Multiple formulations.

TIVs contained H3N2 and H1N1 influenza A viruses and one influenza B virus. These viruses were mixed to improve the breadth of coverage against circulating influenza strains and administered intramuscularly [112]. In 2012, quadrivalent inactivated influenza vaccines (IlVs) containing viruses of the H3N2 and H1N1 influenza A lineages and two influenza B lineages were approved for use to improve vaccine coverage against influenza B viruses. Production, approval, and administration of these vaccines are essentially the same. These new quadrivalent vaccines, in conjunction with the development of live-attenuated vaccines, have resulted in a modification of the nomenclature from TIV to IIV3 and IIV4 for IlVs [103].

Two new, cell culture-generated influenza vaccines were approved in 2012. The first is similar to the classical inactivated vaccines, but the vaccine viruses are grown in Madin-Darby canine kidney (MDCK) cells instead of the more traditional embryonated chicken eggs. This MDCK cell-based vaccine is available as a trivalent vaccine and referred to as ccIIV3 (cell culture-inactivated influenza). More recently, a recombinant HA vaccine consisting of purified recombinant HA proteins generated using insect cells was also approved for use and is referred to as RIV3 (recombinant influenza vaccine) [103]. Strictly speaking, this is not an inactivated vaccine but falls under the umbrella of HA antigen-based vaccines due to its primary antigenic component. Both of these new vaccines avoid reliance on egg availability and potential contraindications due to egg allergies. However, all of these new vaccines are incremental improvements, still administered via injection, and rely upon induction of HA-specific antibody responses.

Live-attenuated, cold-adapted, temperature-sensitive influenza vaccines (LAIV) are also available. These are weakened strains of influenza that only replicate at temperatures present in the upper airways and are reassorted in order to generate expression of HA and NA proteins from influenza A and B viruses expected to circulate during the upcoming influenza season. Live-attenuated influenza vaccines (LAIVs) are typically administered via a nasal spray device and are particularly effective in preventing influenza disease in young children but also are effective in the elderly [114]. Interestingly, the age range for which LAIVs are approved varies significantly by region with Europe allowing use in those 2-18 years of age, the United States from 2-49 years or age, and Canada from 2-59 years of age [90]. These vaccines are trivalent or quadrivalent (LAIV3 and LAIV4, respectively), although only the LAIV4 was utilized in the United States during the 2013-2014 influenza season [103,115].

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