HspX vaccination and role in virulence in the guinea pig model of tuberculosis.

Mycobacterium tuberculosis (Mtb) currently infects billions of people; many of whom are latently infection and at risk for reactivation. Mycobacterium bovis Bacille Calmette-Guerin (BCG) while approved as a vaccine, is unable to prevent reactivation of latent tuberculosis infection (LTBI). Subunit vaccines boosting BCG or given alone are being tested for efficacy in LTBI models. Alpha-crystallin (Acr, HspX), is a latency associated protein and subunit vaccine candidate. In this report, three HspX formulas (native and two recombinant variants) were used as vaccines in the guinea pig model of tuberculosis; none were protective during challenge with WT Mtb. However, recombinant HspX was protective in animals challenged with a strain of Mtb lacking hspX (X4-19), indicating protection was driven by molecules co-purifying with HspX or an adjuvant effect of recombinant HspX in this system. Mtb X4-19 was significantly less virulent than WT Mtb. Quantitative PCR and whole genome sequencing identified several genes (Rv2030c-Rv2032, Rv1062, Rv1771, Rv1907, and Rv3479) with altered expression that may contribute to loss of virulence. Physiological differences required for the establishment of Mtb infection in different hosts may affect the potential of subunit vaccines to elicit protection, supporting the need for rigorous biochemical and modeling analyses when developing tuberculosis vaccines.