Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly

•ACTIVATE is a prospective randomized trial of BCG vaccination in the elderly•BCG increased the time to first infection and decreased the incidence of new infection•Strongest protection was found against viral respiratory tract infections•Epigenetic reprogramming and increased cytokine production was found in monocytes BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%–53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%–36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423). BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%–53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%–36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423). Infection by the novel SARS-CoV-2 virus (also termed COVID-19) has a severe impact on both the health of the populations around the globe, and on the world economy. Many countries are in lockdown, with a third of the world population in some form of movement restrictions, which brings serious financial and societal consequences. The urgent need for the reversal of this situation can be met only through the generation of an immune defense shield to protect the populations from SARS-CoV-2 infection. Many efforts for the development of a vaccine are under way, but it is likely that at least 12–24 months will be needed until an effective vaccine could be available. Interestingly, however, trained immunity induced by some already available vaccines such as Bacille Calmette-Guérin (BCG), oral polio vaccine (OPV), or the measles vaccine have been suggested to be used as a potential protective approach against COVID-19 to bridge the period until a specific vaccine is developed (Netea et al., 2020Netea M.G. Giamarellos-Bourboulis E.J. Domínguez-Andrés J. Curtis N. van Crevel R. van de Veerdonk F.L. Bonten M. Trained immunity: a tool for reducing susceptibility and severity of SARS-CoV-2 infection.Cell. 2020; 181: 969-977Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Trained immunity is the process of epigenetic, transcriptional, and functional reprogramming of innate immune cells (such as myeloid cells or natural killer [NK] cells), leading to an increase in the cytokine production capacity and their antimicrobial function (Kleinnijenhuis et al., 2012Kleinnijenhuis J. Quintin J. Preijers F. Joosten L.A. Ifrim D.C. Saeed S. Jacobs C. van Loenhout J. de Jong D. Stunnenberg H.G. et al.Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.Proc. Natl. Acad. Sci. USA. 2012; 109: 17537-17542Crossref PubMed Scopus (966) Google Scholar; Netea et al., 2016Netea M.G. Joosten L.A. Latz E. Mills K.H. Natoli G. Stunnenberg H.G. O’Neill L.A. Xavier R.J. Trained immunity: A program of innate immune memory in health and disease.Science. 2016; 352: aaf1098Crossref PubMed Scopus (1301) Google Scholar). In models of experimental human infections such as yellow fever vaccine virus (Arts et al., 2018Arts R.J.W. Moorlag S.J.C.F.M. Novakovic B. Li Y. Wang S.Y. Oosting M. Kumar V. Xavier R.J. Wijmenga C. Joosten L.A.B. et al.BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity.Cell Host Microbe. 2018; 23: 89-100Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar) or human experimental malaria (Walk et al., 2019Walk J. de Bree L.C.J. Graumans W. Stoter R. van Gemert G.J. van de Vegte-Bolmer M. Teelen K. Hermsen C.C. Arts R.J.W. Behet M.C. et al.Outcomes of controlled human malaria infection after BCG vaccination.Nat. Commun. 2019; 10: 874Crossref PubMed Scopus (113) Google Scholar), BCG vaccination was able to induce a non-specific protection. These experimental data are accompanied by epidemiological studies in children and adults showing non-specific protection against infections and mortality by BCG vaccination. BCG vaccination reduced the incidence of respiratory syncytial virus infection in children in Africa (Stensballe et al., 2005Stensballe L.G. Nante E. Jensen I.P. Kofoed P.E. Poulsen A. Jensen H. Newport M. Marchant A. Aaby P. 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.Vaccine. 2005; 23: 1251-1257Crossref PubMed Scopus (163) Google Scholar) and protected the elderly against respiratory tract infections in Indonesia (Wardhana et al., 2011Wardhana D. Datau E.A. Sultana A. Mandang V.V. Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly.Acta Med. Indones. 2011; 43: 185-190PubMed Google Scholar) and Japan (Ohrui et al., 2005Ohrui T. Nakayama K. Fukushima T. Chiba H. Sasaki H. [Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations].Nippon Ronen Igakkai Zasshi. 2005; 42: 34-36Crossref PubMed Scopus (55) Google Scholar). Finally, the concept was also successfully tested in healthy volunteers that were vaccinated with placebo or BCG vaccine and 14 days later received a tri-valent influenza A vaccine. Volunteers previous vaccinated by BCG developed significantly greater titers against hemagglutinin A of the influenza A virus, whereas their circulating monocytes were more potent for the production of interferon-gamma (Leentjens et al., 2015Leentjens J. Kox M. Stokman R. Gerretsen J. Diavatopoulos D.A. van Crevel R. Rimmelzwaan G.F. Pickkers P. Netea M.G. BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study.J. Infect. Dis. 2015; 212: 1930-1938Crossref PubMed Scopus (140) Google Scholar). ACTIVATE (a randomized clinical trial for enhanced trained immune responses through BCG vaccination to prevent infections of the elderly) is a randomized trial in which hospitalized elderly patients were vaccinated on the day of hospital discharge with single doses of placebo or BCG. Patients were under follow-up for 12 months, with the last visit of the last patient scheduled for August 2020. However, the pressure rising from the need of protection of the elderly who are considered susceptible to infection by SARS-CoV-2 (Guan et al., 2020Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Liu L. Shan H. Lei C.L. Hui D.S.C. et al.China Medical Treatment Expert Group for Covid-19Clinical characteristics of coronavirus disease 2019 in China.N. Engl. J. Med. 2020; 382: 1708-1720Crossref PubMed Scopus (17220) Google Scholar; Huang et al., 2020Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (27324) Google Scholar) led to an interim analysis of the results of the study. Results of this interim analysis clearly showed protection of the elderly from new infections with major effect on the prevention of respiratory infections. From September 2017 through August 2019, 202 patients were enrolled and randomized to double-blind vaccination with placebo or BCG; four patients withdrew consent and requested removal of all data, leaving a final intention-to-treat analysis cohort of 198 patients. No patient was reported as lost to follow-up (Figure 1). Interim analysis included 78 patients allocated to placebo vaccination and 72 patients allocated to BCG vaccination. Baseline characteristics were similar between the two arms (Table 1; Table S1).Table 1Baseline Characteristics of Enrolled PatientsCharacteristicPlacebo (N = 78)BCG (N = 72)p valueAge, years, mean (SD)79.6 (7.8)79.9 (7.6)0.802Male gender, no. (%)35 (44.9)32 (44.4)1.000Charlson’s Comorbidity Index, mean (SD)5.5 (1.9)5.5 (2.2)0.909ΑPACHE II score on study enrolment, mean (SD)7.9 (3.0)8.1 (2.9)0.701SOFA score on study enrolment, mean (SD)1.2 (1.4)1.0 (1.1)0.586Comorbidities, no. (%)Diabetes mellitus, no. (%)29 (37.2)23 (31.9)0.607 Without organ damage, no. (%)23 (29.5)15 (20.9)0.262 With organ damage, no. (%)6 (7.7)8 (11.1)0.578Chronic heart failure, no. (%)23 (29.5)20 (27.8)0.858Chronic renal disease, no. (%)14 (17.9)12 (16.7)1.000Chronic obstructive pulmonary disease, no. (%)12 (15.4)11 (15.3)1.000Cerebrovascular disease, no. (%)17 (21.8)21 (29.2)0.349Degenerative disease, no. (%)8 (10.3)6 (8.3)0.783Myocardial infarction, no. (%)13 (16.7)9 (12.5)0.498Biliary stones, no. (%)10 (12.8)11 (15.3)0.814Renal stones, no. (%)1 (1.3)1 (1.4)1.000Any surgery, no. (%)30 (38.5)30 (41.7)0.740Dementia, no. (%)15 (19.2)20 (27.8)0.249Hemiplegia, no. (%)1 (1.3)1 (1.4)1.000Peptic ulcer disease, no. (%)3 (3.8)3 (4.2)1.000Peripheral vascular disease, no. (%)1 (1.3)0 (0)1.000Liver disease, no. (%)1 (1.3)1 (1.4)1.000Hypertension, no. (%)56 (71.8)53 (73.6)0.856Atrial fibrillation, no. (%)30 (38.5)22 (30.6)0.391APACHE, acute physiology and chronic health evaluation; SD, standard deviation; SOFA, sequential organ failure assessment. Open table in a new tab APACHE, acute physiology and chronic health evaluation; SD, standard deviation; SOFA, sequential organ failure assessment. Regarding the primary endpoint