Beneficial Non-specific Effects Research Articles

Randomised Clinical Trials of COVID-19 Vaccines: Do Adenovirus-Vector Vaccines Have Beneficial Non-Specific Effects?

Randomised Clinical Trials of COVID-19 Vaccines: Do Adenovirus-Vector Vaccines Have Beneficial Non-Specific Effects?

Oral Polio Vaccine Campaigns May Reduce the Risk of Death from Respiratory Infections.

Oral polio vaccine (OPV) campaigns, but not other campaigns, have been associated with major reductions in child mortality. Studies have shown that OPV reduces the risk of respiratory infections. We analysed the causes of death at 0–2 years of age in Chakaria, a health and demographic surveillance Systems in Bangladesh, in the period 2012–2019 where 13 national campaigns with combinations of OPV (n = 4), vitamin A supplementation (n = 9), measles vaccine (MV) (n = 2), and albendazole (n = 2) were implemented. OPV-only campaigns reduced overall mortality by 30% (95% confidence interval: −10–56%). Deaths from respiratory infections were reduced by 62% (20–82%, p = 0.01) in the post-neonatal period (1–35 months), whereas there was as slight increase of 19% (−37–127%, p = 0.54) for deaths from other causes. There was no benefit of other types of campaigns. Hence, the hypothesis that OPV may have beneficial non-specific effects, protecting particularly against respiratory infections, was confirmed.

Oral vaccination stimulates neutrophil functionality and exerts protection in a Mycobacterium avium subsp. paratuberculosis infection model

Mycobacterium avium subsp. paratuberculosis (Map) causes paratuberculosis (PTB), a granulomatous enteritis in ruminants that exerts high economic impact on the dairy industry worldwide. Current vaccines have shown to be cost-effective against Map and in some cases confer beneficial non-specific effects against other pathogens suggesting the existence of trained immunity. Although Map infection is mainly transmitted by the fecal-oral route, oral vaccination has not been deeply studied. Therefore, the aim of this study was to compare the oral route with a set of mycobacterial and non-mycobacterial vaccines with a subcutaneously administered commercially available vaccine. Training effects on polymorphonuclear neutrophils (PMNs) and homologous and heterologous in vivo protection against Map were investigated in the rabbit infection model. Oral vaccination with inactivated or live vaccines was able to activate mucosal immunity as seen by elevation of serum IgA and the expression of IL4 in peripheral blood mononuclear cells (PBMCs). In addition, peripheral PMN phagocytosis against Map was enhanced by vaccination and extracellular trap release against Map and non-related pathogens was modified by both, vaccination and Map-challenge, indicating trained immunity. Finally, PBMCs from vaccinated animals stimulated in vitro with Map antigens showed a rapid innate activation cytokine profile. In conclusion, our data show that oral vaccination against PTB can stimulate neutrophil activity and both innate and adaptive immune responses that correlate with protection.

Neonatal Bacille Calmette-Guérin vaccination and tuberculin skin test reactions at 2- and 6-months: Effects on mortality up to 1 year of age

BackgroundIn randomized trials, Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced all-cause mortality. BCG-induced Tuberculin Skin Test (TST) reactions have also been associated with reduced all-cause mortality. We aimed to assess the association between TST responses and subsequent mortality in three birth cohorts and conducted a meta-analysis of existing studies. MethodsObservational study within three Guinea-Bissau BCG trial birth cohorts (conducted 2002–04, 2009–2013 and 2014–18) that encompassed children who were BCG-vaccinated within 28 days with TSTs performed at 2- (n = 1389) and 6-months (n = 2635) of age. We evaluated TST reaction determinants by binomial regression and assessed the association between TSTs > 1 mm (reactors) vs. ≤ 1 mm (non-reactors) and subsequent mortality risk up to age 12 months in Cox-models providing Mortality Rate Ratios (MRRs). We searched PubMed for studies to calculate meta-estimates of the association between TST reactivity by age 2- and 6-months and all-cause mortality. ResultsLarge post-vaccination wheal size was associated with 6-month TST positivity and so was receiving BCG-Denmark or BCG-Japan, compared with BCG-Russia. By age 2 months, 22% (302/1389) of infants were TST reactors with a 2–12-month mortality risk of 1.7% (5/302) vs. 3.3% (36/1087) for non-reactors, the corresponding reactor/non-reactor MRR = 0.49 (0.19–1.26). By age 6 months, 44% (1149/2635) of infants were reactors and the 6–12-month mortality risk was 0.4% (4/1149) vs. 0.6% (9/1486) for non-reactors, the MRR = 0.87 (0.27–2.86). The literature search provided 3 studies. The meta-analysis revealed a uniform pattern of reduced mortality associated with TST reactivity, a TST response by 2 months being associated with an MRR of 0.59 (0.39–0.90); for 6-month TST responses the MRR was 0.65 (0.43–1.00). ConclusionAmong BCG-vaccinated infants, TST reactions were associated with markedly reduced mortality. Improved vaccination technique and using certain BCG strains could lead to a higher TST reaction prevalence, which would enhance BCG’s beneficial non-specific effects.

