Vaccine research is at the forefront of everyone’s minds as we collectively await a breakthrough in the fight against coronavirus disease 2019 (COVID-19). I had the privilege to work in vaccine clinical development earlier in my career. Until I began my stroll down this professional path, I had no idea that the process from vaccine discovery to public release could be a long, winding road, often lasting between 10 and 15 years. Today, researchers are working at unprecedented speed to cut this timeline down to within 12 and 18 months. Is this fast-track approach safe? Can we count on the efficacy of a vaccine that is developed this quickly? We don’t know the answers to those questions yet. Let’s take a step back and review the vaccine development process from beginning to end.
 
Vaccine research is a well-defined process involving a standardized set of steps (Centers for Disease Control and Prevention [CDC], 2014; College of Physicians of Philadelphia, 2018).
 
Exploratory Stage (2 – 4 years)
The first step is the exploratory stage in which natural or synthetic antigens that may prevent or treat disease are identified in a laboratory setting. These antigens include live-attenuated viral components, inactivated viral components, recombinant (DNA), conjugate (combined weakened and strong antigens), subunit (no live component of the viral particle), toxoid, and monoclonal antibodies. Gene-based vaccines use genetic engineering to carry nucleic acids (DNA or RNA) that hold instructions for making the viral protein which trigger an immune response (Gould, 2020).
 
Pre-Clinical Stage (1 – 2 years)
Tissue-culture and animal testing are conducted next to evaluate the safety of the vaccine and its ability to elicit an immune response. During this stage, researchers may:

• Assess the immune response that could occur in humans
• Determine a starting dose for clinical trials
• Improve the efficacy of candidate vaccines

Investigational New Drug (IND) Application Stage
Once the vaccine successfully completes the pre-clinical stage, an IND application is submitted by the research sponsor (typically a private company) to the U.S. Food and Drug Administration (FDA). The application will include:

• Description of the vaccine
• Manufacturing and testing methods
• Quality control tests for release
• Summary of the laboratory reports
• Description of the proposed study protocol
• Information about the vaccine’s safety
• Vaccine’s ability to elicit a protective immune response in animal testing

The FDA has 30 days to approve the application, then the vaccine moves on to human clinical trials. Prior to initiating these trials, the protocol must be reviewed by each research site’s institutional review board (IRB). The IRB is an independent committee that reviews and approves research involving human subjects, ensuring the protocol does not infringe on the rights and safety of the participants. Every clinical study protocol must include a detailed informed consent.

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Discussion on COVID-19 Vaccine Research & Development

Clinical Development: Three Phases

Phase I Vaccine Trials (Several months)
Phase I human trials involve a small sample size, typically between 20 and 80 subjects. During this phase, researchers may know whether a vaccine or placebo has been given to a study subject. The primary goals are:

• Assess the safety of the vaccine
• Evaluate the extent of the immune response

Phase II Vaccine Trial (Several months to 2 years)
Phase II trials involve a larger sample size, usually several hundred study participants and often include the target demographic. These trials are randomized, controlled studies, typically dose-ranging, and include a placebo group. The primary goals are to further evaluate (FDA, 2020):

• Safety
• Immunogenicity and efficacy
• Proposed doses
• Schedule of immunization
• Method of delivery 

Phase III Vaccine Trials (1 to 4 years)
Phase III trials are large studies involving thousands to tens of thousands of people. These are randomized, double-blinded studies that test the experimental vaccine against a placebo. Phase III goals are:

• Assess vaccine safety in a large group of people, monitoring for rare side effects that may not appear in a smaller sample size
• Evaluate efficacy:
  • Does the vaccine prevent disease?
  • Does the vaccine prevent infection with the pathogen?
  • Does the vaccine incite production of antibodies or other types of immune responses related to the pathogen?

