key: cord-0829930-cv5th7hd authors: Moorlag, Simone J.C.F.M.; van Deuren, Rosanne C.; van Werkhoven, Cornelis H.; Jaeger, Martin; Debisarun, Priya; Taks, Esther; Mourits, Vera P.; Koeken, Valerie A.C.M.; de Bree, L. Charlotte J.; Doesschate, Thijs ten; Cleophas, Maartje C.; Smeekens, Sanne; Oosting, Marije; van de Veerdonk, Frank L.; Joosten, Leo A.B.; Oever, Jaap ten; van der Meer, Jos W.M.; Curtis, Nigel; Aaby, Peter; Stabell-Benn, Christine; Giamarellos-Bourboulis, Evangelos J.; Bonten, Marc; van Crevel, Reinout; Netea, Mihai G. title: Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: a retrospective cohort study date: 2020-08-05 journal: Cell Rep Med DOI: 10.1016/j.xcrm.2020.100073 sha: fca85e0d0c7817f0479a928ebbd93f144c68adfd doc_id: 829930 cord_uid: cv5th7hd Summary Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last five years or not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (AOR 0.58, P < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection. It is expected that the infection will remain endemic in the population for years to come, with 76 regular outbreaks when quarantine measures are relaxed and in the winter seasons. Vaccination would be the most optimal tool for infection prevention. Although more than 80 78 different initiatives around the world are trying to develop a disease-specific vaccine, it is 79 likely that at least 1.5-2 years will be needed to produce an effective vaccine. Other measures 80 to contain the infection are therefore urgently needed. Table S1 for an overview of survey questions Figure 2A ). Importantly, none of the BCG-vaccinated (or control) individuals reported 151 admission to hospital, suggesting that BCG vaccination is not associated with increased risk 152 of hospitalization during the SARS-CoV-2 pandemic in this population ( Figure 2B ). Serological surveys in the Netherlands show that between 5. Netherlands, resulting in significant regional differences in the number of COVID-19 cases 18 . The large majority of the individuals that participated in this study are either residents of the Similar to the incidence of reported sickness, the incidence of reporting at least one symptom 197 was significantly lower in the BCG-vaccinated group as compared to the control group after 198 adjusting for confounders (AOR 0.65, P < 0.05, model fit P = 0.79) ( Figure 2E , Figure S3 ). The most common reported symptoms were rhinorrhea and sore throat, followed by cough Figure 3A ). In line with these findings, no differences were observed in circulating cytokines 218 for any of the symptoms ( Figure 3B and Figure S4 ). To assess whether the ability to build a trained immunity response following BCG induced TNF-α n = 94). The incidence of self-reported sickness ( Figure 4B ) as well as the 252 incidence of symptoms ( Figure 4C and D, Figure S6 ) was not significantly different between 253 responders and non-responders, indicating that a strong trained immunity profile is not 254 associated with increased sickness or severity of symptoms during the COVID-19 pandemic. In the present study we investigated whether a recent BCG vaccination is safe during the protection against COVID-19 has also raised the concern that the strengthened cytokine University. 29 individuals that participated in the 500FG study also participated later in the 300BCG 517 study and received a BCG vaccination. These participants were therefore considered 518 300BCG participants in this study. As participants from the 500FG cohort were included 519 approximately 7 years ago, a lower response rate might be expected compared to the more was assessed (Figure 1 -4) . Questionnaire data was exported from Castor and analyzed in R version 3.6.1, using dplyr, 585 tidyr, tidyverse and reshape2 for data inspection and transformation, ggplot2 and ggpubr for 586 visualizations including statistics and rcompanion for more in-depth statistical analyses. Chi-587 square tests were used for comparisons of categorical demographic characteristics (Table 1) 588 (e.g. sex, age, BMI). Finally, differences in distribution of BCG-vaccinated and BCG-non- givitCalibrationBelt-plot using the package givitiR (see Figure S3 ). Statistics cytokine production and circulating mediators 605 A multitude of evidence shows that both age and sex can influence circulating cytokines 45 . 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