pandemic situations, as cell supply can be accelerated with the use of high cell density

frozen seed stocks, unlike the longer timelines for egg supply [41,42]. Indeed, egg

supply was shown to be a major bottleneck for vaccine production for a significant part

of active manufacturers [17]. However, in order to encourage influenza vaccine pro-

ducers to shift from the cost-effective and well-established egg-based system to cell-

culture platforms, a number of challenges have yet to be overcome: i) the screening and

development of new host cell lines, with characteristics such as high cell density

suspension growth and the ability to grow in media free from animal-based supple-

ments; ii) the development of cost-effective and scalable high cell density processes,

that maximize productivities; iii) the improvement of culture media and media sup-

plementation specific for virus production; iv) the development of online monitoring

techniques to increase product quality and minimize product losses. Cell-culture pro-

cesses for influenza vaccine manufacturing, as well as its challenges and opportunities

have been reviewed elsewhere [32].

9.4.2

LIVE ATTENUATED INFLUENZA VACCINES (LAIVS)

LAIVs represent around 5% of total influenza vaccine production, being made from a

cold adapted (ca), temperature sensitive (ts), or attenuated (att) virus backbone

containing the relevant antigenic proteins (HA and NA) from recommended seasonal

strains. The resulting viruses are incapable of replicating in the warmer temperatures

of the lower respiratory tract and, being restricted to the nasal passage, stimulate local

humoral and cellular immune responses [19,28,43]. The vaccine, administered in-

tranasally, have shown to be effective in young children but, because of the presence

of live viruses, is not recommended for immunosuppressed individuals [28]. Vaccine

strains are generated either by reassortment in eggs or, more recently, by reverse

genetics recapitulating ca, ts, and att mutations [19]. LAIV antigen content is defined

as 6.5–7.5 log fluorescent focus units (FFUs) for vaccines containing the Ann Arbor

TABLE 9.3

Licensed cell-culture−based IIVs

Commercial

name

Manufacturer

Composition

Cell

platform

Approval

Current

production

status

Preflucel

Baxter

trivalent

Vero

EU

No longer in

production

Celvapan

Baxter

monovalent (H1N1)

Vero

EU

No longer in

production

Flucelvax

Seqirus

trivalent and

quadrivalent

MDCK

FDA/EU

In production

Audenz

Seqirus

monovalent (H5N1)

MDCK

FDA

Not in production

SKYCellflu

SK Bioscience quadrivalent

MDCK

MFDS

In production

Source: Adapted from Silva, et al. [ 32].

230

Bioprocessing of Viral Vaccines