By: Jason Ifeanyi, PharmD Candidate c/o 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain responsible for causing COVID-19, continues to have a profound impact on communities at a local, national and global level. As of August 20, 2020, nearly 5.7 million confirmed cases exist in the United States with a total of over 175,000 deaths. In the State of New York alone, there have been over 450,000 confirmed cases with nearly 33,000 deaths.¹² While there are many clinical trials currently taking place which are investigating the safety and efficacy of certain pharmacological treatments against COVID-19, many people around the world are focused on one thing – the development of a vaccine for COVID-19. In the news, researchers and scientific experts assert that a COVID-19 vaccine could very well be approved and available for administration by the end of 2020. The vaccine’s ability to mitigate the damage this pandemic has caused has been a major topic of debate and there have been varied reactions from the public. Some patients are skeptical of these assertions, some fully believe these assertions, and some are confused as to why a vaccine has not already been developed and made available to the public. These patients’ questions and concerns are legitimate, and as aspiring pharmacists, we are among the most accessible healthcare professional patients can consult to get answers. The nature of our profession not only requires us to possess sufficient knowledge on the nature of various medications, but also requires us to effectively communicate that knowledge to a concerned public in times of crisis so that they are better able to make informed decisions and live healthier lives. As student pharmacists, we owe it not only to ourselves, but to our communities and our profession, to ensure our knowledge on the COVID-19 vaccine development process remains current.

A vaccine is a form of medicine that contains the same infectious pathogen responsible for causing disease. The key difference with a vaccine is that the infectious pathogen has either been killed or weakened to the point that it does not make a person sick; in other words, it will not cause an infection. As a result, the vaccine stimulates one’s immune system to produce antibodies the same way it would if they had been exposed to the disease.² After receiving the vaccine, one develops immunity to the disease, without having contracted it in the first place. This makes vaccines a preventative form of therapy because the goal is not to treat the disease. Rather, the goal is to prevent individuals from getting the disease in the first place.

Vaccines can be developed using one of a few different strategies. The first type of vaccine one can develop is an inactive vaccine. This type of vaccine is composed of an inactivated form of the infectious pathogen. Although it retains the major components of the pathogen required to stimulate an immune response, it will not cause an infection. A second and more recent method for developing vaccines involves recombinant DNA technology. This method involves pulling out components of the virus (parts of its genetic sequence, instead of the full genetic code), and utilizing that as the major component of the vaccine, so that the immune system will recognize it and build up antibodies without getting an infection. The third type of vaccine is live attenuated. This vaccine makes use of a heavily weakened strain of the infectious pathogen so that it does not cause infection after being administered.¹¹

Safety and effectiveness aside, there are five steps in the vaccine development process. The first step involves generating the antigen. As mentioned earlier, the ultimate goal is to stimulate the immune system to produce antibodies in response to an infectious pathogen. For this reason, the vaccine must have some form of the infectious pathogen. This could involve the growth and harvesting of the pathogen itself for later inactivation or isolation of a subunit. It could also involve the generation of a recombinant protein (a protein made from DNA technology) derived from the pathogen. Bioreactors are manufactured devices or systems used to support a biologically active environment. Oftentimes, these are the devices used to grow and culture bacteria. For many viral vaccines, this process begins with small amounts of virus that can be grown in cells. Various cell types can be used such as chicken embryos or cell lines that reproduce repeatedly. ⁷

The second step of vaccine development involves releasing the antigen, including remnants of proteins from bacteria or viruses, from the cells and isolating it from the materials used in its growth. The third step is purification. For vaccines made from recombinant proteins, this may involve chromatography, a strategic way of separating materials, as well as ultrafiltration. Inactivation of the antigen may also occur during this phase. The fourth step involves strengthening the main vaccine components. This may involve the addition of an adjuvant, which is a material that nonspecifically enhances the immune response. Vaccines may also include stabilizers to prolong shelf-life, as well as preservatives, to allow multi-dose vials to be used safely. The last step in the vaccine development process involves distribution. In this step, all the components that make up the final vaccine are combined and mixed uniformly in a single vessel. The vaccine is then filled into a vial or syringe, sealed with sterile stoppers or plungers and labeled for widespread distribution.⁷ 

It is important to emphasize that the five steps described above are a general overview of the vaccine development process. More specifically, the first four steps are components of preclinical studies where the antigen’s structure is researched, and toxicity and pharmacokinetic profiling are evaluated prior to initiating clinical trials with human participants. All this research on safety and efficacy is included in an Investigational New Drug (IND), which  must be submitted prior to commencing to clinical trials.¹⁰

Before a vaccine can be labeled for widespread distribution, which is the fifth and final step in development, it must first be approved for use by the Food and Drug Administration (FDA). In order to obtain approval, the vaccine must adequately demonstrate both safety and effectiveness in three phases of clinical trials in which human participants are enrolled. This is the key step which takes the longest period of time to complete and is the reason why as of August 20, 2020 no COVID-19 vaccine has been FDA-approved for widespread distribution. This key step can be broken down into 4 phases.

