Abstract
The highly pathogenic avian influenza (HPAI) H5N1 virus, a known trigger of diseases in poultry and humans, is perceived as a serious threat to public health. There is a clear need for a broadly protective H5N1 vaccine or vaccines for inducing neutralizing antibodies against multiple clades/subclades. We constructed single, double, and triple mutants of glycan-masked hemagglutiinin (HA) antigens at residues 83, 127 and 138 (i.e., g83, g127, g138, g83+g127, g127+g138, g83+g138 and g83+g127+g138), and then obtained their corresponding HA-expressing adenovirus vectors and recombinant HA proteins using a prime-boost immunization strategy. Our results indicate that the glycan-masked g127+g138 double mutant induced more potent HA-inhibition, virus neutralization antibodies, cross-clade protection against heterologous H5N1 clades, correlated with the enhanced bindings to the receptor binding sites and the highly conserved stem region of HA. The immune refocusing stem-specific antibodies elicited by the glycan-masked H5HA g127+g138 and g83+g127+g138 mutants overlapped with broadly neutralizing epitopes of the CR6261 monoclonal antibody that neutralizes most group 1 subtypes. These findings may provide useful information in the development of a broadly protective H5N1 influenza vaccine.
Highlights
The highly pathogenic avian influenza (HPAI) H5N1 virus, a known trigger of diseases in poultry and humans, is perceived as a serious threat to public health
H5N1 viruses have evolved into distinct antigenic clades and subclades, and uncertainty regarding which strain will be involved in an expected pandemic outbreak increases the stakes for making the correct selection for vaccine development [18]
We found that the glycanmasked g127+g138 and g83+g127+g138 mutants elicited a significantly broader range of neutralizing antibody responses against heterologous H5N1 virus strains by increasing amounts of receptor binding sites (RBS)-specific and stem-specific antibodies
Summary
The highly pathogenic avian influenza (HPAI) H5N1 virus, a known trigger of diseases in poultry and humans, is perceived as a serious threat to public health. The continuing evolution of H5N1 viruses is raising concerns about a potential human pandemic due to their bird-to-human transmission capability. Researchers have reported that several mutations in HA and PB2 proteins support H5N1 transmission among ferrets [2,3]. Reassortant H5N1 viruses bearing 2009/H1N1 virus genes have been identified in guinea pigs [4], suggesting that HPAI H5N1 viruses are capable of adapting so as to support transmission in other mammals. Novel H7N9 viruses showing Q226L or Q226I mutations in HA associated with mammalian adaptation indicate potential for preferential binding to a-2,6-linked sialic acids for effective human-to-human transmission [5,6]. H5N1 viruses have been classified into 10 clades, with recently isolated viruses classified into additional subclades based on phylogenetic analyses of viral hemagglutinin (HA) sequences [7]
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