Ilaria Manini

Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production

In the 20th century, three influenza pandemics killed approximately 100 million people. The traditional method of influenza vaccine manufacturing is based on using chicken eggs. However, the necessity of the availability of millions of fertile eggs in the event of a pandemic has led research to focus on the development of cell culture-derived vaccines, which offer shorter lead-in times and greater flexibility of production. So far, the cell substrates being evaluated and in use include Vero, Madin–Darby canine kidney, PER.C6 and insect cells. However, Vero cells are the most widely accepted among others. This review introduces briefly the concepts of advanced cell culture-derived influenza vaccine production and highlights the advantages of these vaccines in terms of efficiency, speed and immunogenicity based on the clinical data obtained from different studies.

Flucelvax (Optaflu) for seasonal influenza

Conventional egg-based manufacturing technology for seasonal influenza vaccines has several drawbacks, including its inflexibility, reliance on egg supplies, risk of contamination, absence of growth of some isolates and egg-adaptive viral mutations that threaten vaccine matching. To overcome these limitations, cell culture-derived vaccines have been designed, including the trivalent inactivated vaccine Flucelvax®/Optaflu® (brand names in the US/EU, respectively). Flucelvax/Optaflu has gained wide regulatory approval and is currently implemented in several countries. Non-clinical studies have assuaged hypothetical concerns regarding oncogenicity and use in persons allergic to dogs. Ample clinical data suggest the non-inferiority of Flucelvax/Optaflu to egg-based vaccines in terms of immunogenicity, safety and tolerability, and it has fulfilled American and European mandatory requirements. Although Flucelvax/Optaflu is currently indicated only for adults and the elderly, pediatric data indicate its good immunogenicity and safety. This paper provides an update on the clinical development of Flucelvax/Optaflu, its seasonal trials and available post-marketing surveillance data.

Egg-Independent Influenza Vaccines and Vaccine Candidates

Vaccination remains the principal way to control seasonal infections and is the most effective method of reducing influenza-associated morbidity and mortality. Since the 1940s, the main method of producing influenza vaccines has been an egg-based production process. However, in the event of a pandemic, this method has a significant limitation, as the time lag from strain isolation to final dose formulation and validation is six months. Indeed, production in eggs is a relatively slow process and production yields are both unpredictable and highly variable from strain to strain. In particular, if the next influenza pandemic were to arise from an avian influenza virus, and thus reduce the egg-laying hen population, there would be a shortage of embryonated eggs available for vaccine manufacturing. Although the production of egg-derived vaccines will continue, new technological developments have generated a cell-culture-based influenza vaccine and other more recent platforms, such as synthetic influenza vaccines.

Immunogenicity and Safety of the New Inactivated Quadrivalent Influenza Vaccine Vaxigrip Tetra: Preliminary Results in Children ≥6 Months and Older Adults

Since the mid-1980s, two lineages of influenza B viruses have been distinguished. These can co-circulate, limiting the protection provided by inactivated trivalent influenza vaccines (TIVs). This has prompted efforts to formulate quadrivalent influenza vaccines (QIVs), to enhance protection against circulating influenza B viruses. This review describes the results obtained from seven phase III clinical trials evaluating the immunogenicity, safety, and lot-to-lot consistency of a new quadrivalent split-virion influenza vaccine (Vaxigrip Tetra®) formulated by adding a second B strain to the already licensed TIV. Since Vaxigrip Tetra was developed by means of a manufacturing process strictly related to that used for TIV, the data on the safety profile of TIV are considered supportive of that of Vaxigrip Tetra. The safety and immunogenicity of Vaxigrip Tetra were similar to those of the corresponding licensed TIV. Moreover, the new vaccine elicits a superior immune response towards the additional strain, without affecting immunogenicity towards the other three strains. Vaxigrip Tetra is well tolerated, has aroused no safety concerns, and is recommended for the active immunization of individuals aged ≥6 months. In addition, preliminary data confirm its immunogenicity and safety even in children aged 6–35 months and its immunogenicity in older subjects (aged 66–80 years).