BCG-Based Vaccines Elicit Antigen-Specific Adaptive and Trained Immunity against SARS-CoV-2 and Andes orthohantavirus

Abstract

Background:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine mainly administered to newborns and used for over 100 years to prevent the disease caused by Mycobacterium tuberculosis (M. tb). This vaccine can induce immune response polarization towards a Th1 profile, which is desired for counteracting M. tb, other mycobacteria, and unrelated intracellular pathogens. The vaccine BCG has been used as a vector to express recombinant proteins and has been shown to protect against several diseases, particularly respiratory viruses. Methods: BCG was used to develop recombinant vaccines expressing either the Nucleoprotein from SARS-CoV-2 or Andes orthohantavirus. Mice were immunized with these vaccines with the aim of evaluating the safety and immunogenicity parameters. Results: Immunization with two doses of 1 × 108 CFU or one dose of 1 × 105 CFU of these BCGs was safe in mice. A statistically significant cellular immune response was induced by both formulations, characterized as the activation of CD4+ and CD8+ T cells. Stimulation with unrelated antigens resulted in increased expression of activation markers by T cells and secretion of IL-2 and IFN-γ, while increased secretion of IL-6 was found for both recombinant vaccines; all of these parameters related to a trained immunity profile. The humoral immune response elicited by both vaccines was modest, but further exposure to antigens could increase this response. Conclusions: The BCG vaccine is a promising platform for developing vaccines against different pathogens, inducing a marked antigen-specific immune response.

Superinfection with SARS-CoV-2 Has Deleterious Effects on Mycobacterium bovis BCG Immunity and Promotes Dissemination of Mycobacterium tuberculosis

“…However, the little apparent pathology, the low circulating cytokine levels, and the bacterial loads at or below the limit of detection are consistent with our unpublished work in BCG-vaccinated C57BL/6 mice. Other studies have shown that recombinant BCG vaccination in mice ( 30 ), revaccination with BCG in a clinical trial ( 31 ), and other routes of vaccination (intravenous) affect SARS-CoV-2 morbidity and mortality ( 26 ), demonstrating BCG’s unique off-target effects and potential as an adjuvant or booster. However, our study attempted to best experimentally represent what BCG’s effect would be clinically on SARS-CoV-2 given current vaccination regimens, which are intradermal and given at birth.…”

Fiction and Facts about BCG Imparting Trained Immunity against COVID-19

“…This could lead to a better adaptive response or an increased innate immune response. The BCG vaccine is a promising candidate molecule against viral infections such as SARS-CoV-2 and Andes orthohantavirus, inducing a marked antigen-specific immune response [ 106 ]. Presently, there are no reliable or perfect options available for the treatment of COVID-19, as evinced by the incessant mortality and morbidity globally.…”

“…The BCG vaccine has been shown to induce heterologous lymphocyte responses against non-specific antigens by eliciting higher production of memory CD4 T-cells and CD8 T-cells to generate an effective immune response against SARS-CoV-2 [ 103 , 104 , 105 ]. Recently, it was shown that immunization with wild-type or recombinant BCG (expressing viral antigens) resulted in an enhancement of a non-specific immune response, with increased secretion of pro-inflammatory cytokines and T-cell activation upon antigenic stimulation [ 106 ]. Vaccination with BCG promoted a trained immunity profile in the immunized mice, with increased secretions of IL-6 and TNF-α, thereby contemplating a possible reality of BCG vaccines in the immune defense against non-related respiratory diseases [ 73 ] ( Figure 4 ).…”

Current GMP standards for the production of vaccines and antibodies: An overview

“…Examples of vaccines produced under GMP regulations include those based on the innovative technique using recombinant Bacillus Calmette-Guerin (BCG), a live attenuated vaccine widely used since 1921 to prevent disease caused by Mycobacterium tuberculosis (97). This recombinant platform is capable of expressing viral particles that confer immunogenic protection against viruses such as a human respiratory syncytial virus (hRSV), human metapneumovirus (hMPV) (103-106), Andean ortho-hantavirus (ANDV), and SARS-CoV-2, the pathogen responsible for coronavirus disease 2019 (103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118).…”