HspX vaccination and role in virulence in the guinea pig model of tuberculosis
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Agatha E Wieczorek1, Jolynn L Troudt, Phillip Knabenbauer
1Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Abstract:
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.
Insights
Alpha-crystallin (Acr, HspX) subunit vaccines did not protect against Mycobacterium tuberculosis (Mtb) infection in guinea pigs. However, protection was observed against a less virulent Mtb strain lacking hspX.
Area of Science:
- Immunology
- Microbiology
- Vaccinology
Background:
- Mycobacterium tuberculosis (Mtb) infection affects billions globally, with many individuals harboring latent infections at risk of reactivation.
- The Bacillus Calmette-Guerin (BCG) vaccine, while approved, does not prevent latent tuberculosis infection (LTBI) reactivation.
- Subunit vaccines are being investigated to boost BCG efficacy or provide standalone protection against LTBI.
Purpose of the Study:
- To evaluate the efficacy of alpha-crystallin (Acr, HspX) formulas as subunit vaccines against tuberculosis in a guinea pig model.
- To investigate the protective potential of HspX against both wild-type Mtb and a genetically modified strain lacking the hspX gene.
Main Methods:
- Three HspX vaccine formulations (native and two recombinant variants) were administered to guinea pigs.
- Animals were subsequently challenged with either wild-type Mtb or an Mtb strain lacking hspX (X4-19).
- Quantitative PCR and whole genome sequencing were employed to identify genetic differences contributing to virulence.
Main Results:
- None of the HspX vaccine formulations demonstrated protection against challenge with wild-type Mtb.
- Recombinant HspX vaccination conferred protection when animals were challenged with the Mtb X4-19 strain, suggesting co-purifying molecules or adjuvant effects.
- The Mtb X4-19 strain exhibited significantly reduced virulence compared to wild-type Mtb.
- Several genes with altered expression were identified in the X4-19 strain, potentially contributing to its diminished virulence.
Conclusions:
- Alpha-crystallin (HspX) subunit vaccines were not protective against wild-type Mtb challenge in the guinea pig model.
- The observed protection against the Mtb X4-19 strain highlights the need for careful consideration of vaccine components and potential adjuvant effects.
- Host-specific physiological differences may influence the effectiveness of subunit vaccines for tuberculosis, emphasizing the importance of biochemical and modeling analyses in vaccine development.
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