The introduction of BCG vaccination to neonates in Northern Sweden, 1927–31: Re-analysis of historical data to understand the lower mortality among BCG-vaccinated children

BackgroundFollowing 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. MethodsIn 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). ResultsAccording 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). ConclusionHealthy 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.

National immunisation campaigns with oral polio vaccine may reduce all-cause mortality: Analysis of 2004-2019 demographic surveillance data in rural Bangladesh.

BackgroundWest African studies have suggested that national immunisation campaigns with oral polio vaccine (C-OPV) may non-specifically reduce all-cause child mortality rate by 15–25%. We investigated whether C-OPVs had similar non-specific effects in rural Bangladesh from 2004 to 2019.MethodsChakaria, is a health and demographic surveillance system (HDSS) in Southern Bangladesh. From 2004–2011 the HDSS covered a random sample of households; from 2012 to 2019 it covered a random sample of villages. Using Cox proportional hazards models, we calculated hazard ratios (HR) comparing mortality for children under 3 years of age after C-OPV versus before C-OPV to assess the effect of receiving a C-OPV. We allowed for different baseline hazard function in the two periods (2004–2011, 2012–2019), with separate models for each period.FindingsThere were 768 deaths (2.1%) amongst 36,176 children. The HR after C-OPV was 0.69 (95% confidence interval: 0.52–0.90). National campaigns providing vitamin A or measles vaccine did not have similar effects. Each additional dose of C-OPV was associated with a reduction in the mortality rate by 6% (−2 to 13%). The number needed to treat with C-OPV to save one life between 0 and 35 months of age was 88 (81–96).InterpretationThis is the fourth study to show that C-OPV has beneficial non-specific effects on child survival. All studies have shown a beneficial effect of C-OPV on child health. Stopping OPV as planned after polio eradication without any mitigation plan could have detrimental effects for overall child health in low-income countries.FundingThe Chakaria HDSS was funded by international sponsors. No sponsor had any influence on the preparation of the article.

A place for neutrophils in the beneficial pathogen-agnostic effects of the BCG vaccine

The BCG vaccine has long been recognized for reducing the risk to suffer from infectious diseases unrelated to its target disease, tuberculosis. Evidence from human trials demonstrate substantial reductions in all-cause mortality, especially in the first week of life. Observational studies have identified an association between BCG vaccination and reduced risk of respiratory infectious disease and clinical malaria later in childhood. The mechanistic basis for these pathogen-agnostic benefits, also known as beneficial non-specific effects (NSE) of BCG have been attributed to trained immunity, or epigenetic reprogramming of hematopoietic cells that give rise to innate immune cells responding more efficiently to a broad range of pathogens. Furthermore, within trained immunity, the focus so far has been on enhanced monocyte function. However, polymorphonuclear cells, namely neutrophils, are not only major constituents of the hematopoietic compartment but functionally as well as numerically represent a prominent component of the immune system. The beneficial NSEs of the BCG vaccine on newborn sepsis was recently demonstrated to be driven by a BCG-mediated numeric increase of neutrophils (emergency granulopoiesis (EG)). And experimental evidence in animal models suggest that BCG can modulate neutrophil function as well. Together, these findings suggest that neutrophils are crucial to at least the immediate beneficial NSE of the BCG vaccine. Efforts to uncover the full gamut of mechanisms underpinning the broad beneficial effects of BCG should therefore include neutrophils at the forefront.

