An anti-viral vaccine regimen that leverages mycobacteria specific helper T cells induced by prior BCG vaccination

Identification: Ng-Tony


An anti-viral vaccine regimen that leverages mycobacteria specific helper T cells induced by prior BCG vaccination
Tony W. Ng1, Wakako Furuyama2, Ariel A. Wirchnianski1, Neeraj Saini1, John Chan1, William R. Jacobs, Jr.1, Kartik Chandran1, Andrea Marzi2, and Steven A. Porcelli1
1Albert Einstein College of Medicine, Bronx, NY, USA.
2Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.

BCG vaccination induces robust CD4+ T cell (Th) responses but is insufficient to halt the continuing global tuberculosis pandemic caused by Mycobacterium tuberculosis (Mtb). In spite of its limited efficacy as a preventative vaccine for tuberculosis, BCG is widely administered as a neonatal vaccine in most regions with high tuberculosis prevalence, including most African nations and other underdeveloped countries.  With the emergence of viral pathogens, such as SARS-CoV-2 and Ebola virus (EBOV), we sought ways to take advantage of these pre-existing mycobacteria specific Th cells in BCG vaccinated individuals to help drive protective anti-viral antibodies. We designed a recombinant viral vaccine that consists of a viral immunogen fused to the mycobacteria Th cell epitope (P25) of Ag85B. Highly efficient presentation of the P25 epitope by B cells specific for the viral antigen recruited cognate interactions with P25 Th cells to promote virus-specific antibody responses. Experiments in C57BL/6 mice showed BCG priming induced a broad range of Th cells including Th1, Th2, and Tfh subsets. These P25 Th subsets provided a significant dose sparing effect on the P25-viral immunogen vaccine in the induction of anti-viral antibodies, and resulted in increased titers of high affinity neutralizing IgG1 antibodies. The induction of IgG2c antibodies only occurred in BCG primed mice, where BCG vaccination is known to be a strong inducer of Th1 responses that drive class-switching to IgG2c. Microscopy of sections from secondary lymphoid organs of BCG primed mice showed that the majority of P25 Th cells remained in extrafollicular regions outside germinal centers. These extra-follicular foci were most likely responsible for the production of the IgG2c class-switched antibodies, which were weakly neutralizing but capable of mediating antibody-dependent cellular toxicity (ADCC). As a proof of concept study, BCG priming followed by vaccination with a recombinant EBOV glycoprotein modified by inclusion of the P25 epitope protected mice against lethal EBOV infection, thus suggesting a potentially useful strategy for vaccination against viral pathogens in subjects that have previously been vaccinated with BCG. This basic approach can also be applied with other developing strategies for improved vaccination against Mtb, including BCG re-vaccination and development of immunogenic Mtb mutants, which may be even more effective in generating mycobacteria-specific Th cell responses to drive protective anti-viral antibody responses.



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