Last updated 18 April 2022
EDITOR'S NOTE (7 May 2022): Many anti-vaccine people and organizations are not presenting the information in this article in full context. The article below mostly covers vaccines before the current COVID-19 pandemic. Please see the section on the COVID-19 pandemic and Operation Warp Speed for information on the COVID-19 vaccines.
Vaccine development is a long, complex process, often lasting 10-15 years, and involves a combination of public and private involvement.
The current system for developing, testing, and regulating vaccines developed during the 20th century, as the groups involved standardized their procedures and regulations.
In the United States
At the end of the 19th century, several vaccines for humans were developed. They were smallpox, rabies, plague, cholera, and typhoid vaccines. However, no regulation of vaccine production existed.
On July 1, 1902, the U.S. Congress passed "An act to regulate the sale of viruses, serums, toxins, and analogous products," later referred to as the (even though "biologics" appears nowhere in the law). This was the first modern federal legislation to control the quality of drugs. This act emerged in part as a response to , which involved smallpox vaccine and diphtheria antitoxin.
The Act created the Hygienic Laboratory of the U.S. Public Health Service to oversee the manufacture of biological drugs. The Hygienic Laboratory eventually became the National Institutes of Health. The Act established the government’s right to control the establishments where vaccines were made.
The United States Public Service Act of 1944 mandated that the federal government issue licenses for biological products, including vaccines. After a poliovirus vaccine accident in 1954 (known as the Cutter incident), the Division of Biologics Standards was formed to oversee vaccine safety and regulation. Later, the DBS was renamed the Bureau of Biologics, and became part of the Food and Drug Administration. It is now known as the Center for Biologics Evaluation and Research.
Outside of the United States
In the European Union, the European Medicines Agency supervises regulation of vaccines and other drugs. A committee of the World Health Organization makes recommendations for biological products used internationally. Many countries have adopted the WHO standards.
Stages of Vaccine Development and Testing
In the United States, vaccine development and testing follow a standard set of steps. The first stages are exploratory in nature. Regulation and oversight increase as the candidate vaccine makes its way through the process.
First Steps: Laboratory and Animal Studies
This stage involves basic laboratory research and often lasts 2-4 years. Federally funded academic and governmental scientists identify natural or synthetic antigens that could help prevent or treat a disease. These antigens could include virus-like particles, weakened viruses or bacteria, weakened bacterial toxins, or other substances derived from pathogens.
Pre-clinical studies use tissue-culture or cell-culture systems and animal testing to assess the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. Animal subjects may include mice and monkeys. These studies give researchers an idea of the cellular responses they might expect in humans. They may also suggest a safe starting dose for the next phase of research, as well as a safe method of administering the vaccine.
Researchers may adapt the candidate vaccine during the pre-clinical state to try to make it more effective. They may also do challenge studies with the animals, meaning they vaccinate the animals and then try to infect them with the target pathogen.
Many candidate vaccines never progress beyond this stage, because they fail to produce the desired immune response. The pre-clinical stages often last 1-2 years and usually involve researchers in private industry.
A sponsor, usually a private company, submits an application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration. The sponsor describes the manufacturing and testing processes, summarizes the laboratory reports, and describes the proposed study. An institutional review board, representing an institution where the clinical trial will be conducted, must approve the clinical protocol. The FDA has 30 days to approve the application.
Once the IND application has been approved, the vaccine is subject to three phases of testing.
Next Steps: Clinical Studies with Human Subjects
Phase I Vaccine Trials
This first attempt to assess the candidate vaccine in humans involves a small group of adults, usually between 20-80 subjects. If the vaccine is intended for children, researchers will first test adults, and then gradually step down the age of the test subjects until they reach their target. Phase I trials may be non-blinded (also known as open-label in that the researchers and perhaps subjects know whether a vaccine or placebo is used).
