Differences in Glycoproteins and the Potential for Early Protection Using LAIV Based on Drift Variants of the A/H1N1pdm09 Influenza Virus.

Background/objectives: Antigenic drift of influenza A(H1N1pdm09) viruses has led to periodic replacement of vaccine strains. Understanding how structural differences in glycoproteins influence immune protection is crucial for improving vaccine effectiveness.

Methods: We conducted a structural analysis of the hemagglutinin (HA) and neuraminidase (NA) glycoproteins from drifted A(H1N1)pdm09 strains: A/South Africa/3626/2008 and A/Guangdong-Maonan/SWL1/2020, as well as their cold-adapted live attenuated vaccine (LAIV) reassortant strains (A/17/South Africa/2013/01(H1N1)pdm09 and A/17/Guangdong-Maonan/2019/211(H1N1)pdm09). We compared their replication in chicken embryo and mammalian cell culture, assessed type I interferon induction, and evaluated post-vaccine protection in mice after homologous and heterogeneous viral challenges.

Results: The two vaccine strains had distinct glycosylation patterns for HA and NA. However, they had similar replication capacity in embryonated egg and mammalian cells. In the mouse respiratory tract, both strains replicated similarly. A/17/South Africa/2013/01(H1N1)pdm09 induced significantly higher levels of IFN-α and Mx1 in vitro, and it elicited earlier IgM and IgG response after vaccination in mice. At day 6 after immunization, it provided 70% protection from homologous challenge. A/17/Guangdong-Maonan/2019/211(H1N1)pdm09 did not prevent death, but it reduced viral titer in the lungs. Interestingly, A/17/South Africa/2013/01(H1N1)pdm09 provided full protection from heterologous H5N1 challenge, while A/17/Guangdong-Maonan/2019/211(H1N1)pdm09) only provided partial protection.

Conclusions: Differences in HA and NA glycans among A(H1N1)pdm09 strains may influence innate and adaptive immunity, as well as cross-protection. These findings emphasize the importance of glycoprotein structure when selecting vaccine candidates for optimal homologous and cross-protection against influenza.