as a variant of concern on May 6, 2021 [11]. In addition to being more transmissible

than the alpha variant, its reinfection rate was also found to be higher. Studies are

still underway to determine its effect on vaccine effectiveness, although there is

evidence of a modest reduction and some variants have already demonstrated

complete immune escape against certain vaccines [12,13]. Other variants of concern

have been identified thereafter. Vaccines design and production are the subject of

the remainder of this chapter. However, prior to diving into the various vaccines

developed against SARS-CoV-2, we must first discuss the virus’s immunology.

12.3

SARS-COV-2 IMMUNOLOGY AND VACCINE RATIONALE

As with any newly discovered pathogen, especially when it comes to designing

vaccine candidates, understanding the way the body’s immune system interacts with

it is of vital importance. Studies thus far have demonstrated that SARS-CoV-2, as

well as SARS-CoV and MERS-CoV, tend to suppress activation of the innate

immune system. And since it is the effects of the immune system that result in

clinical symptoms, this may help explain the long pre-symptomatic period (up to

14 days) that is seen in COVID-19. Furthermore, it has been suggested that sup-

pression of the innate immune system may also contribute to the dysregulated in-

flammatory response seen in more severe cases [2].

However, vaccine design depends largely on the adaptive immune system. In

general, there are two main components of the adaptive immune system: cellular

immunity mediated by T-cells, and humoral immunity mediated by antibodies se-

creted by B-cells (as detailed in Chapter 3). It has been shown that upon natural

infection, B-cells produce neutralizing antibodies against SARS-CoV-2 in two

manners: firstly, by targeting the S protein and preventing its interaction with ACE2

and secondly, by binding to the virus cytoskeleton including the internal nucleo-

protein and preventing release of the genome [4,7]. Early studies showed that in

patients with COVID-19, antibodies were seen in their serum on average 8 days

after exposure reaching a peak after 14 days [8]. Due to this natural response against

the S protein, it is unsurprising that nearly all vaccines in development have chosen

it as the target antigen for vaccine development. This was even seen in SARS-CoV

where antibodies targeted to the S1 RBD blocked its interaction with ACE2 and

antibodies targeted to other epitopes of the S1 sub-unit inhibited conformational

changes of the S protein required for viral cell-entry [14].

Cellular immunity mediated by T-cells is equally as important in vaccine design.

In a study looking at the immune response of COVID-19 patients, CD4+ and CD8+

T-cells were seen in 100% and 70% of patients, respectively. Furthermore, 27% of

the CD4+ T-cell response was specific for the S protein [15]. Additionally, it has

even been shown that patients with less severe COVID-19 infections have had a

higher number of CD8+ T-cells, which further reinforces their role in the clinical

outcome [16]. It can even be argued that the T-cell response is far more important

than its B-cell counterpart, since, for example, contrary to B-cell epitopes, T-cell

epitopes are located along the full length of the S protein. Therefore, since T-cells

target multiple regions of the S protein, viral mutations have a lesser effect on

cellular immunity [17].

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Bioprocessing of Viral Vaccines