TY - JOUR
T1 - Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine
AU - Prados-Rosales, Rafael
AU - Carreño, Leandro
AU - Cheng, Tingting
AU - Blanc, Caroline
AU - Weinrick, Brian
AU - Malek, Adel
AU - Lowary, Todd L.
AU - Baena, Andres
AU - Joe, Maju
AU - Bai, Yu
AU - Kalscheuer, Rainer
AU - Batista-Gonzalez, Ana
AU - Saavedra, Noemi A.
AU - Sampedro, Leticia
AU - Tomás, Julen
AU - Anguita, Juan
AU - Hung, Shang Cheng
AU - Tripathi, Ashish
AU - Xu, Jiayong
AU - Glatman-Freedman, Aharona
AU - Jacobs, Williams R.
AU - Chan, John
AU - Porcelli, Steven A.
AU - Achkar, Jacqueline M.
AU - Casadevall, Arturo
N1 - Funding Information:
This work was supported in part by grants from the National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) AI105684 and AI096213-01 to JMA, the Aeras TB vaccine foundation and the Food and Drug Administration (FDA; 1U18 FD004012/01 to JMA). RK acknowledges support from the Juergen Manchot Foundation. TLL, MJ and YB acknowledge support from Alberta Glycomics Centre and the Bill and Melinda Gates Foundation. RP-R was supported in part by National Institutes of Health award 1R21AI115091. RPR is a ?Ramon y Cajal? fellow from the Spanish Ministry of Economy and Competitiveness. RPR acknowledge funding from the Ministry of Economy and Competitiveness SAF2016-77433-R. JA acknowledge support from the Ikerbasque, Basque Foundation for Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AB acknowledges Estrategia de Sostenibilidad, Universidad de Antioquia.
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1006250
DO - 10.1371/journal.ppat.1006250
M3 - Article
C2 - 28278283
AN - SCOPUS:85016504809
VL - 13
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 3
M1 - e1006250
ER -