key: cord-0875510-rdr0eb1r authors: Nachega, Jean B.; Maeurer, Markus; Sam-Agudu, Nadia A.; Chakaya, Jeremiah; Katoto, Patrick D.M.; Zumla, Alimuddin title: Bacille Calmette-Guérin (BCG) Vaccine and Potential Cross-Protection against SARS-CoV-2 Infection – Assumptions, Knowns, Unknowns and Need for Developing an Accurate Scientific Evidence Base date: 2021-03-29 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.03.060 sha: 2e9526074d576eaa6cc992827c2a693293ed9718 doc_id: 875510 cord_uid: rdr0eb1r After a century of controversies on its usefulness in protection against TB, underlying mechanisms of action, and benefits in various groups and geographical areas, the BCG vaccine is yet again a focus of global attention- this time due to the global COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Recent studies have shown that human CD4+ and CD8+ T-cells primed with a BCG-derived peptide developed high reactivity to its corresponding SARS-CoV-2-derived peptide. Furthermore, BCG vaccine has been shown to substantially increase interferon-gamma (IFN-g) production and its effects on CD4 + T-cells and these non-specific immune responses through adjuvant effect could be harnessed as cross protection against severe forms of COVID-19.The completion of ongoing BGG trials is important as they may shed light on the mechanisms underlying BCG-mediated immunity and could lead to improved efficacy, increased tolerance of treatment, and identification of other ways of combining BCG with other immunotherapies. It has been more than a hundred years since Jean-Marie Camille Guérin and Albert Calmette developed the Bacille Calmette-Guérin (BCG) vaccine for preventing tuberculosis (Towey, 2015) . After a century of controversies on its usefulness in protection against TB, underlying mechanisms of action, and benefits in various groups and geographical areas (Lienhardt & Zumla, 2005; Locht & Lerm, 2020) , the BCG vaccine is yet again a focus of global attention-this time due to the global COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of 26 January 2021, there have been over 98.8 million confirmed cases of including 2, 124, 193 deaths, n.d.) . The BCG vaccine contains live attenuated Mycobacterium bovis, and is known to induce both humoral and adaptive immunity, activating both non-specific and cross-reactive immune responses in the host (Moorlag et al., 2019) . Combined, these non-specific adjuvant effects of BCG could effectively mount responses to other pathogens, including viruses (Moorlag et al., 2019; Uthayakumar et al., 2018) . It has also been used for treating bladder cancer for the past 40 years although the specific mechanisms of action remain unknown (Sfakianos et al, 2021) . Previous studies have documented associations between BCG vaccination and reductions in the incidence of respiratory tract infections among children and adults, and all-cause mortality in children(Moorlag Uthayakumar et al., 2018) . Furthermore, the vaccine has been reported to exert antiviral effects in experimental models; reduce viremia in an experimental human model of viral infection ; protecting against experimental infection with yellow fever vaccine strain, and enhancing immune responses to other vaccines such as influenza vaccine (Arts et al., 2018) . Many of these broad-spectrum protective effects have been attributed to trained immunity, the epigenetic and metabolic reprogramming of innate immune cells (Arts et al, 2020; Moulson & Av-Gay, 2020) . Based on these reports and epidemiological observations, the potential for BCG vaccination to induce (partial) protection against SARS-CoV-2 infection and prevent serious disease was thus deemed plausible and logical in what was a desperate global situation (Escobar et al, 2020; Patella V et al, 2020) . A pressing question arose: Does prior BCG vaccination reduce host susceptibility to SARS-CoV-2 infection and/or significantly reduce COVID-19 severity and mortality rate? Before the advent and recent rollout of COVID-19-specific vaccines, the desperate search to find interventions which could prevent the high mortality rates, especially in the elderly and those with co-morbidities, sparked off a global debate on the potential use of BCG for management or prevention of COVID-19 (Brooks et al., 2021; Charoenlap et al., 2020; Escobar et al, 2020; Klinger et al, 2020; Lindestam et al, 2020; Junqueira-Kipnis et al., 2020; Kinoshita & Tanaka, 2020; Riccò et al., 2020; ten Doesschate et al., 2020; Yitbarek et al., 2020) . Due to the sense of urgency in addressing the rapidly-progressing pandemic, there were calls to roll out BCG vaccine for protection against SARS-CoV-2 (De Wals et al., 2020; Kangbai et al., 2021; Malik et al., 2020; Salman & Salem, 2020) . There are also concerns about the lack of any convincing data on the effectiveness of BCG in preventing serious disease due to SARS-CoV-2 infection. An additional concern was that indiscriminate BCG use would create a shortage and compromise routine immunization programs (Chimoyi et al., 2020; Kumar & Meena, 2020; Kuroda, 2020; Riccò et al., 2020) . Early in the outbreak, it was noted that rates of SARS-CoV-2 infection and case fatality rate varied significantly in different parts of the world, being relatively higher in North America and Europe, and lower in regions such as South America, South Asia and Africa(Coronavirus Disease (COVID-19) -World Health Organization, n.d.). Epidemiological observations and ecological studies suggested that western countries that were not endemic for TB and thus did not advocate universal BCG vaccination had higher COVID-19 incidence and mortality rates, compared to low and middleincome countries with longstanding mass BCG immunization programs (http://www.bcgatlas.org/ ; Brooks et al., 2021; Riccò et al., 2020; Urashima et al., 2020) . Most of these studies however did not consider major confounding factors such as demographics (e.g., age distribution) or how long and to what extent universal BCG vaccination was implemented. Furthermore, analyses performed in the latter half of 2020 using updated COVID-19 data have failed to show any significant