Stopping Oral Polio Vaccine (OPV) after Defeating Poliomyelitis: A Pyrrhic Victory? Systematic Review of the Non-Specific Effects of OPV

Background: Previous studies revealed that the two live vaccines, BCG and measles vaccine (MV), have beneficial non-specific effects (NSEs) reducing morbidity and mortality more than could be explained by prevention of tuberculosis and measles infection. Since live oral polio vaccine (OPV) is stopped and replaced with inactivated polio vaccine (IPV) in high-income countries and will be stopped globally after polio eradication, we undertook a review of potential NSEs of OPV on mortality. Methods: We searched PubMed for all studies of OPV and death/mortality. In low-income settings, OPV has been provided in three different settings: First, as co-administration of OPV and diphtheria-tetanus-pertussis (DTP) vaccine in three doses from 6 weeks of age. Second, as an early dose at birth (OPV0), often administered together with BCG. Third, in OPV campaigns to eradicate polio infection. We calculated relative risk (RR) of mortality for different combinations of vaccinations and RR of the mortality rate before and after OPV campaigns. Results: The majority of studies was from Guinea-Bissau. First, in three natural experiments, where DTP was missing, OPV-only compared with DTP+OPV co-administered was associated with 3-fold lower mortality rate in two community studies (RR=0.33 (0.14-0.77)) and in a hospital case fatality study (RR=0.29 (0.11-0.77)). Conversely, when OPV was missing, DTP-only was associated with 3-fold higher mortality than co-administration of DTP+OPV (RR=3.23 (1.27-8.21)). Second, in two randomised controlled trials (RCTs), OPV0 vs. no OPV0 was associated with 32% lower infant mortality. The beneficial effects of OPV0 were stronger the earlier the vaccine had been given. Third, in six population-based studies from urban and rural Guinea-Bissau, Burkina Faso and Bangladesh, the mortality rate was lower with a RR=0.75 (0.69-0.82) after OPV campaigns than before OPV campaigns. Furthermore, OPV campaigns changed the mortality effect of health interventions in nine RCTs. The intervention had the strongest beneficial effect before OPV campaigns in all RCTs; hence, OPV campaigns reduced the mortality rate and the difference between randomisation groups disappeared. Interpretation: There have been no polio cases in Guinea-Bissau in this century and no confounding factors or bias would be able to explain these patterns. The only interpretation consistent with all data is that OPV has beneficial NSEs, reducing child mortality. Child mortality may increase again once OPV is removed or replaced with IPV. If no counter-measures are taken, eradicating polio and stopping OPV may become a Pyrrhic victory. Funding: The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3- 2011-261375). CSB held a starting grant from the ERC (ERC-2009-StG-243149). CVIVA was supported by a grant from the Danish National Research Foundation (DNRF108). PA held a research professorship grant from the Novo Nordisk Foundation. Declaration of Interest: Nothing to declare.

Can existing unrelated vaccines boost a COVID-19 vaccine prime?

Can existing unrelated vaccines boost a COVID-19 vaccine prime?

BCG vaccination in health care providers and the protection against COVID-19.

A number of coronavirus disease 2019 (COVID-19) vaccine candidates have shown promising results, but substantial uncertainty remains regarding their effectiveness and global rollout. Boosting innate immunity with bacillus Calmette Guérin (BCG) or other live attenuated vaccines may also play a role in the fight against the COVID-19 pandemic. BCG has long been known for its nonspecific beneficial effects that are most likely explained by epigenetic and metabolic reprogramming of innate immune cells, termed trained immunity. In this issue of the JCI, Rivas et al. add to these arguments by showing that BCG-vaccinated health care providers from a Los Angeles health care organization had lower rates of COVID-19 diagnoses and seropositivity compared with unvaccinated individuals. Prospective clinical trials are thus warranted to explore the effects of BCG vaccination in COVID-19. We posit that beyond COVID-19, vaccines such as BCG that elicit trained immunity may mitigate the impact of emerging pathogens in future pandemics.

BCG vaccine: Worrying proposal for COVID-19

Bacille Calmette-Guérin (BCG) vaccine is proven to be effective in protecting against severe tuberculosis. It has been suggested to be able to exert a non-specific beneficial effect as protection against other infectious diseases. The duration of protection against tuberculosis is estimated to be from 10 to 15 years, but the duration of the protection against other infections is not known, maybe up to 20 years, maybe much shorter than that. We don’t know it for sure. BCG induced trained immunity paradigm is based on experimental models, cohort studies with low number of individuals, and some epidemiological data in which other possible interfering factors are not controlled. The titles and scopes of scientific articles should be cautiously considered as they can promote indications of getting vaccinated or revaccinated with BCG, before its effectiveness is confirmed and recommendations are published. Besides, revaccination with BCG can put at serious risk patients with primary or secondary immunodeficiency. Maybe BCG vaccine is effective in preventing COVID-19 deaths or reducing its severity, but may the effect of this vaccine be relevant even with poor health politics and assistance? It is very difficult to compare the epidemiologic data about COVID-19 in different countries. There are countless factors, mainly social and related to the healthcare system, which can be more decisive than the hypothesis of trained immunity induced by BCG. Until now, we can say that BCG’s protective role is, at least, insufficient, given many other factors that corroborate SARS-CoV-2 infection and/or its severity.

