![]() Influenza vaccines can afford significant protection against influenza illness, even when there is an antigenic mismatch against the predominant circulating virus strains 16, 17. ![]() The final decision on resulting vaccine targets is made by individual regulatory bodies. Identification of the target influenza strains is based on surveillance data collected by World Health Organization (WHO) collaborating centres at six locations in the UK, USA (including the Centers for Disease Control and Prevention ), Japan, China and Australia as part of the WHO Global Influenza Surveillance and Response System (GISRS) 15. The preparation of the annual influenza vaccine firstly requires the identification of the influenza strains and their like strains, most likely to spread during the upcoming season, for inclusion in the vaccine. Although the presence of NA is not required for effective vaccine performance 12, its inclusion in annual influenza vaccination may help to broaden protection and reduce influenza severity 13, 14. Another viral surface protein, neuraminidase (NA), cleaves sialic acid and releases budding virus from the infected cells, thus serving as another important vaccine target. Neutralising antibodies that block HA effectively prevent viral entry into target cells and have been shown to protect the host from infection 10, 11. Expressed as trimeric glycoproteins on the viral surface, HA binds to sialic acid on target cells to facilitate host cell entry and mediates the fusion of the viral envelope to the late endosomal membrane. Haemagglutinin (HA) is the primary antigen in the induction of a protective immune response against the influenza virus, and thus a key vaccine target. Vaccines against such strains are prepared and stockpiled as government initiatives for emergency use in potential future pandemics. In the past century, four novel influenza A virus strains have emerged in this way, each leading to a global pandemic (H1N1 in 1918 H2N2 in 1957 H3N2 in 1968 and H1N1 in 2009). Influenza A subtypes can also give rise to highly pathogenic viruses through cross-over from animal reservoirs to humans 9. Influenza A subtypes H1N1 and H3N2, and influenza B lineages B/Yamagata and B/Victoria circulate routinely in humans and are included in seasonal influenza vaccines 8. Prevention of seasonal influenza epidemics, as well as preparedness for future pandemics, is thus a global priority. Overall, such a high disease burden carries substantial social and economic cost 6, 7. Extra-pulmonary complications of influenza infection constitute a further under-recognised disease burden 4, 5. These numbers are significantly higher in young children and adults aged 65 and older 1, 2, 4. In the USA, influenza was thought to account for 52.7 hospitalisations per 100,000 people during the 2019–2020 season. Seasonal influenza is responsible for 290,000–650,000 deaths per year due to respiratory diseases alone and 3–5 million cases of severe illness worldwide 1, 2, 3. These distinct structural features and purity of the recombinant HA vaccine thus provide a number of benefits in vaccine performance which can be extended to other viral targets, such as for COVID-19. Furthermore, the presence of uniform compact HA oligomers and absence of egg proteins, viral RNA or process impurities, typically found in conventional vaccines, are expected to eliminate potential adverse reactions to these components in susceptible individuals with the use of RIV4. The absence of protease-driven cleavage and addition of simple N-linked glycans help to preserve and expose certain conserved epitopes on HA molecules, which are likely responsible for the high levels of broadly cross-reactive and protective antibodies with rare specificities observed with RIV4. In addition to the sequence integrity, characteristic of recombinant proteins, unique post-translational processing of the rHA in insect cells instills favourable tertiary and quaternary structural features. We describe how the unique structural features of rHA in RIV4 improve protective immune responses compared to conventional influenza vaccines made from propagated influenza virus. ![]() Among these, the recombinant influenza vaccine tetravalent (RIV4), using a baculovirus expression vector system to express recombinant haemagglutinin (rHA) in insect cells, is the only one to have reached the market and has been studied extensively. The influenza vaccine field has been constantly evolving to improve the speed, scalability, and flexibility of manufacturing, and to improve the breadth and longevity of the protective immune response across age groups, giving rise to an array of next generation vaccines in development.
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