A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality

Abstract

Purpose Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops 'herd immunity', or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette-Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses. Methods We developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. Results Our analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro. Conclusions Our results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2. KEY WORDS BCG vaccine. COVID-19. innate immunity. SARS-CoV-2. systems biology ABBREVIATIONS BCG Bacillus Calmette-Guérin BIND Biomolecular interaction network database BioGRID Biological general repository for interaction datasets CMap Connectivity map COVID-19 Coronavirus disease 2019 DIP Database of interacting proteins FDA The Food and Drug Administration GEO Gene expression omnibus GO Gene ontology KEGG Kyoto encyclopedia of genes and genomes Mtb Mycobacterium tuberculosis RCTs Randomized clinical trials STRING Search tool for the retrieval of interacting genes/proteins WHO World Health Organization

Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients

“…Though the CDC and FDA usually follow up on all serious adverse event reports to obtain additional medical, laboratory, death certificates, and/or autopsy records, nonetheless changes in information based on further investigations of serious adverse events may not be reflected on VAERS public data. Secondly, bioinformatics techniques relying on gene expression, pathway over-representation and network biology have the following limitations and biases that we reviewed by Hajjo and Tropsha elsewhere [ 17 ]. While we were finalizing this manuscript, we learned that the CDC is planning an ‘emergency meeting’ on rare post-COVID-19 vaccine heart inflammation [ 63 ].…”

“…We developed an informatics workflow ( Figure 1 ), based on the methods developed by Hajjo et al [ 16 , 17 , 18 , 19 ], to interrogate the network pharmacology of myocarditis/pericarditis to derive a testable mechanistic hypothesis that could explain post-vaccine cardiac adverse events. First, we started by searching VAERS using the following VAERS indexing terms for events: “myocarditis” and “pericarditis”.…”

Reduced mortality during the COVID-19 outbreak in Japan, 2020: a two-stage interrupted time-series design

“… 36 The BCG vaccine also promotes the production and maturation of naïve T cells that lead to enhanced long-term trained immune protection against SARS-CoV-2. 37 Furthermore, small-module BCG mimics such as emetin and lopinavir inhibit the growth of SARS-CoV-2 in vitro , which may contribute to reduce COVID-19 mortality. 37 Although the exact mechanisms of remain unclear, it may result from complex and multifactorial interactions among these and other as-yet unidentified factors.…”

“… 37 Furthermore, small-module BCG mimics such as emetin and lopinavir inhibit the growth of SARS-CoV-2 in vitro , which may contribute to reduce COVID-19 mortality. 37 Although the exact mechanisms of remain unclear, it may result from complex and multifactorial interactions among these and other as-yet unidentified factors.…”

Trained Immunity: An Overview and the Impact on COVID-19

“…Many of these signaling pathways are activated in different cell types within the innate immune system, suggesting that training with BCG may utilize conserved pathways. Since BCG vaccination has been demonstrated to possess therapeutic effects against respiratory infections, it has been hypothesized that BCG may offer heterologous immunity against SARS-CoV-2 infection ( 17 , 30 , 31 ). Therefore, ongoing clinical trials are investigating the relationship between BCG vaccination and protection against COVID-19.…”