The development, authorization, and distribution of hundreds of millions of doses of the COVID-19 vaccine was both an amazing feat of collaboration by scientists, private companies, and governmental organizations and the turning point in one of the darkest periods in public health. The journey of a COVID-19 vaccine: where the vaccine comes from, how it is manufactured, who plays a role in its approval, and how it officially arrives for widespread use is complex. Many regulatory organizations, such as the FDA, CDC, HHS, and WHO, all had a hand in this journey. From the research lab to the patient,, there are several steps in this process that fully vet a vaccine for its safety and efficacy.
Step One: Research
The journey of the COVID-19 vaccine begins with research and lab work. As with any vaccine, there are specific guidelines that must be followed in order to take steps toward proper creation, use, and understanding of the vaccine.
In the Lab
Federally-funded scientific research launches a vaccine into the exploratory stage. Scientists hired by the government identify disease-fighting antigens of either natural or synthetic origin. Once identified, the same researchers may enter pre-clinical studies, performing animal testing to ensure the safety of a vaccine candidate. In the case of mRNA vaccines, such as the COVID-19 vaccine, this research had been performed for decades before COVID-19 ever surfaced.
In fact, in its early stages, mRNA technology has been used as a research tool to study gene expression, protein production, and potential cancer treatment. In 1996, scientists even applied for funding to develop the technology into a treatment for seasonal coronaviruses. Although mRNA technology has met both funding and patent challenges, it has continuously remained in research with several different organizations. By the late 2000s, BioNTech and Moderna had both entered the mRNA research field — particularly in vaccine production.
Typical vaccine research, whether privately funded by pharmaceutical companies or the government, can take anywhere from 10 to 15 years to complete. During this phase, scientists develop potential vaccines based on how the virus causes illness or disease in humans.
The mounting pressure of COVID-19, however, brought increased demand from scientists to complete clinical research in a time frame far shorter than normal. Luckily, due to the previous research performed on coronaviruses by the NIH, and the previous research performed on mRNA technology by different organizations, scientists were quickly able to leverage what had already been in development for years.
Before a vaccine can move forward into clinical trials in humans, researchers must perform efficacy and safety studies.
These studies are typically sponsored and funded by a private manufacturing company. Sometimes, the government (National Institutes of Health) may offer public funding as well. These sponsors submit an Investigational New Drug application, or IND, to the Food and Drug Administration before the clinical trials can begin. In this application, the sponsor’s manufacturing process is outlined and finalized to ensure the safety and consistency of the vaccine from batch to batch (lot to lot), any preliminary research is summarized, and the clinical study is proposed in detail. This information must be reviewed and approved by the institution where the sponsor plans to conduct the research.
The Food and Drug Administration is a government agency part of the United States Department of Health and Human Services (HHS), designed to ensure the safety and efficacy of drugs and foods for human consumption and use. The FDA approves uses for certain drugs, and in this case, vaccines, via the Federal Food, Drug and Cosmetic Act.
Once the FDA has approved the IND, researchers can begin human-based clinical trials. COVID-19 vaccine clinical trials consist of three phases. These trials determine the safety and efficacy of the vaccine. Participants are volunteer-based, and each participant agrees to report any side effects and allows for any follow-up physical examination conducted by scientists.
During the first phase of clinical studies of the COVID-19 vaccination, scientists gather 20 to 100 volunteers to answer the following questions:
- Is this vaccine safe?
- Are there any serious side effects?
- Is the vaccine causing an immune response?
- Which immune responses are triggered at different doses of the vaccine?
After phase one has answered basic questions about the safety of the vaccine, researchers can gather a larger study group consisting of several hundred volunteers. According to the National Institutes of Health, phase two participants and scientists aim to answer the following, more in-depth questions:
- What are the most common short-term side effects?
- What’s the body’s immune response?
- Are there signs that the vaccine protects against infection?
Following the results of phase two, there are now over 1,000 volunteer clinical study participants in phase 3. Just as phase two expanded detail on hypotheses and questions, phase three does as well. However, it is during this phase that the NIH created the COVID-19 Protection Network (CoVPN) to perform these trials. Researchers answered the following questions:
- How do disease rates compare between people who get the vaccine and those who do not?
- How well can the vaccine protect people from disease?
