Editor's Note:This article was written jointly by Drs. Robert R. Winter, DDS and Bobbi Winter, DHSc, MSc, MBA, MSN, RN.
Like many of you, I have had to address the issues raised by employees who do not want to receive a COVID-19 vaccine. In the state of California, where I practice, vaccines have been mandated for all healthcare professionals including dentists and their office staff. In addition, the ADA has requested that all dentists educate their staff and patients about the benefits of vaccines. In California, if staff refuse the vaccine, they are required to undergo mandatory weekly testing to continue working in the office, creating hardship and expense for those who choose to remain unvaccinated. This article is not to meant to take a political or philosophical position on the topic of the Sars-CoV-2 vaccine. Its sole purpose is to provide you with information you may find beneficial in educating staff or patients on the topic.
The main reasons for vaccine hesitancy among my staff was either that the “vaccines were developed too quickly,” or that there is “not enough information on the long-term side effects of the vaccine.” Quite honestly, I am not the one to answer these questions. However, I have learned a lot from my wife who works in my office and has an extensive background in this area. She has provided information on both of these concerns to staff and to patients who have had difficulty making an informed decision. The first part of this series will look at how clinical trials generally progress and why a vaccine for Sars-CoV-2 was able to be developed so “quickly.”
Vaccine and Medication Clinical Trials
The development of vaccines is normally a long and complex process lasting anywhere from 10-15 years1. Other than the development of annual flu vaccines, it typically takes many years to understand the viral structure and functional relationship that defines the vaccine antigen target.2 This process requires a combination of public and private involvement and is very expensive to carry out.
The longest part of the process occurs in the exploratory and pre-clinical phases. The development process for a vaccine is extremely costly, with early development and initial clinical safety trial costs generally ranging from $31 to $68 million. Pharmaceutical companies take their time moving through the process as they are at risk for significant financial losses if the initial trials do not produce the expected results. They generally are working alone rather than in cooperation/coordination with other pharmaceutical companies.
Once vaccines enter clinical trials, recruiting enough people to participate can also take significant amounts of time and money, especially if there is no urgency for the vaccine to reach the market. A recent global analysis of all terminated clinical trials reported that 55% of trials were terminated due to a low accrual rate (meaning not enough people were able to be enrolled in the trial).3 The average enrollment for Phase III and IV of clinical trials is reported to be less than 40% of what is needed to have an adequate amount of data to submit to for approval.2
Globally, more than 80% of all clinical trials fail to enroll enough volunteers on time. This means the study may need to be extended, as the trials will take additional time to recruit the required number of volunteers and/or require new study sites being opened for recruitment and monitoring.4 Retention of a sufficient number of the study participants can also be a problem, resulting in an inability to complete the trials at all, as the remaining number of patients is too small to answer the original research questions appropriately.
There are 4 phases to the clinical trial process:
- Phase I: In this phase, 20 to 100 healthy volunteers or people with the condition being studied are enrolled. This phase is to determine if the vaccine is safe, establish the correct dose for efficacy, and to learn about and minimize side effects.
- Phase II: This phase involves more people to determine how well the new vaccine works and whether it is safe. Researchers recruit up to several hundred patients for exposure to the vaccine during this period in the study.
- Phase III: Generally, this phase involves thousands to tens of thousands of volunteer participants to measures both safety and effectiveness. The phase generally lasts from one to four years depending on the drug or vaccine being tested and the ability to successfully recruit the needed number of volunteers required. The increased study size is needed to see how well the vaccine works in a larger population, if it has side effects, and how it compares to other therapies. Companies submit their results to the FDA at this time for approval and licensure.
- Phase IV: This phase is conducted once the vaccine receives FDA approval. The vaccines are studied over a longer time in larger groups to monitor for long-term effects and how it works compared to other options on the market. During this phase, they often focus on particular groups, such as people of different ages, different genders and ethnic backgrounds, and on people with various existing diseases or who take other medications.5
How Were the COVID-19 Trials Completed So Quickly?
In the case of COVID-19, the world was able to develop the vaccine so quickly because of years of previous research into coronaviruses and how to more rapidly manufacture vaccines, the enormous amount of funding provided to scientists worldwide which allowed clinical trials to progress much faster than normal, and regulators who prioritized the evaluation of research produced in clinical trials.
It is important to understand that researchers were not starting from scratch when the COVID-19 virus burst onto the scene. Scientists have been studying coronaviruses for over 50 years, and have existing data on the genome, structure, and life cycle of this type of virus.6,7,8 SARS-CoV-2 is a member of the coronavirus family, the virus that causes the common cold, severe acute respiratory syndrome (SARS, as in the 2002 epidemic) , and Middle East respiratory syndrome (MERS) that caused concern in 2021.
Research that has taken place on coronaviruses has noted the importance of the spike protein in virus attachment, fusion, and entry of the virus into the host and has been identified as the target for vaccines and antibody therapy. With the onset of a global pandemic, scientists worldwide, working in cooperation with each other, were able to uncover the viral sequence within 10 days of the first reported cases of the disease in Wuhan, China.
Research on DNA vaccines began at least 25 years ago, and RNA vaccines have been the focus of research by several organizations for 10 to 15 years, with much of this research aimed at developing vaccines for cancer. The science surrounding this technology was not new - rather it was waiting for the right opportunity to come into the market. There are numerous articles going back nearly a decade that discuss the safety and efficacy of mRNA vaccines in research.9 If you take the time to read the research available during this time, you can learn about mRNA and how it is an intrinsically safe vector as it is a minimal and only transient carrier of information that does not interact with the genome, a piece of misinformation that seems to have proliferated on the internet.
