By Harit Phowatthanasathian
It’s undeniable that the novel COVID-19 pandemic has flipped the world on its head. Nearly 9 months after its initial confirmation, this outbreak has been compared to the horrific period of the 1918 Spanish Flu, ranking it amongst the worst outbreaks in human history. With the world economy experiencing a collapse comparable to the great depression, the global recovery ambitions depend heavily on the production of an effective vaccine.
To fully understand the process of developing a vaccine, it is appropriate to take a look at history’s examples. The earliest evidence of human inoculations dates back to 1000CE China, where smallpox material was identified to decrease future cases of deadly smallpox, a concept later carried over to Africa, the Americas, and Europe. Edward Jenner, the father of vaccinology, was the first to apply a scientific technique to vaccinations. His utilization of cowpox material to build immunity against smallpox, and its consequent success was proof for this preemptive method to protect humans against viruses. This revolutionary practice initiated a worldwide effort to eradicate smallpox. As smallpox vaccinations transitioned from optional to enforced, the world saw a drastic 99.6% decrease in cases over two hundred years (The College of Physicians of Philadelphia, 2020). With medical advancements over the centuries, the vaccination process has become increasingly complex and comprehensive.
Currently, there are five defined stages of vaccine development, separated into two broader umbrella categories. Preclinical research, the first of the two categories, encompasses the exploratory and preclinical stages. The two to four year exploratory stage identifies specific antigens that could be targeted to prevent or treat diseases. The preclinical stage tests potential compounds on tissue and cell cultures, narrowing down possible targets from five to ten thousand compounds to below two hundred possibilities. The one to two year process is followed by the Investigational New Drug Application (IND), further filtering for the most promising candidates. Remaining candidates enter the clinical phase, the second of the two big umbrellas categories, constituting phase 1, phase 2, and phase 3 trials.
Phase 1 trials are non-blinded and initially target 20-80 healthy adults, which eventually extend to younger and elderly subjects to test the breadth of effectiveness. Phase 1 candidates then progress to phase 2, where 100-500 at-risk participants are tested to develop safety measures, dosage amounts, delivery methods, immunization schedules, and immunogenicity. With one to two potential vaccine candidates proceeding into phases 3 trials, its efficacy and side effects will be assessed on a larger population of a thousand to tens of thousands of participants. After six to seven years in the clinical trial stage, promising vaccines are presented for FDA approval, a process lasting up to two years. The 10-15 year process from identification to FDA approval will still be followed by a surveillance phase for long-term safety (Vaccine Development, Testing, and Regulation | History of Vaccines, 2018). All in all, the traditional paradigm is a lengthy and costly journey.
With the extraordinary circumstances of COVID-19, the WHO has implemented the pandemic paradigm for vaccine development. Previous pandemic level outbreaks like Ebola, Zika, and SARS, saw many of its vaccine trial phases executed in tandem, to reduce as much time as possible. The phase 1 COVID-19 vaccine efforts began on March 16. With the pandemic paradigm in effect, COVID-19 phase 1 human trials proceeded in parallel with animal trials, condensing years of work into a couple of months (Lurie et al., 2020). In preparation for a successful phase 2 candidate, the US and UK have poured hundreds of millions of dollars into large-scale manufacturing technology to further eliminate delays between FDA approval and manufacturing. As of August, the US started their phase 3 trials, introducing randomized and controlled trials with larger populations; a period posing a host of ethical and regulatory barriers. An optimistic estimate has been approximated to August of 2021, 18 months after initial efforts, where the majority of the population will have access to some sort of vaccine (Thompson, 2020).
To contextualize, Malaria, considered one of the deadliest diseases, takes the lives of five hundred thousand to one million per year. Currently, there is no licensed malaria vaccine on the market, even with vaccine efforts starting in the early 2000s (World Health Organization, n.d.). In the case of malaria, potential vaccine candidates do not express high effectiveness and long-lasting immunity up to the WHO regulations of 75% efficacy for a minimum of one year (Beeson et al., 2019). With billions of dollars already contributed for a successful candidate, we still yet cannot guarantee a marketable vaccine for Malaria. Considering historical examples of vaccine efforts, a realistic timeline for COVID-19 is one that considers the many barriers ahead.
Developing a vaccine is a monumental feat in and of itself, but is scattered with economical and regulatory barriers that further hinder the process. Unfortunately, vaccine development is historically seen as a sinkhole by the majority of pharmaceutical companies, because of the high failure rate, the economical prohibitive nature of the process, and the restrictive regulations (Stern et al., 2005). The potential of losing billions with little upside provides little incentive for pharmaceutical companies to participate, leading to vaccine shortages like during the 2004 flu outbreak. In addition, the mountain of safety, manufacturing and distribution protocols required when dealing with biological agents further makes the vaccine business an objectively dangerous endeavor. However, with the world’s government funding billions to push vaccine efforts, we are fortunate to have even seen companies proceed with trials and scaling up production.
COVID-19 has posed one of the biggest disruptions in the past century, with years of lasting effects. The vaccine is just one piece of the puzzle and if trial and production phases go according to plan, it is reasonable to expect market-wide availability by August of 2021. Along with this optimism, we must be fully aware of the trial barriers, the possibility of further delays, and respective effects on society to fully prepare against this microscopic beast.
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Stern, A. and Markel, H., 2005. The History Of Vaccines And Immunization: Familiar Patterns, New Challenges | Health Affairs. [online] Healthaffairs.org. Available at: <https://www.healthaffairs.org/doi/full/10.1377/hlthaff.24.3.611> [Accessed 23 August 2020].