Although the currently licensed influenza vaccines are effective in healthy young adults, Table 1 summarizes several challenges that remain. They include the dependence on embryonated eggs for vaccine production, the lengthy timeline for vaccine production, the need for annual vaccination, the emergence of antigenically novel viruses, the need for improved immunogenicity in the elderly, and the need for an improved correlate of protection. Several approaches have been developed to overcome these challenges and improve the immunogenicity and efficacy of influenza vaccines.

One disadvantage that is shared by IIV and LAIV is the need for embryonated eggs for production. A pandemic will likely result in a higher demand for vaccine, and embryonated eggs may be in short supply if the pandemic virus is pathogenic for poultry (). Several new influenza vaccines have been licensed within recent years that do not rely on production in eggs. Flucelvax is a newly licensed vaccine that is produced in a mammalian cell line and subsequent manufacturing steps are similar to egg-based IIV (). As mentioned previously, the recently licensed recombinant HA vaccine FluBlok is expressed in insect cells. Also, DNA vaccines and virus-like particles (VLPs) are vaccine strategies that are in clinical development and are not manufactured in eggs.

Centers for Disease Control and Prevention Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) — United States, 2014-15 influenza season.

The 2009 pandemic revealed the difficulty in producing and distributing a vaccine against a newly emerged virus within a short timeframe (). The 2009 H1N1pdm IIV was not available in time to prevent the second wave of the pandemic (). One approach to avoid this predicament in the future would be to stockpile vaccine seed viruses against different subtypes that have pandemic potential. This process involves the selection of representative viruses from each subtype prioritized based on epidemiological data and testing of the candidate vaccines in preclinical studies and clinical trials ().

National Center for Immunization and Respiratory Diseases, CDC Centers for Disease Control and Prevention (CDC) Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.

Antigenic characterization of circulating viruses is the most critical criterion for the selection of vaccine strains. The antigenic relationship between circulating viruses is determined by hemagglutination inhibition (HAI) assays, in which their reactivity is tested against a panel of ferret antisera generated against reference strains including the previous year’s vaccine virus. Antigenic change among influenza viruses can be visualized by antigenic cartography (), which is a computational tool for the analysis of HAI assay data that provides a mathematical foundation for quantitative analysis of antigenic data (). Antigenic cartography is now applied to the selection of strains for influenza vaccines.

The selection of strains to include in annual influenza vaccines is based on global surveillance of circulating influenza viruses. Predictions are made months ahead of the arrival of “flu season” in order to accommodate all the steps of vaccine production, including the generation of three or four vaccine seed viruses, amplification, inactivation, purification, and dispensing into vials for IIV and blending and filling of sprayers for LAIV.

Need for Annual Vaccination

The decline in vaccine-specific antibodies and the antigenic drift of influenza viruses over time necessitates annual revaccination. Several strategies are being explored to increase the breadth of protection, or cross-reactivity, of influenza vaccines to avoid the need for annual revaccination. These include the use of a computationally designed HA sequence, induction of antibodies directed at the conserved HA stem, immunization with conserved influenza proteins that target T cell responses, incorporation of an adjuvant, and strategies that combine different vaccine platforms in “prime-boost” formats.

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