Under Operation Warp Speed (OWS), the US government provided the resources and funding for development, production, and stockpiling of COVID-19 vaccines without knowing if they were going to work. Not only did most major pharmaceutical companies actively participate in the race to develop the vaccine, so did key organizations including the NIH which focuses on the science of vaccine development, the CDC which focuses on infection and public health, the FDA which provides regulatory pathways for product licensing, and BARDA (a research and development organization of the Department of Defense or DoD) which provided additional resources.
By November 2020, over $10 billion was invested into 6 distinct candidates from 12 companies in research, clinical development and/or stockpiling candidate vaccines ahead of FDA product approval.2 If one or more of the candidates was successful, they would have doses ready for immediate distribution. OWS assumed the financial risk for multiple private companies and public institutions, investing in multiple vaccine delivery platforms (mRNA and vector) to increase the odds of having a vaccine available for distribution by the beginning of 2021. The European Commission provided $8 billion in funding to several vaccine candidates for research, with the United Kingdom Vaccine Taskforce also contributing funding to help develop the Oxford/AstraZeneca vaccine.10
The initial COVID-19 vaccine clinical trials were conducted as randomized controlled trials (RCTs). This means some people were given the vaccine and others were given a placebo, without the researchers or the volunteer knowing who received which dose. RCTs are considered the gold standard in clinical research, as through this process, it is necessary to omit all possible bias toward determining causality, so no shortcuts in this critical phase were made.
Rather than spending years recruiting an adequate number of volunteers to provide the needed amount of data, approximately 138,600 Americans volunteered to participate in the clinical trials less than two weeks after the launch of the national effort to sign them up. By November, slightly less than one-half million people had volunteered worldwide.11 Under OWS, clinical trial phases were allowed to overlap once the initial safety criteria were satisfied.11 This greatly shortened the timeline for development without compromising the collection and analysis of the needed data.
Compare the number of COVID-19 vaccine trial participants to the number of participants normally able to be recruited, and you will see why the amount of data collected in such a short period of time is so remarkable. The amount of safety and efficacy data collected on the various COVID-19 vaccines, before receiving emergency or full approval, far surpasses that collected on any other medication or vaccine brought to market in modern times.
Ongoing studies continue throughout the world. As of September 24, 2021, there were 2,350 trials testing treatments for the coronavirus disease (COVID-19) worldwide. In addition, there were nearly 1,100 trials of COVID-19 vaccines in some phase of clinical development.12 This makes the COVID-19 one of the most thoroughly studied vaccines to be released in the US.
Hopefully this provides some insight as to how the world was able to come together and produce a vaccine in record time without skipping any steps in the process. Hopefully the things learned during this virus will translate into the faster introduction of vaccines in the future.13 Part two in this series will discuss tracking of long-term effects for vaccines.
Robert Winter, D.D.S., is a member of Spear Resident Faculty.
- Johns Hopkins University. How can COVID-19 vaccine development be done quickly and safely. Retrieved from https://coronavirus.jhu.edu/vaccines/timeline
- Ho RJY. Warp-Speed Covid-19 Vaccine Development: Beneficiaries of Maturation in Biopharmaceutical Technologies and Public-Private Partnerships. J Pharm Sci. 2021 Feb;110(2):615-618. https://doi.org/10.1016/j.xphs.2020.11.010
- Pharmaceutical Technology Enrolment Issues are the Top Factor in Clinical Trial Terminations.2018. Retrieved from https://wwwpharmaceutical-technologycom/comment/reasons-for-clincial-trial-termination
- Clinical Trials AReNA Clinical Trial Delays: America's Patient Recruitment Dilemma.2012. Retrieved from:https://wwwclinicaltrialsarenacom/analysis/featureclinical-trial-patient-recruitment/
- Duke Health. Frequently Asked Questions About VOVID-19 Vaccine Studies. Retrieved from https://wwwdukehealth.org/clinical-trials/covid-vaccine-trails-faq
- Forni D, Cagliani R, Clerici M, Sironi M (2017) Molecular evolution of human coronavirus genomes. Trends in Microbiology, 25(1):35–48. https://doi.org/10.1016/j.tim.2016.09.001./
- Woo PCY, Lau SKP, Lam CSF, Lau CCY, Tsang AKL, Lau JHN et al (2012) Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. Journal of Virology, 86(7):3995–4008. https://doi.org/10.1128/JVI.06540-11
- Weiss, S. R. (2020). Forty years with coronaviruses. Journal of experimental medicine, 17(5). https://doi.org/10.1084%2Fjem.20200537
- Schlake, T., Thess, A., Fotin-Mleczek, M., & Kallen, K. J. (2012). Developing mRNA-vaccine technologies. RNA biology, 9(11), 1319-1330. https://doi.org/10.4161/rna.22269
- Government Digital Services (2020). UK government Vaccines Taskforce (VTF): 2020 achievements and future strategy. Retrieved from https://www.gov.uk/government/publications/uk-government-vaccines-taskforce-vtf-2020-achievements-and-future-strategy<
- US Government Accountability Office (2021). Operation Warp Speed: Accelerated COVID-19 Vaccine Development Status and Efforts to Address Manufacturing Challenges. Retrieved from https://www.gao.gov/products/gao-21-319
- Statistica (2021). Number of coronavirus (COVID-19) clinical trials for drugs and vaccines worldwide as of September 24, 2021, by type. Retrieved from https://www.statista.com/statistics/1119086/coronavirus-drug-trials-by-type-worldwide/
- Nature (2020). The lightning-fast quest for COVID vaccines - and what it means for other diseases. Retrieved from https://www.nature.com/articles/d41586-020-03626-1