A vaccine trial is a clinical trial that aims at establishing the safety and efficacy of a vaccine prior to it being licensed.
Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial – their approval does not mean that the therapy is 'safe' or effective, only that the trial may be conducted.
Vaccine efficacy is the percentage reduction of disease in a vaccinated group of people compared to an unvaccinated group, using the most favorable conditions. Vaccine efficacy was designed and calculated by Greenwood and Yule in 1915 for the cholera and typhoid vaccines. It is best measured using double- blind, randomized, clinical controlled trials, such that it is studied under “best case scenarios.” Vaccine effectiveness differs from vaccine efficacy in that vaccine effectiveness shows how well a vaccine works when they are always used and in a bigger population whereas vaccine efficacy shows how well a vaccine works in certain, often controlled, conditions. Vaccine efficacy studies are used to measure several possible outcomes such as disease attack rates, hospitalizations, medical visits, and costs.
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.
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 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.
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms. Pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence dosing, benefit, and adverse effects. Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference.
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models.
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).
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents. Adjuvants may be added to a vaccine to boost the immune response to produce more antibodies and longer-lasting immunity, thus minimizing the dose of antigen needed. Adjuvants may also be used to enhance the efficacy of a vaccine by helping to modify the immune response to particular types of immune system cells: for example, by activating T cells instead of antibody-secreting B cells depending on the purpose of the vaccine. Adjuvants are also used in the production of antibodies from immunized animals. There are different classes of adjuvants that can push immune response in different directions, but the most commonly used adjuvants include aluminum hydroxide and paraffin oil.
In biology, a pathogen, in the oldest and broadest sense, is anything that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ.
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.
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly. Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance. The ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region, which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.
A statistic (singular) or sample statistic is a single measure of some attribute of a sample. It is calculated by applying a function to the values of the items of the sample, which are known together as a set of data.
A statistical hypothesis, sometimes called confirmatory data analysis, is a hypothesis that is testable on the basis of observing a process that is modeled via a set of random variables. A statistical hypothesis test is a method of statistical inference. Commonly, two statistical data sets are compared, or a data set obtained by sampling is compared against a synthetic data set from an idealized model. A hypothesis is proposed for the statistical relationship between the two data sets, and this is compared as an alternative to an idealized null hypothesis that proposes no relationship between two data sets. The comparison is deemed statistically significant if the relationship between the data sets would be an unlikely realization of the null hypothesis according to a threshold probability—the significance level. Hypothesis tests are used when determining what outcomes of a study would lead to a rejection of the null hypothesis for a pre-specified level of significance.
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.
In biology, immunity is the balanced state of multicellular organisms having adequate biological defenses to fight infection, disease, or other unwanted biological invasion, while having adequate tolerance to avoid allergy, and autoimmune diseases.
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 (~hundreds of people) to determine reactions in a more diverse set of humans and test different schedules.
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 are typically monitor stages that collect information continuously on vaccine usage, adverse effects, and long-term immunity.
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.
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.
An HIV vaccine may have the purpose of protecting individuals who do not have HIV from being infected with the virus, or treating an HIV-infected person. There are two approaches to an HIV vaccine: an active vaccination approach in which a vaccine aims to induce an immune response against HIV; and a passive vaccination approach in which preformed antibodies against HIV are administered.
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.
This is a list of AIDS-related topics, many of which were originally taken from the public domain U.S. Department of Health Glossary of HIV/AIDS-Related Terms, 4th Edition.
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug.
Cutter Laboratories was a family-owned pharmaceutical company located in Berkeley, California, founded by Edward Ahern Cutter in 1897. Cutter's early products included anthrax vaccine, hog cholera virus, and anti-hog cholera serum—and eventually a hog cholera vaccine. The hog cholera vaccine was the first tissue culture vaccine, human or veterinary, ever produced. The company expanded considerably during World War II as a consequence of government contracts for blood plasma and penicillin. After Edward Cutter's death, his three sons—Dr. Robert K. Cutter (president), Edward "Ted" A. Cutter, Jr. (vice-president), and Frederick A. Cutter—ran the company. In the next generation Robert's son David followed his father as president of the company. The Bayer pharmaceutical company bought Cutter Laboratories in 1974.
Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human and other animal. In other words, immunogenicity is the ability to induce a humoral and/or cell-mediated immune responses.
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 are clinical trials concerning H5N1 vaccines, which are intended to provide immunization to influenza A virus subtype H5N1. They are intended to discover pharmacological effects and identify any adverse reactions the vaccines may achieve in humans.
Malaria vaccine is a vaccine that is used to prevent malaria. The only approved vaccine as of 2015 is RTS,S. It requires four injections, and has a relatively low efficacy. Due to this low efficacy, WHO does not recommend the use of RTS,S vaccine in babies between 6 and 12 weeks of age.
GeoVax is a biotechnology company established primarily to develop an effective and safe vaccine against HIV-1. Ultimately the company is to create vaccines for many serious human diseases for which none currently exist. GeoVax is currently conducting multiple site Phase 2 Human clinical trials for HIV/AIDS preventative vaccine products following successful completion of multiple Phase 1 human clinical trials.
HEPACIVAC stands for “New preventative and therapeutic Hepatitis C vaccines: from pre-clinical to phase 1”. HEPACIVAC is a project of the EU 6th Framework Programme.
The phases of clinical research are the steps in which scientists do experiments with a health intervention in an attempt to find enough 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.
Dengue vaccine is a vaccine to prevent dengue fever in humans. The World Health Organization recommends that countries should consider vaccination with the dengue vaccine CYD-TDV only if the risk of severe dengue in seronegative individuals can be minimized either through pre-vaccination screening or recent documentation of high seroprevalence rates in the area. In 2017 the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection, as outcomes may be worsened in those who have not been previously infected. This has caused a scandal in the Philippines where more than 733,000 children and more than 50,000 adult volunteers were vaccinated regardless of serostatus.
Ebola vaccine candidates against Ebola have been developed in the decade prior to 2014, but none have yet been approved for clinical use in humans. Several promising vaccine candidates have been shown to protect nonhuman primates against lethal infection.
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.
BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. It interacts with the human endocannabinoid system. The drug was in development for the treatment of a range of different medical conditions from anxiety disorder to Parkinson's disease, also for the treatment of chronic pain of multiple sclerosis, cancer, hypertension or the treatment of obesity. A clinical trial with this drug was underway in Rennes, France, in January 2016, in which serious adverse events occurred affecting five participants, including the death of one man. The underlying mechanism that caused the acute neurotoxicity of this molecule remains unknown.
A Zika virus vaccine is designed to prevent the symptoms and complications of Zika virus infection in humans. As Zika virus infection of pregnant women may result in congenital defects in the newborn, the vaccine will attempt to protect against congenital Zika syndrome during the current or any future outbreak. As of July 2018, no vaccines has been approved for clinical use, however a number of vaccines are currently in clinical trials. The goal of a Zika virus vaccine is to elicit protective antibodies against the Zika virus to prevent infection and severe disease. The challenges in developing a safe and effective vaccine include limiting side effects such as Guillain-Barré syndrome, a potential consequence of Zika virus infection. Additionally, as dengue virus is closely related to Zika virus, the vaccine needs to minimize the possibility of antibody-dependent enhancement of dengue virus infection.