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

Evangelos J Giamarellos-Bourboulis, Maria Tsilika, Simone Moorlag, Nikolaos Antonakos, Antigone Kotsaki, Jorge Domínguez-Andrés, Evdoxia Kyriazopoulou, Theologia Gkavogianni, Maria-Evangelia Adami, Georgia Damoraki, Panagiotis Koufargyris, Athanassios Karageorgos, Amalia Bolanou, Hans Koenen, Reinout van Crevel, Dionyssia-Irene Droggiti, George Renieris, Antonios Papadopoulos, Mihai G Netea, Evangelos J Giamarellos-Bourboulis, Maria Tsilika, Simone Moorlag, Nikolaos Antonakos, Antigone Kotsaki, Jorge Domínguez-Andrés, Evdoxia Kyriazopoulou, Theologia Gkavogianni, Maria-Evangelia Adami, Georgia Damoraki, Panagiotis Koufargyris, Athanassios Karageorgos, Amalia Bolanou, Hans Koenen, Reinout van Crevel, Dionyssia-Irene Droggiti, George Renieris, Antonios Papadopoulos, Mihai G Netea

Abstract

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).

Keywords: BCG; cytokines; elderly; epigenetic modifications; infection incidence; respiratory infections; trained immunity; vaccination.

Conflict of interest statement

Declaration of Interests E.J.G.-B. has received honoraria from Abbott CH, Angelini Italy, bioMérieux Inc, InflaRx GmbH, MSD Greece, and XBiotech Inc.; independent educational grants from AbbVie, Abbott, Astellas Pharma Europe, AxisShield, bioMérieux Inc, InflaRx GmbH, ThermoFisher Brahms GmbH, and XBiotech Inc; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). M.G.N. was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. M.G.N. is a scientific founder of TTxD. The other authors do not have any competing interests to declare.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Study Flow Chart BCG, Bacillus Calmette-Guérin; HIV, human immunodeficiency virus; IGRA, interferon-gamma releasing assay
Figure 2
Figure 2
Primary Outcome of the ACTIVATE Trial (A) Comparative time to first infection in the two groups of vaccination included in the interim analysis (placebo = 78 patients; BCG = 72 patients) Infections counting against the primary endpoint were respiratory infection of probably viral origin necessitating medical attention, community-acquired pneumonia, hospital-acquired pneumonia, intraabdominal infections, urinary tract infections, bloodstream infections, and acute bacterial skin and skin structure infections (ABSSSIs). The inset shows the same data on an enlarged y axis. The hazard ratio (HR) and the 95% confidence intervals (CIs) of the Cox-regression analysis are shown along with the respective p value of comparison (B) Percentage differences and 95% CIs of the incidence of each type of infection between the two groups of vaccination included in the interim analysis (placebo = 78 patients; BCG = 72 patients) (C) Sensitivity analysis: time to first infection after placebo or BCG vaccination among all study participants (placebo = 98 patients; BCG = 100 patients). This analysis is done taking into consideration that the time of 12-month follow-up has not been completed for 48 patients. The HR and the 95% CIs of the Cox-regression analysis are shown along with the respective p value of comparison
Figure S1
Figure S1
Plot of Schoenfeld Residuals against Time to Event, Related to Figure 2 If the assumption of proportionality of hazards across the two groups is not violated then residuals for the two groups should lie in two parallel straight lines. The above chart confirms this. Therefore the assumption of proportionality of the hazards across the whole time of follow-up is not violated since it remains practically the same.
Figure S2
Figure S2
Time to First Hospitalization after Placebo or BCG Vaccination, Related to Table 2
Figure S3
Figure S3
Time to First Sepsis Episode after Placebo or BCG Vaccination, Related to Table 2
Figure 3
Figure 3
Immunological Effects of BCG Vaccination Participants in the ACTIVATE trial were vaccinated with placebo or with BCG. (A)–(F) report PBMCs isolated at baseline (month 0) and 3 months after vaccination. PBMCs were stimulated for cytokine production. Blood sampling was not done for all participants after 3 months either because some individuals had died or because they were hospitalized at other study sites or because of denial for blood sampling. (A) Percentage of patients vaccinated with placebo and BCG with more than 30% increase of the production of TNF-α after stimulation with Pam3Cys. (B) Percentage of patients vaccinated by placebo and BCG with more than 200% increase of the production of tumor necrosis factor-alpha (TNF-α) after stimulation with heat-killed Candida albicans. (C) Percentage of patients vaccinated by placebo and BCG with more than 36% increase of the production of interleukin (IL)-1β after stimulation with heat-killed C. albicans. (D) Percentage of patients vaccinated by placebo and BCG with more than 73% increase of the production of IL-10 after stimulation with lipopolysaccharide (LPS) of Escherichia coli. (E) Percentage of patients vaccinated by placebo and BCG with more than 8% increase of the production of IL-10 after stimulation with heat-killed C. albicans. (F) Percentage of patients vaccinated by placebo and BCG with more than 200% increase of the production of interferon-gamma (IFN-γ) after stimulation with heat-killed C. albicans. The p values of comparisons by the Fisher’s exact test are provided in (A)–(F). (G) Monocytes were analyzed by chromatin immunoprecipitation (ChIP)-qPCR to determine H3K27ac levels at promoter sites of IL6 and TNFα (n = 7 placebo group, n = 4 BCG group). Participants in the 300BCG study were vaccinated with BCG (H and I) PBMCs were isolated and stimulated ex vivo with LPS, heat-killed Staphylococcus aureus, or Mycobacterium tuberculosis before vaccination and 14 days (D14) and 90 days (D90) after vaccination. Fold increases (compared to baseline) of IFN-γ and IL-6 are shown (n = 14, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 by the Wilcoxon’s signed-rank test. (J) Cell-surface expression molecules in the granulocyte population were analyzed by flow cytometry before vaccination, and 14 days (D14) and 90 days (D90) after vaccination (fold change of median fluorescence intensity as compared to baseline).
Figure S4
Figure S4
Immunological Effects of BCG Vaccination in the Elderly, Related to Figure 3 (A) Healthy volunteers (≥55 years) from the 300BCG cohort were vaccinated with BCG and peripheral blood mononuclear cells (PBMCs) were isolated and stimulated ex vivo with S. aureus or lipopolysaccharide (LPS) of Escherichia coli before vaccination, 14 days (D14) and 90 days (D90) after vaccination. Fold increases (compared to baseline) of interleukin (IL)-1β are shown (n = 14, ∗p < 0.05 by the Wilcoxon’s ranked sum test). (B) Fold changes of circulating IL-6 and IL-18 upon BCG vaccination as compared to baseline (n = 13). See also Table S3 for a complete list of circulating markers that were measured. (C) Absolute monocyte, granulocyte and lymphocyte counts in whole blood before vaccination, 14 days (D14) and 90 days (D90) after vaccination. Mean values and SE are provided in each panel.

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