Development of lipid nanoparticle mRNA vaccines against swine influenza

Swine influenza A viruses (IAV-S) cause highly contagious respiratory disease in pigs and pose zoonotic risk due to bidirectional transmission between humans and swine. Managing IAV-S, particularly the H1 subtype, in pigs is vital both to prevent interspecies transmission and to protect the swine industry. Lipid nanoparticle (LNP)-encapsulated mRNA vaccines encoding specific viral antigens offer a rapid, adaptable platform well-suited for targeting rapidly evolving influenza strains. Hemagglutinin (HA), the viral protein that initiates infection, is a critical target for vaccination due to its central role in influenza infection and its antigenic diversity. This study aimed to design and generate three mRNA-LNP vaccine candidates encoding distinct HA antigens: a Taiwan porcine H1, a swine-to-human H1, and a consensus H1. We then evaluated the immunogenicity and cross-reactive potential of these candidates in a mouse model. In vivo evaluation demonstrated that the swine-to-human H1 vaccine candidate induced the broadest humoral IgG response across all three HA antigens, whereas the Taiwan porcine H1 candidate elicited the narrowest cross-reactive immunity. Serum derived from mice-immunized with all three candidate vaccines neutralized the Taiwan porcine H1N2 virus to varying degrees. However, neither intramuscular nor intranasal administration induced mucosal immunity. These results suggest while the swine-to-human HA construct shows strong potential for providing broad systemic immunity, the consensus HA construct requires further optimization. An effective swine influenza vaccine strategy may require a combined intramuscular and intranasal approach to ensure comprehensive systemic and mucosal immunity, including the induction of broadly neutralizing antibodies. Further analysis of the cross-protection and cellular immunity elicited by these candidates is necessary.