Study By U.S. National Institute of Allergy and Infectious Diseases Claims Bacille Calmette-Guérin Vaccine Could Protect Against COVID-19 Disease Severity

A new study led by researchers from the U.S. National Institute of Allergy and Infectious Diseases, NIH claims that the bacille Calmette-Guérin (BCG) vaccine could offer protection against COVID-19 disease severity and mortality based on study findings involving mice models.

According to the study team, early events in the host response to SARS-CoV-2 are thought to play a major role in determining disease severity. During pulmonary infection, the novel coronavirus encounters both myeloid and epithelioid lineage cells that can either support or restrict pathogen replication as well as respond with host protective versus detrimental mediators.
 
The study team found that in addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer non-specific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment.
 
The study team demonstrated that prior intravenous, but not subcutaneous, administration of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 and results in reduced viral loads in non-transgenic animals infected with an alpha variant. The observed increase in host resistance was associated with reductions in SARS-CoV-2-induced tissue pathology, inflammatory cell recruitment and cytokine production that multivariate analysis revealed to be only partially related to diminished viral load.
 
The study findings propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and the ensuing immunopathology.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.08.30.458273v1.full.pdf
 
The study findings 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).
 
The 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.
 
The bacille Calmette-Guérin or 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.
 
Hence 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.
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Currently 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.
 
The study team 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.
 
The initial mouse model study 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.
 
However the second animal 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.
 
Upon 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.
 
The study team found 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.
 
Furthermore 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.
 
Importantly, 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.
 
The study 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.
 
Rather, the study team proposes 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.
 
Corresponding author Dr Kerry L. Hilligan from the Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health-Maryland told Thailand Medical News, “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. 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.”
 
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