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Background: Measles vaccination is associated with major reductions in child mortality and morbidity. In Guinea-Bissau, to limit vaccine wastage, children are only measles-vaccinated if at least six children aged 9-11 months are present at a vaccination session. Objective: To estimate the incremental cost-effectiveness of providing measles vaccine (MV) to all children regardless of age and number of children present. Methods: We estimated MV coverage among children living in villages cluster-randomized to MV for all children and among children cluster-randomized to the current restrictive MV policy (status quo). Prices of MV and injection equipment were obtained from the United Nations Children's Fund (UNICEF). Cost savings of hospital admissions averted were collected from a sample of health facilities. The non-specific mortality effects of MV were estimated and presented as deaths averted and life years gained (LYG) from providing MV-for-all. Results: MV coverage at 36 months was 97% in MV-for-all clusters and 84% in restrictive MV policy clusters. Conservatively assuming 90% wastage of MV under the MV-for-all policy and 40% under the restrictive MV policy, cost per child vaccinated was USD 3.08 and USD 1.19, respectively. The incremental costs per LYG and death averted of the MV-for-all policy were USD 5.61 and USD 148, respectively. The MV-for-all policy became cost-saving at 88% wastage. Conclusions: Taking the low cost of MV and the beneficial non-specific effects of MV into consideration, a 10-dose MV vial should be reclassified as a '1+ dose vial'. The vial should be opened for a single child, irrespective of age, but can vaccinate up to 10 children.

The central paradigm of vaccination is to generate resistance to infection by a specific pathogen when the vacinee is re-exposed to that pathogen. This paradigm is based on two fundamental characteristics of the adaptive immune system, specificity and memory. These characteristics come from the clonal specificity of T and B cells and the long-term survival of previously-encountered memory cells which can rapidly and specifically expand upon re-exposure to the same specific antigen. However, there is an increasing awareness of the concept, as well as experimental documentation of, heterologous immunity and cross-reactivity of adaptive immune lymphocytes in protection from infection. This awareness is supported by a number of human epidemiological studies in vaccine recipients and/or individuals naturally-resistant to certain infections, as well as studies in mouse models of infections, and indeed theoretical considerations regarding the disproportional repertoire of available T and B cell clonotypes compared to antigenic epitopes found on pathogens. Heterologous immunity can broaden the protective outcomes of vaccinations, and natural resistance to infections. Besides exogenous microbes/pathogens and/or vaccines, endogenous microbiota can also impact the outcomes of an infection and/or vaccination through heterologous immunity. Moreover, utilization of viral and/or bacterial vaccine vectors, capable of inducing heterologous immunity may also influence the natural course of many infections/diseases. This review article will briefly discuss these implications and redress the central dogma of specificity in the immune system.

Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.

Contrary to the long-held belief that the effects of vaccines are specific for the disease they were created; compelling evidence has demonstrated that vaccines can exert positive or deleterious non-specific effects (NSEs). In this review, we compiled research reports from the last 40 years, which were found based on the PubMed search for the epidemiological and immunological studies on the non-specific effects (NSEs) of the most common human vaccines. Analysis of information showed that live vaccines induce positive NSEs, whereas non-live vaccines induce several negative NSEs, including increased female mortality associated with enhanced susceptibility to other infectious diseases, especially in developing countries. These negative NSEs are determined by the vaccination sequence, the antigen concentration in vaccines, the type of vaccine used (live vs. non-live), and also by repeated vaccination. We do not recommend stopping using non-live vaccines, as they have demonstrated to protect against their target disease, so the suggestion is that their detrimental NSEs can be minimized simply by changing the current vaccination sequence. High IgG4 antibody levels generated in response to repeated inoculation with mRNA COVID-19 vaccines could be associated with a higher mortality rate from unrelated diseases and infections by suppressing the immune system. Since most COVID-19 vaccinated countries are reporting high percentages of excess mortality not directly attributable to deaths from such disease, the NSEs of mRNA vaccines on overall mortality should be studied in depth.

