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).

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.

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.

Out-of-Sequence Vaccinations With Measles Vaccine and Diphtheria-Tetanus-Pertussis Vaccine: A Reanalysis of Demographic Surveillance Data From Rural Bangladesh.

BACKGROUND: Due to delays in vaccinations, diphtheria-tetanus-whole-cell-pertussis (DTP) is often given with or after measles vaccine (MV)-out of sequence. We reanalyzed data from Matlab, Bangladesh, to examine how administration of MV and DTP out-of-sequence was associated with child survival. METHODS: In sum, 36 650 children born between 1986 and 1999 were followed with registration of vaccinations and survival. Controlling for background factors using Cox proportional hazards models, survival was analyzed between 9 and 24 months of age. We measured the mortality rate ratio (MRR) to compare vaccination groups. Oral polio vaccine (OPV) campaigns, which started in 1995, reduced the mortality rate and reduced the difference between vaccination groups. In the main analysis, we therefore censored for OPV campaigns; there were 151 nonaccident deaths before the OPV campaigns. RESULTS: Compared with MV administered alone (MV-only), DTP administered with or after MV had MRR 2.20 (1.31-3.70), and DTP-only had MRR 1.78 (1.01-3.11). Compared with MV-only, DTP administered with MV had a female-male MRR 0.56 (0.13-2.38), significantly different to DTP administered after MV, which had MRR 14.83 (1.88-117.1), test of interaction P = .011. Compared with having DTP (no MV) as most recent vaccination, MV-only had a nonaccident MRR of 0.56 (0.32-0.99). CONCLUSION: The negative effects of non-live DTP with or after live MV are not explained merely by selection bias. These observations support a live-vaccine-last policy where DTP should not be given with or after MV.

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.

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

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).

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.

Interacting, Nonspecific, Immunological Effects of Bacille Calmette-Guérin and Tetanus-diphtheria-pertussis Inactivated Polio Vaccinations: An Explorative, Randomized Trial.

BACKGROUND: Certain vaccines, such as Bacille Calmette-Guérin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens. METHODS: We randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed. RESULTS: Tdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination. CONCLUSIONS: Tdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality. CLINICAL TRIALS REGISTRATION: NCT02771782.

Hepatitis B and C in the adult population of Bissau, Guinea-Bissau: a cross-sectional survey.

OBJECTIVE: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are prevalent in West Africa. To address the WHO 2030 goals of a 90% reduction in incidence and a 65% reduction in mortality for both infections, we assessed the prevalence of HBV and HCV from surveys in the general population. METHODS: Participants in this cross-sectional survey were included from randomly selected houses in a demographic surveillance site in Bissau, Guinea-Bissau. Participants were interviewed and had a blood sample drawn for viral analyses (HBsAg, anti-HBs, anti-HBc, anti-HCV and HCV RNA). Risk factors of HBV and HCV infection were determined by binomial regression adjusted for sex and age. RESULTS: A total of 2715 participants were included in this study. The overall HBsAg prevalence was 18.7% (95% CI: 17.3-20.2%). HBsAg was associated with male sex (adjusted risk ratio (aRR): 1.64), and prevalence decreased with age >34 years. HBV exposure was found in 91.9% of participants. Although 72.6% of individuals without sexual debut had been exposed to HBV, ever engaging in a sexual relationship was associated with higher risk of HBV exposure (aRR 1.18). The anti-HCV prevalence was 0.5% (95% CI: 0.3-0.9%), and 78.6% of those had detectable HCV RNA. Risk factors for anti-HCV sero-positivity were age above 55 (aRR 10.60), a history of blood transfusion (aRR 5.07) and being in a polygamous marriage (aRR 3.52). CONCLUSION: In Guinea-Bissau initiatives to implement treatment and widespread testing are needed to reach the WHO 2030 goals.

OBJECTIF: Le virus de l'hépatite B (VHB) et le virus de l'hépatite C (VHC) sont répandus en Afrique de l'Ouest. Pour atteindre les objectifs de 2030 de l'OMS d'une réduction de 90% de l'incidence et de 65% de la mortalité pour les deux infections, nous avons évalué la prévalence du VHB et du VHC à partir d'enquêtes dans la population générale. MÉTHODES: Les participants inclus dans cette enquête transversale provenaient de foyers sélectionnés au hasard dans un site de surveillance démographique à Bissau, en Guinée-Bissau. Les participants ont été interrogés et ont subi un prélèvement d'échantillon de sang pour des analyses virales (HBsAg, anti-HBs, anti-HBc, anti-HCV et ARN du HCV). Les facteurs de risque d'infection par le VHB et le VHC ont été déterminés par la régression binomiale ajustée en fonction du sexe et de l'âge. RÉSULTATS: 2.715 participants ont été inclus dans cette étude. La prévalence globale de l'HBsAg était de 18,7% (IC95%: 17,3-20,2%). L'HBsAg était associé au sexe masculin (rapport de risque ajusté (aRR): 1,64), et la prévalence diminuait avec l'âge >34 ans. Une exposition au VHB a été observée chez 91,9% des participants. Bien que 72,6% des personnes sans début d'activité sexuelle aient été exposées au VHB, le fait de s'engager dans des relations sexuelles était associé à un risque plus élevé d'exposition au VHB (aRR: 1,18). La prévalence d'anti-VHC était de 0,5% (IC95%: 0,3-0,9%) et 78,6% d'entre eux avaient de l'ARN du VHC détectable. Les facteurs de risque de séropositivité anti-VHC étaient l'âge de plus de 55 ans (aRR: 10,60), les antécédents de transfusion sanguine (aRR: 5,07) et le fait d'être dans un mariage polygame (aRR: 3,52). CONCLUSION: En Guinée-Bissau, des initiatives pour mettre en œuvre un traitement et des tests généralisés sont nécessaires pour atteindre les objectifs de l'OMS 2030.

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

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

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

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