An adenovirus-based mucosal vaccine induces cross-neutralizing antibodies and protects against lethal H5N1 infection in ferrets

Background H5N1 highly pathogenic avian influenza (HPAI) has been detected in multiple animal species, including humans, posing a significant threat to public health. Vaccines capable of eliciting robust mucosal and systemic immunity are needed to protect against HPAI infection. Methods First- and second-generation non-replicating adenovirus type-5 vectored vaccines expressing hemagglutinin (HA) from clade 2.1.3.2 (ND1.1) and clade 2.3.4.4b (VXA-H5-02), were administered via peroral route to ferrets. Mucosal and systemic immunogenicity were evaluated. Protective efficacy, viral burden, and shedding was assessed against clade 2.3.4.4b challenge, for clade-matched VXA-H5–02 and clade-mismatched ND1.1 vaccines. Results Immunization elicited mucosal immunity and serum neutralizing activity in ferrets against homologous and heterologous clades. All control animals rapidly succumbed to the lethal 2.3.4.4b clade challenge, compared with survival rates of 38% and 100% in the ND1.1 and VXA-H5–02 vaccine groups, respectively. VXA-H5–02 immunization significantly reduced illness, viral burden, and shedding. Conclusion Second-generation VXA-H5–02 is a promising vaccine candidate capable of inducing systemic and mucosal immunity, offering broad protection against HPAI.