ORIGINAL RESEARCH article
Front. Immunol.
Sec. Mucosal Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1599713
Heterologous prime boost strategies combining mucosal and parenteral routes with different adjuvants enhance and direct long-lived CD4+ T cell responses in lungs
Provisionally accepted
Ranmali Kavishna1*
Thorunn Asta Olafsdottir1,2
Siggeir Fannar Brynjolfsson2
Dennis Christensen3
Tobias Hedberg4
Peter Anderson3,5
Manuela Terrinoni1*Jan Holmgren1
Ali M Harandi1,6*- 1University of Gothenburg, Gothenburg, Sweden
- 2Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
- 3Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Hovedstaden, Denmark
- 4VERIGRAFT AB, Gothenburg, Sweden
- 5Novo Nordisk (Denmark), Copenhagen, Denmark
- 6BC Children's Hospital Research Institute, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Airway mucosa represents the main entry point for several human pathogens, and as such vaccines against respiratory diseases should ideally elicit protective immune responses in the airways. We have previously reported two immunomodulatory adjuvants based on non-toxic derivatives of Cholera toxin (CT), namely mmCT and CTB-CpG with strong ability to mount mucosal immune responses. Herein, we aimed to pinpoint the potential of prime-boost immunization approaches using the fusion-protein based Mycobacterium tuberculosis subunit vaccine candidate H56 as a model antigen, combined with adjuvants CAF01, mmCT, and CTB-CpG in mice. This includes parenteral H56+CAF01 priming followed by an intranasal boost with H56+CAF01, H56+mmCT, or H56+CTB-CpG, compared with repeated homologous intranasal administrations of H56 with each adjuvant. We observed that a parenteral prime with H56+CAF01 followed by an intranasal H56+CTB-CpG booster immunization triggered a Th1-skewed immune response. Conversely, combining the parenteral H56+CAF01 prime with an intranasal H56+mmCT boost resulted in a mixed Th1/Th17-skewed immune response. Notably, the latter combination also engendered anamnestic, long-lived T-cell responses in the lungs which homologous intranasal H56+mmCT immunizations failed to induce. These results suggest that an immunization regimen consists of parenteral priming with H56+CAF01 followed by an airway boosting with H56 protein and mucosal adjuvants holds promise in mounting combined systemic and mucosal immune responses to Mycobacterium tuberculosis, and as such warrants further exploration.
Keywords: adjuvants, Prime-boost immunization, Parenteral route, Mucosal route, T cell response
Received: 25 Mar 2025; Accepted: 29 May 2025.
Copyright: © 2025 Kavishna, Olafsdottir, Brynjolfsson, Christensen, Hedberg, Anderson, Terrinoni, Holmgren and Harandi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ranmali Kavishna, University of Gothenburg, Gothenburg, Sweden
Manuela Terrinoni, University of Gothenburg, Gothenburg, Sweden
Ali M Harandi, University of Gothenburg, Gothenburg, Sweden
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