The bacillus Calmette-Guérin (BCG) vaccine failed to protect against COVID-19 and other respiratory tract infections (RTIs) among older adults with comorbidities, according to a randomized trial from The Netherlands.

In a group of older patients with a median of two comorbidities, COVID infections were reported in 4.2% patients who received the BCG vaccine compared with 3.7% of those given placebo (HR 1.12, 95% CI 0.87-1.44), reported Eva Koekenbier, MD, of University Medical Center Utrecht, and colleagues.

Among the 6,000 participants in the phase III study, clinically relevant RTIs were reported by 66 patients in the BCG vaccine group and 72 in the placebo group (HR 0.92, 95% CI 0.66-1.28), they noted in Clinical Microbiology and Infection.

In addition, COVID-related hospitalizations occurred in 18 BCG recipients and 21 placebo recipients (HR 0.86, 95% CI 0.46-1.61), and 13 BCG recipients died compared with 18 placebo recipients (HR 0.71, 95% CI 0.35-1.43), with five deaths in the BCG group and six in the placebo group related to COVID.

The BCG vaccine, a live attenuated tuberculosis vaccine, has been shown to have benefits beyond protecting from tuberculosis, with potential off-target benefits to the innate immune system, the researchers explained. “It has been suggested that BCG vaccines induce protection against various respiratory infections, including those of viral etiology,” they wrote.

Previous studies including a randomized controlled trial from Greece showed that BCG vaccination in older adults after hospital discharge was associated with lower incidences of RTIs during 1-year follow-up.

The vaccine has also been found to be protective against respiratory syncytial virus (RSV), influenza, and herpes simplex in animals, and benefit in mice was seen when murine models were challenged with “lethal” SARS-CoV-2 .

However, two recent Dutch randomized placebo-controlled trials showed that the BCG vaccine was not effective against COVID in healthcare workers and relatively healthy adults, but “severe COVID-19 events were rare in both trials, limiting the possibility to exclude clinically relevant benefits,” Koekenbier and colleagues noted.

“At the onset of the pandemic, when preventive or curative interventions with demonstrated efficacy were not available, strategies to prevent SARS-CoV-2 infection or to reduce infection severity in older adults with comorbidities were urgently needed to bridge the period until availability of effective vaccines and treatments,” they wrote. “The results of the current trial confirm the higher risk to develop severe COVID-19 in this population, but also confirm the results of other trials that BCG vaccination does not offer protection against COVID-19 or clinically relevant RTI caused by other pathogens.”

This multicenter double-blind study was conducted from September through December 2020 across 20 hospitals in the Netherlands. A total of 6,112 patients ages 60 and older (median age 69) with comorbidities, including hypertension, diabetes, cardiovascular disease, and chronic obstructive pulmonary disease, were included.

Participants were randomized 1:1 to the BCG vaccine (36.8% women) or placebo (37.7% women) and followed for 6 months. Comorbidities were mostly even matched between groups.

Injection site pain and tenderness were common in both groups, though more common with the BCG vaccine, but most events were mild or moderate and resolved within 12 weeks.

Limitations to the study included possible unblinding due to injection site reactions. In addition, COVID infections were based on self-reported PCR or antigen tests, so some positive tests may have been missed, though Koekenbier and team noted that they do not expect this to be different for the BCG and placebo participants.