Large-Scale Structure-Based Screening of Potential T Cell Cross-Reactivities Involving Peptide-Targets From BCG Vaccine and SARS-CoV-2

Abstract

Although not being the first viral pandemic to affect humankind, we are now for the first time faced with a pandemic caused by a coronavirus. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been responsible for the COVID-19 pandemic, which caused more than 4.5 million deaths worldwide. Despite unprecedented efforts, with vaccines being developed in a record time, SARS-CoV-2 continues to spread worldwide with new variants arising in different countries. Such persistent spread is in part enabled by public resistance to vaccination in some countries, and limited access to vaccines in other countries. The limited vaccination coverage, the continued risk for resistant variants, and the existence of natural reservoirs for coronaviruses, highlight the importance of developing additional therapeutic strategies against SARS-CoV-2 and other coronaviruses. At the beginning of the pandemic it was suggested that countries with Bacillus Calmette-Guérin (BCG) vaccination programs could be associated with a reduced number and/or severity of COVID-19 cases. Preliminary studies have provided evidence for this relationship and further investigation is being conducted in ongoing clinical trials. The protection against SARS-CoV-2 induced by BCG vaccination may be mediated by cross-reactive T cell lymphocytes, which recognize peptides displayed by class I Human Leukocyte Antigens (HLA-I) on the surface of infected cells. In order to identify potential targets of T cell cross-reactivity, we implemented an in silico strategy combining sequence-based and structure-based methods to screen over 13,5 million possible cross-reactive peptide pairs from BCG and SARS-CoV-2. Our study produced (i) a list of immunogenic BCG-derived peptides that may prime T cell cross-reactivity against SARS-CoV-2, (ii) a large dataset of modeled peptide-HLA structures for the screened targets, and (iii) new computational methods for structure-based screenings that can be used by others in future studies. Our study expands the list of BCG peptides potentially involved in T cell cross-reactivity with SARS-CoV-2-derived peptides, and identifies multiple high-density “neighborhoods” of cross-reactive peptides which could be driving heterologous immunity induced by BCG vaccination, therefore providing insights for future vaccine development efforts.

Evidence for the heterologous benefits of prior BCG vaccination on COVISHIELD™ vaccine-induced immune responses in SARS-CoV-2 seronegative young Indian adults

“…Apart from these suggested mechanisms, it has been speculated that BCG vaccination might lower thresholds for T cell activation on account of the cytokine milieu that exists due to primed/trained monocytes ( 79 ). It should be noted that boosted T cell responses to COVISHIELD™ in individuals vaccinated with BCG might also be due to presence of cross-reactive epitopes in BCG and SARS-CoV-2 vaccines ( 80 ). Importantly, SARS-CoV-2 specific CD4+ T cell responses too have been demonstrated to be more robust compared to the CD8+ T cell response in the context of vaccination as well as infection ( 81 , 82 ).…”

Evolution, the Immune System, and the Health Consequences of Socioeconomic Inequality

“…If early versions of so many genes evolved long ago in microbes, then essentially all life forms are constructed from closely related building blocks. This may explain why exposure to a very broad diversity of microorganisms, even if entirely harmless, can prime memory T cells that recognize previously unencountered pathogens such as HIV ( 13 ) or the COVID-19 virus ( 14 ).…”

“…1 ) ( 35 , 36 ). Similarly, exposure to a very diverse range of microorganisms from the environment can prime memory T cells that by chance recognize even novel organisms that the individual has never previously encountered, such as HIV or the pathogen causing COVID-19 ( 13 , 14 ). Some of the types of organisms and information that microbial exposures supply to the immune system are listed in Fig.…”

BCG Vaccination: A potential tool against COVID-19 and COVID-19-like Black Swan incidents

“…For example, a recent study involving SARS-CoV-2 found eight new BCG derived peptides with significant homology with NSP3 or NSP13 derived peptides of SARS-CoV-2 [155] , along with several similar studies involving in silico identification of multiple cross-reactive peptides between SARS-CoV-2 and BCG or Mycobacterium sp. antigens, which could drive heterologous immunity induced by BCG vaccination [156] , [157] , [158] , [159] , [160] . Furthermore, it was also found that the first stimulation of BCG-derived peptides could significantly enhance the immunoreactivity of CD4 + and CD8 + T cells to corresponding homologous peptides derived from SARS-CoV-2 [155] , [161] .…”