Is Systemic Dissemination of BCG Following Neonatal Vaccination Required for Protection Against Mycobacterium tuberculosis?

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and is a leading cause of death. BCG is the only licensed TB vaccine. Preclinical studies have shown that in adults, intravenous administration of BCG improves protection against TB.

The importance of quality of health campaign information for outcome evaluation. A case study from Guinea-Bissau and Bangladesh.

Background: Numerous national health intervention campaigns, e.g. supplementary immunization campaigns/activities (SIAs), have been conducted in low- and middle-income countries (LMIC) in the last decades.

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.

Effect of a campaign with oral polio vaccine on general health: A cluster-randomised trial in rural Guinea-Bissau.

Objectives: To investigate in a cluster-randomised trial whether a campaign with oral polio vaccine (C-OPV) reduced mortality and morbidity.

Methods: We randomised 222 village clusters under demographic surveillance to an intervention (health check and C-OPV) or control group (health check only). Children aged 0-8 months were eligible.

Contradictory mortality results in early 2-dose measles vaccine trials: interactions with oral polio vaccine may explain differences.

Objectives: Between 2003 and 2019, three trials (randomised controlled trials [RCTs]) in Guinea-Bissau randomised infants to an early 2-dose measles vaccine (MV) schedule at 4 and 9 months vs standard MV at 9 months. The RCTs produced contradictory mortality results; the effect being beneficial in the 2-dose group in the first but tending to have higher mortality in the last two RCTs. We hypothesised that increased frequency of campaigns with oral polio vaccine (C-OPV) explained the pattern.

Seasonal variation in BCG-induced trained immunity.

The Bacille Calmette-Guerin (BCG) vaccine is a well-established inducer of innate immune memory (also termed trained immunity), causing increased cytokine production upon heterologous secondary stimulation. Innate immune responses are known to be influenced by season, but whether seasons impact induction of trained immunity is not known. To explore the influence of season on innate immune memory induced by the BCG vaccine, we vaccinated healthy volunteers with BCG either during winter or spring.

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.

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.

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.

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.

Effect of national immunisation campaigns with oral polio vaccine on all-cause mortality in children in rural northern Ghana: 20 years of demographic surveillance cohort data.

Background: Studies from Guinea-Bissau and Bangladesh have shown that campaigns with oral polio vaccine (C-OPV) may be associated with 25-31% lower child mortality. Between 1996 and 2015, Ghana had 50 national C-OPVs and numerous campaigns with vitamin A supplementation (VAS), and measles vaccine (MV). We investigated whether C-OPVs had beneficial non-specific effects (NSEs) on child survival in northern Ghana.

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.

Measles vaccination and reduced child mortality: Prevention of immune amnesia or beneficial non-specific effects of measles vaccine?

Measles vaccine (MV) has been observed to reduce all-cause mortality more than explained by prevention of measles infection. Recently, prevention of "measles-induced immune amnesia" (MIA) has been proposed as an explanation for this larger-than-anticipated beneficial effect of measles vaccine (MV). According to the "MIA hypothesis", immune amnesia leads to excess non-measles morbidity and mortality, that may last up to five years after measles infection, but may be prevented by MV.

Using real-life data to model the impact of increasing BCG vaccination coverage and scar prevalence on all-cause infant mortality.

Purpose: Estimating the potential impact on infant mortality of increasing Bacille Calmette-Guérin (BCG) vaccination coverage and BCG scar prevalence.

Methods: Guinea-Bissau Health and Demographic Surveillance System data on BCG vaccination coverage, scar status, and all-cause mortality were used for this study. Mortality risk (MR) by scar status was assessed in Cox models providing adjusted mortality rate ratios (aMRRs).

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.

Randomized clinical trials of COVID-19 vaccines: Do adenovirus-vector vaccines have beneficial non-specific effects?

We examined the possible non-specific effects of novel mRNA- and adenovirus-vector COVID-19 vaccines by reviewing the randomized control trials (RCTs) of mRNA and adenovirus-vector COVID-19 vaccines. We calculated mortality risk ratios (RRs) for mRNA COVID-19 vaccines vs. placebo recipients and compared them with the RR for adenovirus-vector COVID-19 vaccine recipients vs.

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.

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.

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.

The impact of BCG dose and revaccination on trained immunity.

The innate immune system can display heterologous memory-like responses termed trained immunity after stimulation by certain vaccinations or infections. In this randomized, placebo-controlled trial, we investigated the modulation of Bacille Calmette-Guérin (BCG)-induced trained immunity by BCG revaccination or high-dose BCG administration, in comparison to a standard dose. We show that monocytes from all groups of BCG-vaccinated individuals exerted increased TNFα production after ex-vivo stimulation with various unrelated pathogens.