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Intranasal ΔNS1-86 Live Attenuated Vaccines Confer Sterilizing Immunity to Mammalian-Adapted H5N1

ABSTRACT: Influenza A viruses continue to evolve across avian and mammalian hosts, highlighting the need for vaccines that elicit broad and durable immunity. Here, we developed a modular live-attenuated influenza vaccine (LAIV) platform based on a short NS1 truncation (ΔNS1-86) engineered to express heterologous HA1 antigens through a multibasic-cleavage and 2A-peptide system. ΔNS1-86 LAIVs replicated in an attenuated manner while maintaining stable antigen expression. In mice, a single intranasal dose induced strong neutralizing antibodies and robust cross-reactive IFN-γ–producing T cell responses against divergent H5N1 clades and H9N2 lineages. In ferrets, the ΔNS1-86 LAIV provided sterilizing protection against a highly mammalian-adapted North American clade 2.3.4.4b H5N1 virus, completely blocking viral shedding and systemic dissemination—efficacy that surpassed a two-dose inactivated vaccine despite similar neutralization titers. The platform was adaptable to multiple HA/NA backbones and compatible with DIVA diagnostics. These findings establish ΔNS1-86 LAIVs as versatile candidates for broad influenza protection and pandemic preparedness.

ORGANISM(S): Mustela putorius furo

PROVIDER: GSE326254 | GEO | 2026/07/27

REPOSITORIES: GEO

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