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Vaccine development is a long, complex process, often lasting 10-15 years and involving 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.

Government Oversight In the United States

At the end of the 19th century, several vaccines for humans had been 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 Biologics Control Act (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 1901 contamination events in St. Louis and Camden involving smallpox vaccine and diphtheria antitoxin.

The Act created the Hygienic Laboratory of the U.S. Public Health Service to oversee 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 it became part of the Food and Drug Administration. It is now know as the Center for Biologics Evaluation and Research.

Elsewhere

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.

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This stage involves basic laboratory research and often lasts 2-4 years. Federally funded academic and governmental scientists identify natural or synthetic antigens that might 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.

If the exploratory stage yields information that could create a valuable vaccine, the company (referred to as the sponsor of the vaccine) moves on to the next step, the Pre-Clinical stage

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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 that 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 lasts 1-2 years and usually involves researchers in private industry.

If the pre-clinical stage yields information that could create a valuable vaccine, the sponsor of the vaccine moves on to the next step, the IND (Investigational New Drug) Application

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Step 3: IND (Investigational New Drug) Application

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Step 3: IND (Investigational New Drug) Application

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IND Application

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.

If the IND stage yields information that could create a valuable vaccine, the sponsor of the vaccine moves on to the next step, clinical studies with human subjects

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Step 4: Clinical Studies with Human Subjects

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Step 4: Clinical Studies with Human Subjects

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Clinical studies with human subjects involves phases of testing, with the first phase being the safest and with the most precautions and the last phase being the least safe (but still relatively safe). Each phase of testing determines a different set of variables and outcomes, and the next phase can only occur when the previous phase of testing is successful. There are 4 phases, but only the first 3 phases are considered in clinical studies with human subjects because the 4th phase evaluates long term implications of the vaccine after it has been put into production, so it is more of a quality control measure than a clinical study measure.

Phase 1 Testing:
These involve people, and they are mainly done to find the highest dose of the new treatment that can be given safely without serious side effects. Often, the drugs are previously tested in lab and animal studies. The first few people often get low doses of the treatment, and are watched closely. If the side effects are small, the dosage might be increased. The focus is to see the drug’s effect on the body, and safety is the main concern at this point. Placebos are not part of phase 1 trials, and trials include a small number of people, typically up to a few dozen. The purpose of these trials is not yet to determine the effectiveness of the drug.

Phase 2 Testing:
If the treatment is found to be reasonably safe, it proceeds to phase 2 testing. Phase 2 clinical trial is to determine if the drug works. The definition of a successful trial 2 depends on what the doctors or pharmaceutical companies are looking for in terms of the outcome after the treatment. Phase 2 trials often have a larger number of people, anywhere from 25 to 100 people, and all volunteers usually get the same dose, unless the study randomly assigns participants to different treatment groups (different doses) to find the best balance of effectiveness and safety. No placebo is done yet, and because there is a larger amount of patients, there’s a higher chance that less common side effects emerge. If they find that enough patients benefit from the treatment and the side effects aren’t that bad, the treatment proceeds to phase 3 clinical trials.

Phase 3 testing:
Phase 3 clinical trials aim to see if the new treatment is better than what’s already available. They compare the safety and effectiveness of the new treatment to correct standard treatments. They do this with a double blind study, where they first perform a simple random sample (choosing randomly from the population) or a stratified random sample (choosing randomly from groups of people that have similar attributes) to get a good sample of people that represent the population well, and then they administer the treatment through doctors, but neither the doctors nor the patients know which treatment is being administered. This way, they can avoid confounding variables (variables that are very hard to eliminate because they exist by chance, for example, if the doctor knew the treatment, he could convey his feelings of the treatment to the patients unconsciously).

If all 3 phases of testing are successful, the sponsor of the vaccine proceeds to move to the next step, Vaccine Product Approval Process

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Step 5: Vaccine Product Approval Process

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Step 5: Vaccine Product Approval Process

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The FDA (U.S.A Food and Drug Administration) center for Biologics evaluations and Research is responsible for regulating vaccines in the United States. The U.S. incorporates government oversight to ensure the safety of the vaccine in both this step and the quality control step.

The Sponsor of a new vaccine has to follow the following steps to get their vaccine approved:

1. They have to fill out the IND application (see above for more info)

2. They have to complete Pre-Licensure vaccine clinical trials (The Phase 1-4 testing)

3. They have to complete the Biologics License Application (BLA) (the BLA is a request for permission to introduce a biological product into interstate commerce)

4. They have to have an inspection of the manufacturing facility to ensure quality control standards are being met so no vaccine samples are unsafe

5. They have to show usability testing of product labeling to avoid misinformation.

After they complete these steps, the vaccine is approved, but the FDA continues to oversee production to ensure all standards are being met, including quality control (see below), periodic facility inspections, that continue as long as the manufacturer holds the license to produce the vaccine. The FDA can also conduct their own tests on the vaccine.

If the vaccine product approval process is successful, the sponsor of the vaccine is allowed to proceed to the next step and manufacture it.

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In the manufacturing step, the sponsor of the vaccine is responsible to mass produce the vaccine and distribute it to medical practices across the world. This is generally the last step the sponsor completes (other than quality control), but if quality control fails and finds a major side effect the FDA might force the sponsor to do further clinical studies with human subjects or repeat other steps while temporarily halting production.

The next step, Quality Control, is done on an ongoing basis, to ensure the safety of the vaccine.

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In Quality Control, both the company and the FDA monitor the vaccine to ensure no major side effects and to ensure the vaccine is safe. These practices occur as long as the manufacturer holds the license to produce the vaccine. The general practices that are done to ensure safety are as follows:

1. The FDA completes periodic facility inspections
2. The CDC (centers for disease control) and FDA establish VAERS (Vaccine adverse event reporting systems) "to detect possible signs of adverse events associated with vaccines". Doctors and patients can report events such as weird side effects to VAERS for review by the FDA and CDC, and this can help determine potential side effects of the vaccine that might have been missed in the clinical studies with humans due to rarity.
3. The CDC established the VSD (Vaccine Safety Datalink) to allow officials to get data about the vaccine. Data is collected by the monitoring of patients to record the common reaction to the vaccine, and this data can be accessed by researchers by proposing to the CDC their experiment, and it can allow for further scientific development.
4.  In phase 4 clinical trials, researchers often monitor ordinary patients to observe the effects of the drug, specifically to study the side effects caused over time by a new treatment after it has been approved and is on the market. They look for side effects that have not been seen in earlier trials, and see how effective the treatment is over a long period of time. Phase 4 trials include thousands of people.

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“Vaccine Testing and Approval Process.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 1 May 2014, www.cdc.gov/vaccines/basics/test-approve.html.

“Principles and Considerations for Adding a Vaccine to a National Immunization Programme.” World Health Organization, World Health Organization, 21 Sept. 2015, www.who.int/immunization/programmes_systems/policies_strategies/vaccine_intro_resources/nvi_guidelines/en/.

Biologics Evaluation and Research. “Biologics License Applications (BLA) Process (CBER).” U.S. Food and Drug Administration, FDA, www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber.