How to evaluate the preclinical safety of vaccines since they are different from common pharmaceutical products?

Vaccines have effectively controlled many infectious diseases, however, the adverse reactions following vaccination cannot be always avoided. Most adverse reactions are mild and localized, but some vaccines are associated with very rare but serious systemic reactions. Therefore, the production quality of vaccines is strictly controlled. Most of the common pharmaceutical products known to us are chemical drugs for which the safety tests form a system and thus will not be detailed here, while vaccines are subject to safety tests different from those for common drugs because vaccines are in various forms and mainly contain different protein components and nucleic acid components.

Firstly, in China, vaccines are manufactured according to the GMP at the factory, and vaccines are generally supplied by designated enterprises and hospital medical supply companies to prevent safety problems. Secondly, samples and internal test results of each batch of vaccines must be submitted to the national quality supervision authorities, etc. of China before the vaccines are marketed. Finally, some countries require routine animal safety testing so as to detect vaccine toxicity because residual toxicity may cause adverse reactions.

Two main types of vaccine safety evaluation, the first one being animal body weight change test

The first type is to examine the body weight changes of the vaccinated animals, as it is a very important indicator of vaccine safety. To screen for the general toxicity of vaccines, the body weight of animals treated with vaccines can be analyzed for general safety testing. Generally, the animals for screening are animals prone to allergy such as guinea pigs. The specific operational process is: inject 5 mL of the vaccine into the peritoneum of guinea pigs weighing 300-400 g and analyze their weight loss on days 1, 2, 3, 4 and 7 after administration. This method has been uniformly applied to various vaccines and plays an important role in ensuring the safety and consistency of vaccine batches. Besides the routine safety testing, the body weight gain toxicity test in mice is also used to measure the vaccine treatment effects. All mice are weighed on days 0, 1, 2, 3, 4 and 7 after vaccination. And the criterion is that three days after injection, the average body weight should not be less than that at the time of injection. The main principle thereof is that normal mice are growing continuously and their body weight is gradually increasing.

The second one being leukocytosis and leukopenia test

 The second type is to examine the toxicity to leukocytes in vaccinated animals. Generally, 0.5 ml of the vaccine is injected into the peritoneum of mice, and then the leukocytes present in the peripheral blood are counted three days after injection. The reference safety criterion for vaccines is that the mean count of leukocytes in the peripheral blood three days after injection should not exceed 10 times that before injection. On the contrary, for other vaccines that may have leukocyte toxicity, the leukopenia toxicity test may be conducted in vaccinated animals. Peripheral blood leukocytes are counted for mice 12-18 hours after intraperitoneal injection of the vaccine. The criterion is that the leukopenia toxicity of the test sample relative to the toxicity reference sample should not be higher than 80% of the leukocyte count of the toxicity reference sample. Such a test is for special vaccines that may reduce the leukocyte count, and most of the operation in this test is very similar to the above test.

Summary

In recent years, many animal testing methods to assess vaccine safety have been promoted, with the most important and widespread techniques including body weight change test and leukocyte counting test. However, routine animal safety testing methods need to be improved in many aspects, for example, the number of test animals needs to be further reduced, and the test time and period need to be shortened. This is especially true for some vaccines that are urgently needed for development, such as the COVID-19 vaccines. As the vaccines will be applied to a wide population and have huge final production, new and more efficient methods and techniques for safety control testing may need to be explored.