Vaccine trial

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A vaccine trial is a clinical trial that aims at establishing the safety and efficacy of a vaccine prior to it being licensed. [1]

Contents

Methodology

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. [2] 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. [2] 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 statistical significance 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. [3] 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. [3] 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. [4] Phase two will consist of more healthy volunteers in the vaccine target population (~hundreds 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. [4] 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. [5]

Phase Four Trials

Phase four trials are typically monitor stages that collect information continuously on vaccine usage, adverse effects, and long-term immunity. [5]

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. [6] 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. [6]

Related Research Articles

Polio vaccine Vaccine to prevent poliomyelitis

Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all children be fully vaccinated against polio. The two vaccines have eliminated polio from most of the world, and reduced the number of cases reported each year from an estimated 350,000 in 1988 to 33 in 2018.

Cytokine release syndrome (CRS) or cytokine storm syndrome (CSS) is a form of systemic inflammatory response syndrome that can be triggered by a variety of factors such as infections and certain drugs. It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies. Severe cases have been called cytokine storms. When occurring as a result of drug administration, it is also known as an infusion reaction.

Preclinical development Stage of drug development

In drug development, preclinical development, also named preclinical studies and nonclinical studies, is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data are collected.

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Influenza research

Influenza research involves investigating molecular virology, pathogenesis, host immune responses, genomics, and epidemiology regarding influenza. The main goal of research is to develop influenza countermeasures such as vaccines, therapies and diagnostic tools.

H5N1 clinical trials clinical trials of influenza vaccine

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Malaria vaccine

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Bilastine, sold under the brand name Bilaxten among others, is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria (hives).

The phases of clinical research are the steps in which scientists conduct experiments with a health intervention in an attempt to obtain sufficient evidence for a process which would be useful as a medical treatment. In the case of pharmaceutical study, the phases start with drug design and drug discovery then proceed on to animal testing. If this is successful, they begin the clinical phase of development by testing for safety in a few human subjects and expand to test in many study participants to determine if the treatment is effective.

Herpes simplex research includes all medical research that attempts to prevent, treat, or cure herpes, as well as fundamental research about the nature of herpes. Examples of particular herpes research include drug development, vaccines and genome editing. HSV-1 and HSV-2 are commonly thought of as oral and genital herpes respectively, but other members in the herpes family include chickenpox, cytomegalovirus (CMV), and Epstein-Barr (EBV). There are many more members that infect animals other than humans, some of which cause disease in companion animals or have economic impacts in the agriculture industry.

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cAd3-ZEBOV is an experimental vaccine for two ebolaviruses, Ebola virus and Sudan virus, developed by scientists at GlaxoSmithKline (GSK) and tested by National Institute of Allergy and Infectious Disease (NIAID). This vaccine is derived from a chimpanzee adenovirus, Chimp Adenovirus type 3 (ChAd3), genetically engineered to express glycoproteins from the Zaire and Sudan species of ebolavirus to provoke an immune response against them. Simultaneous phase 1 trials of this vaccine commenced in September 2014, being administered to volunteers in Oxford and Bethesda. During October the vaccine is being administered to a further group of volunteers in Mali. If this phase is completed successfully, the vaccine will be fast tracked for use in the Ebola virus epidemic in West Africa. In preparation for this, GSK is preparing a stockpile of 10,000 doses.

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References

  1. 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.
  2. 1 2 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
  3. 1 2 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
  4. 1 2 Bloom, B. R., & Lambert, P. H. (2003). The Vaccine Book. Academic Press. Retrieved from https://books.google.com/books?id=D0QW31ivHcwC&pgis=1
  5. 1 2 Research, Center for Biologics Evaluation and. "Biologics License Applications (BLA) Process (Biologics) - Vaccine Product Approval Process". www.fda.gov. Retrieved 2015-11-15.
  6. 1 2 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.