of the study, BCG vaccination significantly increased the time to first infection: median 16 weeks after BCG vaccine compared to 11 weeks after placebo administration. The incidence of a new infection during the 12-month period of follow-up after vaccination was also significantly decreased; the statistically significant hazard ratio (HR) of 0.55 corresponds to 45% reduction in the risk of a new infection in the BCG group compared to the placebo group (Figure 2A). The incidence of new infection was 42.3% (95% confidence intervals [CIs] 31.9%–53.4%) in the placebo group and 25.0% (95% CIs 16.4%–36.1%) in the BCG group. The difference in the incidence according to the type of infection showed most of the benefit on the prevention of respiratory infections of probable viral origin (Figure 2B); the HR in this case was 0.21 (95% CI 0.06–0.72) corresponding to 79% decrease in the risk for the BCG group in comparison to the placebo group. An analytical presentation of the efficacy of BCG vaccination for all primary and secondary study outcomes is shown in Table 2.Table 2Primary and Secondary Study OutcomesStudy OutcomePlacebo (N = 78)BCG (N = 72)Hazard Ratio (95% CI)p valueIncidence at least one new infection until month 12, no. (%)aSome patients had more than one infection.33 (42.3)18 (25.0)0.55 (0.31–0.97)0.039 Respiratory infections of probable viral origin necessitating medical treatment, no. (%)14 (17.9)3 (4.2)0.21 (0.06–0.72)0.013 Community-acquired pneumonia, no. (%)8 (10.3)3 (4.2)0.38 (0.10–1.43)0.153 Hospital-acquired pneumonia, no. (%)2 (2.6)0 (0)–0.479 All respiratory infections, no. (%)24 (30.1)6 (8.3)0.25 (0.10–0.60)0.002 Intrabdominal infections, no. (%)3 (3.8)4 (5.6)1.39 (0.31–6.21)0.667 Urinary tract infections, no. (%)6 (7.7)8 (11.1)1.38 (0.48–3.97)0.553 Acute bacterial skin and skin structure infections, no. (%)6 (7.7)3 (4.2)0.51 (0.13–2.02)0.335 Bloodstream infection, no. (%)2 (2.6)0 (0)–0.497Incidence of second infection until month 12, no. (%)9 (11.5)5 (6.9)0.59 (0.20–1.77)0.349Incidence of third infection until month 12, no. (%)3 (3.8)1 (1.4)0.36 (0.04–3.45)0.375Rate of hospitalization/patient until month 12, mean (SD)0.49 (0.72)0.43 (0.72)N/A0.383Patient-infections per year, per 100 patients, no. (%)45 (57.7)24 (33.3)N/A0.003Courses of antibiotics until month 12, mean (SD)0.69 (1.66)0.60 (1.25)N/A0.665One-year mortality, no. (%)14 (17.9)10 (13.9)0.68 (0.30–1.54)0.356CI, confidence interval; N/A, not applicable; SD, standard deviation.a Some patients had more than one infection. Open table in a new tab CI, confidence interval; N/A, not applicable; SD, standard deviation. Sensitivity analysis was done for the total of 198 patients taking into consideration that the time of 12-month follow-up has not been completed for 48 patients (Figure 2C; Table S2). This sensitivity analysis confirmed the results of the primary outcome presented in Figure 2A. The confirmation of the primary endpoint of the interim analysis by the sensitivity analysis establishes the absence of any violations on the time-to-event analyses since individuals that are censored have the same probability of experiencing a subsequent event as individuals that remain in the study. The proportionality of the hazards over the total time period of follow-up was validated by plotting the Schoenfeld residuals (Figure S1). Stepwise Cox regression analysis showed that BCG vaccination was an independent protective factor from the incidence of new infection until month 12 (HR 0.56; 95% CI, 0.32–0.99; p = 0.048) (Table 3).Table 3Univariate and Multivariate Analysis of the Effects of Covariates on the Incidence of at Least One Infection until Month 12CovariatesNo. Infection (n = 99)At Least One New Infection (n = 51)Univariate AnalysisMultivariate AnalysisHR95% CIp valueHR95% CIp valueBCG vaccination, no. (%)aCovariates with a significant effect both in the univariate analysis and the multivariate model54 (54.4)18 (35.3)0.550.31–0.970.0350.560.32–0.990.048Male gender, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model40 (40.4)27 (52.9)0.660.38–1.150.145CCI > 4, no. (%)cCovariates with a significant effect in the univariate analysis but failed to enter significantly in the multivariate stepwise Cox regression model61 (61.6)40 (78.4)2.111.08–4.120.028Type 