https://orcid.org/0000-0001-7406-841X
Hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by an enterovirus. which mainly caused by coxsackievirus A16 (CA16) and enterovirus A71 (EV-A71). Children younger than five years are especially prone to HFMD. and those under 3 years are more susceptible to severe or fatal neurological diseases caused by EV-A71.Citation1–3 In 2016, three inactivated EV-A71 vaccines developed by Vigoo (Beijing, China), Sinovac (Beijing, China), and Kunming Institute (Kunming, China) were licensed in China, providing an alternative to previous approaches to prevent severe and fatal hand, foot, and mouth disease. With the development of a successful inactivated EV-A71 vaccine,Citation4 although the proportion of severe cases and mortality have decreased each year, the infection rate remains at a relatively high level and presents some new characteristics, such as the continuous emergence of severe cases caused by CA16 and patients with repeated infections.Citation5,Citation6 Also such as coxsackievirus A6 (CA6) and coxsackievirus A10 (CA10) infection have been increasing in HFMD cases both in China and worldwide in recent years.Citation7–9 So it is important to develop multivalent vaccines that can protect against multiple enterovirus serotypes.
In their study in The Human Vaccines & Immunotherapeutics, Yun Liao and colleaguesCitation10 skillfully tested preclinical safety evaluation of a bivalent inactivated EV71-CA16 vaccine in mice immunized intradermally. A total of 516 Specific pathogen-free (SPF) BALB/c mice were randomly divided into two groups; half of the mice in each group were male and half were female. The main experimental group was divided into five groups: the adjuvant control group was given 0.015 mg/ml Al(OH)3, and the negative control group was given 0.9% sodium chloride. Four satellite groups were used: the negative control group and the bivalent vaccine low-dose group (50 U), medium-dose group (100 U) and high-dose group (200 U), with 24 mice in each group (M 12/F 12). Tested indicators: clinical observation, body weight and food intake, hematological examination, serum biochemistry, CD3+ CD4+ and CD3+ CD8a+ T-cell detection, antinuclear antibody detection, neutralizing antibody detection, bone marrow smear examination, pathological examination, results were recorded. The results showed that there was no significant change at the injection site and no adverse reactions related to the vaccine.
According to guiding principles, the evaluation of nonclinical safety must be carried out before vaccines are applied in clinical trials, and repeated administration toxicity testing is one of the key studies.Citation11 Through repeated administration toxicity tests, the possible clinical adverse reactions caused by the vaccine can be predicted, including the dose effect and time-effect relationship.Citation12 Second, this test can also reveal the toxicity target organ or target tissue after repeated administration of the vaccine.Citation13 Moreover, it can also determine the initial dose for the first clinical trial and provide a safe dose range for clinical trials.Citation14 The results showed that there was no significant change at the injection site and no adverse reactions related to the vaccine.
It is very important for the further development of multivalent vaccines that the bivalent inactivated EV71-CA16 vaccine exhibits good safety in mice, and these results provide a sufficient basis for further clinical trials. Further, CA6 and CA10 vaccines should be taken mice trials.
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References
- Wang Y, Feng Z, Yang Y, Self S, Gao Y, Longini IM, Wakefield J, Zhang J, Wang L, Chen X, et al. Hand, foot, and mouth disease in China: patterns of spread and transmissibility. Epidemiology. 2011;22(6):781–2. doi: 10.1097/EDE.0b013e318231d67a.
- Zhang J, Sun J, Chang Z, Zhang W, Wang Z, Feng Z. Characterization of hand, foot, and mouth disease in China between 2008 and 2009. Biomed Environ Sci. 2011;24(3):214–21. doi: 10.3967/0895-3988.2011.03.002.
- Lee TC, Guo HR, Su HJ, Yang YC, Chang HL, Chen KT. Diseases caused by enterovirus 71 infection. Pediatr Infect Dis J. 2009;28(10):904–10. doi: 10.1097/INF.0b013e3181a41d63.
- Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, Zhang Y, Li Y, Mao Q, Wang J, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014;370(9):829–37. doi: 10.1056/NEJMoa1303224.
- Saguil A, Kane SF, Lauters R, Mercado MG. Hand-foot-and mouth disease: rapid evidence review. Am Fam Physician. 2019;100:408–14.
- Jia J, Kong F, Xin X, Liang J, Xin H, Dong L, Jiang F. Epidemiological characteristics of hand, foot, and mouth disease outbreaks in Qingdao, 2009–2018. Iran J Public Health. 2021;50(5):999–1008. doi: 10.18502/ijph.v50i5.6117.
- Li Y, Chang Z, Wu P, Liao Q, Liu F, Zheng Y, Luo L, Zhou Y, Chen Q, Yu S, et al. Emerging enteroviruses causing hand, foot and mouth disease, China, 2010–2016. Emerg Infect Dis. 2018;24(10):1902–6. doi: 10.3201/eid2410.171953.
- Bian L, Wang Y, Yao X, Mao Q, Xu M, Liang Z. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13(9):1061–71. doi: 10.1586/14787210.2015.1058156.
- Lu QB, Zhang XA, Wo Y, Xu HM, Li XJ, Wang XJ, Ding SJ, Chen XD, He C, Liu LJ, et al. Circulation of coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009–2011. PLoS One. 2012;7(12):e52073. doi: 10.1371/journal.pone.0052073.
- Liao Y, Jiang Q, Huo X, Yu L, Yang J, Zhao H, Li D, Xu X, Jiang G, Zhang C, et al. Preclinical safety evaluation of a bivalent inactivated EV71-CA16 vaccine in mice immunized intradermally. Hum Vaccin Immunother. 2023;19(1):2209472. doi: 10.1080/21645515.2023.2209472.
- CDE. 2008. (China). The general principles for the technical review of pre-clinical safety evaluation of biological products for prevention.
- Verdier F, Barrow PC, Burge J. Reproductive toxicity testing of vaccines. Toxicology. 2003;185(3):213–9. doi: 10.1016/S0300-483X(02)00611-X.
- Lebron JA, Wolf JJ, Kaplanski CV, Ledwith BJ. Ensuring the quality, potency and safety of vaccines during preclinical development. Expert Rev Vaccines. 2005;4(6):855–66. doi: 10.1586/14760584.4.6.855.
- Baldrick P. Dose site reactions and related findings after vaccine administration in safety studies. J Appl Toxicol. 2016;36(8):980–90. doi: 10.1002/jat.3314.