A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19

Abstract

Bacillus Calmette-Guerin (BCG) has been used as a vaccine against tuberculosis since 1921 and remains the only currently approved vaccine for this infection. The recent discovery that BCG protects against initial infection, and not just against progression from latent to active disease, has significant implications for ongoing research into the immune mechanisms that are relevant to generate a solid host defense against Mycobacterium tuberculosis (Mtb). In this review, we first explore the different components of immunity that are augmented after BCG vaccination. Next, we summarize current efforts to improve the efficacy of BCG through the development of recombinant strains, heterologous prime-boost approaches and the deployment of non-traditional routes. These efforts have included the development of new recombinant BCG strains, and various strategies for expression of important antigens such as those deleted during the M. bovis attenuation process or antigens that are present only in Mtb. BCG is typically administered via the intradermal route, raising questions about whether this could account for its apparent failure to generate long-lasting immunological memory in the lungs and the inconsistent level of protection against pulmonary tuberculosis in adults. Recent years have seen a resurgence of interest in the mucosal and intravenous delivery routes as they have been shown to induce a better immune response both in the systemic and mucosal compartments. Finally, we discuss the potential benefits of the ability of BCG to confer trained immunity in a non-specific manner by broadly stimulating a host immunity resulting in a generalized survival benefit in neonates and the elderly, while potentially offering benefits for the control of new and emerging infectious diseases such as COVID-19. Given that BCG will likely continue to be widely used well into the future, it remains of critical importance to better understand the immune responses driven by it and how to leverage these for the design of improved vaccination strategies against tuberculosis.

Keywords: immunity; recombinant BCG; trained immunity; tuberculosis; vaccine.

Figure 1

illustrates the events that follow the intradermal injection of BCG. BCG is phagocytosed by various cells of the innate immune response that includes dendritic cells, macrophages and neutrophils. Dendritic cells are the main antigen presenting cells and BCG antigens are presented to CD4 via the MHC class II molecules and to CD8 T cells via the MHC class I molecules. This is followed by the activation of B cells, cytotoxic T lymphocytes and Th17 cells that collectively constitute the adaptive immune response to BCG vaccination.

Figure 2

illustrates the various prime boost regimens and the recombinant BCG strains that have been investigated in both animal models and human studies. The figure shows the immunological and protective effects following 3 main BCG prime -boost regimens: viral vector expressing mycobacterial antigen boost, DNA vaccine expressing mycobacterial antigen boost and mycobacterial antigen boost. The bottom panel of the figure depicts the various recombinant strains such as recombinant BCG expressing immunodominant antigens, mammalian cytokines, listeriolysin, perfingiolysin and the ESX-1 variant. Their immunological and protective effects have also been shown.

Figure 3

illustrates the “training” of naïve immune cells after BCG vaccination via epigenetic reprograming and metabolic adaptations (left panel). Subsequently, upon a future encounter with an unrelated infectious agent, these “trained” cells of the innate immune system are able to mount an altered immune response that is more effective in the reduction of viremia, clearance of pathogens and a faster recovery.