Vaccine Safety Steps

How do we know if vaccines are safe?

Every vaccine goes through many years of study before it reaches you. At every step, scientists have to prove that the vaccine is safe and that it does what it is supposed to do.

1. Laboratory Studies

The first step is to study the vaccine in test-tube and animal experiments. If it looks promising, the next step is to ask the US Food and Drug Administration (FDA) to allow testing in people, a process called clinical trials.

2. FDA Review

FDA experts review the results of the lab research. The agency checks that the scientists did their tests properly, whether the vaccine looks like it may work, and whether there were any early warning signs about safety. If the agency approves, then the vaccine starts clinical trials.

3. Clinical Trials

Clinical trials have 3 phases.

Phase 1: Is it safe? Does the body respond?

Phase 2: How well does it work? More patients, more diverse

If no major safety problems show up in phase 1, then tests continue on a larger group of people, typically in the hundreds. Researchers aim to include people of different ages, health conditions, and backgrounds to see if any differences among them emerge. Different doses are tested. In this larger group, scientists get a better understanding of how the immune system responds and whether there are side effects in this larger number of people.

Phase 3: Does it work? Are there rare side effects?

If phase 2 shows the vaccine is safe and the immune system responds to it, then the vaccine moves on to phase 3. This step involves thousands or tens of thousands of people.

Patients receive either the new vaccine, a comparison vaccine, or a placebo—a shot that does not include the vaccine's active ingredient. This way, researchers can tell which effects–good and bad–are caused by the vaccine and which are unrelated. Scientists study these volunteers for months or years to see how many get sick with the disease that the vaccine aims to prevent. They also watch for unusual side effects that may not have shown up in earlier phases.

If the vaccine prevented the disease and no serious safety problems emerged, then the scientists send their results to the FDA for approval.

When and When Not to Use a Placebo

Every vaccine clinical trial compares the new vaccine to something different–either a placebo or another vaccine.

Scientists use a placebo when:

The disease is new and no other vaccine exists, such as in the early days of the COVID-19 pandemic
There is no effective vaccine for the disease, such as cytomegalovirus (a type of herpes) or C. diff (Clostridioides difficile).
A vaccine exists but does not work well for the group being studied. For example, new shingles vaccine studies used a placebo because the existing vaccine did not work well in patients over age 70
The disease only lasts a few days, most cases are mild and can be managed with simple treatments such as rest and fluids or over-the-counter medications, and does not cause long-term damage, such as norovirus.

Sometimes using a placebo would be unethical–for example, when a vaccine for the disease is already available.

Scientists testing a new whooping-cough (pertussis) vaccine compared it to an existing vaccine, not a placebo. It would have been unethical not to provide patients in the study with protection against the disease. The studies found that the new vaccine had fewer side effects than the available one.

4. Additional FDA Review

A team of FDA experts reviews the data and determines whether the vaccine is safe and works as intended. FDA weighs whether the benefits of taking the vaccine are greater than the risks of side effects. Once it has considered all the data, then FDA decides whether to allow the vaccine to be licensed and offered to the public.

Before a vaccine is shared with the public, FDA also must review and approve:

the information on the vaccine label
the package insert (a description of the vaccine, clinical trial results, and side effects seen in the clinical trials)
the manufacturing process and potency of vaccine lots

The FDA may also require additional monitoring or a post-marketing study (often called phase 4) to further assess the safety of a vaccine used by the public. This additional monitoring helps assess even more uncommon or unexpected side effects.

5. After Approval: How Vaccine Recommendations Are Made

Once FDA approves a vaccine, another review takes place to decide who should get the vaccine and how it should be used in the US.

Traditionally, this job has been done by an independent group of experts called the Advisory Committee on Immunization Practices (ACIP), which advises the US Centers for Disease Control and Prevention (CDC).

The role of ACIP is to carefully review all available evidence about the vaccine, including how well it works, how safe it is, and the disease it is designed to prevent or make less severe. The committee also considers how the vaccine can be used fairly across different communities (to maintain or improve health equity) and whether the recommendations are practical and acceptable to the public.

After discussion and a vote by ACIP, the recommendations are sent to the CDC director. Once approved by the CDC director, they become official public health policy. These recommendations guide whether vaccines are covered by Medicare, Medicaid, and private health insurance plans.

In addition to ACIP review, several expert groups, including the American Academy of Pediatrics, the American Academy of Family Physicians, and the Vaccine Integrity Project look at the evidence and recommend who should receive the vaccine and when.

Recent ACIP Changes

In June 2025, the US Department of Health and Human Services (HHS) replaced all the members of ACIP. Many healthcare and public health experts have raised concerns that, since this change, vaccine recommendations have not followed the usual transparent, evidence-based review process. Some recent decisions were made without the full public discussion and comprehensive evaluation of scientific evidence that have historically guided ACIP recommendations.

In January 2026, the CDC Director approved a new childhood vaccination schedule based on a limited internal review rather than the full ACIP process. This schedule reversed several long-standing vaccine recommendations. These changes have prompted questions about how vaccine guidance is developed and whether current recommendations reflect the full body of scientific evidence.

6. Ongoing Safety Monitoring

After a vaccine is on the market, there are multiple systems set up to watch for safety problems:

Vaccine Adverse Event Reporting System (VAERS): Anyone who believes a vaccine caused a health problem can report it to VAERS. Reports to VAERS don't prove that a vaccine caused the issue, but they may show scientists that something needs a closer look.
Vaccine Safety Datalink (VSD): Using electronic health records (which include over 10% of the US population) from several large healthcare organizations across the country, VSD researchers can quickly study whether a vaccine is connected to a reported health problem.
FDA Sentinel Initiative and Biologics Effectiveness and Safety (BEST) Initiative: These systems can be used to study the safety of vaccines and other approved medical products to evaluate safety concerns through analysis of health insurance claims.
Clinical Immunization Safety Assessment (CISA): This national network of experts from the Centers for Disease Control and Prevention (CDC) and academic research centers researches vaccine safety issues and consults doctors and other healthcare professionals about individual cases.

FDA also may require the vaccine maker to monitor safety and effectiveness after approval.

Reviewed February 2026

Sources: American Academy of Pediatrics, Centers for Disease Control and Prevention, Food and Drug Administration, World Health Organization