After completing all three phases, the sponsoring organization will submit the results to the FDA for approval. Results from phase three research on COVID-19 vaccines determined that early, experimental versions of the vaccine were safe for consumer use. However, research actively continues through the present day.
Other Clinical Trials
To continue research on potential COVID-19 treatments and vaccinations, the National Institutes of Health (NIH) set up the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) trials.
The treatments actively tested are for patients who have never had COVID-19 and those in every stage of the illness — from minimal symptoms to hospitalizations, to those in recovery.
Step 2: Manufacturing
There are three FDA-approved vaccine manufacturers in the United States, and you’ve likely heard of them: Pfizer-BioNTech, Moderna, and Johnson & Johnson/Janssen. All vaccines approved by the FDA are safe, effective, and reduce your risk of severe illness.
Once all preliminary clinical trials and research have concluded, the FDA can work closely with vaccine manufacturers to create lot-release protocols. These protocols ensure that original manufacturing processes are followed and that consistent testing is maintained to ensure the safety of each lot for consumer use. The FDA will also closely monitor and examine any manufacturing facility to ensure compliance with FDA regulations.
Emergency Use Authorization (EUA)
In this case of the urgent need for COVID-19 vaccinations, manufacturers submitted requests for Emergency Use Authorization. Once the requests were made, researchers in medical and scientific disciplines from the FDA’s Center for Biologics Evaluation and Research (CBER) reviewed Phase 3 clinical trial data. This data was reviewed against EUA criteria (safety, effectiveness, and manufacturing processes), and potential benefits and risks were weighed, resulting in vaccine authorization instead of full FDA licensure.
The EUA process reviews the same core information as a BLA, however, the process is substantially faster in order to meet emergency use demands. Each EUA released by the FDA has adjusted the criteria for patient use (age, pre-existing conditions, etc) and is specific to each manufacturer.
Biologics License Application (BLA)
After the FDA deems the manufacturing process as reliable and consistent, and all clinical research and development is completed, manufacturing companies can submit a Biologics License Application to the FDA. A BLA allows companies to apply for the ability to create and distribute the COVID-19 vaccination in the United States. This application details all clinical data and research information and includes all manufacturing processes and facilities. Currently, manufacturers are beginning to submit Biologics License Applications as a next step toward solidifying the COVID-19 vaccine as an official FDA licensed, common use vaccine in the near future.
Step 3: FDA Approval
Before a vaccine can obtain full “FDA Approval,” there are multiple factors that must be vetted. The FDA will review and inspect the thousands of pages of the BLA before it can move forward to licensing, CDC review, and eventually prescribing and labeling.
Reviews and Inspections
Upon receipt of a Biologics License Application, the FDA will evaluate its comprehensive components. The decision to license (approve) a vaccine comes from an intensive review of any beneficial or risk-oriented outcomes of vaccine use versus the disease the vaccine is intended to prevent.
The FDA’s “Vaccine Development 101” list comprises an average FDA scientific team that reviews this information and the BLA closely: “physicians, chemists, statisticians, pharmacologists/toxicologists, microbiologists, experts in postmarketing safety, clinical study site inspectors, manufacturing and facility inspectors, and labeling and communications experts.”
During this time, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) gives input to the FDA on any scientific or public health data before vaccine approval. VRBPAC is a panel of independent experts in diverse scientific or public health fields that may provide input in a public-facing meeting.
If all criteria have been met for a Biologics License Application, and the FDA has determined the benefits of the COVID-19 vaccine outweigh its potential risks and the risks of COVID-19 itself, the vaccine is officially approved and licensed by the FDA.
Prescribing and Labeling
After licensing the vaccine, the FDA will return to the information found in the BLA. A careful review of this information allows the FDA to determine the accuracy of prescribing information. This includes determining dosing and usage. Prescribing and labeling information is updated by the FDA on an as-needed basis in accordance with the most current COVID-19 and vaccine information available.
After final approval, the CDC’s Advisory Committee on Immunization Practices (ACIP) will review the newly licensed vaccine to determine recommendation eligibility.
What is the CDC?
The Centers for Disease Control (CDC) is a government agency part of the United States Department of Health and Human Services, designed to protect Americans from threats to health security. The CDC equips Americans with health information to stay safe in times of health crisis and sets schedules for immunizations based on ACIP recommendations.
What is the ACIP?
