Safety and immunogenicity of the first Kazakh inactivated vaccine for COVID-19

Abstract

This article describes the results of a preclinical safety and immunogenicity study of QazCovid-in®, the first COVID-19 vaccine developed in Kazakhstan, on BALB/c mice, rats, ferrets, Syrian hamsters and rhesus macaques (Macaca mulatta). The study's safety data suggests that this immunobiological preparation can be technically considered a Class 5 nontoxic vaccine. The series of injections that were made did not produce any adverse effect or any change in the general condition of the model animals' health, while macroscopy and histology studies identified no changes in the internal organs of the BALB/c mice and rats. This study has demonstrated that a double immunization enhances the growth of antibody titers as assessed by the microneutralization assay (MNA) and the enzyme-linked immunosorbent assay (ELISA) in a pre-clinical immunogenicity test on animal models. The best GMT results were assessed in MNA and ELISA 7 days after re-vaccination; however, we noted that GMT antibody results in ELISA were lower than in MNA. A comparative GMT assessment after the first immunization and the re-immunization identified significant differences between model animal groups and a growth of GMT antibodies in all of them; also, differences between the gender groups were statistically significant. Moreover, the most marked MNA immune response to the QazCovid-in® vaccine was seen in the Syrian hamsters, while their SARS-CoV-2-specific antibody activity as assessed with ELISA was the lowest.

Keywords: COVID-19; immunogenicity; preclinical trials; safety; toxicity; vaccine.

Figure 1.

Process flowchart in the sub-acute toxicity study.

Figure 2.

An analysis of body weight changes in BALB/c mice and rats before and 14 days after immunization. Body weight change (g) of vaccinated BALB/c mice (a). Body weight change (g) of vaccinated rats (b). The observation period was 14 days; the standard deviations (SD) for the mean body weight values of the groups are presented as error bars. CG: control group, EG: experimental group.

Figure 3.

An analysis of change in the percentage deviation of the body weight (g) in the study of sub-acute toxicity of the QazCovid-in® in animals that received the vaccine IM. The observation period totaled 7 days, and the standard deviations (SD) for the mean percent deviation of body weight values of the groups are presented as error bars. CG – control group, EG – experimental group.

Figure 4.

Typical histological structure of various organs (HE x 200). Normal histology of vaccinated groups (a). Liver, regular histological structure; (b). Kidney, regular histological structure; (c). Lung, regular histological structure; (d). Heart, regular histological structure; (e). Spleen, regular histological structure. Control group #1 (a). Hepatic tissue of a healthy rat; (b). Renal tissue of a healthy rat; (c). Lung tissue of a healthy rat; (d). Cardiac tissue of a healthy rat; (e). Spleen tissue of a healthy rat.

Figure 5.

Typical pathological results (HE x 200). №6 Experimental group. (a) Vascular congestion; hepatocyte dystrophy and necrocis microfoci; (b). Kidney vascular congestion; microfoci of tubule epithelium dystrophy (c). Focal proliferation of interalveolar septum cells in lungs; (d). Cardiac edema and hemorrhages; (e). Lymphoid follicle proliferation with hemorrhage microfoci.

Figure 6.

Body temperature of macaques immunized with QazCovid-in®, an inactivated COVID-19 vaccine. An analysis of change in body weight and temperature of re-vaccinated rhesus macaques (Macaca mulatta). An analysis of daily readings of body temperatures in macaques (with standard deviation) of the test and control groups for 14 days after the first (a) and second (b) vaccination did not identify any deviations from normal values. The observation period totaled 14 days, and the standard deviations (SD) for mean values of body temperature in groups are provided as error bars.

Figure 7.

Antibody response in vaccinated BALB/c mice, Syrian hamsters, ferrets and rhesus monkeys (Macaca mulatta). The GMT of antibody against QazCovid-in® determined by MNA (a) and ELISA (b). An analysis of GMT using Dunnett’s Multiple Comparisons Test with a confidence interval of 95% after the first and second immunization identified statistically significant differences between experimental and control group given commercial PBS (** = p < .0002, *** = p < .001). The bars show of increase of antibodies at observation days in both gender groups. At 14, 21 days after first vaccination and 7 days following the re-vaccination no specific antibodies to saline were detected.