Vaccine Development in Depth

When researchers develop a new vaccine, they have to follow a strict process to make sure it is safe and effective. Whether it’s for a vaccine against a new infection or a new take on an old vaccine, the process follows similar steps.

The first stages, often called “discovery,” involve no vaccine testing in humans. They may involve studying people who have been naturally infected, but any testing is done in either cells or animals. This work typically lasts for years, and it sometimes goes on for decades.

• Exploratory research. The first step is to learn as much as possible about the virus. Researchers study its genetic sequence, its structure, and how much it can vary. From studying people who have had the infection, they learn how the virus behaves and how the body naturally fights it. Once they know the basics, researchers can choose an approach for developing a vaccine (e.g., whole virus, protein, nucleic acid, etc.). In choosing an approach, researchers draw on lessons learned from past vaccine successes and attempts.

• Pre-clinical testing. Before a new vaccine is put into a single person, there’s a lot of testing and refining that happens. The earliest tests are done on cells or tissues growing in a dish. After several rounds of testing and improvements, researchers can start testing in animals. That is, if a good animal model is available. Animal trials are tightly regulated to make sure they are done only when necessary, as few animals as possible are used, and all animals are treated ethically.

Testing in cells and animals can tell us a lot. But the only way to know if a vaccine is safe and effective for people is to test it with people. That’s where clinical trials come in. Clinical trials are tightly regulated processes, overseen by a government agency. They follow three phases, which may overlap. If at any stage concerns arise over safety or efficacy, the regulating agency can require new tests or even stop trials altogether.

• Phase 1 (I). Big question: Is it safe?

  In this phase, the vaccine is given to a small number of people—from less than 10 to a few dozen. Volunteers get a dose of vaccine, followed by close monitoring for any signs of harmful reactions. Their blood is tested to see how the immune system is reacting to the vaccine. If they show signs of an immune response that's specific to the virus and no harmful reactions, Phase 2 trials can begin.

• Phase 2 (II). Big questions: Does it cause a specific immune response? What dose is best?

  This phase involves more volunteers—usually thousands. Often, Phase 2 is carried out over time as multiple smaller studies with 100 or so volunteers each. These trials help to sort out how much vaccine to use, the number and timing of doses (schedule), and how to give the dose (e.g., injection, oral, nasal). Volunteers are divided into groups where these factors are varied. Then researchers compare the immune responses and any side effects within and between groups. They look for a dose and schedule that gives a strong, specific, and consistent immune response while causing minimal side effects.

  Vaccines can be approved only for use in the people they’ve been tested in. For example, if your vaccine will eventually be given to children, you might test it first in adults. But then you would also have to test it in children.

• Phase 3 (III): Are there very rare side effects? Does it protect people in their communities?

  This phase involves thousands or tens of thousands of volunteers. After stage 2, there’s enough data to show that the vaccine is generally safe. With more participants, there’s a better chance to observe any very rare side effects that may appear, like allergic reactions. It’s important to identify any possible side effects during testing. That way, the vaccine’s risks and benefits can be properly weighed. And if the vaccine is later given to millions of people, patients and doctors can know what to look for and what treatments could help in the very rare cases where serious side effects occur.

  Phase 3 studies are usually set up as a randomized controlled trial (RCT), though some studies use other designs. In an RCT, volunteers are randomly assigned to get either the vaccine or a placebo. The placebo could be a saline solution or a different vaccine. Importantly, volunteers don’t know which treatment they’re getting. Volunteers go about their lives as they normally would. By comparing how many people in each group get the infection, researchers can calculate how well the vaccine protects people. (It can take a while, like years, for the efficacy information to come in, especially with an infection that isn’t all that common.)

Only 6% of vaccine candidates that have started clinical trials have made it all the way to approval. That means only the safest and most effective vaccines make it to broad use. Still, approval does not mean the end of oversight!

• Manufacturing and distribution

  Even after production methods are approved, there are some logistics to sort out. Often vaccines need to be scaled up to make doses for hundreds of millions of people. If multiple doses are needed for full protection, this may mean making billions of doses, which all need to be packaged and distributed. Vaccine production facilities need regular inspections to make sure they’re following all the proper guidelines. And every batch has to go through testing for quality control.

• Phase 4 (IV) trials

  Some vaccine makers choose to conduct voluntary Phase 4 trials. These studies look at things like how long protection lasts and whether there are longer-term effects (these are very rare).

• Public surveillance programs

  Most countries have programs to monitor the number of people who receive vaccines, as well as the number of vaccine-preventable infections. From this data, health officials can get an idea of how effective vaccination programs are at achieving herd immunity or how well they protect vulnerable groups.

  Through the Vaccine Adverse Event Reporting System (VAERS), anyone in the US can report an effect they think may be a result of the vaccine. Reports go to the Centers for Disease Control for follow-up. (You can find it at vaers.hhts.gov)