Study shows bacille Calmette-Guérin vaccine can protect mice against lethal SARS-CoV-2 challenge

A recent US study, currently available on bioRxiv* preprint server, implies that vaccination with bacille Calmette-Guérin (BCG) can limit the infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by targeting innate immune pathways and could thus be used as a platform for pinpointing early immunologic events affecting the outcome of coronavirus disease (COVID-19).

Clinical presentation and pathologic events seen in severe manifestations of COVID-19 are purportedly driven by an overeager and sustained innate immune response. Disease severity positively correlates with high levels of pro-inflammatory proteins known as cytokines, but also myeloid cell activation.

Study: Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge. Image Credit: Numstocker / Shutterstock

BCG represents a live attenuated vaccine that is in wide use for a long time for the prevention of disseminated tuberculosis in infants and young children. However, its non-specific effects linked to epigenetic and metabolic reprogramming of the innate immune system are also well-known.

This is why BCG administration has been touted as a potential prophylactic measure in preventing SARS-CoV-2 infection – especially since a plethora of ecological studies have linked prior BCG vaccination with a lower incidence of COVID-19.

Albeit a controversial concept, many clinical trials are underway with an end goal to formally test it. Moreover, recent pre-clinical studies have shown BCG can be used as an adjuvant to boost specific vaccine-induced protection against SARS-CoV-2.

This novel study, led by Dr. Kerry L. Hilligan and Dr. Sivaranjani Namasivayam from the National Institutes of Health in Bethesda, US, systematically appraised the effects of prior BCG inoculation on SARS-CoV-2 pathogenesis in two experimental mouse models.

Two salient mouse models

The first of the two models used K18-hACE2 mice. These are highly susceptible to lethal infection, since they express a transgene for the human ACE2 receptor. These mice also support neurotropism of coronaviruses (i.e., viral brain predilection), which can contribute to mortality.

The second model involved a challenge with an alpha SARS-CoV-2 variant (B.1.1.7) that is able to productively infect wild-type (i.e., non-transgenic animals). SARS-CoV-2 viruses used in the study were propagated in tissue culture in Vero cells, which are kidney epithelial cells from an African green monkey.

After the infection, mice were monitored every day for changes in their weight and clinical signs of disease by a blinded observer. Each animal was assigned with a disease score based on the previously established criteria, before the results were analyzed and interpreted.

A high level of protection against SARS-CoV-2

In short, the researchers have demonstrated that intravenous delivery of BCG can actually confer a high level of protection against SARS-CoV-2 in both models. More specifically, K18-hACE2 animals were protected from lethal SARS-CoV-2 challenge, while BCG also reduced SARS-CoV-2 alpha variant viral loads in the lungs of K18-hACE2 and wild-type mice.

In addition, prior inoculation with intravenous BCG significantly reduced pulmonary pathology associated with the virus, inflammatory cell recruitment, as well as chemokine production. Antigen distribution was also limited in these mice.

Finally, cytokine responses driven by SARS-CoV-2 were shown to be dampened in BCG-inoculated mice, even though the suppression of inflammatory response modules in mice inoculated with BCG was unrelated to lower viral loads.

Experimental proof-of-concept

Overall, these findings suggest the reduction of viral burden by BCG may not be the only variable that can explain the robust inhibition of the SARS-CoV-2 inflammatory response and successful defense from lethal challenge.

Instead, these researchers propose that a major effect of prior exposure to BCG is limiting pathological effects of the host’s innate response to the virus, which may stem from the local effects of BCG-induced cytokines on the pulmonary myeloid and epithelioid compartments.

“While intravenous administration of BCG is currently not a clinically acceptable practice, the experimental proof-of-concept that prior BCG can trigger potent protection against lethal SARS-CoV-2 challenge may be of value in the design of other strategies for COVID-19 prophylaxis that target the innate response to the virus”, explain study authors in this bioRxiv paper.

In any case, further animal studies will be needed to assess the correlates of the innate immune response, as clinical trials are now already looking at whether the BCG vaccine can actually reduce SARS-CoV-2 infection or COVID-19 symptom severity in humans.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university – University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.