In a recent study posted to the bioRxiv* preprint server, researchers tested the effectiveness of the Bacillus Calmette Guérin (BCG) vaccine in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected Syrian hamsters.
Study: Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation. Image Credit: ffikretow/Shutterstock
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
The need to constantly review the currently available vaccines against SARS-CoV-2 is critical from the viewpoint that its novel variants are capable of causing breakthrough infections in vaccinated individuals. Moreover, SARS-CoV-2 may never be eradicated and continue to evolve with multiple lineages, so repetitive vaccination campaigns with increasingly effective vaccines will be required in the future, as is the case with the influenza virus.
Several past works have demonstrated the ability of the BCG vaccine to induce heterologous immunity. Accordingly, several human clinical trials launched in early 2020 evaluated the efficacy of the BCG vaccine against coronavirus disease 2019 (COVID-19).
One such study reported that immunization with BCG reduced the risk of COVID-19 diagnoses by approximately 68% compared to unvaccinated controls. Further, BCG is a well-established vaccine adjuvant with the potential to boost the immunogenicity of protein subunit, deoxyribonucleic acid (DNA), and viral vector-based vaccines in preclinical trials.
Overall, studies evaluating BCG as a COVID-19 vaccine alone or in combination with other licensed vaccines could fetch promising results and are most urgently warranted.
About the study
In the current study, researchers evaluated the impact of intravenous BCG vaccination in SARS-CoV-2-infected golden Syrian hamsters, particularly their lung viral titers and tissue pathology.
They made three groups with 13 hamsters for the study analysis. They immunized three animals with the BCG vaccine (group 1), group 2 had four SARS-CoV-2-infected animals (two infected on day four and two on day seven), and group 3 had six animals vaccinated with BCG and later challenged with SARS-CoV-2 (three on day four and three on day seven). They used a higher dose of BCG vaccine (5x106 colony-forming units (CFU)), a higher SARS-CoV-2 challenge dose (5x105 plaque-forming units (PFU)), and sacrificed the test animals on day four, at peak infection.
According to the authors, this is the first study to use droplet-based single-cell ribonucleic acid (RNA) sequencing (scRNAseq) to obtain a higher resolution of pulmonary immune responses linked to BCG immunization during SARS-CoV-2 infection in the lungs of the test animals. For analysis of cell populations, the research team used flow cytometry supplemented scRNAseq. The team performed scRNAseq on 194,536 cells, and after filtering out low-quality cells, including red blood cells, and doublets, they analyzed 112,928 cells.
They analyzed 11,249, 8,643, and 7,434 cells per test animal in BCG-vaccinated lungs, SARS-CoV-2-infected lungs, and BCG vaccinated + SARS-CoV-2-infected lungs, respectively. For experimental evaluations, they used histopathology, immunohistochemistry (IHC), positron emission tomography (PET), and computed tomography (CT).
Study findings
The study analysis showed that the BCG vaccination prevented SARS-CoV-2 replication at the time of peak infection in test animals, as indicated by median tissue culture infectious dose (TCID50) values of lung homogenates. Further, it reduced the probability of contracting bronchopneumonia on days four and seven.
The authors noted an association of BCG vaccination with the appearance of macrophages in the lungs of the test animals. Further, it diminished T cell lymphopenia in the lungs and decreased granulocyte lung infiltration.
The scRNAseq data revealed that BCG vaccination four weeks before the SARS-CoV-2 challenge shifted cell populations in lungs and associated differentially expressed genes (DEGs) expression. Accordingly, BCG accelerated the induction of immunoglobulin-producing plasma cells in the lung and overall antibody production against SARS-CoV-2.
The authors also observed elevated CD4+ T cell levels, including T helper type 1 (Th1) and regulatory T cells (Treg). These cells express high levels of type I interferon (IFN)-associated genes in the lungs of vaccinated animals, suggesting BCG has immuno-tolerizing activity. BCG's ability to shift several cell types from expressing IFN-associated genes further demonstrates its immuno-tolerizing activity. Furthermore, BCG-vaccination led to decreased exhaustion scores in the gene expressions of some of these T lymphocytes.
Furthermore, scRNAseq revealed that the BCG vaccination recruited high levels of alveolar macrophages (AMs) to the lungs, cells associated with low inflammation potential, and pathogen clearance from the host body. However, upon the SARS-CoV-2 challenge, AM levels dropped in BCG-vaccinated animals.
A salutary immunologic effect of BCG prevented excess pro-inflammatory interstitial macrophage (IM) recruitment. Consequently, their populations were less in BCG-vaccinated animals. Further, they observed AM and IM that strongly expressed metabolic and repair genes in the lungs of BCG-vaccinated animals.
Conclusions
The study results suggested that BCG vaccination has a tolerizing effect on SARS-CoV-2-mediated lung inflammation and may overall accelerate antiviral antibody responses in mice. Using BCG vaccination with the existing COVID-19 vaccines could offer synergistic protection.
*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.
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