Overview of vaccine development

Overview of vaccine development.

The road a vaccine candidate has to follow in order to first be developed and produced while proving its safety and efficacy is long and quite bumpy. After many trials and errors, it usually takes 10 to 15 years for a vaccine to make it to full approval and public marketing. This long road before being produced for the public market is necessary to ensure that the cure is not worse than the disease.

  1. Laboratory and pre-clinical studies

The first stages are exploratory in nature. Regulation and oversight increase as the candidate vaccine makes its way through the process.

This is initiated when 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.

Pre-clinical studies is the first stage to assess the safety of the vaccine candidate. This involves studies using different tissue cultures to evaluate the immune response. Pre-clinical studies also involve animals in order to give researchers an idea of what to expect for human trials; this usually involve mice models and monkeys. The animals are often subjected to challenge trials where the animal is injected with the vaccine candidate i.e. target antigen( live, attenuated virus etc.),  followed by injection with the infectious agent. These trials help researchers to establish the starting dose as well of the safe method of administration to create acceptable protection. This first step is also called research and development. A decade ago this step would take between five to ten years. Nowadays, due to the advances in sciences and technologies a new vaccine candidates can make it through this pre-clinical stage within 1 to 3 years, but  many candidate vaccines will not go further due to negative results of preclinical trials.

  1. Next Steps: Clinical Studies with Human Subjects

Once the vaccine candidate has performed well in the preclinical they can pursue into the clinical trials in three phases

Phase I

The safety of the candidate vaccine is evaluated by giving it to a small group of young healthy adult  volunteers (20-80 subjects). The purpose of this step is to confirm the immune response in humans, evaluate the proper dosage and assess the safety of the candidate vaccine. A successful phase 1 trial establishes that it is safe for healthy individuals and enables the vaccine candidate to progress into phase 2 clinical trial.

Phase II

A larger group of several hundred individuals participates in Phase II testing to study safety, immunogenicity, proposed doses and method of delivery. This phase includes individuals at risk of acquiring the disease, mainly people for whom the vaccine candidate is intended for.  There could be many phase two trials to test different groups. These trials are randomized and well controlled, and include a placebo in that group that didn’t get the vaccine. This placebo group is very important, as it will make sure that any effect appearing in the vaccinated group is actually from the vaccine candidate injection.

Phase III

Successful Phase II candidate vaccines move on to larger trials, involving thousands to tens of thousands of people. These Phase III tests are randomized and double blind and involve the experimental vaccine being tested against a placebo (the placebo may be a saline solution, a vaccine for another disease, or some other substance).

The purpose of the phase III trials is to assess vaccine safety in a large group of people. Certain rare side effects might not surface in the smaller groups of subjects tested in earlier phases. For example, suppose that an adverse event related to a candidate vaccine might occur in 1 of every 10,000 people. To detect a significant difference for a low-frequency event, the trial would have to include 60,000 subjects, half of them in the control, or no vaccine, group (Plotkin SA et al. Vaccines, 5th ed. Philadelphia: Saunders, 2008). 

Vaccine efficacy is tested as well. These factors might include 1) Does the candidate vaccine prevent disease? 2) Does it prevent infection with the pathogen? 3) Does it lead to production of antibodies or other types of immune responses related to the pathogen?

Next Steps: Approval and Licensure

After a successful Phase III trial, the vaccine developer will submit a Biologics License Application to the FDA. Then the FDA will inspect the factory where the vaccine will be made and approve the labeling of the vaccine.

After licensure, the FDA will continue to monitor the production of the vaccine, including inspecting facilities and reviewing the manufacturer’s tests of lots of vaccines for potency, safety and purity. The FDA has the right to conduct its own testing of manufacturers’ vaccines.

Post-Licensure Monitoring of Vaccines

A variety of systems monitor vaccines after they have been approved. They include Phase IV trials, the Vaccine Adverse Event Reporting System, and the Vaccine Safety Datalink, this is often called pharmacovigilance.

Reference Paul Offit, MD, describes the general process of making a vaccine.
The College of Physicians of Philadelphia

Phase IV Trials

Phase IV trial are optional studies that drug companies may conduct after a vaccine is released. The manufacturer may continue to test the vaccine for safety, efficacy, and other potential uses.