The Advisory Committee on Immunization Practices consists of a panel of 15 medical and health experts who vote on recommendations in vaccine use for United States disease control. Additionally, there are 30 non-voting members who are highly regarded healthcare professionals.
Before a vaccine has received FDA approval, the ACIP actively reviews all information available, allowing for thorough preparation for recommendations by the time the vaccine is approved. After FDA approval, however, the ACIP considers several factors of a vaccine before making an official recommendation. These factors include:
- Vaccine efficacy and safety at specific ages
- Disease severity compared to vaccine efficacy
- Recommendation practicality (feasibility for the American public)
All ACIP recommendations are unofficial until the Director of the CDC has given approval. Then, ACIP recommendations become official CDC public health guidance.
Step 4: Public Release
By Step 4, a COVID-19 vaccine has received FDA licensing and CDC recommendation and is ready for public release. However, it must undergo safety surveillance as vaccine lots are released for production.
Vaccine Safety Surveillance
Following FDA approval, the COVID-19 vaccine will undergo safety surveillance. Using the Vaccine Adverse Event Reporting System (VAERS), Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment Project (CISA), the CDC and FDA monitor the safety and efficacy of the vaccine after FDA approval. These surveillance systems remain active after the public release of the vaccine in order to track adverse effects and monitor updated safety risks.
Vaccine Adverse Event Reporting System (VAERS)
VAERS is a vaccine monitoring system run by both the CDC and FDA. It collects reports of negative effects after vaccination. Anyone is able to flag an adverse event, including patients, caregivers or parents, and healthcare professionals.
Vaccine Safety Datalink (VSD)
The CDC collaborates with several healthcare organizations to monitor vaccine administration in real-time. This data allows for continued vaccine research.
Clinical Immunization Safety Assessment Project (CISA)
Several medical research centers, in collaboration with the CDC, provide healthcare providers with answers to vaccine safety questions on behalf of their patients. Additionally CISA conducts continued clinical research to maintain vaccine safety.
Following final safety checks, the FDA releases a “lot” of the COVID-19 vaccine to manufacturers for production. If a manufacturer is permitted to produce the vaccine lot, the FDA has reviewed and approved vaccine safety criteria, such as sterility, potency, and consistency.
The federal government distributes FDA-authorized COVID-19 doses on a state and jurisdiction basis weekly. Additionally, the government created specialized programs to distribute vaccines to high-risk communities directly. Through the Federal Retail Pharmacy Program, 40,000 pharmacies in high-risk zip codes receive COVID-19 vaccines. Community health centers that administer the COVID vaccine can apply for the Health Center COVID-19 Vaccine Program. Medically underserved rural communities are distributed COVID-19 vaccine lots through the Rural Health Clinic COVID-19 Vaccine Distribution (RHCVD) Program. Beyond these programs, all states, territories and tribes are responsible for developing a plan for distribution to people who live in their communities.
Many organizations formulate campaigns to increase and maintain public knowledge and education about the COVID-19 vaccine and preparedness. Two of the biggest contributors to this educational goal are the United States Department of Health and Human Services (HHS) and the World Health Organization (WHO).
The HHS is a government agency that houses the FDA and the CDC. It is a resource for anyone looking for updated vaccination processes, treatment information, and general education about COVID-19. However, it has also initiated the COVID-19 Public Education Campaign, which aims to increase consumer confidence surrounding COVID-19 vaccinations. Additionally, the HHS has an official government website dedicated to empowering Americans to “Combat Covid” in their local communities and acts as a resource for healthcare professionals who must advise their patients.
The World Health Organization has consistently worked to keep the public informed about COVID-19 preparedness and vaccination since the start of the pandemic and throughout vaccine development. WHO is an agency of the United Nations that aims to promote worldwide health and health education. They are responsible for compiling the COVID-19 Strategic Preparedness and Response Plan (SPRP) and other plans of action.
From the science lab to consumer use, the journey of a COVID-19 vaccine is intensive and rigorous. Through clinical trials, manufacturing processes, and other inspections, the FDA and CDC/ACIP closely monitor the vaccine for safety and efficacy before it reaches the consumer. Education of the vaccine stems from organizations such as WHO or HHS, and is available for the public. It is through the collaboration of these organizations that COVID-19 vaccinations are widely available for the safety of Americans.