Date Published: March 9, 2017
Publisher: Public Library of Science
Author(s): Rafael Prados-Rosales, Leandro Carreño, Tingting Cheng, Caroline Blanc, Brian Weinrick, Adel Malek, Todd L. Lowary, Andres Baena, Maju Joe, Yu Bai, Rainer Kalscheuer, Ana Batista-Gonzalez, Noemi A. Saavedra, Leticia Sampedro, Julen Tomás, Juan Anguita, Shang-Cheng Hung, Ashish Tripathi, Jiayong Xu, Aharona Glatman-Freedman, Williams R. Jacobs, John Chan, Steven A. Porcelli, Jacqueline M. Achkar, Arturo Casadevall, Padmini Salgame.
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.
Mycobacterium tuberculosis (Mtb), the causative agent of TB, can establish latent or progressive infection despite the presence of a fully functioning immune system. The capacity of Mtb to avoid immune-mediated clearance reflects a necessary association with the human host that has led to an evolved and coordinated program of immune evasion strategies, including interference with antigen presentation to prevent and/or alter the quality of T-cell responses . There is strong evidence to suggest that the mycobacterial cell envelope is of key importance for survival in the host . The mycobacterial envelope consists of three major components: the plasma membrane, the cell wall, and an outermost capsule . Bacterial capsules are protective structures important for the interaction with and successful colonization of the host . Toxic substances have recently been found in the mycobacterial capsule, suggesting the contribution of this compartment to mycobacterial pathogenesis .
Here, we demonstrate that immunization with mycobacterial capsular arabinomannan (AM) conjugates elicited responses that contribute to protection against Mtb infection. In this study we, (i) isolated capsular AM from the H37Rv strain of Mtb and developed conjugates with the Mtb related protein Ag85b and Mtb unrelated PA from B. anthracis; (ii) found that immunization with different AM conjugates elicited antibody populations with different specificities; (iii) showed that surface-specific antibodies could directly modify the transcriptional profile and metabolism of mycobacteria; (iv) observed a prolonged survival and a reduction in bacterial numbers in lungs and spleen in mice immunized with Ag85b-AM conjugates after infection with Mtb; (v) observed that the presence of AM-binding antibodies was associated with modest prolongation in survival and a marked reduction in mycobacterial dissemination; (vi) and demonstrated that AM is antigenically variable and could potentially form the basis for a serological characterization of mycobacteria based on serotypes.