Good old BCG - what a century-old vaccine can contribute to modern medicine.

Good old BCG - what a century-old vaccine can contribute to modern medicine.

The Effect of BCG on Mortality Beyond Infancy: 30-Year Follow-Up of a Double-Blind Randomised Placebo-Controlled Trial of BCG Re-Vaccination in Malawi

Background: Trials of BCG to prevent COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of BCG’s beneficial non-specific effects come largely from data on mortality in infants, and from in vitro and animal studies. We assess all-cause mortality following a large BCG re-vaccination trial in Malawi. Methods: A population-based double-blind randomised trial comparing BCG re-vaccination vs placebo to prevent tuberculosis and leprosy was initiated in Karonga District, Malawi, in 1986-9, in individuals aged 3 months to 75 years. Active follow-up was carried out in northern areas of the district in 1991-94 and in a southern area in 2002-2018 covering 15.8% (7389 individuals) and 12.0% (5616 individuals) of the trial population respectively. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality rates. Findings: There was no difference in mortality rate between the BCG and placebo group in either follow-up, overall or by age group. Mortality rates in the northern areas were 6.6/1000 person years at risk (pyar), 95% confidence interval 5.5-7.8, and 7.0/1000pyar (5.9-8.2) for those who received BCG and placebo, respectively. In the southern area they were 6.3/1000 pyar, (5.5-7.1), and 5.9/1000 pyar, (5.2-6.8), respectively. Interpretation: We found no evidence of any beneficial effect of BCG re-vaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, may obscure any benefits. Funding Statement: The original trial was funded by primarily by the British Leprosy Relief Association (LEPRA), with assistance from the International Federation of Anti-Leprosy Organizations (ILEP), and the Immunology of Leprosy component of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (IMMLEP/TDR), with support of the Malawian Ministry of Health. The later follow-up was funded by The Wellcome Trust There was no specific funding for this analysis.Declaration of Interests: We declare no competing interests.Ethics Approval Statement: The trial protocol was approved in 1985 by the Health Sciences Research Committee of the Malawi Ministry of Health, the Standing Committee on Research in Human Subjects of WHO, and the Ethics Committee of the London School of Hygiene & Tropical Medicine. Follow-up of the population has been approved in the context of other studies by the Health Sciences Research Committee of the Malawi Ministry of Health and the Ethics Committee of the London School of Hygiene & Tropical Medicine.

A REVIEW ON CONNECTION BETWEEN BCG VACCINATION AND COVID 19 CASES: FACTS AND FIGURES

Apart from its magnificent effect against the tuberculosis disease, the BCG vaccine has other nonspecific beneficial effects on the immune system that protect against a wide range of other infections Scientific Community around the globe is linking this non-specific immunity raised by BCG with incidence of the morbidity and mortality associated with Corona Virus infection Research is going on to find its role in shielding effect towards respiratory infection secondary to COVID-19 infection Authors are presenting a review of literature available for the same along with possible mechanism of action of BCG against SARS-COVID and reporting the incidence of COVID infections in countries with and without BCG as Standard Immunization

BCG-induced trained immunity: can it offer protection against COVID-19?

Bacillus Calmette–Guerin (BCG) vaccination has been reported to decrease susceptibility to respiratory tract infections, an effect proposed to be mediated by the general long-term boosting of innate immune mechanisms, also termed trained immunity. Here, we discuss the non-specific beneficial effects of BCG against viral infections and whether this vaccine may afford protection to COVID-19. Could the BCG vaccine be used to bridge the gap until a specific COVID-19 vaccine is developed? Luke O’Neill and Mihai Netea discuss the science behind this approach.

Virus-Induced T Cell-Mediated Heterologous Immunity and Vaccine Development.

