An Ad5-vectored platform generating self-assembling VLPs elicits potent mucosal immunity against influenza A virus and SARS-CoV-2

• 成果类型: Article
• 署名作者: Zhang, Yuan; Wang, Caiqian; Zheng, Yanhong; Chen, Feiyu; Feng, Yaya; Fang, Lingying; Wang, Zongmei; Zhou, Ming; Fu, Zhen F.; Zhao, Ling
• 署名单位: Huazhong Agricultural University; Huazhong Agricultural University; Huazhong Agricultural University; University System of Georgia; University of Georgia; Hubei Hongshan Laboratory; Hubei Jiangxia Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2519857123
• 发表日期: 2026-05-05
• 页码: e2519857123
• 关键词: universal vaccine platform; virus-like particles; mucosal delivery; broad-spectrum protection; in vivo self-assembly; CD4(+) T-LYMPHOCYTES; LIGAND APRIL; cells; innate; differentiation; plasticity; phenotype; survival; triggers

摘要

Integrating complementary vaccine modalities is essential for combating emerging pathogens. Although the recent mRNA-VLP hybrids enable spontaneous virus-like particles (VLPs) self-assembly, thereby enhancing immunogenicity, they fail to elicit robust pulmonary mucosal immunity against respiratory pathogens. Here, we developed Ad5-Envp-VLP, a chimeric adenoviral platform enabling spontaneous in vivo assembly of envelope protein-displaying VLPs using advanced technology that recruits ESCRT (endosomal sorting complex required for transport) via the EABR (ESCRT and ALIX-binding region). Compared with the intramuscular route, intranasal administration of a single-dose Ad5-HA-VLP confers long-lasting protection against both homologous and heterologous influenza A strains. Integrated single-cell RNA sequencing and flow cytometry analyses reveal that intranasal delivery of Ad5-HA-VLP recruits and functionally reprograms lung innate immune cells, promoting antigen presentation and driving robust mucosal secretory IgA (sIgA) secretion and cytotoxic T lymphocyte responses. Similarly, intranasal delivery of Ad5-S-VLP elicits potent cross-neutralizing antibody titers against SARS-CoV-2 variants. Importantly, intranasal immunization with Ad5-S-HA-VLP (coexpressing S- and HA-VLPs) generates dual influenza and SARS-CoV-2 neutralizing antibodies, alongside pulmonary antigen-specific sIgA, confirming Ad5-Envp-VLP as a promising single-dose multiplexed mucosal vaccine against respiratory pathogens. Further extended applications show that Ad5-RVDG-VLP also induces broad protective immunity in mouse, dog, and cat models, verifying its feasibility as an efficient rabies vaccine. Collectively, the Ad5-Envp-VLP platform represents a universal and versatile mucosal vaccine strategy, leveraging pulmonary delivery of vectors that encode in vivo-assembling VLPs to concurrently elicit robust mucosal and systemic immunity against a wide spectrum of pathogens.