Abstract
Introduction: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a major global health threat. The only available vaccine Bacille Calmette-Guérin (BCG) does not prevent adult pulmonary TB. New effective TB vaccines should aim to stimulate robust T cell responses in the lung mucosa to achieve high protective efficacy. We have previously developed a novel viral vaccine vector based on recombinant Pichinde virus (PICV), a non-pathogenic arenavirus with low seroprevalence in humans, and have demonstrated its efficacy to induce strong vaccine immunity with undetectable anti-vector neutralization activity. Methods: Using this tri-segmented PICV vector (rP18tri), we have generated viral vectored TB vaccines (TBvac-1, TBvac-2, and TBvac-10) encoding several known TB immunogens (Ag85B, EsxH, and ESAT-6/EsxA). A P2A linker sequence was used to allow for the expression of two proteins from one open-reading-frame (ORF) on the viral RNA segments. The immunogenicity of TBvac-2 and TBvac-10 and the protective efficacy of TBvac-1 and TBvac-2 were evaluated in mice. Results: Both viral vectored vaccines elicited strong antigen-specific CD4 and CD8 T cells through intramuscular (IM) and intranasal (IN) routes as evaluated by MHC-I and MHC-II tetramer analyses, respectively. The IN inoculation route helped to elicit strong lung T cell responses. The vaccine-induced antigen-specific CD4 T cells are functional, expressing multiple cytokines as detected by intracellular cytokine staining. Finally, immunization with TBvac-1 or TBvac-2, both expressing the same trivalent antigens (Ag85B, EsxH, ESAT6/EsxA), reduced Mtb lung tissue burden and dissemination in an aerosol challenge mouse model. Conclusions: The novel PICV vector-based TB vaccine candidates can express more than two antigens via the use of P2A linker sequence and elicit strong systemic and lung T cell immunity with protective efficacy. Our study suggests the PICV vector as an attractive vaccine platform for the development of new and effective TB vaccine candidates.
Original language | English (US) |
---|---|
Article number | 1127515 |
Journal | Frontiers in immunology |
Volume | 14 |
DOIs | |
State | Published - Feb 8 2023 |
Bibliographical note
Funding Information:We thank Dr. Conzelmann (Ludwig-Maximilians-Universität, Germany) for the BSRT7-5 cells and Leanne Zhang for technical assistance with Mtb mouse infection experiments. The following reagents were obtained through BEI Resources, NIAID, NIH: purified native Ag85B protein (Gene Rv1886c) from M. tuberculosis Strain H37Rv (NR_NR-14857), Recombinant Protein ESAT-6/EsxA (NR-49424), peptide arrays of Mtb Ag85B (NR-34828) and ESAT-6/EsxA (NR-50711), rabbit polyclonal anti-ESAT6/EsxA (NR-13803) and anti-Ag85 Complex (NR-13800) antisera. We acknowledge the NIH Tetramer Core Facility at Emory University (contract HHSN272201300006C) for provision of MHC-I (EsxH) and MHC-II (both control and Ag85B) tetramers.
Funding Information:
The project was partly supported by a University of Minnesota Academic Health Center (AHC) Seed Grant (ADT). NK is supported by NIH T32 Comparative Medicine and Pathology postdoctoral Fellowship OD010993. Acknowledgments
Publisher Copyright:
Copyright © 2023 Kirk, Huang, Vrba, Rahman, Block, Murphy, White, Namugenyi, Ly, Tischler and Liang.
Keywords
- Mtb mouse model
- Pichinde virus vector
- T cell immunity
- T cell vaccines
- tuberculosis vaccine
- vaccine immunity
- viral vector based vaccines
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural