It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity

Abstract

Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.

The quest for vaccine-induced immune correlates of protection against tuberculosis

“…Immune responses to Mtb are complex, include many immune cell subsets and effector mechanisms of the immune system and are affected by the extra-cellular milieu and pre-existing immunity [ 22 , 23 ]. Available evidence from pre-clinical models, particularly non-human primates (NHP), as well as cohort studies investigating immune correlates of risk for TB were considered to delineate the “immunological space” to be covered by the pilot studies and to outline the primary hypotheses to be tested using several state-of-the-art technological approaches ( Figure 1 and Table 2 ).…”

Therapeutic efficacy against Mycobacterium tuberculosis using ID93 and liposomal adjuvant formulations

“…There is new excitement in the numerous ways that vaccine-or M.tb.-induced antibody responses may be beneficial for host-induced protective responses. Several functional attributes of antibodies could potentially play a role in protection against M.tb which have been described in depth in 10.3389/fmicb.2022.935444 Frontiers in Microbiology frontiersin.org excellent reviews, which include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) among several other well-characterized functions (Achkar et al, 2015;Lu et al, 2016Lu et al, , 2018Larsen et al, 2022). In the case of intravenous administration of BCG in rhesus macaques, where six out of 10 of the NHPs were completely protected (with no signs of infection) against M.tb (Darrah et al, 2020), an enhanced anti-lipoarabinomannan (LAM) IgM response was induced and measured in the plasma, which negatively correlated with the burden of M.tb in the lungs (Irvine et al, 2021).…”

Impact of SIV infection on mycobacterial lipid-reactive T cell responses in Bacillus Calmette-Guérin (BCG) inoculated macaques

“…Multiple studies have provided important insights into the adaptive immune responses of CD4 T cells in TB immunity ( 9 – 11 ). Distinct T lymphocytes with different cytokine profiles contribute to either resistance or susceptibility to TB ( 12 ). For instance, Type 1 responses by CD4 T cells, including the induction of IFN-γ, IL-2, and cytolytic activity, have been shown to be important in mycobacterial immunity ( 13 – 16 ).…”

“…Further, IFN-g responses have been associated with protective mycobacterial immunity in active and latent TB (17)(18)(19), as well as in PBMC from BCG-vaccinated individuals (17)(18)(19)(20). Besides, Th1-type CD4 T cell responses, early gd Tcell, invariant natural killer T cell (iNKT), natural killer (NK) cell, B-cell, neutrophil, myeloid dendritic cell (mDC), and mucosal-associated invariant T (MAIT) cell responses are also observed following BCG inoculation (12). Additionally, mounting evidence points toward the anti-mycobacterial potential of unconventional CD1-restricted T cell responses targeting Mtb lipid antigens via Th1-type and cytotoxic effector functions (21)(22)(23)(24).…”