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<p>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&#xa0;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 × 10<sup>5</sup> to 1 × 10<sup>8</sup> TCID<sub>50</sub>) 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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • 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,
  • Michael B. Zheng,
  • Natallia Kazhdan,
  • Anna Dvorkin-Gheva,
  • Lawrence Mbuagbaw,
  • Maria Fe C. Medina,
  • Nermin Diab,
  • Danica L. Brister,
  • Gail M. Gauvreau,
  • Brian D. Lichty,
  • Matthew S. Miller,
  • Fiona Smaill,
  • Zhou Xing

摘要

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.