key: cord-299676-6wt9rn1a authors: Gursel, Mayda; Gursel, Ihsan title: Is global BCG vaccination‐induced trained immunity relevant to the progression of SARS‐CoV‐2 pandemic? date: 2020-04-27 journal: Allergy DOI: 10.1111/all.14345 sha: doc_id: 299676 cord_uid: 6wt9rn1a nan In January, WHO Director General Tedros Adhanom Ghebreyesus said his "greatest concern" was COVID-19 spreading in countries with fragile health systems. Although countries like India, Philippines,Thailand, and Nepal have reported their first confirmed cases of the SARS-CoV-2 virus in January, widespread community spread have not been reported. Contrary to such justified expectations/predictions, on March 13 2020, WHO declared Europe as the epicenter of the pandemic. Even though we are still in the midst of the coronavirus pandemic, the disproportionately smaller number of cases reported from disadvantaged/low income countries remains puzzling. We hypothesize that general BCG vaccination policies adopted by different countries might have impacted the transmission patterns and/or COVID-19 associated morbidity and mortality. Vaccines provide protection to a particular pathogen by inducing effector mechanisms directed to that pathogen. However, certain attenuated vaccines like the Bacillus Calmette-Guerin (BCG), can also protect against unrelated pathogens, some of which cause acute respiratory tract infections 1,S1-S6 . The underlying mechanism for the BCG vaccinationinduced non-specific protection is thought to be mediated via the induction of innate immune memory, or "trained immunity, as was first proposed by Netea and collaborators. 2 Trainedimmunity inducing agents reprogramme bone marrow hematopietic stem cells and multipotent progenitors through epigenetic and metabolic changes, resulting in a more robust response in differentiated innate immune cells, following encounter with a pathogen S7-S8 . Of interest, in a randomized placebo-controlled human study, BCG vaccination was demonstrated to induce epigenetic reprograming in monocytes, conferring protection against experimental infection with an attenuated yellow fever virus vaccine strain. 3 Based on these observations, we hypothesized that countries who continue BCG immunization programs would contain the spread of this new coronavirus better than those that did not have or have ceased their national BCG vaccination programs. To check the validity of this hypothesis, we compared the number of cases and deaths per million people from all countries with at least 500 (23 March) or 1000 cases (29 This article is protected by copyright. All rights reserved Table 1 ). Cases/million in countries with a national BCG vaccination programme were statistically significantly lower than those that did not have/ceased their national BCG vaccination programs (P<0.0001). We also compared the number of deaths per million. Results showed that COVID-19associated deaths relative to the size of the population were significantly lower in countries with a national BCG vaccination programme than those without BCG vaccination (P<0.0058 and P<0.0001 for 23 March and 29, 31 March, respectively). To correct for different stages of the spread of disease, we downloaded the data showing the total confirmed deaths since the 5th death from Our World in Data web site (https://ourworldindata.org/grapher/covidconfirmed-deaths-since-5th-death). Instead of the 5th death as day 0, we chose the 100th death as day 0. The total deaths on 14th or 20th days after the 100th death were divided by the population of each country to obtain deaths/million. All countries that had data on these days were included and the comparison between the BCG vaccinated and unvaccinated populations were made (Figure 1 C). Using this "disease stage normalized" data, there was still a highly significant difference between countries that adhered to national BCG vaccination policy versus those that had ceases/never had a national programme ( Figure 1C ). If BCG vaccination has a general non-specific protective effect against spread of SARS-CoV-2 or COVID-19-associated morbidity and mortality, then BCG re-vaccination of populations offer a viable alternative of partial protection until a specific vaccine is available. The duration of BCG-induced trained immunity or how different vaccine strains compare in terms of longevity of induced innate memory is not known. Work by Netea et al show that the "trained immunity status" is maintained for at least a year (the maximum time point they measured) S9 . BCG-induced protection against tuberculosis lasts for approximately 20 years and wanes thereafter S10 . If one assumes that BCG-induced non-specific protective effect also lasts for 20 years and gradually wanes, then there should be a difference between countries that have stopped BCG vaccination earlier versus later. To assess this possibility, we analysed data from 13 European Countries that have ceased their national BCG vaccination programmes (Supplementary Table 2 ). According to this, 5 Countries (Norway, This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved methoxymycolate-producing early strains are more potent immunostimulating agents than the late strains. 6 Mycolic acids can condition macrophages to produce higher levels of IFN-γ, myeloperoxidase and TNF-α upon renewed exposure to innate triggers. 7 Accordingly, mycolic acids constitute an important group of ligands capable of inducing trained immunity. Methoxymycolic acids are inflammatory and can activate macrophages, whereas, ketomycolic acids promote anti-inflammatory, alternatively activated macrophages. 7 Since the persistence and immunostimulatory properties of BCG strains differ, their potential to induce trained immunity in vaccinated individuals could also vary. When we analyzed available data on BCG vaccine strains used in different countries Routine vaccinations and child survival: Follow up study in Trained immunity: a memory for innate host defense BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity Genome plasticity of BCG and impact on vaccine efficacy A point mutation Mycobacterium bovis BCG strains obtained after 1927 Comparable studies of immunostimulating activities in vitro among Mycobacterium bovis bacillus Calmette-Guérin (BCG) substrains Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern Mapping the global use of different BCG vaccine strains The BCG World Atlas: a database of global BCG vaccination policies and practices Conflict of Interest Statement: Dr. Gursel has nothing to disclose. Dr. Gursel has nothing to disclose This article is protected by copyright. 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