Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine

Abstract

Currently there are a dozen or so of new vaccine candidates in clinical trials for prevention of tuberculosis (TB) and each formulation attempts to elicit protection by enhancement of cell-mediated immunity (CMI). In contrast, most approved vaccines against other bacterial pathogens are believed to mediate protection by eliciting antibody responses. However, it has been difficult to apply this formula to TB because of the difficulty in reliably eliciting protective antibodies. Here, we developed capsular polysaccharide conjugates by linking mycobacterial capsular arabinomannan (AM) to either Mtb Ag85b or B. anthracis protective antigen (PA). Further, we studied their immunogenicity by ELISA and AM glycan microarrays and protection efficacy in mice. Immunization with either Abg85b-AM or PA-AM conjugates elicited an AM-specific antibody response in mice. AM binding antibodies stimulated transcriptional changes in Mtb. Sera from AM conjugate immunized mice reacted against a broad spectrum of AM structural variants and specifically recognized arabinan fragments. Conjugate vaccine immunized mice infected with Mtb had lower bacterial numbers in lungs and spleen, and lived longer than control mice. These findings provide additional evidence that humoral immunity can contribute to protection against Mtb.

The Damage–Response Framework as a Tool for the Physician-Scientist to Understand the Pathogenesis of Infectious Diseases

“…Another way antibodies can dampen inflammation is via direct microbial effects. Antibodies to bacteria, mycobacteria, and fungi that alter microbial transcription, metabolism, or growth have been described [48][49][50][51] and may hold promise as therapeutic agents.…”

Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection

“…Elevated AM‐specific immunoglobulin G (IgG) titers in BCG‐vaccinated healthy donors correlated with improved mycobacterial opsonophagocytosis and intracellular growth inhibition in human macrophages . In murine Mtb challenge models, AM‐protein conjugate vaccines extended the survival time of animals . Antibodies against cell wall‐associated glycolipid lipoarabinomannan, which structurally overlaps with AM, could contribute to containment of M. tuberculosis infection in children.…”

“…41 In murine Mtb challenge models, AM-protein conjugate vaccines extended the survival time of animals. 45,46 Antibodies against cell wall-associated glycolipid lipoarabinomannan, which structurally overlaps with AM, could contribute to containment of M. tuberculosis infection in children. The lack of lipoarabinomannanspecific antibodies in children with TB disease predisposed them to disseminated TB.…”

Mycobacterium Tuberculosis and Interactions with the Host Immune System: Opportunities for Nanoparticle Based Immunotherapeutics and Vaccines

“…Moreover, in vitro and animal studies using antibodies to M. tuberculosis antigens have shown enhanced protection with increased survival and reduced bacterial burden (77,78). Recent immunization studies with mycobacterial capsular arabinomannan conjugates have demonstrated antibody and T cell responses that contribute to protective immunity against M. tuberculosis (79). These findings provide evidence for the potential role of humoral immunity in TB vaccine development strategies.…”