Vaccine Safety

by US Department of Health and Human Services

The gasping for breath and desperate hacking of whooping cough. The iron lungs and braces of polio. Birth defects from rubella. For many people today, those signs of terrible diseases are the stuff of history books, thanks to vaccines. But the rare case of vaccine-associated polio or the death of an infant soon after receiving a dose of pertussis vaccine may make people wonder — are vaccines safe enough, or could they be safer?

For the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER), vaccine safety, along with effectiveness, is central to regulation of these preparations.

Clinical Trials

The first step to licensing a new vaccine is safety testing in animals. If the laboratory animals immunized with the vaccine don't have serious reactions, FDA consults with the vaccine manufacturer or sponsor on further refining of the manufacturing process.

Because the weakened viruses used for vaccines are grown in animal or human cells, "we spend a tremendous amount of time studying the safety of those cells," says M. Carolyn Hardegree, M.D., director of CBER'S office of vaccine research and review.

For example, the manufacturer of the recently licensed Varicella (chickenpox) vaccine had to prove the human cell line used to grow the virus was not contaminated with any other viruses, such as hepatitis.

Only after those studies have been done does testing in people begin.

FDA requires new vaccines to undergo several phases of clinical trials — testing in people — for safety and effectiveness.

Phase 1 trials evaluate basic safety and identify only very serious or very common adverse events. These trials are small — between 20 and 100 patients — and last just several months.

Phase 2 trials include several hundred patients and last anywhere from several months to two years. This allows for more information on safety and preliminary information on effectiveness to be collected.

Unless severe reactions or a lack of effectiveness surfaces during the first two phases, the trials are expanded in Phase 3 to include several hundred to several thousand people. These trials continue to measure effectiveness and safety.

If, towards or at the end of the Phase 3 trials, the manufacturer believes there are adequate data to show that the vaccine is safe and effective for its intended use, the manufacturer applies to FDA for two licenses — one for the vaccine (product license) and one for the manufacturing plant (establishment license).

An internal FDA committee then reviews the clinical data, proposed labeling, and manufacturing protocols that ensure a consistent product, and the results of the agency's own confirmatory tests of the vaccine's components and the final product. The review process includes an inspection of the manufacturing facility.

Advisory Committees

FDA advisory committees are groups of experts outside government that review data and issues associated with products and recommend what action the agency should take.

"Advisory committees may be brought in at any stage in the review process," says Hardegree. "For example, before we went into Phase 1 trials of some of the first AIDS vaccines, we showed the [proposed studies] to the Vaccines and Related Biological Products Advisory Committee. As we move into determining what might be appropriate efficacy studies, we might let them see that early on." Involving the committees throughout the process is a good idea, she says, because these expert advisors bring a wealth of scientific background to address vaccine issues confronting FDA.

"Through the years, we've been very fortunate to have an outstanding advisory group," says Hardegree. "We've had members who have been willing to serve as consultants for many years after their four-year term, and they provide a continuity on some of the issues that were discussed years ago and are still being studied today."

Committee recommendations are not binding on FDA, but the agency considers them carefully when deciding whether to license a vaccine for marketing.

Green Light

Licensing of a vaccine is only the beginning of FDA's oversight. Manufacturers must submit samples of each vaccine lot and results of their own tests for potency, safety and purity to the agency before release.

Each lot must be tested because vaccines are derived from living organisms that are sensitive to environmental factors and are susceptible to contamination.

"Tests generally applicable to all products include those for bacterial and fungal sterility, general safety, purity, identity, suitability of constituent materials, and potency," explains Hardegree. "Sterility testing is performed on both bulk- and final-container material. In addition, cell-culture-derived vaccines must be tested for [disease-causing organisms]. All ingredients such as diluents, preservatives or adjuvants must meet generally accepted standards of purity."

The importance of these tests was established years ago. In 1955, the virus-inactivated Salk polio vaccine first went on the market. Unfortunately, virus in some batches of the vaccine produced by one manufacturer was not totally inactivated, and some of the children who got that vaccine developed polio. (See "Assessing Risks with Polio Vaccines".)

Inadequate tests were the culprit, explains Hardegree.

About the Author

The Department of Health & Human Services is the United States government's principal agency for protecting the health of all Americans and providing essential human services, especially for those who are least able to help themselves. The department includes more than 300 programs, covering a wide spectrum of activities.