Abstract
Seasonal epidemics caused by influenza A (H1 and H3 subtypes) and B viruses are a major global health threat. The traditional, trivalent influenza vaccines have limited efficacy because of rapid antigenic evolution of the circulating viruses. This antigenic variability mediates viral escape from the host immune responses, necessitating annual vaccine updates. Influenza vaccines elicit a protective antibody response, primarily targeting the viral surface glycoprotein hemagglutinin (HA). However, the predominant humoral response is against the hypervariable head domain of HA, thereby restricting the breadth of protection. In contrast, the conserved, subdominant stem domain of HA is a potential “universal” vaccine candidate. We designed an HA stem-fragment immunogen from the 1968 pandemic H3N2 strain (A/Hong Kong/1/68) guided by a comprehensive H3 HA sequence conservation analysis. The biophysical properties of the designed immunogen were further improved by C-terminal fusion of a trimerization motif, “isoleucine-zipper”, or “foldon”. These immunogens elicited cross-reactive, antiviral antibodies and conferred partial protection against a lethal, homologous HK68 virus challenge in vivo. Furthermore, bacterial expression of these immunogens is economical and facilitates rapid scale-up.
Highlights
Influenza virus infection causes respiratory illness in humans
We have previously demonstrated the soluble expression of HA stem-fragments in Escherichia coli (E. coli) by maintaining the interaction network within the HA stem and introducing designed mutations
Binding of Antisera to Full-Length Recombinant HAs The binding of antibodies elicited by the test immunogens to a panel of full-length recombinant HAs (rHAs) proteins was determined by ELISA
Summary
Preventive vaccination is the best way of controlling influenza infections [1]. Antiviral medications such as oseltamivir, zanamivir, and peramivir are used to treat influenza infections [2, 3]. The influenza A viruses are further classified on the basis of their surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), into 18 HA and 11 NA subtypes [8]. H17 and H18 HAs are putative HA-like molecules, since their hemagglutination activity has not been established. NA activity of N10 and N11 NAs has not been shown. Antigenic relatedness within HA facilitates clustering influenza A viruses into two major phylogenetic groups: group 1 (subtypes: H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18) and group 2
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