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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Vaccines and Molecular Therapeutics

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1655910

Harnessing outer membrane vesicles derived from Bordetella pertussis to overcome key limitations of acellular pertussis vaccines

Provisionally accepted
  • 1Laboratory of Health Vaccines, Institute of Biotechnology and Molecular Biology (IBBM), La Plata., Argentina
  • 2Instituto de Estudios Inmunologicos y Fisiopatalogicos, La Plata, Argentina

The final, formatted version of the article will be published soon.

Abstract 1 Acellular pertussis (aP) vaccines have markedly reduced the global burden of severe 2 pertussis. However, their limited ability to elicit mucosal and durable immunity has 3 been linked to waning protection and sustained Bordetella pertussis circulation. 4 Selective pressure exerted by widespread aP vaccination has contributed to the 5 emergence and regional dissemination of pertactin-deficient (PRN⁻) strains, raising 6 additional concerns regarding vaccine effectiveness. In this context, we investigated 7 whether incorporating outer membrane vesicles (OMVs) derived from B. pertussis into 8 the aP vaccine could enhance its immunological profile, specifically by promoting 9 Th1/Th17 polarization, inducing tissue-resident memory (TRM) T cells, and 10 broadening protective coverage to include PRN⁻ isolates, while maintaining aP-induced 11 immunity against lower respiratory tract colonization. Using a murine intranasal 12 challenge model with a two-dose vaccination schedule, we assessed the safety, 13 immunogenicity, and protective capacity of the OMV+aP vaccine prototype 14 (combined) versus aP vaccine. The combined formulation was well tolerated and 15 induced robust systemic and mucosal responses, characterized by higher IgG2a/IgG1 16 ratios, increased Th1/Th17 cytokine production (IFN-γ, IL-17, and IL-22), and elevated 17 anti-B. pertussis IgA titers. Flow cytometric analyses revealed lung-and nasal-resident 18 CD4⁺ TRM cells in the combined immunized mice, which were absent in those 19 receiving aP alone. Functionally, OMV+aP formulation conferred superior protection 20 in pulmonary and nasal compartments, significantly reducing lung bacterial loads 21 (including against PRN⁻ strains) and uniquely diminishing nasal colonization even 22 under high-dose challenge conditions. Passive transfer experiments confirmed the role 23 of cellular and humoral immunity in bacterial clearance. These results demonstrate that 24 OMVs synergize with aP to enhance immune response magnitude and quality, 25 addressing key gaps in current aP vaccines and offering a next-generation strategy to 26 prevent both disease and transmission.

Keywords: Bordetella pertussis, outer-membrane vesicles, Pertussis, combined vaccine, Th1, modulator, CD4+TRM cells

Received: 28 Jun 2025; Accepted: 19 Aug 2025.

Copyright: © 2025 Locati, Daniela, Carriquiriborde, López, Pschunder, Zurita, Martin Aispuro, GAILLARD and Hozbor. 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: Daniela Hozbor, Laboratory of Health Vaccines, Institute of Biotechnology and Molecular Biology (IBBM), La Plata., Argentina

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