Vaccine Development Process

By: Mohamad Toutounji, Kawthar Braysh, Alex Prokopienko, Alejandro Barquero, Alvaro Eguileor Giné and Lucas Klemm

Vaccine development is at the top of newsfeeds with the COVID-19 pandemic and hope for an effective vaccine. Here, we will provide an introduction of the general vaccine development process and current vaccine strategies.

At the beginning of a bacterial or viral infection, our bodies react with a systematic activation of specific cells such B lymphocytes. This type of cells and with support of the macrophages and the antigen presenting cells, the bacteria or virus undergoes endocytosis and proteasomic degradation. Specific pieces of the degraded bacterial and viral peptides are being exposed to the extracellular space via binding with the major histocompatibility complexes (MHCs). This leads to its recognition via the T and B lymphocytes, which then upon antigen recognition, produce antibodies against the presented antigen. The antibodies normalize the infection though binding with the antigen related to the infection. However, some infectious microorganisms can conquer the immune mechanism and attack/disrupt new cells. Discovering this pathway led to strategies using weakened bacteria and viral infections to boost the body for producing antibodies against antigen. In this way, scientists can immunize against several infectious diseases.

The development of a vaccine undergoes many stages:

●       Exploratory stage

Boosting the immune system by infecting the body with weakened bacteria and viruses was the first approach used by Pasteur in 1798 for smallpox. Today′s discoveries showed that using a single bacterial or viral peptide could achieve the same goal of boosting the immune system. In this approach, a synthetic peptide of 20–30 amino acids that is made in vitro out of in silico studies, is screened and tested in cell culture and introduced into the human body to trigger the desired immune response. While peptide vaccines could limit significantly the chances for allergenic and/or reactogenic complications, they require carriers and adjuvants to counterbalance the low-molecular nature of oligopeptides and thus low efficiency. As of 2019, no human peptide vaccine has been approved. Many peptide vaccines are still in different stages of clinical testing. Since the uptake of the peptide and dealing with it as an antigen via the cells is an uncertain process, scientists developed an approach depending on the mRNA encoding a full bacterial of viral protein. This approach achieved many successes in the developing phase and currently there are no RNA vaccines approved for human use. Last researches on gene editing approaches showed preliminary data on virus deactivating through cutting its RNA or DNA molecule using CRISPR/Cas system however this approach need to be optimized for using in human.

The traditional vaccines are prepared enriched to the human body with adjuvants. Adjuvants help create a stronger immune response in bodies receiving the vaccine. However, most vaccines developed today include just small components of germs, such as their proteins, rather than the entire virus or bacteria. Adjuvanted vaccines (Table 1) can cause more local reactions (such as redness, swelling, and pain at the injection site) and more systemic reactions (such as fever, chills and body aches) than non-adjuvanted vaccines.

Table 1. Adjuvants Used in Vaccines. Obtained from CDC (Center for Disease Control and Prevention)

Vaccine development is a complex, long, and expensive process that typically follows a linear pathway as other drugs with multiple checkpoints for data evaluation. During outbreaks, such as the case of Sars-Cov-2, the urgent need for developing a safe and effective vaccine requires a new pandemic paradigm with a fast start where the clinical trials and animal testing are executed in parallel. The FDA controls the pathway to licensure of safe and efficacious vaccines by providing guidance for industry regarding the data required to facilitate clinical development, manufacturing, and approval processes.

Pre-clinical stage: uses tissue culture or cell culture approaches and animal testing to assess the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. This stage often lasts 1-2 years.

●      Clinical development: is a three-phase process. Phase I, includes small groups of people to receive the trial vaccine. In Phase II, the clinical study is expanded and the vaccine is given to people who have characteristics (such as age and physical health) similar to those for whom the new vaccine is intended. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety. Many vaccines undergo Phase IV formal, ongoing studies after the vaccine is approved and licensed.

Figure 1. Stages of Vaccine Review and Regulation

●       Regulatory review and approval: When the vaccine is ready to be manufactured and sold, an Investigational New Drug application (IND) is needed to be submitted to the FDA. The IND describes the vaccine, its method of manufacture, and quality control tests for release. Also included are information about the vaccine's safety and ability to elicit a protective immune response (immunogenicity) in animal testing, as well as the proposed clinical protocol for studies in humans (Figure 1).

●       Manufacturing: this stage requires the provision of adequate product labeling to allow health care providers to understand the vaccine's proper use, including its potential benefits and risks, to communicate with patients and parents, and to safely deliver the vaccine to the public. Even the vaccine has been approved, the FDA, and in order to ensure the safety, continues to oversee the production of vaccines after the vaccine and the manufacturing processes.

●       Quality control: The monitoring of the product and of production activities continue as long as the manufacturer holds a license for the product. If requested by the FDA, manufacturers are required to submit to the FDA the results of their own tests for potency, safety, and purity for each vaccine lot. They may also be required to submit samples of each vaccine lot to the FDA for testing.

An emerging challenge to vaccine development is the uptake or use of vaccines due to “vaccine deniers”. Although, as previously controlled disease like measles reemerge due to inadequate immunity within communities (i.e., “herd immunity”), the benefits of vaccines versus theoretical/misinformed risks are being realized.

Our working group will be developing a series of articles to discuss COVID-19 and the potential for a vaccine. This series will include a FAQ about a COVID vaccines, historical overview of pandemics, current COVID-19 vaccines, medications for COVID-19, vaccines for tumors, flu vaccine development, and COVID vaccine development status. Stay tuned!

The vaccine can enter the market as all the previous mentioned points are done.