A Case for Antibodies as Mechanistic Correlates of Immunity in Tuberculosis

Abstract

Tuberculosis infects one quarter of the world's population and is the leading cause of death by a single infectious agent, responsible for a reported 1.3 million deaths in 2017. While Mycobacterium tuberculosis is treatable with antibiotic therapy, the increased prevalence of drug resistance, coupled with the variable efficacy of the only widely approved vaccine, has highlighted the need for creative approaches to therapeutic and vaccine development. Historically, a productive immune response to M. tuberculosis has been thought to be nearly entirely cell-mediated, with humoral immunity being largely dismissed. However, in this review, we will discuss the historical skepticism surrounding the role of the humoral immune response to M. tuberculosis , and examine more recent evidence suggesting that antibodies may play a valuable role in host defense against the pathogen. Despite the amount of data portraying antibodies in a negative light, emerging data have begun to highlight the unexpected role of antibodies in M. tuberculosis control. Specifically, it has become clear that antibody features of both the variable and constant domain (Fc) ultimately determine the extent to which antibodies modulate disease. Thus, a more precise definition of the antigen-binding and innate immune recruiting functions of antibodies that contribute to M. tuberculosis restriction, are sure to help guide the development of next-generation therapeutics and vaccines to curb this global epidemic.

Tools for Assessing the Protective Efficacy of TB Vaccines in Humans: in vitro Mycobacterial Growth Inhibition Predicts Outcome of in vivo Mycobacterial Infection

“…Levels of IgG following BCG infection were also weakly associated with improved control of mycobacterial growth in the MGIA in the BCG-vaccinated volunteers and with in vivo clearance of BCG from the site of infection. Although humoral immunity has long been neglected in the field due to the intracellular nature of mycobacteria, there is a growing body of evidence indicating a role for B cells and antibodies in immunity from TB ranging from modulation of the T cell response to antibody-dependent cellular phagocytosis and cytotoxicity (53,54). O'Shea et al reported a study of individuals with active TB disease or latent TB infection (LTBI) in which IgG1 responses to M.tb-specific antigens correlated with improved mycobacterial control in the direct whole blood MGIA (29).…”

Role of the Microbiota in the Modulation of Vaccine Immune Responses

“…Novel analytical approaches, able to integrate diverse facets of the humoral immune response and define the relationships between antibody populations and functions, are now available. These approaches reveal features of vaccine-induced “fingerprints” and offer new insights concerning polyclonal antibody immune responses elicited by vaccines (Chung et al, 2015; Kawahara et al, 2019).…”

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

“…Current TB vaccine design strategies generally target enhanced cell-mediated immunity, whereas antibody-based approaches have been largely dismissed until recently (Achkar and Casadevall, 2013;Cywes-Bentley et al, 2018;Kawahara et al, 2019;Tanner et al, 2019). Recent evidence also supports the contribution of trained innate immunity to vaccine protection (Khader et al, 2019;Koeken et al, 2019).…”