Phase 1 marks the first stage of research involving human participants. The enrolled participants in Phase 1 studies are relatively small, usually 20 healthy volunteers.³ The vaccine is given at different doses to each of the volunteers, and this helps researchers determine the right dose for the next step in the testing process that is sufficient to elicit an immune response. Phase 1 clinical trials are also meant to rule out major safety concerns. After completing Phase 1, the vaccine proceeds to Phase 2 clinical trials, which involves a larger group of participants consisting of approximately one hundred to two hundred enrollees. This phase may include up to one thousand patient volunteers if multiple Phase 2 trials are necessary. In this phase, the dose that was determined in Phase 1 is administered alongside other routine vaccines to the healthy volunteers. This phase is meant to ensure that the vaccine provides a consistent immune response. In addition to monitoring participants for common adverse effects, including local swelling and fever, researchers monitor for less common and potentially more severe adverse effects. Subsequently, the vaccine progresses to Phase 3 clinical trials. This phase involves thousands of healthy volunteers. This phase determines whether the vaccine protects against natural infection and allows researchers to identify rare problems not observed in smaller studies. If the vaccine passes all these stages of clinical trials, there are additional regulatory components that must be satisfied before it proceeds to Phase 4, also known as Post-Marketing Surveillance. ⁶

The FDA center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines in the United States. Once clinical trials have been completed, the sponsor of the new vaccine must submit a Biologics License Application (BLA). This application serves as a request for permission to introduce, or deliver for introduction, a biologic product into the market. This process involves presentations of clinical trial findings to FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC). Additionally, the manufacturing facility will be inspected, and tests will be done to assess usability and labeling of the vaccine. Only once these requirements have been met, and the BLA has been approved, will the vaccine be introduced to market.²

In Phase 4, the vaccine undergoes widespread distribution and is continuously monitored for side effects and long-term adverse events that were not observed in preclinical and clinical trials. The Vaccine Adverse Event Reporting System (VAERS) is a national vaccine surveillance program co-sponsored by the FDA and CDC. It is strongly encouraged for all concerned individuals to make a report  of any unexpected side effects that occur. This includes patients, parents, pharmacists, physicians and vaccine manufacturers. ² With this information in mind, one can see why an established vaccine against COVID-19 has yet to be approved for widespread use. There are many steps involved not only in developing the actual vaccine, but in the testing of the vaccine to ensure its safety and efficacy. Additionally, the necessary approval process of the FDA and other regulatory boards is a crucial step that furthers slows the entire process down.

One point that should be noted is the difference between clinical trials for vaccines and clinical trials for medications. A much larger patient population is included in Phase 3 trials for vaccines because researchers want to detect any highly rare side effects caused by the vaccine. There is a much lower tolerance level for side effects in vaccine trials compared to other medicine trials, and for good reason. The patient volunteers, and the future target group for the vaccine, are healthy to begin with.⁶ The last thing researchers want to do is cause a healthy patient to become unhealthy and possibly die, due to receiving a poorly tested vaccine. For these reasons, vaccines can usually take up to ten or more years to develop, costing nearly five hundred million dollars, according to Wellcome Trust, a United Kingdom Charity. Discovery research can take anywhere from two to five years – two years for preclinical trials, one to two years for Phase 1 clinical trials, two to three years for Phase 2 clinical trials, two to four years for Phase 3 clinical trials, and one to two years for regulatory review and approval.⁵

This is a major cause of confusion among patients. On one hand, many politicians and scientific experts are making assertions that an effective vaccine will be available by the end of 2020, yet history has shown us that it takes much longer than 12-18 months  to develop a safe and effective vaccine. If a COVID-19 vaccine were to be ready by the end of the year, that would make its development time faster than the current record holder, the Mumps Vaccine, which took 4 years to develop. ⁸  While there is uncertainty as to whether this is a practical timeframe or mere wishful thinking, one thing is certain – researchers and pharmaceutical companies are working relentlessly to fast-track the COVID-19 vaccine development process.

