Influenza viruses as vaccine vectors: Historical background and future directions

Influenza viruses have served as experimental vaccine vectors for more than three decades, combining such advantages as mucosal delivery, segmented reverse genetics and clinically established attenuation strategies. This review summarizes historical insights into vector design based on influenza A and B viruses and proposes future applications for this platform. Particularly, we suggest using a trivalent live attenuated influenza vaccine (LAIV) as a reusable seasonal multi-vector system. In this approach, the A/H1N1, A/H3N2 and influenza B vaccine strains could each carry distinct foreign antigenic cassettes from multiple human respiratory viruses. Annual strain replacement, already intrinsic to influenza vaccination, would then also provide repeated mucosal boosting against selected non-influenza pathogens. For influenza A viruses, a substantial body of knowledge has been accumulated regarding the design of chimeric constructs carrying heterologous antigenic cassettes derived from other viruses or bacteria. Extensive animal studies and clinical trials have confirmed the functionality of this platform and underscored the promise of attenuated influenza A viruses as delivery vehicles for target antigens, capable of eliciting robust immunity. In contrast, data on influenza B virus-based vectors remain scarce and fragmented. However, given that influenza B strains in trivalent LAIVs are particularly potent inducers of immune responses, further development of this vector platform could not only overcome the packaging constraints of the influenza genome for foreign inserts but also enable the creation of effective multivalent vaccines against the most epidemiologically relevant respiratory pathogens.