The ID93 + GLA-3M-052-LS vaccine candidate elicits mucosal and systemic immunogenicity and protective efficacy against Mycobacterium tuberculosis challenge in BCG-primed Collaborative Cross inbred mice

Voigt, E. A.; Alsharaydeh, A.; Kasal, D. N.; Jennewein, M. F.; Brandt, D. S.; Lin, S.; Singh, J.; Bakken, J.; Mohamath, R.; Fusco, P.; Torrelles, J. B.; Beamer, G.; Fox, C. B.

doi:10.1101/2025.10.31.685426

bioRxiv · 10.1101/2025.10.31.685426

The ID93 + GLA-3M-052-LS vaccine candidate elicits mucosal and systemic immunogenicity and protective efficacy against Mycobacterium tuberculosis challenge in BCG-primed Collaborative Cross inbred mice

Voigt, E. A.·Alsharaydeh, A.·Kasal, D. N.·Jennewein, M. F.·Brandt, D. S.·Lin, S.·Singh, J.·Bakken, J.·Mohamath, R.·Fusco, P.·Torrelles, J. B.·Beamer, G.·Fox, C. B.

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Abstract

New vaccine approaches are needed against tuberculosis (TB). We sought to optimize mucosal immunogenicity and protective efficacy by modulating the adjuvant component and route of immunization of a next-generation TB vaccine using the recombinant TB vaccine antigen (Ag) ID93. ID93-specific mucosal and systemic immunogenicity and protective efficacy were assessed in the Collaborative Cross 004 mouse strain, a mouse strain susceptible to Mycobacterium tuberculosis (Mtb) infection, as a suitable model of Mtb susceptible populations. Immunogenicity data from various vaccine candidates were used to select lead vaccine candidates with the most preferred immunostimulatory profiles using a pre-determined desirability index. A liposomal adjuvant system containing synthetic TLR4 and TLR7/8 ligands (GLA-3M-052-LS), administered by a heterologous intramuscular-intranasal regimen, induced an optimal comprehensive immune response profile including high levels of mucosal antibody and Th1 CD4+ T cells in the lungs. In BCG-primed mice, immunization with intramuscular followed by intranasal ID93 + GLA-3M-052-LS boosts significantly reduced Mtb burden in the lungs after challenge vs. BCG vaccinated mice alone. Thus, ID93 + GLA-3M-052-LS represents a promising next-generation TB vaccine candidate suitable for testing in additional preclinical models.

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Voigt, E. A., Alsharaydeh, A., Kasal, D. N., Jennewein, M. F., Brandt, D. S., Lin, S., Singh, J., Bakken, J., Mohamath, R., Fusco, P., Torrelles, J. B., Beamer, G., Fox, C. B.. 2025-11-01. The ID93 + GLA-3M-052-LS vaccine candidate elicits mucosal and systemic immunogenicity and protective efficacy against Mycobacterium tuberculosis challenge in BCG-primed Collaborative Cross inbred mice. https://doi.org/10.1101/2025.10.31.685426

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