[preprint]Clade 2.3.4.4b but not historical clade 1 HA replicating RNA vaccine protects against bovine H5N1 challenge

The ongoing circulation of influenza A H5N1 in the United States has raised concerns of a pandemic caused by highly pathogenic avian influenza. Although the United States has stockpiled and is prepared to produce millions of vaccine doses to address an H5N1 pandemic, the currently circulating influenza A H5N1 contains multiple mutations within the immunodominant head domain of HA compared to the antigens used in stockpiled vaccines. It is unclear if these stockpiled vaccines will need to be updated to match the contemporary H5N1 strains. Here we show that a replicating RNA vaccine expressing the hemagglutinin (HA) of an H5N1 isolated from a US dairy cow confers complete protection against homologous lethal challenge in mice. Strikingly, a repRNA encoding the HA of a pre-pandemic H5 subtype from 2004 (A/Vietnam/1203/2004), only conferred partial protection. Our data highlight the utility of nucleic acid vaccines to be rapidly updated to match emergent viruses of concern while demonstrating that contemporary bovine H5N1 viruses can evade immunity elicited by historical HA antigens.