The goals of Phase 1 testing are to assess the safety of the candidate vaccine and determine the type and extent of immune response that the vaccine provokes. In a small minority of Phase 1 vaccine trials, researchers may use the challenge model, attempting to infect participants with the pathogen after the experimental group has been vaccinated. The participants in these studies are carefully monitored, and conditions are carefully controlled. In some cases, an attenuated, or modified, version of the pathogen is used for the challenge.
A promising Phase 1 trial will progress to the next stage.
Phase II Vaccine Trials
A larger group of several hundred individuals participates in Phase II testing. Some individuals may belong to groups at risk of acquiring the disease. These trials are randomized and well controlled, and include a placebo group.
The goals of Phase II testing are to study the candidate vaccine’s safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery.
Phase III Vaccine Trials
Successful Phase II candidate vaccines move on to larger trials, involving thousands to tens of thousands of people. These Phase III tests are randomized and double blind, and involve the experimental vaccine being tested against a placebo (the placebo may be a saline solution, a vaccine for another disease, or some other substance).
One Phase III goal is to assess vaccine safety in a large group of people. Certain rare side effects might not surface in the smaller groups of subjects tested in earlier phases. For example, suppose that an adverse event related to a candidate vaccine could occur in 1 of every 10,000 people. To detect a significant difference for a low-frequency event, the trial would have to include 60,000 subjects, half of them in the control, or no vaccine, group (Plotkin SA et al. Vaccines, 5th ed. Philadelphia: Saunders, 2008).
Vaccine efficacy is also tested. These factors might include 1) Does the candidate vaccine prevent disease? 2) Does it prevent infection with the pathogen? 3) Does it lead to the production of antibodies or other types of immune responses related to the pathogen?
Next Steps: Approval and Licensure
After a successful Phase III trial, the vaccine developer will submit a Biologics License Application to the FDA. The FDA will then inspect the factory where the vaccine will be made and approve the labeling of the vaccine.
After licensure, the FDA will continue to monitor the production of the vaccine, including inspecting facilities and reviewing the manufacturer’s tests of lots of vaccines for potency, safety and purity. The FDA has the right to conduct its own testing of manufacturers’ vaccines.
Post-Licensure Monitoring of Vaccines
A variety of systems monitor vaccines after they have been approved. They include Phase IV trials, the Vaccine Adverse Event Reporting System, and the Vaccine Safety Datalink.
Phase IV Trials
Phase IV trial are optional studies that drug companies may conduct after a vaccine is released. The manufacturer may continue to test the vaccine for safety, efficacy, and other potential uses.
The CDC and FDA established in 1990. According to the CDC, VAERS' goal is “to detect possible signals of adverse events associated with vaccines.” (A signal in this case is evidence of a possible adverse event that emerges in the data collected.) About 30,000 events are reported each year to VAERS. Between 10% and 15% of these reports describe serious medical events that lead to hospitalization, life-threatening illness, disability, or death.
VAERS is a voluntary reporting system. Anyone, such as a parent, a health care provider, or friend of the patient, who suspects an association between a vaccination and an adverse event, may report that event and information about it to VAERS. The CDC then investigates the event and tries to find out whether the vaccination actually caused the adverse event.
The CDC states they monitor VAERS data to
- Detect new, unusual, or rare vaccine adverse events
- Monitor increases in known adverse events
- Identify potential patient risk factors for particular types of adverse events
- Identify vaccine lots with increased numbers or types of reported adverse events
- Assess the safety of newly licensed vaccines
Not all adverse events reported to VAERS are actually caused by a vaccination. The two occurrences may be related only in time. And, it is probable that not all adverse events resulting from vaccination are reported to VAERS. The CDC states that many adverse events, such as swelling at the injection site, are underreported. Serious adverse events, according to the CDC, “are probably more likely to be reported than minor ones, especially when they occur soon after vaccination, even if they may be coincidental and related to other causes.”