2 diabetes mellitus, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model31 (31.6)21 (41.2)1.340.76–2.330.310Chronic heart failure, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model26 (26.5)17 (33.3)1.350.75–2.420.313Chronic renal disease, no. (%)aCovariates with a significant effect both in the univariate analysis and the multivariate model13 (13.3)13 (25.2)1.961.05–3.690.0361.951.04–3.660.038COPD, no. (%)aCovariates with a significant effect both in the univariate analysis and the multivariate model10 (10.2)13 (25.5)2.141.14–4.020.0182.121.13–3.990.019Cerebrovascular disease, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model27 (27.6)11 (21.6)0.770.40–0.510.450Degenerative disease, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model7 (7.1)7 (13.7)1.910.86–4.250.111Myocardial infarction, no. (%)cCovariates with a significant effect in the univariate analysis but failed to enter significantly in the multivariate stepwise Cox regression model10 (10.2)12 (23.5)2.051.07–3.920.030Biliary stones, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model15 (15.3)6 (11.8)0.810.34–1.890.620Any surgery, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model40 (40.8)20 (39.2)0.920.53–1.620.783Dementia, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model22 (22.4)13 (25.5)1.260.67–2.370.472Peptic ulcer disease, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model4 (4.1)2 (3.9)0.880.22–3.630.863Hypertension, no. (%)bCovariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression model75 (76.5)34 (66.7)0.690.39–1.240.215Atrial fibrillation, no. (%)cCovariates with a significant effect in the univariate analysis but failed to enter significantly in the multivariate stepwise Cox regression model29 (29.6)23 (45.1)1.720.99–2.990.053CCI, Charlson’s comorbidity index; CI, confidence intervals; COPD, chronic obstructive pulmonary disease; HR, hazard ratio.a Covariates with a significant effect both in the univariate analysis and the multivariate modelb Covariates without any significant effect in the univariate analysis and not entered in the multivariate stepwise Cox regression modelc Covariates with a significant effect in the univariate analysis but failed to enter significantly in the multivariate stepwise Cox regression model Open table in a new tab CCI, Charlson’s comorbidity index; CI, confidence intervals; COPD, chronic obstructive pulmonary disease; HR, hazard ratio. A major benefit from BCG vaccination was observed in the main secondary endpoint patient-infections per year. This was 57.7 per 100 patients in the placebo group and 33.3 per 100 patients in the BCG group (p = 0.003) (Table 2). No difference in the other secondary endpoints was found between the two groups (Table 2; Figures S2 and S3).Figure S3Time to First Sepsis Episode after Placebo or BCG Vaccination, Related to Table 2View Large Image Figure ViewerDownload Hi-res image Download (PPT) In a sub-group of 57 participants (31 placebo and 26 BCG vaccinated), we assessed production of innate immune responses at 2 time points (before and 3 months after vaccination) in peripheral blood mononuclear cells (PBMCs). Heterologous production of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-10 (trained immunity induction) (Figures 3A–3E) but not of IL-6 (data not shown) by PBMCs after stimulation with non-mycobacterial ligands was amplified among BCG-vaccinated individuals compared to placebo-vaccinated individuals. A trend toward amplified interferon-gamma (IFN-γ) (heterologous T cell responses) responses was also found (Figure 3F). Unfortunately, the number of BCG-vaccinated individuals in which cytokine data are available is too small to permit the prediction of trained immunity responses as correlates of protection. Various studies have shown that the increased cytokine responses upon BCG vaccination are the result of epigenetic reprogramming of monocytes (Arts et al., 2018Arts R.J.W. Moorlag S.J.C.F.M. Novakovic B. Li Y. Wang S.Y. Oosting M. Kumar V. Xavier R.J. Wijmenga C. Joosten L.A.B. et al.BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity.Cell Host Microbe. 2018; 23: 89-100Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar; Kleinnijenhuis et al., 2012Kleinnijenhuis J. Quintin J. Preijers F. Joosten L.A. Ifrim D.C. Saeed S. Jacobs C. van Loenhout J. de Jong D. Stunnenberg H.G. et al.Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.Proc. Natl. Acad. Sci. USA. 2012; 109: 17537-17542Crossref PubMed Scopus (966) Google Scholar). In order to examine potential differences in the epigenetic profile between BCG-vaccinated individuals and controls, we determined at pro-inflammatory genes the level of histone H3 acetylation at lysine 27 (H3K27ac), a mark of active promoters and enhancers. In line with previous findings, we observed increased levels of H3K27ac at the regions of IL-6 and TNF-α in BCG-vaccinated individuals as compared to individuals that received placebo, suggestive of epigenetic reprogramming upon BCG vaccination (Figure 3G). To further validate the solidity of the observation that BCG induces trained immunity responses in the elderly, we assessed immune responses before BCG vaccination, 2 weeks and 3 months after vaccination in 14 healthy volunteers aged 55 years or older that took part in an independent BCG-vaccination study (300BCG cohort, www.humanfunctionalgenomics.org). All individuals in this cohort were vaccinated with the same BCG strain used in the ACTIVATE trial and PBMCs were isolated and stimulated ex vivo with Staphylococcus aureus, lipopolysaccharide (LPS), or Mycobacterium tuberculosis, before and after vaccination to assess the magnitude of the immune memory responses. We observed a significant increase in IFN-γ upon stimulation with M. tuberculosis after BCG vaccination (Figure 3H), indicative of induction of adaptive immune memory response. In addition, cytokine production also significantly increased in the elderly when cells were exposed to non-mycobacterial stimuli such as S. aureus and LPS (Figure 3I; Figure S4A), indicative of induction of trained immunity. Furthermore, we observed long-term changes in neutrophil phenotype 3 months upon BCG vaccination as compared to baseline (Figure 3J). Together, these findings indicate sustained trained immunity responses in the elderly and support our previous observation of non-specific beneficial effects against unrelated infections in the elderly upon BCG vaccination. In addition, we employed a targeted proteome platform to measure 92 inflammatory markers before and after BCG vaccination, which revealed no significant changes in the concentrations of circulating inflammatory proteins, including IL-6 and IL-18 after BCG (Figure S4B; Table S3). Similarly, no significant changes in monocyte, granulocyte, or lymphocyte count were observed upon vaccination (Figures S4C–S4E). This demonstrates that, while BCG vaccination induces trained immunity and cell responsiveness, it is not followed by excessive systemic inflammation. A trend for lower serious adverse events was recorded in the BCG vaccination group than in the placebo group (Table 4). Moreover, the incidence of non-serious adverse events did not differ between the two groups. None of the adverse events were related to the study intervention. None of the patients developed tuberculosis.Table 4List of Severe Adverse Events and Non-severe Adverse Events Reported during the Study PeriodSerious Adverse Events (SAEs)Placebo (N = 78)BCG (N = 72)p valuePresence of at least one SAE,aSome patients had more than one SAE and/or more than one AE. no. (%)30 (38.5)17 (23.6)0.055Death — no. (%)8 (10.3)5 (6.9)0.568SAEs with hospitalization,aSome patients had more than one SAE and/or more than one AE. no. (%)20 (25.6)10 (13.9)0.101Reason for hospitalization, no. (%)Arrythmia1 (1.3)0 (0)1.000Stroke2 (2.6)1 (1.4)1.000Acute kidney injury0 (0)1 (1.4)0.480Deep vein thrombosis1 (1.3)0 (0)1.000Epilepsy1 (1.3)0 (0)1.000Electrolyte disturbance1 (1.3)0 (0)1.000Pulmonary edema1 (1.3)0 (0)1.000Anemia1 (1.3)0 (0)1.000ST-segment elevation at ECG1 (1.3)0 (0)1.000Elective surgery2 (2.6)2 (2.8)1.000SAEs without hospitalization, no. (%)Stroke, no. (%)1 (1.3)0 (0)1.000Syncope0 (0)1 (1.4)0.480Anemia1 (1.3)0 (0)1.000Non-serious adverse events (AEs)At least one non-serious AE,aSome patients had more than one SAE and/or more than one AE. no. (%)20 (25.6)26 (36.1)0.215Type of non-serious AE, no. (%)Varicella-zoster eruption1 (1.3%)0 (0)1.000Helicobacter pylori infection3 (3.8)0 (0)0.246Dacryocystitis0 (0)1 (1.4)0.480Hip fracture2 (2.6)0 (0)0.490Non-infection associated cough4 (5.1)11 (15.3)0.055Asymptomatic bacteriuria2 (2.6)7 (9.7)0.088Breast cancer1 (1.3)1 (1.4)1.000Renal cancer0 (0)1 (1.4)0.480Squamous skin carcinoma0 (0)1 (1.4)0.480Rash at the injection site0 (0)2 (2.8)0.229Otitis0 (0)1 (1.4)0.480Dental infection2 (2.6)1 (1.4)1.000SAEs and deaths due to infections counting against the primary endpoint are not encountered here since per protocol they should not be reported as adverse events.a Some patients had more than one SAE and/or more than one AE. Open table in a new tab SAEs and deaths due to infections counting against the primary endpoint are not encountered here since per protocol they should not be reported as adverse events. The ACTIVATE study was conducted from 2017 with the aim to assess the potential of BCG vaccination to protect the elderly with an increased risk for infection against new infectious episodes. As a target population we have chosen to investigate elderly patients returning home from a hospital admission, as it is known that this population is at a high risk to develop infections (Bender, 2003Bender B.S. Infectious disease risk in the elderly.Immunol. Allergy Clin. North Am. 2003; 23: 57-64, viAbstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). This approach using BCG vaccination is justified due to the increasing number of experimental and epidemiological studies suggesting that BCG can protect against respiratory infections in general, and viral infections, in particular (Moorlag et al., 2019Moorlag S.J.C.F.M. Arts R.J.W. van Crevel R. Netea M.G. Non-specific effects of BCG vaccine on viral infections.Clin. Microbiol. Infect. 2019; 25: 1473-1478Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). Indeed, the data shown here demonstrate that BCG vaccination led to a lower number of infections of all causes, and especially respiratory tract infections, arguing for a protective effect. Epidemiological data suggest beneficial effects of BCG on all-cause mortality in children in countries with high infectious pressure. This protection has been attributed to lower incidence of neonatal sepsis and respiratory tract infections (Garly et al., 2003Garly M.L. Martins C.L. Balé C. Baldé M.A. Hedegaard K.L. Gustafson P. Lisse I.M. Whittle H.C. Aaby P. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?.Vaccine. 2003; 21: 2782-2790Crossref PubMed Scopus (219) Google Scholar), which in children are often viral as etiological cause. This assumption is also supported by the data indicating protective effects of BCG vaccination against RSV infection (Stensballe et al., 2005Stensballe L.G. Nante E. Jensen I.P. Kofoed P.E. Poulsen A. Jensen H. Newport M. Marchant A. Aaby P. 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.Vaccine. 2005; 23: 1251-1257Crossref PubMed Scopus (163) Google Scholar). The protection in children was also complemented more recently by studies showing protective effects of BCG vaccination against respiratory tract infections in adolescents (Nemes et al., 2018Nemes E. Geldenhuys H. Rozot V. Rutkowski K.T. Ratangee F. Bilek N. Mabwe S. Makhethe L. Erasmus M. Toefy A. et al.C-040-404 Study TeamPrevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination.N. Engl. J. Med. 2018; 379: 138-149Crossref PubMed Scopus (355) Google Scholar) and in elderly individuals (Wardhana et al., 2011Wardhana D. Datau E.A. Sultana A. Mandang V.V. Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly.Acta Med. Indones. 2011; 43: 185-190PubMed Google Scholar). In line with this, the incidence of infection in the ACTIVATE trial was significantly lower in the elderly individuals vaccinated with BCG, compared to the non-vaccinated participants. Moreover, this protection was mainly due to respiratory tract infections of probable viral origin, with HR 0.21 in the BCG vaccinated group, which is in line with the 70%–80% reduction in respiratory tract infections in studies done in Indonesia and Japan (Ohrui et al., 2005Ohrui T. Nakayama K. Fukushima T. Chiba H. Sasaki H. [Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations].Nippon Ronen Igakkai Zasshi. 2005; 42: 34-36Crossref PubMed Scopus (55) Google Scholar; Wardhana et al., 2011Wardhana D. Datau E.A. Sultana A. Mandang V.V. Jim E. The efficacy of Bacillus