Robust IgM responses following vaccination are associated with prevention ofMycobacterium tuberculosisinfection in macaques

Abstract

Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). However, recent work has shown that compared to standard intradermal Bacille Calmette-Guerin (BCG) vaccination, intravenous (IV) BCG vaccination provides nearly complete protection against TB in rhesus macaques. While studies have focused on cellular immunity in this setting, the antibody response elicited by IV BCG vaccination remains incompletely defined. Using an agnostic antibody profiling approach, here we show that IV BCG drives superior antibody responses in the plasma and the bronchoalveolar lavage fluid (BAL). While IV BCG immunization resulted in the broad expansion of antibody titers and effector functions, surprisingly, IgM titers were among the strongest markers of reduced bacterial burden in the plasma and BAL of BCG immunized animals. Moreover, IgM immunity was also enriched among animals receiving protective vaccination with an attenuated Mtb strain. Finally, a LAM-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and as a functional mediator of protection against TB.

Re-evaluating the Role of Antibodies in Tuberculosis

“…Mycobacteria-specific IgM titers in plasma and BAL negatively correlated with Mtb burden in lungs (Irvine et al, 2021). LAM-specific antibodies from intravenously vaccinated macaques induced significantly (though moderately) higher antibody-dependent neutrophile phagocytosis (Irvine et al, 2021). Although endobronchial or intravenous vaccination may not be suitable routes for humans, these studies show that mycobacteria-specific antibodies can be protective and targeted by vaccine strategies.…”

“…Another study induced robust BCG-specific IgM responses in plasma and BAL by vaccinating macaques intravenously with BCG. Mycobacteria-specific IgM titers in plasma and BAL negatively correlated with Mtb burden in lungs (Irvine et al, 2021). LAM-specific antibodies from intravenously vaccinated macaques induced significantly (though moderately) higher antibody-dependent neutrophile phagocytosis (Irvine et al, 2021).…”

Immune correlates of early clearance ofMycobacterium tuberculosisamong tuberculosis household contacts in Indonesia

“…They also had similar concentrations of IgG, IgM and IgA antibodies to different Mtb antigens as IGRA-positive contacts (6). Other studies, in humans (7) as well as primates (8), have also found in anti-Mtb antibodies, and suggested that they may protect against Mtb infection as well TB disease (9) in an IFN-γ-independent way.…”

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

“…The compartmentalization of immune responses between peripheral and local mucosa is well reviewed here ( 383 ). Recent studies have shown that aerosol and mucosal delivery of TB vaccine candidates help drive some IL-17-dependent cellular immunity ( 384 ) and increase vaccine-induced protective IgM antibody responses ( 385 ). Aerosol delivery of an adenovirus TB vaccine candidate has been described as safe and induces enhanced polyfunctional airway responses, including CD8+ T cells, outperforming intramuscular delivery of the same vaccine in mouse models of Mtb challenge ( 349 , 386 ) and a phase 1 human clinical trial ( 387 ).…”