Approval and Licensure
Following positive results from Phase III, the vaccine researchers will submit a Biologics License Application (BLA) to the FDA’s Center for Biologics Evaluation and Research (CBER). This includes the efficacy and safety information needed to make a risk/benefit assessment. During this phase, the FDA will inspect the factory where the vaccine will be manufactured and approve the vaccine label. Product labeling is extremely important as it provides clinicians with accurate information on the vaccine’s proper use as well as the benefits and risks that must be communicated to patients and family members (FDA, 2020).
 
After licensure, the FDA will monitor vaccine production, periodically inspect facilities, and review the manufacturer’s tests for strength, safety and purity. Manufacturers may also be required to submit samples of each vaccine lot to the FDA for testing. FDA monitoring will continue as long as the manufacturer holds a license for the vaccine product.
 
Post-Licensure Monitoring of Vaccines (FDA, 2020)
Phase IV Trials
Until a vaccine is administered to the general population, every potential adverse event can’t be anticipated. Phase IV studies are optional trials conducted after the vaccine is on the market and include testing for safety, efficacy, and other possible uses.
 

Is a COVID-19 Vaccine on the Horizon?

The vaccine development process is complex, labor-intensive and takes time. However, the Department of Health and Human Services (HHS), the CDC, the National Institutes of Health (NIH), the Biomedical Advanced Research and Development Authority (BARDA), and the Department of Defense (DoD) have partnered to accelerate the development, manufacturing, and distribution of COVID-19 vaccines through a program called Operation Warp Speed (OWS) (HHS, 2020). Their goal is to bring 300 million doses of a safe and effective vaccine to the general public by January 2021. In order to achieve this, OWS is providing government support to the most promising vaccine candidates and steps in the traditional development timelines are occurring simultaneously. For example, manufacturing of the vaccine on a large scale will begin before researchers have demonstrated vaccine efficacy and safety.
 
According to the HHS (2020), fourteen potential vaccines have been selected from over 100 contenders currently in development. Leading the pack (as of November 5, 2020), are Moderna’s mRNA-1273 vaccine undergoing phase 3 trials and Pfizer and BioNTech’s BNT162b2 vaccine in a combined phase 2-phase 3 trial (Roush, 2020). Both vaccines utilize messenger RNA (mRNA) to carry genetic material that codes for viral proteins to the cell. Once inside the cell, mRNA instructs the cell to make copies of that protein, stimulating the immune system to respond. These vaccines can be produced rapidly and efficiently.
 
Many candidate vaccines will not make it through the rigorous clinical development process. Even if one vaccine completes these stages in record speed, our fight against COVID-19 remains an uphill battle. According a Pew Research Center survey about half of U.S. adults (51%) say they would get vaccinated against COVID-19 while 49% say they definitely or probably would not get vaccinated, stating safety and effectiveness as major concerns (Tyson et al., 2020). The FDA said it would authorize a COVID-19 vaccine if it was safe and at least 50% effective in preventing the disease or decreasing the severity of infection (Tyson et al., 2020). However, one study conducted by Bartsch et al. (2020) found that the coronavirus vaccine has to have an efficacy of at least 70% to prevent an epidemic and at least 80% to extinguish an epidemic without any other measures (i.e. physical distancing).
 
A vaccine will certainly get us one step closer to normalcy but only if it is proven safe and effective and achieves widespread acceptance. It is a waiting game and like all good things, we must be patient.

Update November 9, 2020
Pfizer and BioNtech announced their vaccine candidate against COVID-19 has achieved success in its first interim analysis from their Phase III study. Their vaccine was found to be more than 90% effective in preventing COVID-19 in study participants without evidence of prior SARS-CoV-2 infection. The interim analysis included 94 confirmed cases of COVID-19 participants from over 43,000 study subjects enrolled. No serious safety concerns have been observed. Pfizer and BioNtech will submit an application for Emergency Use Authorization (EUA) to the FDA after they reach a required safety milestone. They must observe for adverse events for at least two months and that two-month mark will occur at the end of November. The clinical trial will continue through final analysis when 164 confirmed cases are evaluated (Pfizer, 2020).

