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Influenza continues to cause severe illness in millions and deaths in hundreds of thousands annually. Vaccines are used to prevent influenza outbreaks, however, the influenza virus mutates and annual vaccination is required for optimal protection. Vaccine effectiveness is also affected by other potential factors such as the human immune system, a mismatch with the chosen candidate virus, and egg adaptation associated with egg-based vaccine production. This article reviews the influenza vaccine development process and describes the implications of the changes to the cell-culture process and vaccine strain recommendations by the World Health Organization since the 2017 season. The traditional manufacturing process for influenza vaccines relies on fertilized chicken eggs that are used for vaccine production. Vaccines must be produced in large volumes and the complete process requires approximately 6 months for the egg-based process. In addition, egg adaptation of seed viruses occurs when viruses adapt to avian receptors found within eggs to allow for growth in eggs. These changes to key viral antigens may result in antigenic mismatch and thereby reduce vaccine effectiveness. By contrast, cell-derived seed viruses do not require fertilized eggs and eliminate the potential for egg-adapted changes. As a result, cell-culture technology improves the match between the vaccine virus strain and the vaccine selected strain, and has been associated with increased vaccine effectiveness during a predominantly H3N2 season. During the 2017–2018 influenza season, a small number of studies conducted in the United States compared the effectiveness of egg-based and cell-culture vaccines and are described here. These observational and retrospective studies demonstrate that inactivated cell-culture vaccines were more effective than egg-based vaccines. Adoption of cell-culture technology for influenza vaccine manufacturing has been reported to improve manufacturing efficiency and the additional benefit of improving vaccine effectiveness is a key factor for future policy making considerations.

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Background: Standard influenza vaccines are produced using egg-based manufacturing methods. Through the process, the resulting egg-adapted viral strains may differ from the selected vaccine strain. Cell-derived influenza vaccine manufacturing prevents egg-adaptation of the antigen which can improve vaccine effectiveness. We evaluated the cost-effectiveness of quadrivalent cell-derived influenza vaccine (QIVc) versus an egg-based quadrivalent influenza vaccine (QIVe) in preventing seasonal influenza from German societal and payer perspectives. Methods: Adapted version of the individual-based dynamic 4Flu transmission model was combined with a decision-tree to calculate the impact of QIVc versus QIVe on influenza over 20 seasons in Germany. Egg-adaptation, resulting in lower effectiveness of QIVe versus QIVc towards the H3N2 influenza strain, is sourced from a US retrospective study and assumed in 100% (base case) or 55% (conservative scenario) of years. Influenza-related probabilities of outpatient visits, hospitalizations, productivity loss, and mortality, with associated (dis)utilities/costs, were extracted from literature. Costs and outcomes were discounted 3.0%/year. Results: Replacing QIVe with QIVc in subjects aged ! 9 years can annually prevent 167,265 symptomatic cases, 51,114 outpatient visits, 2,091 hospitalizations, and 103 deaths in Germany. The annual number of quality-adjusted life-years (QALYs) increased by 1,628 and healthcare costs decreased by e178 M from societal perspective. From payer perspective, the incremental cost-effectiveness ratio was e2,285 per QALY. Scenario analyses confirmed results robustness. Conclusions: The use of QIVc compared to QIVe, in the German Immunization Program, could significantly prevent outpatient visits and hospitalizations and would enable substantial savings from a societal perspective.

BackgroundLower influenza vaccine effectiveness (VE) against circulating H3N2 strains compared with other influenza viruses is partly explained by antigenic mismatch between circulating strains and the vaccine strain (Belongia 2016). This mismatch has recently been linked to a new glycosylation site introduced in the egg-adaptation step (Zost 2017) and HA L194P substitution (Wu 2017) for H3N2. Vaccine manufactured using seed virus wholly grown in mammalian (e.g., Madin–Darby Canine Kidney—MDCK) cells, as with the NH17-18 version of Flucelvax®, avoids these mutations. Preliminary reports suggest that this cell-based vaccine showed greater VE than did similar egg-based vaccines [FDA Statement]. This study aimed to compile existing data on antigenic similarity to measure the degree of match with circulating wild-type isolates of egg- and MDCK-propagated versions of the vaccine H3N2 virus over multiple seasons.MethodsUsing publicly available reports from the Worldwide Influenza Centre, London (Crick), we compiled data on antigenic similarity, defined as H3N2 circulating wild-type virus isolates showing no more than a 4-fold reduction in titer to antisera raised against wholly MDCK- or egg-propagated versions of the vaccine H3N2 viruses. Titers were compared using hemagglutination inhibition (HI) assays and/or plaque reduction neutralization assays (PRNA).ResultsData from Northern Hemisphere influenza seasons of 2011–2012 to 2017–2018 show a substantially higher proportion of tested circulating influenza H3N2 viruses matched the MDCK-propagated reference viruses than did corresponding egg-propagated reference vaccine viruses (Figures 1 and 2). In half of the seasons evaluated, there was little to no antigenic similarity between circulating viruses and the egg-based vaccine viral seed.ConclusionThese data suggest higher levels of mismatch have occurred consistently with egg-propagated H3N2 reference viruses compared with MDCK-propagated reference viruses when measured against circulating wild-type isolates and may further explain the potential for lower VE observed against H3N2 historically. Furthermore, these data point to the importance of continuing to utilize cell-derived seeds in creating seasonal influenza vaccines for this strain. Disclosures S. Rajaram, Seqirus: Employee, Salary. J. Van Boxmeer, Seqirus: Employee, Salary. B. Leav, Seqirus: Employee and Shareholder, Salary. P. Suphaphiphat, Seqirus: Employee, Salary. I. Iheanacho, Seqirus: Consultant, Research support. K. Kistler, Seqirus: Consultant, Research support.