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Background <p>Vaccination has been central to mitigating the COVID-19 pandemic; however, the continual emergence of SARS-CoV-2 variants of concern (VOCs) has reduced the effectiveness of current intramuscular vaccines that primarily target the Spike (S) protein. Although updated formulations are periodically introduced, there remains a critical need for next-generation vaccine platforms capable of inducing broad, variant-independent protection. Here we evaluate a heterologous intranasal (i.n.) prime-boost vaccination strategy using bovine adenoviral (BAd) and chimpanzee adenoviral (ChAd) vectors expressing the S1 subunit in combination with either full-length membrane (M) and nucleocapsid (N) proteins (Ad-S1 + N + M) or multiepitope constructs derived from M and N (Ad-S1 + Epi/N + Epi/M). The constructs were incorporated with the autophagy-inducing peptide C5 (AIP-C5) to enhance antigen-specific T-cell responses.</p> Results <p>In BALB/c mice, Ad-S1 + Epi/N + Epi/M vaccination induced robust S1-specific immunity while simultaneously inducing strong N- and M-specific humoral and cellular responses that were comparable to or greater than those induced by Ad-S1 + N + M. All S1-containing formulations generated high neutralizing antibody titers (~ 3.8 log₁₀) against Omicron B.1.1.529 and BA.2.86 variants, although titers against the ancestral Wuhan strain were approximately one log₁₀ lower. In K18-hACE2 mice, i.n. immunization with S1-expressing vectors provided near-complete protection against BA.2.86 challenge, with undetectable lung viral titers and viral genome copies.</p> Conclusion <p>An i.n. multiepitope adenoviral vaccine incorporating conserved SARS-CoV-2 antigens induces robust mucosal, humoral, and cellular immune responses and confers significant protection following SARS-CoV-2 challenge.</p> Graphical abstract <p></p>

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A Multiepitope Intranasal Adenoviral Vaccine Induces Robust Mucosal Immunity and Protection against SARS‑CoV‑2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Ahmed Elkashif,
  • Muralimanohara S. T. Murala,
  • Carolyn M. Lee,
  • Raksha Suresh,
  • Marwa Alhashimi,
  • Wen-Chien Wang,
  • Vivek Gairola,
  • Andrea Pires dos Santos,
  • Patricia A. Boley,
  • Jennifer Schrock,
  • Scott Kenney,
  • Ekramy E. Sayedahmed,
  • Gourapura J. Renukaradhya,
  • Suresh K. Mittal

摘要

Background

Vaccination has been central to mitigating the COVID-19 pandemic; however, the continual emergence of SARS-CoV-2 variants of concern (VOCs) has reduced the effectiveness of current intramuscular vaccines that primarily target the Spike (S) protein. Although updated formulations are periodically introduced, there remains a critical need for next-generation vaccine platforms capable of inducing broad, variant-independent protection. Here we evaluate a heterologous intranasal (i.n.) prime-boost vaccination strategy using bovine adenoviral (BAd) and chimpanzee adenoviral (ChAd) vectors expressing the S1 subunit in combination with either full-length membrane (M) and nucleocapsid (N) proteins (Ad-S1 + N + M) or multiepitope constructs derived from M and N (Ad-S1 + Epi/N + Epi/M). The constructs were incorporated with the autophagy-inducing peptide C5 (AIP-C5) to enhance antigen-specific T-cell responses.

Results

In BALB/c mice, Ad-S1 + Epi/N + Epi/M vaccination induced robust S1-specific immunity while simultaneously inducing strong N- and M-specific humoral and cellular responses that were comparable to or greater than those induced by Ad-S1 + N + M. All S1-containing formulations generated high neutralizing antibody titers (~ 3.8 log₁₀) against Omicron B.1.1.529 and BA.2.86 variants, although titers against the ancestral Wuhan strain were approximately one log₁₀ lower. In K18-hACE2 mice, i.n. immunization with S1-expressing vectors provided near-complete protection against BA.2.86 challenge, with undetectable lung viral titers and viral genome copies.

Conclusion

An i.n. multiepitope adenoviral vaccine incorporating conserved SARS-CoV-2 antigens induces robust mucosal, humoral, and cellular immune responses and confers significant protection following SARS-CoV-2 challenge.

Graphical abstract