n an era of antimicrobial resistance, where the already existing antimicrobials are not sufficient, the development of new strategies for the prevention and treatment of infections is of great interest. This approach becomes more and more mandatory in our current era of the financial crisis where bacterial infections by multidrug-resistant emerge and impose heavily on the financial burden of the disease. These infections occur more frequently among elderly patients leading to prolonged hospitalization where unfavorable outcome is not infrequent1. Vaccination is the traditional approach of infection prevention. A classic example focusing on the need to prevent morbid re-infection is vaccination with pneumococcal vaccine the incidence of pneumococcal pneumonia and bacteremia is enormously increasing among the elderly2. The principle of vaccination is to develop memory B-lymphocytes so that early and adequate antibody titers are produced upon re-exposure to the same antigen. This is called the memory function of the adaptive immune system.

Well before adaptive immunity develops proper recognition of a bacterial pathogen is done through binding of well-preserved structures known as pathogen-associated molecular patterns (PAMPs) on pattern-recognition receptors (PRRs) of the innate immune system and mainly of blood monocytes and tissue macrophages. Through a series of experiments in cell systems and animals, it was found that exposure of macrophages to small amounts of PAMPs like the β-glucan of Candida albicans and constituents of Mycobacterium tuberculosis may prevent death upon re-exposure to lethal bacterial challenges like C.albicans and Staphylococcus aureus3-6. Initial exposure to small amounts of PAMPs leads to epigenetic changes that induce the capacity of macrophages and monocytes to produce high amounts of pro-inflammatory cytokines like tumour necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) that clear efficiently the pathogen3. This enhancement of the immune cells reaction after appropriate priming to stimuli totally different from the initial ones is called trained immunity and it could be a potential pathway of preventing serious infections without having severe adverse effects.

The concept has also been tested in healthy volunteers that were vaccinated with placebo or BCG (Baccillus Calmette Guérin) vaccine. These volunteers were injected 14 days latter 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 IFNγ7. Finally, a small study has recently reported that BCG vaccination of the elderly may protect against infections8, but larger studies are necessary to confirm these findings. This generates hopes that vaccination by BCG may increase immune resistance and/or tolerance of elderly patients upon exposure to bacterial infections.

This generates hopes that vaccination by BCG may increase immune tolerance of elderly patients upon exposure to bacterial diseases.

The aim of the study is to demonstrate in a double-blind, placebo-controlled approach if vaccination of elderly patients with BCG vaccine may modulate their disease susceptibility for bacterial diseases. This will be validated using both clinical and immunological criteria.

An article published in the Frontiers in Immunology describes the findings of this randomized clinical trial ACTIVATE confirmed that recent vaccination with BCG in elderly (>65 years) protects against new infections. In this trial in which 198 elderly people participated, it was demonstrated the difference between the incidence of new infections after placebo vaccination (42.3%) and BCG vaccination (25.0%), being most of the protection against respiratory tract infections. Furthermore, vaccinated individuals took longer to get infected (16 weeks) than the ones vaccinated with placebo (11 weeks). Further statistical analysis indicated a 79% decreased on the risk of acquiring at least one new respiratory infection in a 12 months period for BCG vaccinated group. These benefits were suggested to be mediated by pro-inflammatory cytokines, such as IL-10 TNFα and IL1-β, and therefore associated with the induction of trained immunity. Supporting this view, all BCG vaccinated patients showed an increased proinflammatory pattern after a second stimulation of peripheral blood mononuclear cells (PBMCs) with heat-killed C. albicans or LPS, although insufficient data was obtained in order to correlate the effect (16). The study concluded that BCG vaccination is safe, as recently reported by the same group (17), and can protect the elderly against infections. The study also suggests that BCG vaccination may be able to protect health workers or vulnerable individuals against SARS-CoV-2 virus infection, although larger and specific studies are needed to assess BCG protection against COVID-19.