BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny.

Asimenia Angelidou,Robert N Husson,Maria Giulia Conti,Kinga K Smolen,Ofer Levy,David J Dowling,Simon Daniël Van Haren,Joann Diray-Arce

doi:10.3389/fmicb.2020.00332

Abstract

Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-Guérin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (∼50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces “heterologous” protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed “trained immunity.” In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TB-specific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCG’s innate immune activation, suggesting that aspects of BCG’s effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines.

Highlights

Reviewed by: Eva Kaufmann, McGill University Health Centre, Canada Frank Verreck, Biomedical Primate Research Centre, Netherlands
This study showed clear differences in the efficacy of Bacille Calmette-Guérin (BCG) grown in these different culture media, including variation in persistence within macrophages in vitro, apoptosis of infected cells, as well as cellular and humoral immune responses in mice in vivo (Venkataswamy et al, 2012)
The impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life was examined in two African birth cohorts (Kiravu et al, 2019), where BCG Denmark vaccinated infants mounted significantly higher frequencies of polyfunctional CD4+ T cells, compared with infants vaccinated with BCG Bulgaria and BCG Russia

Summary

Introduction

Reviewed by: Eva Kaufmann, McGill University Health Centre, Canada Frank Verreck, Biomedical Primate Research Centre, Netherlands. The impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life was examined in two African birth cohorts (Kiravu et al, 2019), where BCG Denmark vaccinated infants mounted significantly higher frequencies of polyfunctional CD4+ T cells, compared with infants vaccinated with BCG Bulgaria and BCG Russia.

Results

Conclusion