Update November 16, 2020
Moderna, Inc., announced today that their COVID-19 vaccine mRNA-1273 was found to have an efficacy of 94.5%. The interim analysis was conducted by an independent NIH-appointed Data Safety Monitoring Board (DSMB) for their Phase 3 study. The study enrolled over 30,000 participants in the U.S. in collaboration with the National Institute of Allergy and Infectious Disease (NIAID), part of the NIH and BARDA. The first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group that statistically points to an estimated vaccine efficacy of 94.5%. A secondary endpoint evaluated 11 severe cases of COVID-19 and all 11 cases occurred in the placebo group and none in the vaccinated group. Concurrent review by the DSMB of safety data revealed no safety concerns and adverse events indicate the vaccine was generally well tolerated. Moderna will submit for an EUA with the FDA in the coming weeks. This vaccine is part of Operation Warp Speed and by the end of 2020, Moderna expects to have 20 million doses of the vaccine ready to ship to the U.S. (Moderna, 2020).
 
Moderna’s vaccine has a key advantage over the Pfizer vaccine in that it can be stored at minus 20 degrees Celsius. The Pfizer vaccine must be stored at minus 75 degrees Celsius and provider offices and pharmacies do not have freezers that can be kept at temperatures that low. Another advantage is that Moderna’s vaccine can be stored for 30 days in the refrigerator whereas Pfizer’s vaccine can last only 5 days in the refrigerator (CNN, 2020).
 

References:
 
Bartsch, S.M., O’Shea, K.J., Ferguson, M.C., Bottazzi, M.E., Wedlock, P.T., Strych, U., McKinnell, J.A., Siegmund, S.S., Cox, S.N., Hotez, P.J. & Lee, B.Y. (2020). Vaccine efficacy needed for a COVID-19 coronavirus vaccine to prevent or stop an epidemic as the sole intervention. American Journal of Preventive Medicine, 59(4), 493-503. doi: 10.1016/j.amepre.2020.06.011
 
Centers for Disease Control and Prevention (CDC) (2020). Vaccine Testing and the Approval Process. Retrieved from https://www.cdc.gov/vaccines/basics/test-approve.html
 
CNN (2020). Moderna’s coronavirus vaccine is 94.5% effective, according to company data. Retrieved from https://www.cnn.com/2020/11/16/health/moderna-vaccine-results-coronavirus/index.html

Department of Health and Human Services (HHS). (2020). Fact Sheet: Explaining Operation Warp Speed. Retrieved from https://www.hhs.gov/coronavirus/explaining-operation-warp-speed/index.html
 
Gould, K. A. (2020). Tracking a vaccine and developing therapeutics for COVID-19. Dimensions of Critical Care Nursing, 39(6), 293-297. doi: 10.1097/dcc.0000000000000447

Moderna, Inc. (2020). Moderna’s COVID-19 Vaccine Candidate Meets Its Preliminary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study. Moderna Press Release Retrieved from https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy
 
Roush, K. (2020). The Race to develop a COVID-19 vaccine – Many challenges lie ahead, including public acceptance. American Journal of Nursing, 120(10), 14 – 15. doi: 10.1097/01.NAJ.0000718556.85319.00
 
Pfizer. (2020). Pfizer and BioNtech Announce vaccine candidate against COVID-19 achieved sucess in first insterim analysis from Phase 3 study. Retrieved from https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against  

The College of Physicians of Philadelphia. (2018). The History of Vaccines - Vaccine Development, Testing, and Regulation. Retrieved from https://www.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation
 
Tyson, A., Johnson, C., & Funk. C. (2020). U.S. Public Now Divided Over Whether to Get COVID-19 Vaccine. Pew Research Center. Retrieved from https://www.pewresearch.org/science/2020/09/17/u-s-public-now-divided-over-whether-to-get-covid-19-vaccine/ 
 
U.S. Food and Drug Administration (FDA) (2020). Vaccine Product Approval Process. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-product-approval-process