75-1.26) or all-cause hospitalisations (1.10, 0.80-1.50), but BCG was associated with more respiratory symptoms (1.21, 1.10-1.33). BCG reduced the incidence of acute infections among participants <75 years (0.82, 0.70-0.95) but not among those >75 years (1.14, 0.88-1.47). In participants, who were COVID-19 vaccinated before enrolment, BCG was associated with lower incidence of acute infections (0.65, 0.50-0.85). CONCLUSION: BCG did not reduce risk of acute infections among Danish seniors overall, but the effect was modified by age group and COVID-19 vaccination. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04542330) and EU Clinical Trials Register (EudraCT number 2020-003904-15). Full trial protocol is available at ClinicalTrials.gov. SUMMARY: In a randomised clinical trial among Danish senior citizens, BCG vaccination did not reduce the overall risk of acute infection, but BCG was associated with reduced risk in participants <75 years and participants who received COVID-19 vaccines prior to enrolment.

Influenza vaccine effectiveness in immunocompromised patients with cancer: A Danish nationwide register-based cohort study.

BACKGROUND: Influenza vaccination is free of charge for Danish citizens with acquired immunodeficiency but recommendations do not specifically target patients with cancer. This study investigated whether influenza vaccination reduces the main outcome of overall mortality and the secondary outcomes of influenza requiring treatment, pneumonia, myocardial infarction, stroke, heart failure, and venous thromboembolism in patients with cancer. METHODS: This was a register-based nationwide cohort study. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for overall mortality and secondary outcomes were estimated using Cox proportional hazards models. Analyses were conducted separately for four subgroups: patients aged <65 years with solid tumors, patients aged ≥65 years with solid tumors, patients aged <65 years with hematological cancer, and patients aged ≥65 years with hematological cancer. RESULTS: A total of 53,249 adult patients with solid tumors who received chemotherapy and 22,182 adult patients with hematological cancer were followed for up to five influenza seasons in the study period of 2007-2018. In the main analysis covering December-March, influenza vaccination was associated with reduced overall mortality in all four subgroups. The reduction was most pronounced in patients with hematological cancer aged <65 years (aHR, 0.66; 95% CI, 0.51-0.87) and smallest in patients with solid tumors aged <65 years (aHR, 0.91; 95% CI, 0.84-0.99). In sensitivity analyses covering January-March, the aHR was 0.87 (95% CI, 0.65-1.16) in patients with hematological cancer aged <65 years and 1.01 (95% CI, 0.92-1.10) in patients with solid tumors aged <65 years. Results for the secondary outcomes were inconclusive. CONCLUSIONS: The results of this study cannot reject that influenza vaccination reduces overall mortality in immunocompromised patients with cancer. The results must be interpreted with caution because of potential unmeasured confounding, which can result in the overestimation of influenza vaccine effectiveness.

The mark of success: The role of vaccine-induced skin scar formation for BCG and smallpox vaccine-associated clinical benefits.

Skin scar formation following Bacille Calmette-Guérin (BCG) or smallpox (Vaccinia) vaccination is an established marker of successful vaccination and 'vaccine take'. Potent pathogen-specific (tuberculosis; smallpox) and pathogen-agnostic (protection from diseases unrelated to the intentionally targeted pathogen) effects of BCG and smallpox vaccines hold significant translational potential. Yet despite their use for centuries, how scar formation occurs and how local skin-based events relate to systemic effects that allow these two vaccines to deliver powerful health promoting effects has not yet been determined. We review here what is known about the events occurring in the skin and place this knowledge in the context of the overall impact of these two vaccines on human health with a particular focus on maternal-child health.

Maternal Bacille Calmette-Guérin Scars and Mortality Risk for Male and Female Newborns: Observational Study From Guinea-Bissau.

