In a recent study published in Cell Reports, researchers investigated the effectiveness of the Bacillus Calmette-Guerin (BCG) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections using three animal models.
Innate immunity plays a vital role in protecting the host against infectious pathogens. The administration of live attenuated vaccines (LAVs) such as the BCG vaccine leads to the generation of host innate immunological memory consisting of trained immune responses by competent cytokine-releasing monocytes in humans. This innate immune response is based on epigenetic reprogramming of immune cells at central and peripheral levels in hematopoietic stem cells (HSCs) of bone marrow (BM) and specific tissues of the human body, respectively.
According to previous studies, BCG vaccination offered protection against a wide spectrum of infections such as viral infections with Herpes, Influenza, tuberculosis, yellow fever, infantile sepsis, fungal diseases, and parasitic infections. However, BCG vaccine effectiveness against SARS-CoV-2 is unknown.
About the study
In the present study, the researchers assessed BCG vaccine efficacy against SARS-CoV-2 by the administration of BCG vaccines intravenously in wild-type of C57BL/6J mice and subcutaneously into transgenic mice expressing the viral spike (S) glycoprotein binding- K18- human angiotensin-converting enzyme (hACE2) receptors in lethal as well as sublethal doses similar to that administered intradermally or intravenous in human beings.
Four weeks after BCG vaccination, a sublethal dose of Influenza A virus (IAV) was injected intranasally into the mice. Pulmonary viral load was assessed three days after IAV injection by quantitative polymerase chain reaction (qPCR). K18-hACE2 expressing mice were infected with lethal doses of SARS-CoV-2/SB2 strain belonging to B.4 cellular lineage.
Following the development of severe and rapidly progressing neurological diseases and associated deaths in mice intranasally infected with SARS-CoV-2/SB2 strain previously, the animals were injected with the same viral strains intratracheally. Due to low levels of hACE2 levels expressed by transgenic mice, Syrian and Roborovski hamsters were injected with SARS-CoV-2/SB2 and SARS-CoV-2/RIM-1 strains along with IAV to evaluate and compare BCG vaccine efficacy.
Pulmonary histological analysis and SARS-CoV-2 ribonucleic acid (RNA) viral loads were assessed to determine the presence of lung pathologies and their role in viral dissemination to various organs of the human body, respectively. Monocytes from humans voluntarily participating in this study were infected with SARS-CoV-2 and IAV before and after approximately three months post-BCG vaccination to determine whether they react differently to SARS-CoV-2 and IAV.
Results and discussion
Although BCG vaccination significantly protected mice and Syrian and Roborovski hamsters against IAV, as indicated by a substantial reduction in viral loads, mortality, morbidity, and maintenance of body weight, it was ineffective against SARS-CoV-2-associated morbidity. This was suggested by the absence of significant changes in pulmonary leukocytic and myeloid counts, serum interleukin-6 (IL-6), and interferon-beta (IF-β) levels or viral loads five days post-vaccination. Genes associated with viral multiplication such as N2 and upE were also detected in SARS-CoV-2-infected animals due to increased intracellular viral replication. No deaths were observed in the animals after intratracheal administration of vaccines and injections containing SARS-CoV-2 and IAV.
Histopathological analysis revealed the presence of pulmonary hemorrhage, microthrombi, and lymphocytic infiltration in vascular endothelium as well as peri-vascular tissues in all the animal models. Elevated levels of SARS-CoV-2 RNA were obtained in the BM of animals infected with SARS-CoV-2, the central location for developing trained innate immune memory. The vascular damage observed in pulmonary macrophages, endothelial cells, and pneumocytes were unique to SARS-CoV-2 infections.
The researchers concluded that the BCG vaccine does not confer effective protection against SARS-CoV-2 strains based on the present study findings. This conclusion was due to severe pulmonary endothelial and perivascular cellular injuries that facilitate SARS-CoV-2 dissemination from the lung vasculature into extrapulmonary organs such as the BM, liver, heart, kidneys, and brain that increases viral susceptibility and diminishes trained targeted immune memory generation in the host by the BCG vaccine.
Future studies using uniform BCG strains (Pasteur or Tick) across all the samples, larger sample sizes, and epigenomic or transcriptomic procedures are required to provide more accurate information on BCG vaccine efficacy against mild as well as moderate SARS-CoV-2 infections. The development of immunological strategies and novel vaccines capable of genetic reprogramming procedures could enable the administration of BCG vaccines as a protective measure against coronavirus disease (COVID-19).