The vaccine is a generic term for various biological products containing antigenic substances that induce specific active immunity in humans. In preclinical studies of vaccine, it is crucial to examine the safety of vaccines by performing preclinical safety evaluations with relevant animals. Drug safety evaluation in preclinical studies of new medicines refers to the use of greater than clinical doses or more prolonged than clinical dosing times to administer drugs to animals to discover and evaluate the potential toxic effects on the animal organism, the manifestations of toxicity, and the reversibility of target organ damage. This study helps to find toxic doses, detect harmful effects, determine safe dose ranges, search for unhealthy target organs, and assess the reversibility of toxicity.
The difficulty of drug safety evaluation in vaccines is that the vaccine does not directly exert preventive or therapeutic effects but acts by inducing the immune system to produce antibodies or activate T cells. Medicilon is a preclinical CRO that specializes in providing customizable preclinical trial service solutions with expertise in drug metabolism, pharmacokinetics, pharmacodynamic studies, and toxicology. Provides clients with high-quality data and fast turnaround times to support various drug development, preclinical and clinical studies.
We need to consider the safety issues that may arise in vaccine development.
1,What are the possible safety problems of vaccines?
(1) Direct damage to the organism by the vaccine component as a toxic substance.
For chemical drugs, the toxic effects of the substance are the main safety concern. Since the immunization dose of vaccines is usually low, and the number of immunizations is small, the direct toxic effects of vaccine components are rare and easy to be suggested from acute toxicity tests.
(2) Immune-related toxicity caused by the vaccine-induced immune system.
These include immunotoxicity related to the vaccine's immunostimulatory effect and the vaccine's stimulatory effect on the existing immune response in the organism. Preclinical safety evaluation of new drugs may reveal the former through testing of relevant animals, but for the latter, preclinical animal testing cannot be predicted due to the lack of suitable animal models.
(3) Toxicity due to contaminants and residual impurities.
Various aspects of the process of vaccine preparation have the potential to introduce contaminants or cause the presence of residual impurities, and control of such toxicity is also a significant objective of quality control studies.
(4) If the vaccine vector mutates in vivo, it will threaten the patient's life.
(5) Other unknown toxicity.
2, Toxicological tests in the preclinical study of new vaccine drugs
(1)Acute Toxicity Test
In principle, all new active ingredients should be implemented in this test, and more than two kinds of animals should be selected, emphasizing mastering the symptoms of poisoning and changes over time and dose-response relationships and not necessarily requiring the determination of LD50. The primary purpose of the acute toxicity test is to examine the direct damage of the vaccine component as a toxic substance to the organism, so the toxicity test does not necessarily require using relevant animals.
(2) Repeated dosing toxicity test
It is the core part of vaccine safety evaluation, and the leading idea of its test design is to simulate the clinical immunity effect of humans as much as possible. The test should select relevant animals as test animals, the route of administration should affect the clinical route of administration as far as possible, and the immunization interval is generally determined according to the time of immune response of animals.
(3) General pharmacological test
Conventional general pharmacological tests do not apply to vaccines, and the detection of relevant indexes of available pharmacological tests is established in repeated dosing tests.
(4) Reproductive toxicity test
The FDA believes that all vaccines used in adolescents, adults, and women who may become pregnant should undergo reproductive toxicity testing and that vaccines used in pregnant women should be completed before clinical studies. Vaccines intended for use in women who may become pregnant can provide reproductive toxicity testing information when they are declared for production. Still, subjects should use contraception during the clinical study.
(5) Allergy testing
Allergic reactions are most common in vaccine clinics. However, how to predict allergic reactions to biological products, including vaccines, through preclinical animal testing is a major problem faced by toxicologists and drug review authorities. Active systemic allergic reaction (ASA) and passive skin allergy test (PCA) in guinea pigs are commonly used in China to predict the likelihood of clinically induced allergic reactions to compounds or biological products. In addition, the mouse local lymph node assay (LLNA) is a test method that has the potential to be used to predict allergic reactions in humans, which has received more attention in foreign studies in recent years.
(6) Adjuvants
Adjuvants are used to improve the immunogenicity of non-replicating inactivated vaccines, to enhance the immune response in low-response populations, to improve the immunogenicity of vaccines administered via the mucosal route, and to modulate inappropriate immune responses, thereby improving protective immunity. The use of adjuvants can reduce the cost by reducing the amount of antigens used. Aluminum salt adjuvant is the most widely used class of adjuvants. In addition, it has been found that many active ingredients of traditional Chinese medicine (such as glycosides and polysaccharides) have sound immunomodulatory effects, among which QS-21 and ISCOM have entered clinical trials. Also, Huang Zhi polysaccharide (APS) has shown good application prospects.
There are different opinions on the preclinical safety evaluation of new adjuvants in the international arena. One believes that conventional toxicological tests of adjuvants should be conducted before the safety evaluation of vaccines, and the other believes that when adjuvants and antigens are used in combination, their physicochemical properties or biological activities are different from those when they are used alone, so it is not practical to conduct conventional toxicological studies of adjuvants independently.
Since vaccines are essentially a particular class of drugs administered to healthy people, most of which are used in healthy children, the consideration of safety is critical during their study.