BACKGROUND: Maternal priming with bacille Calmette-Guérin (BCG) has been associated with reduced mortality in male offspring. We investigated this association in a cohort of healthy BCG-vaccinated neonates. METHODS: This observational study within a randomized controlled trial comparing different BCG strains was conducted in Guinea-Bissau from 2017 to 2020. As part of trial inclusion procedures, on the day of discharge from the maternity ward, maternal BCG scar status was evaluated by visual inspection, followed by offspring BCG and polio vaccination. Through mortality data collected at telephone interviews at 6 weeks and 6 months of age, we assessed all-cause mortality risk in Cox proportional hazards models adjusted for maternal schooling and BCG strain, providing adjusted mortality rate ratios (aMRRs). RESULTS: In total, 64% (11 070/17 275) of mothers had a BCG scar, which was not associated with admission risk, admission severity, or all-cause mortality for females and the overall sample. By 6 months of age, the mortality rate (MR) was 4.1 (200 deaths/4919 person-years) for the maternal BCG scar cohort and 5.2 (139/2661) for no maternal scar (aMRR, 0.86; 95% Confidence Interval [CI], .69-1.06). In males, 6-month MRs were 4.3 (109 deaths/2531 person-years) for maternal BCG scar vs 6.3 (87/1376) for no scar (aMRR, 0.74; 95% CI, .56-.99). In females, 6-month MRs were 3.8 (91 deaths/2388 person-years) vs 4.0 (52/1286), respectively (aMRR, 1.04; 95% CI, .74-1.47; for interaction with sex, P = .16). CONCLUSIONS: While we cannot rule out an association in females, being born to a mother with a BCG scar reduced the risk of death during early infancy for BCG-vaccinated males, reproducing findings from previous studies.

Discovering Subgroups of Children With High Mortality in Urban Guinea-Bissau: Exploratory and Validation Cohort Study.

BACKGROUND: The decline in global child mortality is an important public health achievement, yet child mortality remains disproportionally high in many low-income countries like Guinea-Bissau. The persisting high mortality rates necessitate targeted research to identify vulnerable subgroups of children and formulate effective interventions. OBJECTIVE: This study aimed to discover subgroups of children at an elevated risk of mortality in the urban setting of Bissau, Guinea-Bissau, West Africa. By identifying these groups, we intend to provide a foundation for developing targeted health interventions and inform public health policy. METHODS: We used data from the health and demographic surveillance site, Bandim Health Project, covering 2003 to 2019. We identified baseline variables recorded before children reached the age of 6 weeks. The focus was on determining factors consistently linked with increased mortality up to the age of 3 years. Our multifaceted methodological approach incorporated spatial analysis for visualizing geographical variations in mortality risk, causally adjusted regression analysis to single out specific risk factors, and machine learning techniques for identifying clusters of multifactorial risk factors. To ensure robustness and validity, we divided the data set temporally, assessing the persistence of identified subgroups over different periods. The reassessment of mortality risk used the targeted maximum likelihood estimation (TMLE) method to achieve more robust causal modeling. RESULTS: We analyzed data from 21,005 children. The mortality risk (6 weeks to 3 years of age) was 5.2% (95% CI 4.8%-5.6%) for children born between 2003 and 2011, and 2.9% (95% CI 2.5%-3.3%) for children born between 2012 and 2016. Our findings revealed 3 distinct high-risk subgroups with notably higher mortality rates, children residing in a specific urban area (adjusted mortality risk difference of 3.4%, 95% CI 0.3%-6.5%), children born to mothers with no prenatal consultations (adjusted mortality risk difference of 5.8%, 95% CI 2.6%-8.9%), and children from polygamous families born during the dry season (adjusted mortality risk difference of 1.7%, 95% CI 0.4%-2.9%). These subgroups, though small, showed a consistent pattern of higher mortality risk over time. Common social and economic factors were linked to a larger share of the total child deaths. CONCLUSIONS: The study's results underscore the need for targeted interventions to address the specific risks faced by these identified high-risk subgroups. These interventions should be designed to work to complement broader public health strategies, creating a comprehensive approach to reducing child mortality. We suggest future research that focuses on developing, testing, and comparing targeted intervention strategies unraveling the proposed hypotheses found in this study. The ultimate aim is to optimize health outcomes for all children in high-mortality settings, leveraging a strategic mix of targeted and general health interventions to address the varied needs of different child subgroups.

Is vaccination against measles, mumps, and rubella associated with reduced rates of antibiotic treatments among children below the age of 2 years? Nationwide register-based study from Denmark, Finland, Norway, and Sweden.

