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Mycobacterium tuberculosis arabinomannan-protein conjugates protect against tuberculosis
Beston Hamasur1, Melles Haile, Andrzej Pawlowski
1Swedish Institute for Infectious Disease Control, S-17182 Solna, Sweden.
Abstract:
Lipoarabinomannan (LAM) is a major structural surface component of mycobacteria. Arabinomannan (AM) oligosaccharides derived from LAM of Mycobacterium tuberculosis H37Rv were isolated and covalently conjugated to tetanus toxoid (TT) or to short-term culture filtrate proteins (antigen 85B (Ag85B) or a 75kDa protein) from M. tuberculosis strain Harlingen. The different AM oligosaccharide (AMOs)-protein conjugate vaccine candidates proved to be highly immunogenic, inducing boosterable IgG responses against the AMOs portion of the conjugates in rabbits and guinea-pigs. Proliferation of T-cells from C57BL/6 mice immunized with the conjugates was seen upon in vitro stimulation with PPD. In C57BL/6 mice subcutaneous immunization with the AMOs-antigen 85B conjugate in alum provided significant protection compared to sham (alum only) immunized mice (P < 0.021) as estimated by long term survival against intravenous challenge with 10(5) M. tuberculosis H37Rv. Subcutaneous immunization followed by nasal boost with an AMOs-TT conjugate in Eurocine L3 adjuvant provided high (P < 0.025) protection as determined by long term survival after intranasal challenge with 10(5) virulent M. tuberculosis strain Harlingen. This level of protection was comparable to that obtained with the conventional live attenuated BCG vaccine. In guinea-pigs, immunization with AMOs-Ag85B in Eurocine L3 adjuvant followed by aerogenic challenge with M. tuberculosis H37Rv resulted in increased survival and reduced pathology in lungs and spleens relative to non-immunized animals.
Insights
New tuberculosis (TB) vaccine candidates using arabinomannan oligosaccharides conjugated to proteins were highly immunogenic. These conjugates showed significant protection in mice and guinea-pigs against Mycobacterium tuberculosis challenge, comparable to BCG.
Area of Science:
- Immunology
- Vaccinology
- Microbiology
Background:
- Lipoarabinomannan (LAM) is a key surface component of mycobacteria.
- Developing effective vaccines against Mycobacterium tuberculosis remains a global health priority.
Purpose of the Study:
- To evaluate the immunogenicity and efficacy of novel arabinomannan oligosaccharide (AMO)-protein conjugate vaccine candidates against tuberculosis.
- To assess protection conferred by AMOs-protein conjugates in preclinical models.
Main Methods:
- Isolated arabinomannan oligosaccharides from Mycobacterium tuberculosis LAM.
- Conjugated AMOs to tetanus toxoid (TT) or M. tuberculosis antigens (Ag85B, 75kDa protein).
- Assessed immunogenicity (IgG response, T-cell proliferation) and protective efficacy in mouse and guinea-pig models via challenge studies.
Main Results:
- AMO-protein conjugates were highly immunogenic, inducing robust IgG responses and T-cell proliferation.
- Subcutaneous immunization with AMOs-Ag85B conjugate provided significant protection in mice against intravenous M. tuberculosis challenge.
- Combined subcutaneous and nasal immunization with AMOs-TT conjugate offered high protection in mice against intranasal challenge, comparable to BCG.
- AMO-Ag85B conjugate immunization increased survival and reduced lung/spleen pathology in guinea-pigs post-aerogenic M. tuberculosis challenge.
Conclusions:
- AMO-protein conjugates represent promising vaccine candidates for tuberculosis.
- These novel conjugates demonstrate significant protective efficacy in preclinical models, warranting further investigation.
- The findings support the potential of targeting LAM components for developing next-generation TB vaccines.