VAERS has successfully identified several rare adverse events related to vaccination. Among them are
- An intestinal problem after the first vaccine for rotavirus was introduced in 1999
- Neurologic and gastrointestinal diseases related to yellow fever vaccine
According to Plotkin et al., VAERS identified a need for further investigation of MMR association with a blood clotting disorder, encephalopathy after MMR, and syncope after immunization (Plotkin SA et al. Vaccines, 5th ed. Philadelphia: Saunders, 2008).
Vaccine Safety Datalink
The CDC established this system in 1990. The VSD is a collection of linked databases containing information from large medical groups. The linked databases allow officials to gather data about vaccination among the populations served by the medical groups. Researchers can access the data by proposing studies to the CDC and having them approved.
The VSD has some drawbacks. For example, few completely unvaccinated children are listed in the database. The medical groups providing information to VSD may have patient populations that are not representative of large populations in general. Additionally, the data come not from randomized, controlled, blinded trials, but from actual medical practice. Therefore, it may be difficult to control and evaluate the data.
Rapid Cycle Analysis is a program of the VSD, launched in 2005. It monitors real-time data to compare rates of adverse events in recently vaccinated people with rates among unvaccinated people. The system is used mainly to monitor new vaccines. Among the new vaccines monitored in Rapid Cycle Analysis are the conjugated meningococcal vaccine, rotavirus vaccine, Tdap vaccine, and the HPV vaccine. Possible associations between adverse events and vaccination are then further studied.
The COVID-19 Pandemic and Operation Warp Speed
In late 2019, . By January 2020, the virus causing the pneumonia cluster was identified as a novel coronavirus, designated "SARS CoV-2." The genetic sequence of the virus was shared by Chinese researchers with the world, along with samples of the virus. Laboratories around the world began working on a vaccine.
In the United States, that could be delivered quickly and used as effective countermeasures against the pandemic. Traditionally, vaccine manufacturers would not begin phase II trials until phase I trials were done, and phase III would start after phase II. That process ensured that vaccines showing no promise in earlier trials would not waste resources in later trials. With the government money as a form of insurance against losses, vaccine manufacturers were able to perform different phases simultaneously.
This process allowed all safety and efficacy testing to be done simultaneously with the vaccine manufacturing. Under the original way of developing the vaccines, vaccine manufacturing at a large scale would not begin until the phase III trial results were done. With Operation Warp Speed, manufacturing began soon after the vaccines were found to be safe, and during the efficacy studies. If the vaccines were not efficacious, money from Operation Warp Speed would cover the losses.
The three vaccines ( and one viral vector) that resulted from Operation Warp Speed had all the same safety and efficacy studies as other vaccines before the pandemic. They used the same number of people in the same number of phases. The same safety checks were followed, and the data submitted to independent reviewers was the same as previous vaccines. The only change came from a compressed timeline, and that was possible because of funding to cover any losses previously covered by the manufacturers.
Vaccines are developed, tested, and regulated in a similar manner to other drugs. In general, vaccines are even more thoroughly tested than non-vaccine drugs, because the number of human subjects in vaccine clinical trials is usually greater. In addition, the Centers for Disease Control and the FDA closely examine post-licensure monitoring of vaccines.
- VAX. IAVI Report. Volume 1, no. 1. August 2003. Accessed 01/17/2018.
- Plotkin, S.A., Orenstein, W.A., Offit, P.A., eds. Vaccines, 5th ed. Philadelphia: Saunders, 2008. Chapters 3 and 73.
- Table above from . National Academies Press. Accessed 01/17/2018
- U.S Department of Health and Human Services. . U.S. Food and Drug Administration. Updated 01/09/2018. Accessed 01/17/2018.
- U.S. Department of Health and Human Services. . U.S. Food and Drug Administration. Updated 10/05/2017. Accessed 01/17/2018.
- Lilienfeld, D.E. The first pharmacoepidemiologic investigations: national drug safety policy in the United States, 1901-1902. Perspectives in Biology and Medicine. 51.2 (2008): 192-96.