Recombinant Pichinde viral vector expressing tuberculosis antigens elicits strong T cell responses and protection in mice

Natalie M Kirk, Qinfeng Huang, Sophia Vrba, Mizanur Rahman, Alisha M. Block, Hannah L Murphy, Dylan White, Sarah B. Namugenyi, Hinh Ly, Anna D. Tischler, Yuying Liang

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4 Scopus citations

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 languageEnglish (US)
Article number1127515
JournalFrontiers in immunology
Volume14
DOIs
StatePublished - 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

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