Abstract
Split inactivated influenza vaccines remain one of the primary preventative strategies against severe influenza disease in the population. However, current vaccines are only effective against a limited number of matched strains. The need for broadly protective vaccines is acute due to the high mutational rate of influenza viruses and multiple strain variants in circulation at any one time. The neuraminidase (NA) glycoprotein expressed on the influenza virion surface has recently regained recognition as a valuable vaccine candidate. We sought to broaden the protection provided by NA within the N1 subtype by computationally engineering consensus NA sequences. Three NA antigens (NA5200, NA7900, NA9100) were designed based on sequence clusters encompassing three major groupings of NA sequence space; (i) H1N1 2009 pandemic and Swine H1N1, (ii) historical seasonal H1N1 and (iii) H1N1 viruses ranging from 1933 till current times. Recombinant NA proteins were produced as a vaccine and used in a mouse challenge model. The design of the protein dictated the protection provided against the challenge strains. NA5200 protected against H1N1 pdm09, a Swine isolate from 1998 and NIBRG-14 (H5N1). NA7900 protected against all seasonal H1N1 viruses tested, and NA9100 showed the broadest range of protection covering all N1 viruses tested. By passive transfer studies and serological assays, the protection provided by the cluster-based consensus (CBC) designs correlated to antibodies capable of mediating NA inhibition. Importantly, sera raised to the consensus NAs displayed a broader pattern of reactivity and protection than naturally occurring NAs, potentially supporting a predictive approach to antigen design.
Highlights
Vaccination is the cornerstone of protection against influenza
The virus constantly evolves under the immune pressure induced by seasonal influenza vaccines or natural infection, and this antigenic drift is most pronounced in the two surface glycoproteins HA and NA,[1] the major immunogens of licensed influenza vaccines
Anti-NA7900 immune serum mediated neuraminidase inhibition (NI) against all four seasonal H1N1 viruses tested (PR8/34, USSR/77, NC/99 and Bris/07) and NIBRG-14, displaying a broader NI span than anti-serum raised against NC/99 Recombinant tetrameric NAs (rNA) (Fig. 2a,b)
Summary
Available influenza vaccines are intended to antigenically match the hemagglutinin (HA) and neuraminidase (NA) of the prevailing circulating human influenza A and B strains. The virus constantly evolves under the immune pressure induced by seasonal influenza vaccines or natural infection, and this antigenic drift is most pronounced in the two surface glycoproteins HA and NA,[1] the major immunogens of licensed influenza vaccines. This represents a burden for the influenza vaccine manufacturers because new vaccine strains (for H1N1, H3N2 and the two influenza B lineages) may have to be substituted into the vaccine for any given year. There is a need for broadly protective vaccination strategies which cannot only control current circulating strains, but which are cross-reactive with antigenic variants that arise overtime
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