with immunoglobulins was implemented, certainly an innovative intervention for

the time [6]. The 1957 influenza pandemic was the first in which a vaccine was

available, but only 30 million doses were available globally and the vaccine had

poor protection [6]. During the 2009 H1N1 pandemic, the vaccine did not become

available until after the peak of the pandemic had passed. Therefore, it was clear

that if a vaccine were to make any difference in the current pandemic, new

methodologies would be required, rather than the conventional technologies of

producing vaccines in embryonated chicken eggs. New platforms that could be

quickly upscaled and that were not necessarily reliant on growing a virus in a cell

culture were needed.

At the time of this writing, there are 121 vaccines in clinical development and

194 in pre-clinical development. Of those in the clinical phase, 40% are protein sub-

unit or viral-like particle (VLP) vaccines, 21% are viral vector vaccines, 15% are IV

or LAV vaccines, and 26% are nucleic acid vaccines. Of the eight candidates that

have made it to phase 3 trials, three are protein sub-unit vaccines (38%), two are IV

(25%), and three are RNA (38%). In Europe, licensed vaccines are 50% based on

mRNA technologies and 50% based on viral vectors [24]. Most of these vaccines

use a recombinant S glycoprotein as the vaccine antigen [17].

The general concepts, production methods, and the pros and cons of the various

vaccine platforms including nucleic acid, viral vectors, protein sub-units/VLPs, and

IV/LAVs are discussed below.

12.4.1

RNA VACCINES

Using DNA or RNA as a means of in vivo therapeutic treatment is not a new

concept. DNA gene therapies, and work with mRNA for vaccines and cancer has

been a field of research since the 1990s. Since there are not currently any DNA

vaccines approved for the treatment of COVID-19, this section will primarily focus

on mRNA technology.

The basis of nucleic acid vaccine technology is simple. These methods rely on the

delivery of genetic sequences either in the form of RNA or DNA to host cells, and the

host cells produce the antigens in vivo. The fully formed antigen is then recognized by

the immune system and immune memory ensues [25,26]. Because this platform can

induce an immune response against any protein of interest, it provides new oppor-

tunities to design vaccines and drugs for previously undruggable targets ranging from

infectious pathogens to cancer and even heart disease [27,28].

These vaccines have been widely and rapidly developed due to their cost-

effectiveness, safety profile, ease of design, and potential for rapid scale-up [26], in

contrast to conventional vaccines such as IVs or LAVs, which are time consuming

due to the cell culture involved and have safety concerns due to working with live,

potentially very virulent viruses [2]. For example, the Moderna mRNA vaccine

reached clinical trials 63 days after identification of the sequence for the S protein, a

full month before conventional platforms using IVs and LAVs [18]. This is also in

stark contrast to the SARS-CoV and MERS-CoV outbreaks where clinical trials did

not begin for 25 and 22 months, respectively; or in an even more striking case,

during the Dengue and Chikungunya outbreaks, where trials were not reached for

COVID-19 vaccines

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