OBJECTIVES: Previous studies have shown that vaccination against measles, mumps, and rubella (MMR) may have beneficial non-specific effects, reducing the risk of infections not targeted by the vaccine. We investigated if MMR vaccine given after the third dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP3), was associated with reduced rates of antibiotic treatments. METHODS: Register-based cohort study following children from the age of recommended MMR vaccination until age 2 years. We included 831,287 children born in Denmark, Finland, Norway, and Sweden who had received DTaP3 but not yet MMR vaccine. Cox proportional hazards regression with age as the underlying timescale and vaccination status as a time-varying exposure was used to estimate covariate-adjusted Hazard Ratios (aHRs) and inverse probability of treatment weighted (IPTW) HRs of antibiotic treatments. Summary estimates were calculated using random-effects meta-analysis. RESULTS: Compared with only having received DTaP3, receipt of MMR vaccine after DTaP3 was associated with reduced rates of antibiotic treatments in all countries: the aHR was 0.92 (0.91-0.93) in Denmark, 0.92 (0.90-0.94) in Finland, 0.84 (0.82-0.85) in Norway, and 0.87 (0.85-0.90) in Sweden, yielding a summary estimate of 0.89 (0.85-0.93). A stronger beneficial association was seen in a negative control exposure analysis comparing children vaccinated with DTaP3 vs two doses of DTaP. CONCLUSIONS: Across the Nordic countries, receipt of MMR vaccine after DTaP3 was associated with an 11% lower rate of antibiotic treatments. The negative control analysis suggests that the findings are affected by residual confounding. Findings suggest that potential non-specific effects of MMR vaccine are of limited clinical and public health importance for the milder infections treated out-of-hospital in the Nordic setting.

Effects of Neonatal BCG-Japan Versus BCG-Russia Vaccination on Overall Mortality and Morbidity: Randomized Controlled Trial From Guinea-Bissau (BCGSTRAIN II).

Background: Vaccination with the Danish strain of bacille Calmette-Guérin (BCG) has been associated with pronounced reductions in all-cause neonatal mortality and morbidity. Developing a skin reaction postvaccination is associated with markedly reduced mortality risk. It is unknown whether the beneficial nonspecific effects are maintained across different BCG strains. Methods: This was an open-label randomized controlled trial in Guinea-Bissau, comparing BCG-Japan (n = 8754) versus BCG-Russia (n = 8752) for all-cause hospital admission risk by 6 weeks of age (primary outcome) and 6 months of age. Additional secondary outcomes were in-hospital case-fatality risk (CFR), all-cause mortality, and BCG skin reaction prevalence. Participants were followed through telephone calls at 6 weeks and 6 months, with a subgroup also visited at home. We assessed admission and mortality risk in Cox models providing incidence rate ratios (IRRs) and mortality rate ratios. CFR and skin reactions were assessed by binomial regression providing risk ratios. Analyses were done overall and stratified by sex. Results: BCG strain was not associated with admission risk, the BCG-Japan/BCG-Russia IRR being 0.92 (95% confidence interval [CI], .81-1.05) by 6 weeks and 0.92 (95% CI, .82-1.02) by 6 months. By 6 months of age, there were significantly fewer BCG-Japan infants with no skin reaction (1%) than for BCG-Russia (2%), the risk ratio being 0.36 (95% CI, .16-.81). BCG-Japan skin reactions were also larger. Conclusions: Both vaccines induced a skin reaction in almost all participants. The BCG strains had comparable effects on morbidity and mortality, but BCG-Japan was associated with more and larger skin reactions that are indicators of lower mortality risk. Clinical Trials Registration: NCT03400878.

The coverage of influenza vaccination and predictors of influenza non-vaccination in Danish cancer patients: A nationwide register-based cohort study.

