Making Vaccines: Process of Vaccine Development

Initial ideas

Vaccine development typically begins not at a pharmaceutical company, but in a research laboratory in a university, medical center or small biotech company. Scientists in these laboratories are most often funded by grants from the government or private foundations. These scientists often spend years researching whether their ideas work, developing reagents and tests to measure their success (or lack thereof), and finally, using animals to test their ideas. In some cases the ideas are tested in small animals like mice, rats or rabbits and then again in larger animals like monkeys.

During this time, several different scientists or groups of scientists may be working toward the same goals: developing a vaccine against a certain virus or bacteria. The progress of these scientists is evaluated by other scientists through presentations at scientific meetings and peer-reviewed papers in journals. Scientists working at pharmaceutical companies often attend these meetings and review journals to see what ideas seem to be working. If any of the work seems promising, the pharmaceutical scientists may approach those working on it about expanding their research toward product development. This process may take five to 10 years.

The great majority of university scientists never develop ideas that are turned into products — most enjoy the success of adding to the general body of knowledge that is science.

Phase I trials

Once an idea appears promising, it must be tested in a small number of healthy adults. These studies usually include less than 100 people and answer two main questions: does the vaccine generate the expected immune response and is the vaccine safe?

During Phase I trials, scientists at the pharmaceutical company must study how to make the vaccine in a quantity large enough for preliminary trials. They also must determine what preservatives or stabilizers to add so that the vaccine does not break down and whether any adjuvants are necessary to generate a strong enough immune response. Any preservatives, stabilizers or adjuvants that are going to be in the final vaccine must be used in the trials.

In addition, company personnel must develop tests that consistently show positive results when expected and negative results when expected, and they must complete an application to inform the Food and Drug Administration (FDA) of their intentions.

This phase often takes one to two years to complete.

Phase II trials

The next phase of trials involves several hundred people. During this phase, scientists try to determine the proper dose of vaccine to be given, and they continue to study the vaccine's safety. They also continue to define methods for manufacturing the vaccine, stabilizing the product, determining packaging vials, and establishing assays necessary for the trials. An important aspect of this phase is to establish manufacturing consistency, so that each lot comes out with similar results.

The manufacture of the vaccine must also be completed in the building that would be used to make the final product. The company must continue to keep the FDA apprised of its progress and results during this time. At any time during this process the company or the FDA can decide against continued development.

While Phase II trials can take as little as two years, it often takes much longer to complete all of the work necessary for this phase of development.

Phase III trials

This is the final stage of development before a company requests product licensing, and it takes three to four years to complete.

Studies in this phase of development include thousands of study participants who are similar to the population that will receive the vaccine (e.g., infants for a new infant product). The number of participants is calculated so that statistical differences between the experimental group and control group can be observed. These calculations depend on frequency of disease in the population, estimated participant dropout rates, and ability of the assays being used to show differences. For example, trials on the rotavirus vaccine (RotaTeq® and Rotarix®) required about 130,000 participants because the companies had to determine that these two vaccines did not cause a bowel obstruction caused by an older version of the vaccine (Rotashield®).

During this phase, the company must also continue working on final facility and assay specifications and study how long the vaccine can be used before it expires, taking into account how it will get to the users (doctors' offices, for example) and how it will be stored. Any testing sites (those recruiting patients or testing samples) must be monitored to ensure that protocols are being followed consistently. Samples must be collected and analyzed to study the participants' immune responses, whether they get the disease, and whether they suffer adverse reactions.

During these studies, as with the previous phases, no one working with the patients, testing the samples collected from patients, or calculating the results, knows which participants received the vaccine and which did not.

After completion of these studies, it takes another year and a half to two years for the company to review the data, complete the product license request, and launch the product. The FDA, which does site visits throughout the entire process, then takes about 10 months to further study the data before the product can be offered to the public.

After licensure, experts for the Centers for Disease Control and Prevention (CDC) will also review the data and determine who should be able to get the vaccine. This is essentially the third set of scientists reviewing the same data. Often, the company or healthcare providers who helped run the Phase III studies will also publish the results in a scientific journal for review by other scientists.

By the time the product is offered to the public, it has been studied for at least 15 to 20 years (sometimes longer) in tens of thousands of study participants, by thousands of scientists, statisticians, healthcare providers and other personnel, and has cost at least $1 billion dollars to produce. There are many products that never reach this stage. Companies are constantly evaluating a product during the trials to determine whether they are worth pursuing. Many ideas are abandoned during the different trial phases.

Phase IV (after licensure)

Once the vaccine begins to be distributed, additional studies occur. These studies are called Phase IV studies. Because some rare side effects may not have been detected in the Phase III trials, vaccine safety is continually monitored by the CDC. These studies take at least four forms:

  • First, the CDC will have certain health departments (usually in areas where there is a high occurrence of disease and hence, high vaccine distribution) monitor every person who receives the vaccine and report to it regularly.
  • Second, the CDC monitors disease that is reported to every health department in the country, so they will see if there are any abnormal occurrences of disease after the vaccine is introduced and consider whether the two events may be related.
  • Third, there is a Vaccine Adverse Event Reporting System (or VAERS). If a doctor, nurse or consumer believes that a person who received a vaccine had a significant negative side effect, he or she can file a report in this system, which is continuously monitored for trends in the data.
  • Fourth, the Vaccine Safety DataLink (VSD) includes about 6 million people in six large HMOs on the West Coast to look at who did and did not receive the vaccine and answer safety questions. The VSD is one of the most effective post-licensure measures we have.

These systems proved their utility in 1999 when a newly licensed rotavirus vaccine was found to be a rare cause of intussusception, a folding of the intestine into itself that may require emergency surgery and can result in death if untreated. Once the relationship was confirmed, use of that rotavirus vaccine was discontinued. A few years later, safer rotavirus vaccines were developed, and Phase III studies were of sufficient size to make sure these newer versions were not also causing intussusception.

Reviewed by Paul A. Offit, MD on November 20, 2014

Materials in this section are updated as new information and vaccines become available. The Vaccine Education Center staff regularly reviews materials for accuracy.

You should not consider the information in this site to be specific, professional medical advice for your personal health or for your family's personal health. You should not use it to replace any relationship with a physician or other qualified healthcare professional. For medical concerns, including decisions about vaccinations, medications and other treatments, you should always consult your physician or, in serious cases, seek immediate assistance from emergency personnel.