is then added resulting in the formation of protein nanoparticles consisting of S-

proteins held together with a polysorbate 80 micellar core [65]. The S-protein

nanoparticles are co-delivered with a saponin-based Matrix-M1 adjuvant, which

enhances the immune response [65,66]. Clinical trial data demonstrated efficacies of

96.4% and 86.3% against the wild-type virus and B.1.1.7 variant, respectively [67].

Although several sub-unit vaccines, including VLP vaccines produced in plant

cells, are in advanced clinical trials, at the time of the writing of this chapter, no

COVID-19 sub-unit vaccines have been licensed.

12.5

NEXT STEPS AND FUTURE PERSPECTIVES

The vaccine development process seen for the COVID-19 pandemic is an incredible

feat of human engineering and ingenuity. This holds true not only for the new vaccine

technologies that emerged but also the speed at which the conventional platforms

made it into the clinic. Pandemic preparedness theory espouses that an ideal vaccine

platform would progress within a few weeks or months from viral sequencing to

clinical trials and eventually authorization, while being suitable for large-scale

manufacturing. This is precisely what has been seen during the COVID-19 pandemic.

Furthermore, it has also been demonstrated that vaccine development can take place at

a very rapid pace, while maintaining a strong focus on safety. Due to the high safety

margins, capability for rapid up-scaling and ability to rapidly re-orient design to adapt

to emerging variants, it is likely that future vaccines will be fully synthetic, such as the

mRNA vaccines seen in the COVID-19 pandemic.

Despite all the successes, many challenges remain. First, there is no guarantee

that a vaccine, even if it has progressed to late clinical trials, will be effective

against the COVID-19 infection. As seen from the clinical course of a natural

COVID-19 infection, people’s response to immune challenges varies significantly

and, therefore, one cannot predict efficacy based on theory or even based on neu-

tralizing antibody titers. Furthermore, not all immune responses are induced

equally. It is notoriously difficult to design efficacious vaccines against respiratory

viruses. This is because the respiratory tract mucosa is protected by IgA antibodies.

However, the antibodies typically measured in clinical trials are IgG or total blood

immunoglobulins [18]. Therefore, rather than delivering vaccines against re-

spiratory viruses intramuscularly, it might be more effective to deliver them orally

or intranasally so that the respiratory tract is directly exposed. They may be further

advantageous, because unlike intramuscular vaccines which require nanoparticles

for delivery and thus cold temperature storage, oral vaccines are produced within

thermally stable capsules to avoid gastrointestinal degradation and, therefore, do not

require refrigerated storage [7]. There are several oral vaccines in development

against SARS-CoV-2, which have been shown to elicit stronger CD8+ T-cell re-

sponses and higher levels of IgA antibodies [1]. One such example is Symvivo’s

DNA-based, probiotic oral vaccine. The vaccine contains the bacteria B. lungum

transformed with a DNA plasmid encoding the S-protein. Within the bacteria, the

plasmid can replicate, and the vaccine can, therefore, be given in a single dose [68].

Many of the current challenges lie in the post-production phase, accessibility

being a major one. Vaccines do not save lives, vaccinations do. Therefore, it is

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Bioprocessing of Viral Vaccines