•Paratuberculosis vaccination extends productive life of dairy cattle.•Paratuberculosis vaccination induces a reduced mortality non-specific effect (NSE)•This NSE fits the expected according to the trained immunity mechanism.•This inactivated vaccine has a positive effect on females.•Extended paratuberculosis vaccination could help reduce antibiotic use. Records of cattle vaccination against paratuberculosis (PTB) have been analyzed to determine whether or not non-specific effect (NSE) on overall mortality similar to that observed in BCG vaccinated humans occurs in animals. The results of a previously reported slaughterhouse study on PTB prevalence were used as a reference on the age incidence of advanced patent (clinical) epidemio-pathogenic forms. In the proper vaccine study, cows in 30 cattle farms in the Basque Country, Spain were followed-up for between 1 and 13 years. Vaccinated groups were composed by 1008 (592 right-censored) animals younger than 3 months treated as calves and by 3761 (3160 right-censored) vaccinated at any older age. Controls were 339 (157 right-censored) and 4592 (2213 right-censored) age matched animals, respectively. Individual last year presence in the annual testing was considered age at culling or death. A survival analysis was carried out according age at vaccination of vaccinated versus non-vaccinated animals. PTB age incidence in the slaughterhouse study was subtracted from the difference between vaccinated and non-vaccinated animals at the same age in order to estimate PTB-specific and non-specific effects. The maximum difference was observed at the 2–3 years interval with a 33.9% mortality reduction in the calf vaccinated group. This corresponded also with the maximum NSE that was 24.5% for a PTB incidence of 9.5%. Overall, vaccination afforded to calves a 26.5% yearly mortality protection, split between 11.1% PTB-specific and 15.4% NSE. These results support a NSE on total mortality associated with PTB vaccination that appeared to persist for up to 6–7 years. This confirms for the first time in an animal field study the innate immune system memory predicted by the recently proposed trained immunity theory. Contrasting the literature, no deleterious effects of killed vaccines on females were observed. Mortality reduction would offset vaccination costs and could improve livestock systems efficiency and potentially reduce antibiotic use. Clinical trial registered with Spanish Agency for Drugs and Sanitary products (AEMPS) as 11/012/ECV.

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. 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)-1β, 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). 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-1β, 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. 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.

•Innate immune memory underlies non-specific effects reported for some vaccines.•Vaccine non-specific effects have always been unknown at the time of licensure.•Non-specific effects if known, may influence benefit-risk ratio of new vaccines.•New approaches are required for early investigation of vaccine non-specific benefits. Immune memory was for a long time thought to be an exclusive feature of the adaptive immune system. Emerging evidence has shown that the innate immune system may exhibit memory which has been termed as trained immunity or innate immune memory. Trained immunity following vaccination may produce non-specific effects leading to reduction in morbidity and mortality from heterologous pathogens. This review looked at trained immunity as a mechanism for vaccine induced non-specific effects, mechanisms underlying trained immunity and known vaccine non-specific effects. A discussion is also made on the implications these vaccine non-specific effects may have on overall risk–benefit ratio evaluation by National Medicines Regulatory Authorities (NMRAs) during licensure of new vaccines. Epigenetic remodeling and “rewiring” of cellular metabolism in the innate immune cells especially monocytes, macrophages, and Natural Killer (NK) cells have been suggested to be the mechanisms underlying trained immunity. Trained immunity in other innate cells has largely remained elusive up to date. Non-specific effects have been extensively documented with Bacille Calmette-Guerin (BCG), measles vaccine and oral polio vaccine but it remains unclear if other vaccines may exhibit similar effects. All known vaccine non-specific effects have come from observations in epidemiological studies conducted post-vaccine licensure and roll out in target populations. It remains to be seen if early identification of non-specific effects especially those with protective benefits during the clinical development of new vaccines may contribute to the overall risk–benefit ratio evaluation during licensure by NMRAs.

Respiratory tract infections (RTI) are among the leading causes of hospitalisation and death for children under 5 years. We aimed to determine if neonatal BCG vaccination reduces early life hospitalisations for lower RTI (LRTI) in a low-tuberculosis endemic setting. Neonates were randomised 1:1 to receive BCG-Denmark vaccination (BCG group) or no intervention (Control) in a phase 3 randomised controlled trial in Australia (NCT01906853). Hospitalisation for infection was determined by parent-reported questionnaires. The effect of BCG vaccination on the incidence of hospitalisation for LRTI in the first five years was analysed by intention-to-treat with multiple imputation. Complete case data to five years was available for 711 (56 %) of the 1272 participants. In the time-to-event analysis of the 1272 infants randomised, 14.2 % had one or more hospitalisations due to infection by five years. The predominant cause of hospitalisation for infection was LRTI in the first year of life (37 % of first hospitalisations), and upper RTI (33 %) by five years. In the multiple imputation analysis of the 1272 participants, the adjusted incidence of hospitalisation for LRTI in the first five years was 9.6 % in the BCG group compared to 12.4 % in the Control group (adjusted risk difference [aRD] −2.8 percentage points; 95 % CI −7.8 to 2.3). Secondary outcomes of hospitalisation for any infection and any respiratory illness were also lower in the BCG group. No interaction was observed between the effect of BCG vaccination on hospitalisation for LRTI and maternal BCG vaccination, sex or delivery mode. In a low-mortality setting, there was not clear evidence that neonatal BCG vaccination significantly reduces the incidence of early life hospitalisation for LRTI, infections or respiratory illness. The ability to detect any effect of BCG may have been limited by the increasing missing data over the course of follow-up. •Neonatal BCG did not reduce hospitalisation for infection in the first 5 years.•Hospitalisation for infection was most commonly due to respiratory tract infections.•There was no effect of maternal BCG, sex or delivery mode on the effect of BCG.

