Polio eradication: Addressing the hurdles on the last mile.

1988, the World Health Assembly committed to eradicate poliomyelitis, a viral disease that can cause permanent paralysis. Today, only type 1 of the three wild poliovirus types remains circulating in limited geographic areas following widespread use of different poliovirus vaccines. While we are close to zero new cases of wild polio, it is a fragile situation, and there are many remaining and new hurdles to overcome. Here, experts discuss how to address them.

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses.

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (TFH cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting TFH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFH cell differentiation and a promising target for TFH cell-skewing vaccine adjuvants.

Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges.

Vaccines can have nonspecific effects through their modulation of responses to infections not specifically targeted by the vaccine. However, lack of knowledge about the underlying immunological mechanisms and molecular cause-and-effect relationships prevent use of this potentially powerful early-life intervention to its greatest benefit. The World Health Organization has identified investigations into the molecular basis of nonspecific vaccine effects as a research priority.

Maternal BCG 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: Observational study within a randomized controlled trial comparing different BCG strains conducted in Guinea-Bissau from 2017-2020. 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 six weeks and six 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: 64% (11,070/17,275) of mothers had a BCG scar, which for females and overall was not associated with neither admission risk, admission severity nor all-cause mortality. By six months of age, the mortality rate (MR) was 4.1 (200 deaths/4,919 person-years) for the maternal BCG scar cohort and 5.2 (139 deaths/2,661 person-years) for no maternal scar, aMRR=0.86 (0.69-1.06). In males, six-month MRs were 4.3 (109/2,531) for maternal BCG scar vs 6.3 (87/1,376) for no scar, the maternal scar/no scar aMRR being 0.74 (0.56-0.99). In females, six-month MRs were 3.8 (91/2,388) vs 4.0 (52(1,286), the aMRR being 1.04 (0.74-1.47), p for interaction with sex=0.16. CONCLUSION: 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.

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.

Old vaccines for new infections: Exploiting innate immunity to control COVID-19 and prevent future pandemics.

The COVID-19 pandemic triggered an unparalleled pursuit of vaccines to induce specific adaptive immunity, based on virus-neutralizing antibodies and T cell responses. Although several vaccines have been developed just a year after SARS-CoV-2 emerged in late 2019, global deployment will take months or even years. Meanwhile, the virus continues to take a severe toll on human life and exact substantial economic costs. Innate immunity is fundamental to mammalian host defense capacity to combat infections. Innate immune responses, triggered by a family of pattern recognition receptors, induce interferons and other cytokines and activate both myeloid and lymphoid immune cells to provide protection against a wide range of pathogens. Epidemiological and biological evidence suggests that the live-attenuated vaccines (LAV) targeting tuberculosis, measles, and polio induce protective innate immunity by a newly described form of immunological memory termed "trained immunity." An LAV designed to induce adaptive immunity targeting a particular pathogen may also induce innate immunity that mitigates other infectious diseases, including COVID-19, as well as future pandemic threats. Deployment of existing LAVs early in pandemics could complement the development of specific vaccines, bridging the protection gap until specific vaccines arrive. The broad protection induced by LAVs would not be compromised by potential antigenic drift (immune escape) that can render viruses resistant to specific vaccines. LAVs might offer an essential tool to "bend the pandemic curve," averting the exhaustion of public health resources and preventing needless deaths and may also have therapeutic benefits if used for postexposure prophylaxis of disease.

Mortality Risk Among Frail Neonates and Maternal BCG Vaccine Scar Status: Observational Study From Guinea-Bissau.

BACKGROUND: Maternal priming with the Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced offspring mortality rates. 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 to 2017. At NICU admission and after informed consent, the maternal scar status was evaluated by visual inspection before neonates were randomized 1:1 to receive BCG + oral polio vaccine immediately or at hospital discharge. Stratified by maternal scar status, we assessed overall in-hospital and postdischarge mortality rates through 42 days of age in Cox proportional hazards models providing adjusted mortality rate ratios (aMRRs). RESULTS: Overall, 62% of mothers (903 of 1451) had a BCG vaccine scar. During NICU admission, the mortality risk was 1.7% (15 of 903) for neonates born to mothers with a scar versus 3.3% (18 of 548) for those born to mothers with no scar; the aMRR for maternal scar versus no scar was 0.53 (95% CI, .26-1.05), 0.39 (95% CI, .13-1.05) for unvaccinated and 0.70 (95% CI, .26-1.87) for vaccinated neonates. CONCLUSIONS: This small study indicates that maternal BCG vaccine might be associated with reduced all-cause NICU mortality rate. If confirmed elsewhere, this finding would have substantial ramifications for global health.