BACKGROUND: Influenza vaccination is recommended and provided free-of-charge to Danish citizens aged ≥65 years and to individuals with acquired immunodeficiency. We aimed to estimate influenza vaccination coverage and investigate predictors of influenza non-vaccination in Danish cancer patients. METHODS: A nationwide cohort study of all Danish citizens aged ≥18 years with an incident cancer diagnosis between 2002 and 2017. Using national registries, we assessed information on influenza vaccination and potential predictors of influenza non-vaccination. We estimated adjusted prevalence ratios (aPR) of influenza non-vaccination for patients aged <65 years and ≥65 years. RESULTS: We observed 269,863 patients during 840,876 influenza vaccination seasons. The influenza vaccination coverage was 14 % for cancer patients <65 years and 51 % for those ≥65 years. No influenza vaccination in the previous season was associated with non-vaccination in the current season (<65 years: aPR = 2.75, 95 %CI = 2.71-2.80; ≥65 years: aPR = 5.15, 95 %CI = 5.10-5.21). Haematological cancer patients receiving chemotherapy had lower vaccination prevalence compared with those not receiving chemotherapy. CONCLUSIONS: The influenza vaccination coverage was low among cancer patients. Influenza non-vaccination in the previous season was the strongest predictor of not receiving influenza vaccination in the current season. Haematological cancer patients on current chemotherapy had lower vaccination prevalence than those not currently receiving chemotherapy.

The association between BCG scars and self-reported chronic diseases: A cross-sectional observational study within an RCT of Danish health care workers.

INTRODUCTION: The live-attenuated vaccines Bacillus Calmette-Guérin (BCG) and Vaccinia have been associated with beneficial non-specific effects. We assessed the prevalence of BCG and Vaccinia vaccine scars in a cohort of Danish health care workers and investigated the association between the presence of vaccine scars and self-reported chronic diseases. METHODS: Cross-sectional study utilizing baseline data collected during 2020-2021 at enrollment in a BCG trial aiming to assess the effect of BCG vaccination on absenteeism and infectious disease morbidity during the SARS-COV-2 pandemic. In Denmark, Vaccinia was discontinued in 1977, and BCG was phased out in the early 1980s. We used logistic regression analysis (adjusted for sex, birth year, and smoking status) to estimate the association between scar status and chronic diseases, providing adjusted Odds Ratios (aORs) with 95 % Confidence Intervals, for participants born before 1977, and born from 1965 to 1976. RESULTS: The cohort consisted of 1218 participants (206 males; 1012 females) with a median age of 47 years (Q1-Q3: 36-56). Among participants born 1965-1976 (n = 403), who experienced the phase-outs, having BCG and/or Vaccinia scar(s) vs. having no vaccine scars yielded an aOR of 0.51 (0.29-0.90) of self-reported chronic disease; an effect primarily driven by BCG. In the same birth cohort, having vaccine scar(s) was most strongly associated with a lower prevalence of chronic respiratory and allergic diseases; the aORs being 0.39 (0.16-0.97) and 0.39 (0.16-0.91), respectively. CONCLUSION: Having a BCG scar was associated with a lower prevalence of self-reported chronic disease.

Using BCG Vaccine to Enhance Nonspecific Protection of Health Care Workers During the COVID-19 Pandemic: A Randomized Controlled Trial.

BACKGROUND: The BCG (Bacillus Calmette-Guérin) vaccine can induce nonspecific protection against unrelated infections. We aimed to test the effect of BCG on absenteeism and health of Danish health care workers (HCWs) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A single-blinded randomized controlled trial included 1221 HCWs from 9 Danish hospitals. Participants were randomized 1:1 to standard dose BCG or placebo. Primary outcome was days of unplanned absenteeism. Main secondary outcomes were incidence of COVID-19, all-cause hospitalization, and infectious disease episodes. RESULTS: There was no significant effect of BCG on unplanned absenteeism. Mean number of days absent per 1000 workdays was 20 in the BCG group and 17 in the placebo group (risk ratio, 1.23; 95% credibility interval, 0.98-1.53). BCG had no effect on incidence of COVID-19 or all-cause hospitalization overall. In secondary analyses BCG revaccination was associated with higher COVID-19 incidence (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.07-5.71), but also reduced risk of hospitalization (HR, 0.28; 95% CI, .09-.86). The incidence of infectious disease episodes was similar between randomization groups (HR, 1.09; 95% CI, .96-1.24). CONCLUSIONS: In this relatively healthy cohort of HCWs, there was no overall effect of BCG on any of the study outcomes. CLINICAL TRIALS REGISTRATION: NCT0437329 and EU Clinical Trials Register (EudraCT number 2020-001888-90).

Sex-Differential and Non-specific Effects of Vaccines Over the Life Course.

