A vaccine candidate drug is first identified through preclinical evaluations that could involve high throughput screening and selecting the proper antigen to invoke an immune response. The preclinical stages are also necessary to determine approximate dose ranges and proper drug formulations (i.e., tablet, injection etc…) This is also the stage in which the drug candidate may be first tested in laboratory animals prior to moving to the phase one trials. Vaccines such as the oral polio vaccine have been first tested for adverse effects and immunogenicity in monkeys as well as non-human primates. Recent scientific advances have helped to use transgenic animals as a part of vaccine preclinical protocol in hopes to more accurately determine drug reactions in humans. Understanding vaccine safety and the immunological response to the drug, such as toxicity, are necessary components of the preclinical stage. Other drug trials focus on the pharmacodynamics and pharmacokinetics; however, in vaccine studies it is essential to understand toxic effects at all possible dosage levels and the interactions with the immune system.
Phase One Trials
The following stage in vaccine trials is the phase one study, which consists of introducing the drug into the human population.
A vaccine trial might involve forming two groups from the target population. For example, from the set of trial subjects, each subject may be randomly assigned to receive either a new vaccine or a "control" treatment: The control treatment may be a placebo, or an adjuvant-containing cocktail, or an established vaccine (which might be intended to protect against a different pathogen).
After the administration of the vaccine or placebo, the researchers collect data on antibody production, on health outcomes (such as illness due to the targeted infection or to another infection). This data is summarized as a statistic, which is used to estimate the protective efficacy of the vaccine. Then, following the trial protocol, the specified statistical test is performed to gauge the statistically significant of the observed differences in the outcomes between the treatment and control groups.
Side effects of the vaccine are also noted, and these too contribute to the decision on whether to license it.
One very typical version of phase one studies in vaccines involves an escalation study, which is used in mainly medicinal research trials. The drug is introduced into a small cohort of healthy volunteers. Vaccine escalation studies aim to minimize chances of serious adverse effects (SAE) by slowly increasing the drug dosage or frequency. The first level of an escalation study usually has two or three groups of around 10 healthy volunteers. Each subgroup receives the same vaccine dose, which is the expected lowest dose necessary to invoke an immune response (the main goal in a vaccine - to create immunity). New subgroups can be added to experiment with a different dosing regimen as long as the previous subgroup did not experience SAEs. There are variations in the vaccination order that can be used for different studies. For example, the first subgroup could complete the entire regimen before the second subgroup starts or the second can begin before the first ends as long as SAEs were not detected. The vaccination schedule will vary depending on the nature of the drug (i.e. the need for a booster or several doses over the course of short time period). Escalation studies are ideal for minimizing risks for SAEs that could occur with less controlled and divided protocols.
Phase Two Trials
The transition to phase two relies on the immunogenic and toxicity results from phase one and the small cohort of healthy volunteers. Phase two will consist of more healthy volunteers in the vaccine target population (~100s of people) to determine reactions in a more diverse set of humans and test different schedules.
Phase Three Trials
Similarly, phase three trials continue to monitor toxicity, immunogenicity, and SAEs on a much larger scale. The vaccine must be shown to be safe and effective in natural disease conditions before being submitted for approval and then general production. In the United States, the Food and Drug Administration (FDA) is responsible for approving vaccines.
Phase Four Trials
Phase four trials are typically monitor stages that collect information continuously on vaccine usage, adverse effects, and long-term immunity.
Methodological issues and problems
Vaccine trials may take months or years to complete, since a sufficient time period must elapse for the subjects to react to the vaccine and develop the required antibodies.
Vaccine Trial Regulation Errors
Poliomyelitis, a viral disease, has the potential to damage the central nervous system and leave children paralyzed. Jonas Salk developed an attenuated vaccine to combat the rising prevalence of the disease around the world. In 1955 the results from the preliminary trial of Salk’s vaccine were announced to the general public and within 2 hours it was licensed. Due to a lack of regulations on pharmaceutical manufacturers the vaccine was not always as pure as possible or done correctly to prevent adverse effects associated with inserting an attenuated virus into a healthy person. The famous Cutter Incident resulted in many recipients of the defective polio virus from the Cutter company contracting a virulent strain of polio causing paralysis. Vaccine trials and manufacturing must be handled with extreme caution to avoid infecting recipients or causing adverse effects. The public has not returned to the same confidence level in science and vaccines since the Cutter Incident, which risks public health for everyone.
- Halloran, M. Elizabeth; Longini, Ira M., Jr.; Struchiner, Claudio J. (2010). Design and analysis of vaccine studies. Statistics for biology and health. New York: Springer. pp. xviii+387. ISBN 978-0-387-40313-7. MR 2572061.
- World Health Organization. (2012). Standard Operating Procedure: Neurovirulence test of types 1, 2, or 3 live attenuated poliomyelitis vaccines (oral) in transgenic mice susceptible to poliovirus. Retrieved November 10, 2015, from http://www.who.int/biologicals/vaccines/TgmNVT_SOPv6_Final_09112012.pdf
- Saul, A. (2005). Models of phase 1 vaccine trials: Optimization of trial design to minimize risk of multiple serious adverse events. Vaccine, 23, 3068–3075. http://doi.org/10.1016/j.vaccine.2004.10.048
- Bloom, B. R., & Lambert, P. H. (2003). The Vaccine Book. Academic Press. Retrieved from https://books.google.com/books?id=D0QW31ivHcwC&pgis=1
- Research, Center for Biologics Evaluation and. "Biologics License Applications (BLA) Process (Biologics) - Vaccine Product Approval Process". www.fda.gov. Retrieved 2015-11-15.
- Blume, S. S. (2004). "Lock in, the state and vaccine development: Lessons from the history of the polio vaccines". Research Policy. 34: 159–173. doi:10.1016/j.respol.2004.12.001.
- Vaccine Research Center Information regarding preventative vaccine research studies