Current and Emerging Cell Culture Manufacturing Technologies for Influenza Vaccines

Abstract

Annually, influenza virus infects millions of people worldwide. Vaccination programs against seasonal influenza infections require the production of hundreds of million doses within a very short period of time. The influenza vaccine is currently produced using a technology developed in the 1940s that relies on replicating the virus in embryonated hens' eggs. The monovalent viral preparation is inactivated and purified before being formulated in trivalent or tetravalent influenza vaccines. The production process has depended on a continuous supply of eggs. In the case of pandemic outbreaks, this mode of production might be problematic because of a possible drastic reduction in the egg supply and the low flexibility of the manufacturing process resulting in a lack of supply of the required vaccine doses in a timely fashion. Novel production systems using mammalian or insect cell cultures have emerged to overcome the limitations of the egg-based production system. These industrially well-established production systems have been primarily selected for a faster and more flexible response to pandemic threats. Here, we review the most important cell culture manufacturing processes that have been developed in recent years for mass production of influenza vaccines.

Salmonella in Shell Eggs: Mechanisms, Prevention and Detection

“…One egg is equivalent to one to two doses of vaccine [22,23]. More than 150 million doses of human flu vaccine are produced in eggs each year [24,25].…”

Murine polyomavirus VLPs as a platform for cytotoxic T cell epitope-based influenza vaccine candidates

“…Production of this type of vaccine is limited by chicken egg availability, and this becomes a major limiting factor in pandemics by strains originating from chicken (Milian and Kamen 2015;Singh et al 2010). A further advancement of currently licensed influenza vaccine includes live-attenuated influenza vaccines also grown in eggs (Jin and Subbarao 2015), insect cell derived subunit vaccines (FDA 2013), and cell derived inactivated vaccines (Dormitzer 2015;Kistner et al 1998).…”

“…However, traditional vaccine production takes 4 to 6 months to complete and might not match the newly mutated circulating strain (Milian and Kamen 2015;Soema et al 2015).…”

“…A broadly cross-protective influenza vaccine could reduce updating frequency or provide some level of protection to slow initial stages of a pandemic (Brown and Kelso 2009). This may be achieved by targeting the more conserved internal proteins to stimulate cellular immunity (Houser and Subbarao 2015;Milian and Kamen 2015;Soema et al 2015), by delivering conserved Tc-epitopes into dendritic cells to be presented via the Major Histocompatibility Complex (MHC) Class I pathway (Brown and Kelso 2009;Sette et al 2002;Woolard and Kumaraguru 2010). A versatile delivery system capable of performing this function needs to be developed while maintaining short production time, low production cost, as well as high production capacity.…”

“…Even though Tc-epitope-based vaccine cannot prevent infection due to a prerequisite of pathogen entry into the cell, this type of vaccine can reduce the severity of the disease and prevent further spread of the pathogen in the host (Brown and Kelso 2009). Moreover, Tc-epitope presentation via the MHC Class I and MHC Class II pathways allows targeting of conserved internal proteins of influenza virus, and thus may provide broad protection against heterologous strains, possibly reducing vaccine updating frequency (Milian and Kamen 2015;Soema et al 2015). Thus, it could be used as prepandemic vaccine before conventional vaccine specific to the pandemic strain becomes available (Woolard and Kumaraguru 2010), or between influenza seasons by boosting pre-existing T cell immunity (Gilbert 2012).…”