Heterologous immunity (H.I.) is a consequence of an encounter with a specific antigen, which can alter the subsequent immune response to a different antigen. This can happen at the innate immune system level—often called trained immunity or innate immune memory—and/or at the adaptive immune system level involving T memory cells and antibodies. Viruses may also induce T cell-mediated H.I., which can confer protection or drive immunopathology against other virus subtypes, related or unrelated viruses, other pathogens, auto- or allo-antigens. It is important to understand the underlying mechanisms for the development of antiviral “universal” vaccines and broader T cell responses rather than just subtype-specific antibody responses as in the case of influenza. Furthermore, knowledge about determinants of vaccine-mediated H.I. may inform public health policies and provide suggestions for repurposing existing vaccines. Here, we introduce H.I. and provide an overview of evidence on virus- and antiviral vaccine-induced T cell-mediated cross-reactive responses. We also discuss the factors influencing final clinical outcome of virus-mediated H.I. as well as non-specific beneficial effects of live attenuated antiviral vaccines such as measles and vaccinia. Available epidemiological and mechanistic data have implications both for the development of new vaccines and for personalized vaccinology, which are presented. Finally, we formulate future research priorities and opportunities.

The effect of early measles vaccination on morbidity and growth: A randomised trial from Guinea-Bissau

BackgroundMeasles vaccine (MV) has beneficial non-specific effects protecting against non-measles infections in some situations. Within a trial of the effect of MV on mortality, we assessed effects of early MV on the secondary outcomes consultations and growth, overall, and by sex and exposure to campaigns with oral polio vaccine (OPV). Materials and methodsChildren were randomly assigned to MV at 4.5 + 9 months or MV at 9 months as recommended. At enrolment and 9 months children had their mid-upper-arm-circumference (MUAC) and weight measured. Consultations (out/inpatient) were registered at monthly home visits. Weight-for-age and MUAC-for-age Z-scores were obtained using the WHO growth reference and compared by group in linear regression models. Consultation rates between enrolment and 9 months were compared in Cox proportional hazards models, providing consultation Hazard Ratios (HRs) for early MV versus no early MV. We tested whether the effect of early MV was modified by OPV campaigns by splitting observation time at exposure to OPV campaigns. ResultsAmong 3548 children enrolled between 2012 and 2015, early MV had no effect on MUAC-for-age (mean difference comparing early MV vs. no MV −0.01, 95% CI −0.06–0.04), weight-for-age (mean difference −0.03, 95% CI −0.07–0.02) or rates of consultations (HR = 1.03, 95% CI 0.92–1.16). The rate of consultations for children enrolled was lower after exposure to OPV campaigns (HR = 0.81, 95% CI 0.71–0.92). The effect of MV differed before exposure to OPV campaigns (HR = 1.12, 95% CI 0.98–1.29) and after OPV campaigns (HR = 0.83, 95% CI 0.67–1.03) (test for interaction: p = 0.03). Associations did not differ by sex. ConclusionEarly MV had no overall effect on consultation rates and growth between enrolment and 9 months of age. However, early MV tended to have beneficial effects for children subsequently exposed to OPV campaigns. As beneficial effects were observed in subgroups, the results should be interpreted with caution.Clinical trials registration:NCT01644721.

Bacille Calmette-Guérin vaccination at birth and differential white blood cell count in infancy. A randomised clinical trial

BackgroundThe Bacille Calmette-Guérin (BCG) vaccine against tuberculosis (TB) may have beneficial non-specific effects (NSEs) beyond the protection against TB. This may be related to modifications of the innate immune system. We investigated the effect of BCG at birth on differential white blood cell (WBC) count in healthy, Danish infants. MethodThe Danish Calmette Study randomised newborns to BCG at birth (Danish strain 1331, Statens Serum Institut) or no intervention. A sub-group of infants had blood samples collected 4 days after randomisation (n = 161), and at age 3 months (n = 152) and 13 months (n = 300). We evaluated the effect of BCG on WBC differential count (total leucocytes, lymphocytes, monocytes, eosinophil, neutrophil and basophil granulocytes (109 cells/L)) measured in peripheral blood. ResultsOverall, we found no effect of BCG on differential WBC counts at any time point. ConclusionBCG at birth did not affect WBC count in our cohort of healthy, Danish infants.

Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study

ObjectivesTo assess the association between neonatal BCG vaccination and mortality between 28 days and 3 years of age among tuberculosis (TB)-exposed and TB-unexposed children.DesignProspective cohort study.SettingBandim Health Project runs an...

Will bacille Calmette-Guerin immunization arrest the COVID-19 pandemic?

Will bacille Calmette-Guerin immunization arrest the COVID-19 pandemic?