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. Similarly, we observed increased amounts of T-cell-derived IFNγ after M. tuberculosis exposure, regardless of the BCG intervention. NK cell cytokine production, especially after heterologous stimulation with the fungal pathogen Candida albicans, was predominantly boosted after high dose BCG administration. Cytokine production capacity before vaccination was inversely correlated with trained immunity. While the induction of a trained immunity profile is largely dose- or frequency independent, baseline cytokine production capacity is associated with the magnitude of the innate immune memory response after BCG vaccination.

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.

The Effect of a Second Dose of Measles Vaccine at 18 Months of Age on Nonaccidental Deaths and Hospital Admissions in Guinea-Bissau: Interim Analysis of a Randomized Controlled Trial.

BACKGROUND: The world is set on the eradication of measles. Continuation of the measles vaccine (MV) after eradication could still reduce morbidity because the MV has so-called beneficial nonspecific effects. We evaluated the effect of a "booster" dose of the MV on overall severe morbidity. METHODS: We conducted a randomized controlled trial among children aged 17.5 to 48 months in Guinea-Bissau, where the MV is recommended only at 9 months of age. At the time of this interim analysis, 3164 children had been allocated 1:1 to a second dose of measles vaccine (MV2) at 18 months of age or to no vaccine. Severe morbidity (a composite outcome of nonaccidental 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 nonaccidental 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% confidence interval [CI], .38-1.38). At 12 months of follow-up, the number needed to treat to prevent 1 severe morbidity event was 137 children. After OPV campaigns, the estimated effect of MV2 was reduced to 9% (SMRR, 0.91; 95% CI, .46-1.81). CONCLUSIONS: MV2 may reduce nonmeasles 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. CLINICAL TRIALS REGISTRATION: NCT02943681.

Non-specific effects of vaccines: Current evidence and potential implications.

Besides protection against specific microorganisms, vaccines can induce heterologous or non-specific effects (NSE). Epidemiological data suggest that vaccination with live-attenuated vaccines such as Bacillus Calmette-Guérin (BCG), measles vaccine, and oral polio vaccine results in increased overall childhood survival, and several of these observations have been confirmed in randomized trials. Immunological mechanisms mediating NSE include heterologous lymphocyte effects and induction of innate immune memory (trained immunity). Trained immunity induces long-term functional upregulation of innate immune cells through epigenetic and metabolic reprogramming. An overview of the epidemiological evidence of non-specific effects of vaccines and the latest insights regarding the biological mechanisms behind this phenomenon is presented, and future research priorities and potential implications are discussed.

Diphtheria-Tetanus-Pertussis (DTP) Vaccine Is Associated With Increased female-Male Mortality. Studies of DTP administered before and after measles vaccine.

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.

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

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

National Immunization Campaigns With Oral Polio Vaccine May Reduce All-cause Mortality: An Analysis of 13 Years of Demographic Surveillance Data From an Urban African Area.

BACKGROUND: Between 2002 and 2014, Guinea-Bissau had 17 national campaigns with oral polio vaccine (OPV) as well as campaigns with vitamin A supplementation (VAS), measles vaccine (MV), and H1N1 influenza vaccine. We examined the impact of these campaigns on child survival. METHODS: We examined the mortality rate between 1 day and 3 years of age of all children in the study area. We used Cox models with age as underlying time to calculate adjusted mortality rate ratios (MRRs) between "after-campaign" mortality and "before-campaign" mortality, adjusted for temporal change in mortality and stratified for season at risk. RESULTS: Mortality was lower after OPV-only campaigns than before, with an MRR for after-campaign vs before-campaign being 0.75 (95% confidence interval [CI], .67-.85). Other campaigns did not have similar effects, the MRR being 1.22 (95% CI, 1.04-1.44) for OPV + VAS campaigns, 1.39 (95% CI, 1.20-1.61) for VAS-only campaigns, 1.32 (95% CI, 1.09-1.60) for MV + VAS campaigns, and 1.13 (95% CI, .86-1.49) for the H1N1 campaign. Thus, all other campaigns differed significantly from the effect of OPV-only campaigns. Effects did not differ for trivalent, bivalent, or monovalent strains of OPV. With each additional campaign of OPV only, the mortality rate declined further (MRR, 0.86 [95% CI, .81-.92] per campaign). With follow-up to 3 years of age, the number needed to treat to save 1 life with the OPV-only campaign was 50 neonates. CONCLUSIONS: OPV campaigns can have a much larger effect on child survival than otherwise assumed. Stopping OPV campaigns in low-income countries as part of the endgame for polio infection may increase child mortality.