Biological sex and age have profound effects on immune responses throughout the lifespan and impact vaccine acceptance, responses, and outcomes. Mounting evidence from epidemiological, clinical, and animal model studies show that males and females respond differentially to vaccination throughout the lifespan. Within age groups, females tend to produce greater vaccine-induced immune responses than males, with sex differences apparent across all age groups, but are most pronounced among reproductive aged individuals. Females report more adverse effects following vaccination than males. Females, especially among children under 5 years of age, also experience more non-specific effects of vaccination. Despite these known sex- and age-specific differences in vaccine-induced immune responses and outcomes, sex and age are often ignored in vaccine research. Herein, we review the known sex differences in the immunogenicity, effectiveness, reactogenicity, and non-specific effects of vaccination over the lifespan. Ways in which these data can be leveraged to improve vaccine research are described.

Immunogenicity of Bacillus Calmette-Guérin in pigs: potential as a translational model of non-specific effects of BCG.

Background: Clinical and immunological studies in humans show that the live attenuated Bacillus Calmette-Guérin (BCG) vaccine has beneficial non-specific effects, increasing resistance against diseases other than tuberculosis. The underlying mechanisms are currently being explored. The pig exhibits considerable physiological similarity to humans in anatomy and physiology, suggesting that similar responses to BCG could be expected. Studies of the non-specific effects of BCG in pigs are scarce. We investigated the feasibility of using pigs as a large animal model to investigate the non-specific immunological effects of BCG. Methods: In a series of experiments, we randomized newborn or young piglets from conventional farms to receiving BCG or placebo and investigated the persistence of live BCG bacteria in various tissues, the immunogenicity of BCG in ex vivo blood and in vitro stimulation assays, and the acute phase protein and clinical responses to heterologous infectious challenge with influenza A virus or Actinobacillus pleuropneumoniae. Results: The BCG vaccine was generally well tolerated. In contrast to humans, no skin reaction in the form of abscesses, ulcers, or scars was observed. Live BCG was recovered from draining lymph nodes in 2/13 animals 20 weeks after vaccination. Specific in vitro responses of IFN-γ to antigen-specific re-stimulation with mycobacterial antigen were increased but not TNF-responses to TLR2 or TLR4 agonists. A few genes were differentially expressed in blood after vaccination, including the antiviral genes RIG-I and CSF1, although the effect disappeared after correction for multiple testing. Clinical symptoms after heterologous bacterial or viral respiratory infections did not differ, nor did virus copies in nasopharyngeal samples after the challenge. However, the acute phase protein response was significantly reduced in BCG-vaccinated animals after influenza challenge but not after A. pleuropneumoniae challenge. Discussion: BCG was safe in pigs, inducing specific immunological responses, but our model did not corroborate the innate immunological responsiveness to BCG seen in humans. The dose of BCG or the bacterial and viral challenges may have been sub-optimal. Even so, the acute phase protein response to influenza infection was significantly reduced in BCG-vaccinated animals.

The role of trained immunity in COVID-19: Lessons for the next pandemic.

Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks.

Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines.

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

RTS,S/AS01 malaria vaccine-proven safe and effective?

In October, 2021, WHO recommended that the RTS,S malaria vaccine, with its strong safety profile and high impact, be provided to children from age 5 months in regions with moderate to high Plasmodium falciparum malaria transmission. The evidence base included phase 3 trials in seven African countries and an ongoing malaria vaccine implementation programme (MVIP) in three African countries. We highlight problems with the MVIP mortality data, including potential confounding, inappropriate use of severe malaria as a surrogate marker, a statistically non-significant effect, and assessment after 2 years instead of the stipulated 4 years, which could have inflated the benefits and deflated the risks associated with the vaccine. We conclude that the claimed impact of the MVIP on mortality is not based on enough scientific evidence and that the MVIP findings do not rule out the possibility of increased mortality among vaccinated girls compared with vaccinated boys, as observed in the phase 3 studies. The MVIP should adhere fully to the planned analyses and the data should be made available for independent assessment. Roll-out of the vaccine elsewhere should include rigorous evaluation, especially of its safety.

Predictors of serum- per- and polyfluoroalkyl substance (PFAS) concentrations among infants in Guinea-Bissau, West Africa.

