Efficacy of BCG Vaccination Against Respiratory Tract Infections in Older Adults During the Coronavirus Disease 2019 Pandemic

Abstract

Background: Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19.

Methods: In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses.

Results: The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval, .65-2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval, .71-1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine.

Conclusions: BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection.

Clinical trials registration: EU Clinical Trials Register 2020-001591-15 ClinicalTrials.gov NCT04417335.

Keywords: BCG vaccination; COVID-19; SARS-CoV-2; trained immunity.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Enrollment of participants, randomization, and follow-up.

Figure 2.

Cumulative incidence of respiratory tract infections (RTIs) requiring medical intervention and of documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A, Cumulative incidence of clinically relevant RTIs, defined as new onset or sudden aggravation of preexisting symptoms, as reported by the participant or documented in medical records, including ≥1 respiratory symptom and ≥1 systemic symptom that required medical intervention within a span of 5 days. After medical assessment in primary or secondary care, intervention was defined as initiation of antibiotic, antiviral or corticosteroid treatment, adaptation of pulmonary maintenance medication, or hospitalization. B, Cumulative incidence of documented SARS-CoV-2 infections diagnosed using polymerase chain reaction test and nasopharyngeal swab samples.

Figure 3.

Innate cytokine and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody responses. A, Blood samples were obtained from participants who had received BCG vaccine (n = 50) or placebo (n = 55) 12 months earlier. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated ex vivo with influenza for 24 hours or 7 days. Values represent production by PBMCs of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor (TNF) α after 24-hour stimulation and interferon (IFN) γ after 7-day stimulation with influenza H1N1 California strain. A–C, Values represent medians with interquartile ranges. *P < .05 (Mann–Whitney U test); NS, not significant. B, PBMCs from participants without any previous documented SARS-CoV-2 infection (40 in the placebo and 36 in the BCG vaccine group) were stimulated ex vivo with SARS-CoV-2 Wuhan Hu-1 strain. IL-1β, IL-6, and TNF-α levels were determined after 24 hours and IFN-γ after 7 days of stimulation. C, Immunoglobulin (Ig) G responses against SARS-CoV-2 spike (S) glycoprotein, the nucleocapsid (N) protein, and the receptor-binding domain (RBD) from participants (15 each in the placebo and BCG vaccine groups) who tested positive for SARS-CoV-2 infection with polymerase chain reaction between September 2020 and February 2021 and had received BCG vaccine or placebo 12 months earlier.