[26,47]. One of the most notable uses of a viral vector vaccine was the use of a

recombinant VSV vector during the 2013 Ebola outbreak [47].

12.4.2.1

Adenovirus Vectored Vaccines

Perhaps the most widely researched viral vector for both vaccines and gene therapy

are adenoviruses. Adenoviruses are non-enveloped double-stranded DNA viruses

that typically cause respiratory and ocular infections [44]. Over 150 primate ser-

otypes have been identified [25]. When used as vectors for vaccines or gene

therapy, the viral genome is specifically engineered by replacing the E1 and E3

adenoviral genes with the transgene of interest. The E1 gene plays a central role in

viral replication and, therefore, its deletion inactivates the virus. Whereas deletion

of the E3 gene allows for the insertion of large transgenes up to 8 kb [25]. Further

modifications include engineering the viral capsid for altered tropism and reduced

immunogenicity. This can lead to viral vectors capable of evading pre-existing

immunity, targeting specific cells such as dendritic cells and even altering the

stability of the vector allowing for longer shelf lives [21].

One of the reasons adenoviruses are so widely used for gene delivery is their

inability to integrate their viral DNA into the host’s genome. Therefore, since their

DNA remains as an episome in the nucleus, there is little risk of activating an on-

cogene [25]. Furthermore, they have naturally evolved mechanisms for very high

gene transduction and expression. Additionally, since the vector is a virus, it naturally

activates the immune system resulting in an excellent response to the antigen. This is

in contrast to plasmid DNA vaccines, which tend to induce poor responses [26].

Other major advantages of adenoviral vector vaccines are their affordability and

accessibility in low-income countries since they can be stored at 2–8°C [2]. Further,

they can be rapidly scaled-up for mass production at GMP making them great can-

didates for pandemic vaccines. For example, they can be easily grown in 20 L

bioreactors, which would yield enough doses for 15,000 patients, assuming two doses

per patient (considering downstream losses) and scale-up to 500 L is possible [25].

As with all vaccine technologies, viral vectors possess their own list of dis-

advantages. One safety concern is the possibility for integration into the host

genome. While this is unlikely due to the viral vectors used for gene delivery, it is

nevertheless a possibility. This could have a major health consequence if integrated

into an oncogene or tumor suppressor gene [45]. The other potential drawback is the

existence of pre-existing immunity against the viral vector components. For ex-

ample, adenoviruses are quite ubiquitous in human populations and, therefore,

many people are seropositive against adenovirus. Studies have shown that people

with higher pre-existing immunity generated half as many neutralizing antibodies

against the S protein, which demonstrates that pre-existing immunity decreases

vaccine response [44]. Furthermore, if multiple dosing regimens are necessary, then

there is the possibility of developing antibodies against the vector components after

the first dose even in individuals who were originally seronegative. This problem

can be partially circumvented through a heterologous vaccine approach, where two

different vector serotypes are used for the first and second doses. Taking it even

further, many companies have begun using chimpanzee adenoviruses and other

viruses to which humans are naïve.

COVID-19 vaccines

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