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Induction of lung mucosal immunity by a next-generation inhaled aerosol COVID-19 vaccine: an open-label, multi-arm phase 1 clinical trial

Author

Listed:
  • Mangalakumari Jeyanathan

    (McMaster University
    McMaster University
    McMaster University)

  • Sam Afkhami

    (McMaster University
    McMaster University
    McMaster University)

  • Michael R. D’Agostino

    (McMaster University
    McMaster University
    McMaster University)

  • Imran Satia

    (McMaster University)

  • Dominik K. Fritz

    (McMaster University
    McMaster University
    McMaster University)

  • Kate Miyasaki

    (McMaster University
    McMaster University
    McMaster University)

  • Jann C. Ang

    (McMaster University
    McMaster University
    McMaster University)

  • Anna Zganiacz

    (McMaster University
    McMaster University
    McMaster University)

  • Karen J. Howie

    (McMaster University)

  • Marilyn Swinton

    (McMaster University
    McMaster University
    McMaster University)

  • Emilio Aguirre

    (McMaster University)

  • Michael B. Zheng

    (McMaster University
    McMaster University
    McMaster University)

  • Natallia Kazhdan

    (McMaster University
    McMaster University
    McMaster University)

  • Anna Dvorkin-Gheva

    (McMaster University
    McMaster University)

  • Lawrence Mbuagbaw

    (McMaster University)

  • Maria Fe C. Medina

    (McMaster University
    McMaster University
    McMaster University)

  • Nermin Diab

    (McMaster University)

  • Danica L. Brister

    (McMaster University)

  • Gail M. Gauvreau

    (McMaster University)

  • Brian D. Lichty

    (McMaster University
    McMaster University
    McMaster University)

  • Matthew S. Miller

    (McMaster University
    McMaster University
    McMaster University)

  • Fiona Smaill

    (McMaster University
    McMaster University
    McMaster University)

  • Zhou Xing

    (McMaster University
    McMaster University
    McMaster University)

Abstract

The current COVID-19 vaccines are suboptimal against the evolving SARS-CoV-2 variants, particularly in high-risk populations. A next-generation vaccine strategy capable of effective induction of respiratory mucosal immunity remains to be clinically developed. Here, we report an open-label, multi-arm phase 1 study (NCT05094609) to evaluate a multi-antigenic COVID-19 vaccine delivered once via inhaled aerosol to the lung of intramuscular mRNA-vaccinated humans without or with prior SARS-CoV-2 infection (uninfected vs infected). Escalating doses of a human adenoviral (HuAd)-vectored or chimpanzee Ad (ChAd)-vectored vaccine are evaluated in the uninfected cohort. A selected Ad vaccine is further evaluated in the infected cohort. The safety is assessed as a primary outcome. Ag-specific immune responses (secondary outcome) are assessed in peripheral blood and in respiratory tract via bronchoscopy at baseline and at timepoint(s) post-vaccination. Eighteen-65-year-old, healthy participants who have received at least 3 doses of mRNA COVID-19 vaccine are enrolled with those vaccinated with any Ad-vectored COVID-19 vaccine excluded. At baseline, there is minimally detectable mucosal immunity in the lung of uninfected or infected humans. While all tested doses (1 × 105 to 1 × 108 TCID50) of HuAd and ChAd vaccines are safe, ChAd vaccine markedly outperforms the HuAd counterpart in immunogenicity. Thus, an optimal aerosol dose of ChAd vaccine induces the tripartite respiratory mucosal immunity consisting of T cell, trained innate and antibody immunity. Our study thus presents a promising next-generation aerosol COVID-19 vaccine strategy for further clinical development.

Suggested Citation

  • Mangalakumari Jeyanathan & Sam Afkhami & Michael R. D’Agostino & Imran Satia & Dominik K. Fritz & Kate Miyasaki & Jann C. Ang & Anna Zganiacz & Karen J. Howie & Marilyn Swinton & Emilio Aguirre & Mich, 2025. "Induction of lung mucosal immunity by a next-generation inhaled aerosol COVID-19 vaccine: an open-label, multi-arm phase 1 clinical trial," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60726-0
    DOI: 10.1038/s41467-025-60726-0
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