Abstract

Background/Objectives: Pandemic influenza remains a persistent global threat, and while vaccination is the primary preventive measure, conventional vaccines often induce narrow, strain-specific immunity. This study evaluated the immunogenicity, protective efficacy, and cross-protective potential of a CpG-adjuvanted trivalent inactivated influenza vaccine (CpG-TIV) administered intramuscularly at high and low doses in ferrets. Methods: Groups of influenza-seronegative ferrets received two intramuscular injections, 3 weeks apart, of high- or low-dose CpG-TIV or a commercial non-adjuvanted trivalent vaccine. Three weeks after the second immunization (Day 42), serum was obtained, and the ferrets were subsequently challenged intranasally with homologous H1N1 and influenza B viruses, as well as a heterologous drifted H3N2 strain. Clinical signs, body weight, nasal viral load, and lung histopathology were monitored following the viral challenge. Results: CpG-TIV induced significantly higher dose-dependent HI and IgG antibodies than the commercial unadjuvanted vaccine. High-dose CpG-TIV markedly reduced weight loss, clinical symptoms, nasal viral load (by up to 99%), and lung pathological damage. Notably, high-dose CpG-TIV provided significant cross-protection against heterologous H3N2, whereas the commercial vaccine showed no protective effect. At Day 42, HI GMTs in the high-dose group reached 500, 254, and 594 against H1N1, H3N2, and B strains, respectively, with a maximal 2.58 log10 reduction in H1N1 viral load. Conclusions: High-dose CpG-TIV demonstrates strong immunogenicity and robust dose-dependent homologous and heterologous cross-protection in ferrets. The combination of a CpG adjuvant and high-dose antigen broadens protection against drifted influenza viruses, overcoming the narrow coverage of conventional vaccines. These data support further clinical development of this broad-spectrum influenza vaccine candidate.

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