humans on a small group of healthy volunteers who have not been pre-

viously exposed to the pathogen.

• Phase 2 clinical trials (2–3 years): The focus of this phase is expanded

safety, immunogenicity, and, to a lesser extent, efficacy. These experi-

ments are performed on a larger group of individuals and the effects of

gender, age, and ethnicity on immune response will be assessed.

• Phase 3 clinical trials (2–3 years): The focus of this phase is vaccine

efficacy and is conducted during an active outbreak. These experiments are

performed in a large group of individuals across many sites to gain enough

statistical power to properly determine efficacy in terms of reduction in

cases or in severity of disease.

• Review and Approval (1–2 years): Regulatory bodies will review the

clinical trial data and decide if the vaccine should be approved. Vaccines

may also be approved for emergency use authorization in the case of a

pandemic. Additionally, in the case of vaccine a post-licensure mandatory

phase 4 is implemented to monitor any side effect related to vaccination

campaigns.

One can clearly see how, when these phases are carried out in series, the vaccine

development process can take a very long time. However, in the case of a pandemic,

such as COVID-19, these phases can be carried out in parallel, thus drastically re-

ducing the time required between pre-clinical and the end of phase 3. Furthermore,

vaccines may be approved for emergency use rather than go through the full approval

process to expedite their availability to the public [21].

When it comes to vaccine safety, there are many elements to consider. However,

one that should be mentioned is a phenomenon called antibody dependent enhance-

ment (ADE). ADE occurs when antibodies produced against a vaccine pathogen are

unable to effectively neutralize the virus and end up exacerbating the natural infec-

tion. It is caused by the Fc antibody portion of the virus-antibody complex binding

more efficiently to cells with Fc receptors like macrophages and dendritic cells, thus

increasing viral cell-entry [6,22]. This is especially important for potential vaccines

against SARS-CoV-2, because this phenomenon was previously seen in SARS-CoV,

MERS-CoV, and other respiratory viruses such as RSV and measles [23]. Even

though ADE is particularly a concern for inactivated vaccines, it must be kept in mind

for all other vaccine platforms [21].

Ensuring that the structure of the vaccine antigen is identical or nearly identical

to the natural antigen is also of vital importance. A poorly represented antigen may

result in low quality antibodies and may also result in a skewed immune response

towards CD4+ Th2 cells, which can serve to suppress the CD8+ T-cell response

resulting in a more severe pathology [2,22].

The fact that there have already been over 6.2 billion vaccine doses administered

worldwide only 1.5 years out from the beginning of the pandemic is truly an in-

credible feat [5]. Previous pandemics certainly did not see the level of resource

mobilisation and global cooperation as the COVID-19 pandemic. That is not to say,

though, that pharmacological interventions were not attempted during previous

pandemics. For instance, in the 1918 Spanish Flu epidemic, passive immunization

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Bioprocessing of Viral Vaccines