Reactivation of BCG vaccination scars after vaccination with mRNA-Covid-vaccines: two case reports.

BACKGROUND: From May 2020 to January 2021, we enrolled 1233 health care workers (HCW) from Danish Hospitals in a randomized trial evaluating whether Bacille Calmette-Guérin (BCG) provides protection against COVID-19. Participants were randomized 1:1 to BCG vs saline and followed for 6 months. From December 2020, Covid-19 vaccines were offered to the HCW. In most cases, BCG vaccination results in a characteristic scar. Reactivation of the BCG scar has been described in children during viral infections and following influenza vaccination, but is mostly associated to Kawasaki's disease, a disease entity with pathogenesis likely similar to the child Covid-19 complication MIS-C: Multi-System Inflammatory Syndrome. Reactivation of scars after neonatal BCG vaccination has recently been described in four women after Covid-19 mRNA vaccination. Two of our trial participants experienced reactivation of their novel BCG scars after receiving mRNA Covid-19 vaccination 6 to 8 months post-BCG. CASE PRESENTATIONS: Two female HCW participants that had been randomly allocated to BCG in the BCG-DENMARK-COVID trial, spontaneously reported itching and secretion at the BCG scar site after having received mRNA Covid-19 vaccination (Moderna and Pfizer-BioNTech) 6 to 8 months following inclusion and BCG vaccination. One participant, who had a larger BCG skin reaction, noticed re-appearing symptoms after both the first and the second COVID-vaccine dose, while the other participant only noted symptoms after the second dose. Both had been BCG vaccinated during childhood, and no reactivation was noted in the older scars. No treatment was needed or provided. CONCLUSIONS: The reactivation of the BCG scar after receiving mRNA vaccine might have been caused by cross-reactivity between BCG and SARS-CoV-2. In both cases, the symptoms were bothersome, but self-limiting and left no sequelae. The risk of reactivation at the scar site is thus not a reason to avoid vaccination with either vaccine.

Early Vaccination With Bacille Calmette-Guérin-Denmark or BCG-Japan Versus BCG-Russia to Healthy Newborns in Guinea-Bissau: A Randomized Controlled Trial.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination remains a cornerstone against tuberculosis. Randomized controlled trials (RCTs) have demonstrated that BCG-Denmark lowers all-cause mortality, but a recent RCT found no effect of BCG-Russia. Observational studies indicate that the genetically divergent BCG strains have different effects. METHODS: This was a parallel-group, open-label RCT conducted at the National Hospital in Guinea-Bissau. Healthy neonates were randomized 1:1 to BCG-Denmark (2851 randomized, 2840 analyzed) vs BCG-Russia (2845 randomized, 2837 analyzed). We hypothesized that BCG-Denmark would reduce morbidity (primary outcome) and mortality while inducing more BCG reactions and purified protein derivative (PPD) responses (secondary outcomes). Halfway through the trial, production of BCG-Denmark was halted, and the trial continued comparing BCG-Japan (3191 neonates randomized, 3184 analyzed) with BCG-Russia (3170 randomized, 3160 analyzed). Mortality and morbidity data were collected by telephone, at home visits, and at the National Hospital and assessed in Cox models providing 6-week mortality rate ratios (MRRs) and hospitalization incidence rate ratios (IRRs). RESULTS: By age 6 weeks, there were 140 and 130 admissions among neonates vaccinated with BCG-Denmark and BCG-Russia, respectively (IRR, 1.08 [95% confidence interval {CI}, .84-1.37]). For BCG-Japan, there were 185 admissions vs 161 admissions for BCG-Russia (IRR, 1.15 [95% CI, .93-1.43]). The 6-week mortality did not differ: BCG-Denmark/BCG-Russia (MRR, 1.15 [95% CI, .74-1.80]); BCG-Japan/BCG-Russia (MRR, 0.71 [95% CI, .43-1.19]). BCG-Denmark and BCG-Japan induced more BCG scars and PPD reactions than BCG-Russia. CONCLUSIONS: BCG strains did not affect morbidity. BCG-Denmark and BCG-Japan were more immunogenic than BCG-Russia by the measures traditionally viewed as surrogates for successful immunization. The implications of strain differences for tuberculosis protection and overall health warrant further study. CLINICAL TRIALS REGISTRATION: NCT02447536.