Abstract
Avian influenza virus remains a threat for humans, and vaccines preventing both avian and human influenza virus infections are needed. Since virus-like particles (VLPs) expressing single neuraminidase (NA) subtype elicited limited heterosubtypic protection, VLPs expressing multiple NA subtypes would enhance the extent of heterosubtypic immunity. Here, we generated avian influenza VLP vaccines displaying H5 hemagglutinin (HA) antigen with or without avian NA subtypes (N1, N6, N8) in different combinations. BALB/c mice were intramuscularly immunized with the VLPs to evaluate the resulting homologous and heterosubtypic immunity upon challenge infections with the avian and human influenza viruses (A/H5N1, A/H3N2, A/H1N1). VLPs expressing H5 alone conferred homologous protection but not heterosubtypic protection, whereas VLPs co-expressing H5 and NA subtypes elicited both homologous and heterosubtypic protection against human influenza viruses in mice. We observed that VLP induced neuraminidase inhibitory activities (NAI), virus-neutralizing activity, and virus-specific antibody (IgG, IgA) responses were strongly correlated with the number of different NA subtype expressions on the VLPs. VLPs expressing all 3 NA subtypes resulted in the highest protection, indicated by the lowest lung titer, negligible body weight changes, and survival in immunized mice. These results suggest that expressing multiple neuraminidases in avian HA VLPs is a promising approach for developing a universal influenza A vaccine against avian and human influenza virus infections.
Highlights
Introduction iationsAvian influenza outbreaks have caused vast economic losses throughout the world, with damage costs to the poultry industry being estimated to be in the billions [1]
We found that neuraminidase inhibition activity against the homologous virus (H5N1) and heterosubtypic virus (H3N2, H1N1) was positively correlated with the number of NA subtypes, with virus-like particles (VLPs) displaying all three NA subtypes conferring the strongest heterosubtypic protection against human influenza virus infections
Influenza virus antigens are constantly evolving, with frequent antigenic drift contributing to annual outbreaks and occasional pandemics
Summary
Avian influenza outbreaks have caused vast economic losses throughout the world, with damage costs to the poultry industry being estimated to be in the billions [1]. The truly devastating aspect of avian influenza viruses requiring continuous monitoring is their potential for causing global pandemics via genetic reassortment and interspecies transmission. Sequence analysis results of the 1918 H1N1 influenza virus suggest that its nucleoprotein amino acid sequences were strikingly similar to those of avian influenza viruses currently found in wild birds [3,4]. Subsequent pandemics, which occurred in the years 1957 and 1968 by H2N2 and H3N2 influenza viruses, respectively, were reported to be of avian origin and underwent genetic reassortment with the circulating human H1N1 influenza virus [4].
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