BACKGROUND: Knowledge about PFAS exposure in Africa is limited. We have previously detected six types of PFAS in the serum of infants from Guinea-Bissau, West Africa. The aim of this study was to identify predictors of the infant serum-PFAS concentrations. METHODS: This cross-sectional study was based on a subset of data from a randomized controlled trial of early measles vaccination performed in 2012-2015 in three rural regions of Guinea-Bissau. Blood samples were obtained from 237 children aged 4-to-7 months, and six types of PFAS were quantified in serum. Location of residence was recorded, and information about predictors related to socioeconomic status as well as maternal and child characteristics were obtained through structured interviews with the mothers through routine surveillance. Associations between potential predictors and infant serum-PFAS concentrations were examined in linear regression models while adjusting for potential confounding and mediating factors as identified in a directed acyclic graph. RESULTS: Infants from the Cacheu region had the lowest concentrations of perfluorooctanoic acid (PFOA), while infants from the Oio region had the lowest concentrations of all other PFAS. Compared to infants from Oio, infant serum-perfluorooctane sulfonic acid (PFOS) concentrations were 94.1% (95% CI: 52.4, 147.1%) and 81.9% (95% CI: 45.7, 127.1%) higher in Cacheu and Biombo, respectively. Higher maternal age and lower parity were associated with slightly higher child-serum perfluorohexane sulfonic acid (PFHxS) concentrations, while infants with higher socioeconomic status and infants breastfed without supplementary solid foods at inclusion had higher average concentrations of most PFAS, although the confidence intervals were wide and overlapped zero. DISCUSSION: Location of residence was the most important determinant of serum-PFAS concentrations among Guinea-Bissau infants, indicating a potential role of diet as affected by the global spread of PFAS, but future studies should explore reasons for the regional differences in PFAS exposure.

Cohort Profile: Childhood morbidity and potential non-specific effects of the childhood vaccination programmes in the Nordic countries (NONSEnse): register-based cohort of children born 1990-2017/2018.

PURPOSE: The aim of the NONSEnse project is to investigate the non-specific effects of vaccines and immunisation programmes on the overall health of children by using information from the extensive nationwide registers on health and sociodemographic factors in Denmark, Finland, Norway and Sweden. PARTICIPANTS: The cohort covers 9 072 420 children aged 0-17 years, born 1990-2017/2018 and living in Denmark, Finland, Norway or Sweden. All countries use a unique identification number for its permanent residents, which makes it possible to link individual-level information from different registers. FINDINGS TO DATE: Data collection and harmonisation according to a common data model was completed in March 2022. As a prerequisite for comparing the effects of childhood vaccinations on the overall health of children across the Nordic countries, we have identified indicators measuring similar levels of infectious disease morbidity across these settings. So far, studies pertaining to non-specific effects of vaccines are limited to investigations that could be undertaken using aggregated data sets that were available before the NONSEnse cohort with individual-level information was completely set up. FUTURE PLANS: We are currently performing several studies of the effects on non-targeted infectious disease morbidity across the countries following vaccination against measles, mumps, rubella, diphtheria, tetanus, pertussis, human papillomavirus, rotavirus and influenza. Multiple studies are planned within the next years using different study designs to facilitate triangulation of results and enhance causal inference. REGISTRATION: No clinical trials will be conducted within the NONSEnse project.

Genetic regulators of cytokine responses upon BCG vaccination in children from West Africa.

Genetic variation is a key factor influencing cytokine production capacity, but which genetic loci regulate cytokine production before and after vaccination, particularly in African population is unknown. Here, we aimed to identify single-nucleotide polymorphisms (SNPs) controlling cytokine responses after microbial stimulation in infants of West-African ancestry, comprising of low-birth-weight neonates randomized to bacillus Calmette-Guérin (BCG) vaccine-at-birth or to the usual delayed BCG. Genome-wide cytokine cytokine quantitative trait loci (cQTL) mapping revealed 12 independent loci, of which the LINC01082-LINC00917 locus influenced more than half of the cytokine-stimulation pairs assessed. Furthermore, nine distinct cQTLs were found among infants randomized to BCG. Functional validation confirmed that several complement genes affect cytokine response after BCG vaccination. We observed a limited overlap of common cQTLs between the West-African infants and cohorts of Western European individuals. These data reveal strong population-specific genetic effects on cytokine production and may indicate new opportunities for therapeutic intervention and vaccine development in African populations.