key: cord-0707055-qharpann
authors: Jansson, Moritz K.; Neuber, Kerstin; Rudolf, Henrik; Podbielski, Andreas; Virchow, J. Christian; Warnke, Philipp
title: Childhood Bacille Calmette‐Guérin vaccination seems to selectively protect adult males from COVID‐19 infection
date: 2021-12-03
journal: Allergy
DOI: 10.1111/all.15186
sha: 911104aff711915680b93a290a20e8cd8091f36c
doc_id: 707055
cord_uid: qharpann

nan

To the Editor, Many studies have suggested a beneficial, non-specific effect of the now 100-year-old Bacille Calmette-Guérin (BCG) vaccine on child mortality due to a reduction in neonatal sepsis and respiratory tract infections as well as protection against various specific viral diseases. [1] [2] [3] [4] [5] [6] Two mechanisms have been demonstrated by which non-specific protection against unrelated pathogens is thought to occur: (i) epigenetic training of macrophages and natural killer (NK) cells and (ii) heterologous T helper 1 (Th1) and Th17 immune responses. 7 In the first wave of the COVID-19 pandemic, some countries had a substantially lower mortality and morbidity due to SARS-CoV-2. Early on, some ecological studies concluded that BCG vaccination might be one of the underlying causes of the observed difference between countries, while others did not find such a correlation. 3, 4, 8, 9 We used a case-control design to investigate whether BCG vaccination during childhood affects the risk of COVID-19infection in adults. The study was conducted in East Germany at a time of the COVID-19 pandemic before the so-called 'variants of concern' emerged in our region. We took advantage of a federally imposed contact tracing system in Germany to selectively include uniformly defined close contacts of COVID-19-infected persons thereby having a comparable risk of COVID-19-transmission. Close contacts were considered cases if they had a positive SARS-CoV-2-PCR test and/or if SARS-CoV-2-specific antibody testing-which was performed at least three weeks after contact-returned a positive result. BCG vaccination status was individually assessed under consideration of vaccination certificates and additional supportive parameters by a medical professional (Appendix S1). 800 persons were invited (response rate 28.9%). Due to rigorous BCG vaccination policy in East Germany until the year 1990, age-adjusted analysis could not be conducted for older age groups due to the lack of BCGnon-vaccinated participants. 147 of 190 included individuals from 17 to 46 years of age were therefore selected for final analysis to form three age groups (17-26, 27-36 and 37-46). There were 87 females (59.2%) and 60 males (40.8%) ( Table 1 ). Likelihood ratio tests performed to test for interaction by sex and age yielded a P value of 0.015 and 0.79, respectively, indicating that the association between BCG status and COVID-19 infection was modified by sex but not by age. Therefore, a final model of the relationship between BCG vaccination and COVID-19 infections was fitted that included age as a confounder and sex as an effect modifier. BCG vaccination status was associated with a lower likelihood of COVID-19 infection for men but not for women (ORs 0.13 and 1.04, respectively). For men, we found a highly significant association with 95% CIs ranging from 0.04 to 0.48 (p = 0.002), while for women, 95% CIs ranged from 0.40 to 2.71 (p = 0.938) ( Table 2 ). Grossly, we observed comparatively more infected BCG-non-vaccinated males and fewer infected BCGvaccinated males than females which resulted in a roughly balanced distribution of COVID-19 infections between males and females in our study (OR: 1.06, 95% CI 0.53-2.09 p = 0.876). BCG vaccination might differentially affect men by turning them from a natural state of being at higher risk of COVID-19 infection to a state of being at lower risk compared with women.

Bacille Calmette-Guérin vaccination status did not seem to affect COVID-19-related symptoms (fever, shortness of breath, joint pains, fatigue, dry cough and loss of smell), and no correlation between impact of symptoms on state of health and BCG vaccination status was found (overall estimate and conducted separately for males and females and two age groups [≤30 and >30 years of age] using chisquared test and Fisher's exact test as appropriate, Appendix S1).

A cross-sectional study conducted in Los Angeles found evidence of a protective effect of BCG vaccination but did not mention results from sex-stratified analysis. 10 BCG vaccination was never part of the US routine vaccination programme. A case-control study from Canada evaluated COVID-19-related health outcomes for BCG-vaccinated and BCG-non-vaccinated born between 1956 and 1976 and did not find evidence of a protective effect from BCG vaccination. 11 Participants in the present study tended to be much younger limiting comparability.

Epidemiological investigations of sex-dependent differences in non-specific effects of BCG vaccination are scarce. A randomized trial (RCT) found that non-specific effects of BCG vaccination concerning all-cause mortality and morbidity in the neonatal period differed between males and females in the first weeks of life. infection, especially caused by respiratory syncytial virus, that was most marked in girls. 2 In contrast, a case-control study conducted in Kenya found a statistically significant reduction in communityacquired pneumonia in BCG-vaccinated males (study population: 15-54 years of age), while no effect was present in women. 6 The lon- In light of sex dependencies with respect to IFNγ release after BCG vaccination and the recent evidence for T cell cross-reactivity between BCG and SARS-CoV-2-derived peptides, a mechanism involving heterologous immune responses mediated by Th1 cells could be hypothesized.

As the effect seen in the present study was limited to COVID-19 infection with no influence on symptoms, instantaneous defence mechanisms such as pattern recognition receptors suitable to prevent infection differentially expressed by BCG-vaccinated males might play a role but cannot be elucidated from the evidence currently available.

Adjustment for confounding factors other than age and sex was impeded by the study's limited sample size. Analysis of effect mod- Note: Due to effect modification of BCG status by sex for the odds of COVID-19 infection, specific odds ratios are presented for the effect of BCG status on COVID-19 infections for males and females and the effect of sex on COVID-19 infections for BCG vaccinated and BCG-non-vaccinated. a Odds ratios and 95% confidence intervals included within brackets.

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Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls: Community based case-control study

Is BCG vaccination affecting the spread and severity of COVID-19?

Could anti-tubercular vaccination protect against COVID-19 infection?

Rapid protective effects of early BCG on neonatal mortality among low birth weight boys: observations from randomized trials

Risk factors for community-acquired pneumonia among adults in Kenya: a case-control study. Pneumonia (Nathan Qld)

Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity

Is global BCG vaccination-induced trained immunity relevant to the progression of SARS-CoV-2 pandemic?

Reconcile the debate over protective effects of BCG vaccine against COVID-19

BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers

Does BCG provide longterm protection against SARS-CoV-2 infection? A case-control study in Quebec

BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner

BCG vaccine derived peptides induce SARS-CoV-2 T cell cross-reactivity