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

Rafael Prados-Rosales,John Chan,Julen Tomás,Brian Weinrick,Jacqueline M Achkar,Leticia Sampedro,Noemi A Saavedra,Maju Joe,Ashish Tripathi,Arturo Casadevall,Yu Bai,Todd L Lowary,Steven A Porcelli,Caroline Blanc,Rainer Kalscheuer,Jiayong Xu,Adel Malek,William R Jacobs ,Juan Anguíta ,Leandro J Carreño ,Shang‐Cheng Hung ,Aharona Glatman‐Freedman ,Ana Batista‐González ,Andrés Baena ,Tingting Chen

doi:10.1371/journal.ppat.1006250

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.

Highlights

Mycobacterium tuberculosis (Mtb), the causative agent of TB, can establish latent or progressive infection despite the presence of a fully functioning immune system
We demonstrate that immunization with mycobacterial capsular arabinomannan (AM) conjugates elicited responses that contributed to protection against Mtb infection
We developed two different conjugates including capsular AM linked to the Mtb related protein Ag85b or the Mtb unrelated protective antigen (PA) from B. anthracis and found that immunization with AM conjugates elicited antibody populations with different specificities

Summary

Introduction

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 [1]. There is strong evidence to suggest that the mycobacterial cell envelope is of key importance for survival in the host [2]. The mycobacterial envelope consists of three major components: the plasma membrane, the cell wall, and an outermost capsule [2]. Bacterial capsules are protective structures important for the interaction with and successful colonization of the host [3]. Toxic substances have recently been found in the mycobacterial capsule, suggesting the contribution of this compartment to mycobacterial pathogenesis [4]

Methods

Results

Discussion

Conclusion