On May 15, 2020, the White House announced a new initiative entitled, Operation Warp Speed (OWS). This initiative aims to fast-track multiple COVID-19 vaccine candidates, with the goal of delivering 100 million doses across America in November 2020, and another 200 million by January 2021.⁹ This initiative entails a partnership among a variety of agencies within the Department of Health and Human Services (HHS) including the Centers for Disease and Control and Prevention (CDC), FDA) the National Institutes of Health (NIH), and the Biomedical Advancement Research and Development Authority (BARDA), partnered with Department of Defense (DoD).⁹  Currently, there are over one hundred and thirty five vaccine candidates in preclinical trials internationally; twenty in Phase 1 clinical trials, eleven in Phase 2 clinical trials, eight in Phase 3 clinical trials, and two that have been approved, albeit with a large degree of uncertainty, as they have not been FDA approved in the US. One of the vaccines that is not FDA-approved, was developed by CanSino Biologics of China and was developed from an adenovirus called Ad5. Although it was announced on August 9^th that they plan on initiating a Phase 3 clinical trial in Saudi Arabia, the vaccine was approved for limited use on June 25, 2020 by the Chinese military. ⁴

More recently, Russia’s Gamaleya National Research Institute of Epidemiology and Microbiology launched a Phase 1 clinical trial in June of 2020 for a vaccine called, Gam-Covid-Vac-Lyo. It is a combination of two adenoviruses, Ad5 and Ad6, both engineered with a Coronavirus gene. On August 11, 2020, Russian President Vladimir Putin announced that a Russian healthcare regulator had approved the vaccine, renaming it Sputnik V, before Phase 3 trials began.⁴  It is important to note that a number of US experts have denounced these vaccines due to the haste with which they were approved. One such US expert includes. Dr. Fauci, director of the National Institute of Allergy and Infectious Disease (NSAID). In an interview with ABC news reporter Deborah Roberts, this is what Dr. Fauci had to say. “Having a vaccine, Deborah, and proving that a vaccine is safe and effective are two different things…If we wanted to take the chance of hurting a lot of people, or giving them something that doesn’t work, we could start doing this, you know, next week if we wanted to. But that’s not the way it works.” ¹

In conclusion, the vaccine development process is multifaceted. It involves preclinical research, where the structure of the infectious pathogen is determined and manipulated in order to develop a specific vaccine type. Different strategies for developing a vaccine involve recombinant DNA technology, inactivating the infectious pathogen, or weakening the infectious pathogen so that the vaccine is able to stimulate an immune response while simultaneously avoiding the development of an infection. Once researchers determine the type of vaccine that is needed, they then culture, isolate and release, and purify the antigen followed by strengthening the vaccine components. At this point, the vaccine candidate undergoes three phases of clinical trials to determine whether it is both safe and effective in the prevention of COVID-19 in human patients. A variety of American and European pharmaceutical companies are currently in Phase 2 and Phase 3 clinical trials for the COVID-19 vaccine. As aspiring pharmacists, it is imperative that we understand the vaccine development process and its impact on our communities. As we are in the midst of a pandemic, many patients are scared, confused and skeptical of the health-related information they are bombarded with every day. They have questions about when the COVID-19 vaccine will be available, why it is taking so long to develop and want answers to these questions which we can make a conscious effort to provide them with. Although we cannot predict the future, we can stay educated about the vaccine development process, and explain it to our patients in a way they helps them understand it while simultaneously eliminating fear of the unknown.

Sources:

1. Andreano C. Fauci says he has serious doubts Russia’s COVID-19 vaccine is safe, effective. abcnews.go.com. https://abcnews.go.com/US/fauci-doubts-russias-covid-19-vaccine-safe-effective/story?id=72309297. Published 08/11/2020. Acceded 08/20/20.
2. Basics of Vaccines. https://www.cdc.gov/vaccines/vpd/vpd-vac-basics.html. Published 03/15/12. Accessed 08/05/20.
3. Commissioner, O. Step 3: Clinical Research. https://www.fda.gov/patients/drug-development-process/step-3-clinical-research. Accessed 08/20/20
4. Corum, J., Grady, D., Wee, S., & Zimmer, C. Coronavirus Vaccine Tracker https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html.  Published 08/20/20. Accessed 08/20/20.
5. Douglas Broom, S. 5 carts that tell the story of vaccines today. https://www.weforum.org/agenda/2020/06/vaccine-development-barriers-coronavirus/. Accessed 08/05/20.
6. Finnegan, G. How are new vaccines developed? https://www.vaccinestoday.eu/stories/how-are-new-vaccines-developed/. Published 04/12/17. Accessed 08/05/20.
7. How are vaccines made: History of Vaccines. https://www.historyofvaccines.org/content/how-vaccines-are-made. Accessed 08/05/20.

Published by Rho Chi Post