association with BCG vaccination-or the lack thereof . As of 26 January, 2021, there are at least 20 ongoing clinical trials in Africa, Australia, South Asia, North and South America and Europe, that are expected to provide more robust data on the effectiveness of BCG vaccination in modulating susceptibility to SARS-CoV-2 infection and disease (Home -ClinicalTrials.Gov, n.d.) . However, to date, available evidence is relatively weak. Recent studies have shown that human CD4+ and CD8+ T-cells primed with a BCG-derived peptide developed high reactivity to its corresponding SARS-CoV-2-derived peptide (Eggenhuizen et al., 2020; Urban et al, 2020) . Peptide sensitization using BCG has been found to produce cross-reactive T-cells specific to SARS-CoV-2. They identified 8 BCG-derived peptides in silico with considerable sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Due to human leukocyte antigen (HLA) differences between individuals, not all persons develop immune responses every one of the 8 BCG-derived peptides. Overall, the study results suggest that CD4+ and CD8+ T-cells specific for BCG-derived peptides are cross-reactive to SARS-CoV-2-derived peptides. This may explain the epidemiologic observation that BCG vaccination may protect against COVID-19 disease or death by triggering cross-reactive SARS-CoV-2-specific T-cell response. While this awaits confirmation by demonstrating that SARS-CoV-2 specific T-cell clones recognize naturally processed and presented BCG -epitopes (and vice versa), 'trained immunity' imposed by BCG on the quality and quantity of cellular immune responses has been suggested, although this is often short lived and the protective role of BCG regarding clinical severe COVID-19 has been disputed (Arlahamn et al., PNAS, Oct13, Vol., 117, 15203-25204, 2020) . Other, not mutually exclusive factors need to be considered: BCG vaccine has been shown to substantially increase interferon-gamma (IFN-g) production and its effects on CD4+ T cells (Flynn JL et al, 1993) and these non-specific immune responses could be harnessed as cross protection against severe forms of COVID-19 (Sohrabi Y et al, 2020; Mosaddeghi P et al, 2020) . Severe forms of COVID-19 have been described in patients with inborn errors of type I IFN responses or those who have autoantibodies directed against IFN . There are currently over 20 clinical trials in progress to determine the effectiveness of BCG vaccination for prevention of SARS-CoV-2 infection or reduce the severity of COVID-19(Home -ClinicalTrials. Gov, n.d.) . Currently, at least three SARS-CoV-2 vaccines have been shown to be effective in randomized controlled trials and are licensed and approved for global roll out (Commissioner, 2021; Kim et al., 2021; Singh & Upshur, 2020) . Therefore, one question arises: is there any role for BCG in COVID-19 prevention or treatment, and do the ongoing trials need to be abandoned? Based on the data reviewed and the safety and widespread use of the BCG vaccine, its low cost and easy availability, and the low priority given by vaccine manufacturers (Gupta, 2020) it is certainly reasonable to continue the trials of BCG. Furthermore, the data may provide a better J o u r n a l P r e -p r o o f Lack of evidence for BCG vaccine protection from severe COVID-19 BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Autoantibodies against type I IFNs in patients with life-threatening COVID-19 The association of Coronavirus Disease-19 mortality and prior bacille Calmette-Guerin vaccination: A robust ecological analysis using unsupervised machine learning Potential role of Bacillus Calmette-Guérin (BCG) vaccination in COVID-19 pandemic mortality: Epidemiological and Immunological aspects An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19 COVID-19 Vaccines COVID-19) -World Health Organization Can BCG be useful to mitigate the COVID-19 pandemic? A Canadian perspective BCG vaccine derived peptides induce SARS-CoV-2 T cell cross-reactivity BCG vaccine protection from severe coronavirus disease 2019 (COVID-19) An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection New disease old vaccine: Is recombinant BCG vaccine an answer for COVID-19? Novel Use of an Existing Vaccine (BCG) Alliance: The NUEVA Trial Lack of evidence for BCG vaccine protection from severe COVID-19 Good old BCG -what a century-old vaccine can contribute to modern medicine BCG vaccine: A hope to control COVID-19 pandemic amid crisis Harnessing the nonspecific immunogenic effects of available vaccines to combat COVID-19 Non-specific effects of BCG vaccine on viral infections. Clinical Microbiology and Infection: The Official Publication of the BCG immunomodulation: From the 'hygiene hypothesis' to COVID-19 Epub ahead of print The bacillus Calmette-Guérin vaccination allows the innate immune system to provide protection from severe COVID-19 infection Stop playing with data: There is no sound evidence that Bacille Calmette-Guérin may avoid SARS-CoV-2 infection Routine childhood immunization may protect against COVID-19 Bacillus Calmette-Guerin (BCG): Its fight against pathogens and cancer The granting of emergency use designation to COVID-19 candidate vaccines: Implications for COVID-19 vaccine trials. The Lancet Infectious Diseases Trained immunity as a novel approach against COVID-19 with a focus on Bacillus Calmette-Guérin vaccine: mechanisms, challenges and perspectives Two Randomized Controlled Trials of Bacillus Calmette-Guérin Vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: A structured summary of the study protocols for two randomised controlled trials Léon Charles Albert Calmette and Jean-Marie Camille Guérin. The Lancet Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations Identification of similar epitopes between severe acute respiratory syndrome coronavirus-2 and Bacillus Calmette-Guérin: potential for cross-reactive adaptive immunity The effect of Bacillus Calmette-Guérin (BCG) vaccination in preventing severe infectious respiratory diseases other than TB: Implications for the COVID-19 pandemic Inborn errors of type I IFN immunity in patients with life-threatening COVID-19