Assessing the efficacy of BCG vaccination in a pre-clinical model of SARS-CoV-2 infection

National Institute Of Allergy And Infectious Diseases

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Abstract

The bacillus Calmette-Gurin (BCG) vaccine has been widely used to protect against disseminated tuberculosis in infants and children since the 1930s, and is currently included in the national vaccine programme in over 150 countries. In addition to providing some protection against tuberculosis, BCG vaccination is associated with lower all-cause mortality in infants and is reported to reduce viremia following a yellow fever vaccine challenge in adults. BCG has also proved successful in stimulating anti-tumor immune responses in cancer patients and is considered to be the gold-standard treatment for bladder cancer. Together, these observations provide evidence for beneficial non-specific effects of BCG in humans, which have been attributed to epigenetic and metabolic re-programming of the innate immune system, as well as the re-direction of haematopoiesis towards the rapid generation of protective myeloid cells. Given the reported non-specific protection afforded by BCG vaccination, it has been hypothesised that BCG may offer some protection against the novel coronavirus, SARS-CoV-2. A number of epidemiologic studies have reported an association between mass BCG vaccination and lower incidence of SARS-CoV-2 infection as well as mortality from COVID-19. These preliminary correlative studies have been the subject of much debate within the scientific community, with a number of published reports finding no positive correlation between BCG vaccination status and susceptibility to SARS-CoV-2 infection. Nonetheless, significant interest has been generated in the public health and scientific arenas, and at least eighteen clinical trials were registered on clinicaltrials.gov (as of August 14th, 2020) aiming to formally test the efficacy of BCG vaccination in protecting against SARS-CoV-2 infection and mortality in adults. Our own unpublished data (see accompanying report AI001044-14) demonstrates that BCG immunization, particularly when administered via the intravenous (i.v.) route, profoundly alters the composition and phenotype of the pulmonary myeloid compartment, creating an environment that restricts the ability of Mycobacterium tuberculosis to gain entry into the lung parenchyma. These changes include a prolonged depleion of alveolar macrophages. In the present COVID-19 study, we have assessed the efficacy of BCG vaccination in the K18-hACE2 transgenic mouse model of SARS-CoV-2 infection and a second, variant virus susceptible murine model with the aim of providing pre-clinical vaccine trial data. At the same time, we are examining whether the pulmonary myeloid changes we have documented in i.v. BCG vaccinated mice impact on SARS-CoV-2 infection and disease. Our findings demonstrate that prior administration of BCG intravenously, but not subcutaneously, consistently protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 and in addition results in reduced viral loads in non-transgenic animals infected with the hypervirulent alpha variant. The observed protection was associated with diminished SARS-CoV-2-induced tissue pathology, inflammatory cell recruitment and cytokine production. Multivariate analysis of the data indicates that the latter changes are not simply the result of the decreased viral loads occurring in the vaccinated and challenged animals. In addition, no alteration in hACE tissue expression and localization were observed in the lungs of BCG infected transgenic mice ruling out this possible explanation of the increased viral resistance induced. Instead, we propose that this protection stems from BCG-induced myeloid remodeling triggered in lung tissue by the intravenously administered bacteria and consequently, that interventions targeting the myeloid compartment may be beneficial in reducing SARS-CoV-2 disease.