Department of Biotechnology, Faculty of Applied Sciences, AIMST University, Semeling 08100, Kedah, Malaysia.
Unit of Pharmacology, Faculty of Pharmacy, AIMST University, Semeling 08100, Kedah, Malaysia.
Vaccine. 2019 Jan 29;37(5):711-720. doi: 10.1016/j.vaccine.2018.12.027. Epub 2019 Jan 7.
The repeated dose toxicity of a prototype cold chain-free, live, attenuated oral cholera vaccine containing 5 × 10 CFU/mL of the VCUSM14P strain was evaluated in Sprague Dawley (SD) rats (single dose administered daily for 30 days) to ascertain its safety for clinical use. Repeated dose toxicity studies for cholera vaccines in the literature have administered 2 or 3 fixed doses at 7, 14, 21 or 69 day intervals. The present study reports an evaluation of 30 repeated doses of cholera vaccine administered at three different concentrations (Group II (1.25 × 10 CFU), Group III (2.5 × 10 CFU) and Group IV (5 × 10 CFU)) in SD rats. The liquid vaccine was administered orally to the rats with the respective dose every day, and normal saline was administered to the control group (Group I). No significant difference (P > 0.05) was observed in the body weights and biochemical parameters of the rats after 15 and 30 repeated doses compared to those of the control group. However, compared to those of Group I, a significant increase (P < 0.05) in the organ to body weight ratios of the lungs, ureter, liver, kidney, heart and spleen was found in G-II, G-III and G-IV. In the haematological analysis, a significant increase in the WBC was observed in G-II and G-IV compared to that in G-I. The histopathological findings indicated mild to moderate degeneration in the liver, kidney, heart and spleen in the treated rats. Mild to moderate lymphocytic infiltration in the lungs was observed in the G-II and G-III rats, and severe infiltration was observed in the G-IV rats. These histopathological findings may be attributed to the 30 doses of vaccine given in daily succession without an interval. In the acute toxicity study, a single dose of vaccine up to 10 × 10 CFU did not cause any adverse effects and lethality in SD rats.
本研究旨在评估原型冷链免费、活、减毒口服霍乱疫苗的重复剂量毒性，该疫苗含有 5×10 CFU/mL 的 VCUSM14P 株，以确定其在临床应用中的安全性。文献中关于霍乱疫苗的重复剂量毒性研究，给予 2 或 3 个固定剂量，间隔 7、14、21 或 69 天。本研究报告了对 30 个不同浓度的霍乱疫苗重复剂量（第 II 组（1.25×10 CFU）、第 III 组（2.5×10 CFU）和第 IV 组（5×10 CFU））在 SD 大鼠中的评估。口服给予大鼠相应剂量的液体疫苗，对照组（第 I 组）给予生理盐水。与对照组相比，15 次和 30 次重复剂量后大鼠的体重和生化参数无显著差异（P>0.05）。然而，与第 I 组相比，第 II 组、第 III 组和第 IV 组的肺、输尿管、肝、肾、心和脾的器官体重比显著增加（P<0.05）。在血液学分析中，与第 I 组相比，第 II 组和第 IV 组的白细胞计数（WBC）显著增加。组织病理学检查结果表明，治疗组大鼠的肝、肾、心和脾有轻度至中度变性。第 II 组和第 III 组大鼠的肺有轻度至中度淋巴细胞浸润，第 IV 组大鼠有严重浸润。这些组织病理学发现可能归因于每天连续给予 30 剂疫苗而没有间隔。在急性毒性研究中，SD 大鼠单次给予高达 10×10 CFU 的疫苗不会引起任何不良反应和致死性。