•Post hoc analysis of the effect of introducing oral BCG in Northern Sweden, 1927–31.•BCG was voluntary and mostly not provided to sick or moribund neonates.•Receiving BCG was associated with a ~80% reduction in tuberculosis deaths.•BCG appeared to protect against death from other respiratory infections. Following the introduction of oral Bacille Calmette-Guérin (BCG) a century ago, Albert Calmette suggested that BCG both provided protection against death from tuberculosis (TB) and other causes. The findings were not pursued. Today, there is considerable evidence that intradermal BCG have beneficial non-specific effects (NSEs). We re-analyzed data from BCG’s introduction 1927–1931 in Sweden hypothesizing that BCG reduced infectious deaths. In three papers published by Dr Carl Näslund, the progress of oral neonatal BCG rollout provided free-of-charge and the effects on child mortality in the highly TB-prevalent region Norrbotten was sequentially updated. We analyzed cause-specific post-neonatal mortality by vaccination status excluding deaths from congenital conditions. Due to apparent differences in effects during study years, effects were assessed overall and separately in two periods (1927–1929, 1930–1931). According to Näslund, TB households were slightly more likely to accept vaccination; fewer newborns that were sick or had congenital problems were vaccinated. BCG coverage was 28.3% (5659/20,012); 8.7% (1746/20,012) died. The BCG/unvaccinated Risk Ratio (RR) of post-neonatal childhood death was 0.53 (0.45–0.62). BCG was associated with 80% (49–92%) reduced mortality from TB. From 1927 to 29, BCG appeared to protect strongly against deaths from all diseases, including the non-infectious, RR = 0.09 (0.02–0.36), presumably reflecting selection bias. From 1930 to 1931, there was no protection against non-infectious deaths, RR = 0.92 (0.49–1.70) indicating less bias (p = 0.004 for same effect). During 1930–1931, BCG was associated with reductions in non-TB infectious deaths (RR = 0.75 (0.58–0.97)); 2/3 were caused by respiratory infections, against which the BCG/unvaccinated RR was 0.61 (0.43–0.84). Other causes of death were less frequent and provided no clear pattern, except that BCG was associated with more meningitis deaths, RR = 6.85 (2.20–21.4). Healthy vaccinee bias, particularly in 1927–1929, resulted in strongly beneficial overall BCG effects. However, the 1930–1931 data provided some support that BCG both protected against TB deaths and deaths from respiratory infections.

Nigeria contributes a substantial number of under-5 deaths and ‘zero dose’ children (i.e. children with no routine vaccinations) to the global burden each year. Vaccines are a lifesaving intervention proven to reduce child mortality from specific diseases. Non-specific effects of vaccines may further affect all-cause child mortality. This analysis explores the association between vaccination status and child survival for children 12–59 months of age, using data from the INSPIRING trial in Jigawa, Nigeria (registration: ISRCTN39213655). Descriptive analysis and logistic regression were used, with multivariate models adjusting for the study design and child age, sex, malnutrition, maternal education, maternal age, compound size and wealth quintile. Interaction effects for child sex were explored given evidence for non-specific effects of vaccines. We found all groups of vaccinated children to have reduced mortality compared to unvaccinated children. Children that completed the Nigerian vaccination schedule, i.e. received the second measles vaccine dose, had the lowest odds of death, with a 70 % reduction in mortality compared to an unvaccinated child (AOR: 0.30, CI: 0.18, 0.49, p-value <0.001). A child that had basic antigens and the 1st measles dose had 30 % lower odds of death than an unvaccinated child (AOR: 0.70, CI: 0.49, 0.98, p-value 0.038). This study supports evidence that vaccines have non-specific effects on all-cause child mortality. Unvaccinated children had the highest odds of death between 12 and 59 months of age and must be reached through vaccination to improve their chances of survival. In this setting, receiving a second measles vaccine was associated with a large reduction in child mortality, and may be an effective focus for outreach campaigns in Northern Nigeria.