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Study on Infection Animal Model and Mucosal Adjuvant for the Development of Hand-Foot-Mouth Disease Vaccine

초록/요약

Hand-foot-mouth disease (HFMD) is a viral infectious disease that occurs in children under 5 years of age. It is highly contagious and is mainly spread through direct contact with saliva, bodily fluids, or feces. HFMD shows symptoms such as a blistering rash around the hands, feet, and mouth. The main causes of HFMD are coxsackievirus A16 (CVA16) and enterovirus71 (EV71). CVA16 is the most important causative virus and in severe cases causes myocarditis and pneumonia in adults. Enterovirus is the second major causative virus and has a lower incidence than coxsackievirus, but in severe cases, it leads to central nervous system infection and death. The EV71 C4a, a dominant sub-genotype in Korea, China, and Taiwan, has the disadvantage of not infecting wild-type mice. To overcome these drawbacks, hSCARB2 transgenic mice were used. Monovalent and bivalent antisera effectively protected against EV71 C4a and CVA16 infection, and high-dose bivalent antiserum showed 100% survival against both viruses. Monovalent and bivalent antisera reduced brainstem viral RNA in EV71 C4a infection and decreased brainstem and muscle viral RNA in the CVA16 virus. Mongolian gerbils were used to confirm the protective ability against viral infection by active immunity after vaccination. Mongolian gerbils were vaccinated bivalently with a mixture of inactivated EV71 and inactivated CVA16. As a result of antibody production and cytokine analysis after vaccination, antigen-specific IgG production was effectively induced, and cytokine levels were also increased at high doses. Bivalent vaccination protected against EV71 C4a and CVA16 virus infection in a dose-dependent manner. In addition, because of confirming viral RNA in the brainstem, muscle, heart, and spleen, all immunization groups significantly decreased, and tissue staining also alleviated heart and muscle damage in a dose-dependent manner. Because enteroviruses are primarily transmitted via the fecal-oral route and target the gastrointestinal epithelium, the development of mucosal vaccines has also been attempted. The first line of defense, the mucosal surface in contact with the external environment, protects the body from infection by various microorganisms. Injectable vaccines also induce T cell immune responses and systemic immunity that produces serum IgG, but mucosal immunity by mucosal vaccines also induces various mucosal immune responses, including systemic immunity and secretory IgA. Curdlan, a 1-3- glucan, exhibits potent immunostimulatory effects when delivered as a vaccine adjuvant. Concomitant administration of curdlan and OVA increased the production of OVA-specific IgG and IgA antibodies in serum and mucosal secretions. In addition, differentiation of OVA-specific Th1/Th17 cells was induced. Intranasal administration of enterovirus recombinant VP1 protein mixed with curdlan induced a VP1-specific Th17 immune response. Antiserum mixed with VP1 and curdlan effectively protected against EV71 C4a infection. In Mongolian gerbils, intranasal administration of VP1 and curdlan effectively protected against EV71 C4a infection. It also reduced viral titers in muscle, brainstem, and spleen, and prevented muscle damage. In this study, hSCARB2 transgenic mice and Mongolian gerbils were used as animal models for the development of a vaccine for HFMD. It was confirmed that infection of EV71 C4a and CVA16 was protected by passive immunization in hSCARB2 transgenic mice. Mongolian gerbils were used to induce active immunity by vaccination. Antibody production and cytokine production were effectively induced in Mongolian gerbils when the bivalently inactivated virus was vaccinated.

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목차

Introduction 1
1. Hand-foot-mouth disease (HFMD) 1
2. Enterovirus and Coxsackievirus 1
3. HFMD vaccine 2
4. Enterovirus life cycle 3
5. Human scavenger receptor B2 transgenic mice and Mongolian gerbil 5
6. Mucosal immunity 5
7. Vaccine adjuvant 6
8. Curdlan 7
9. Purpose of the study 9
Materials and Methods 10
1. Animal 10
2. Virus challenge in hSCARB2 transgenic mice 10
3. Virus challenge after Mongolian gerbil immunization 11
4. Curdlan immunization in mice 11
5. Antibody analysis 12
6. Cytokine analysis 13
7. Viral RNA determination 13
8. Histology 14
9. Statistics 14
Results 16
Part I. Efficacy evaluation model for HFMD vaccine development 16
1. Monovalent antisera effectively protect against EV71 C4a infection. 16
2. Monovalent antisera reduce viral titers in the brainstem in EV71 C4a infection. 22
3. Bivalent antisera protect against both EV71 C4a and CVA16 infections. 32
4. In Mongolian gerbils, bivalent inactivation vaccination induces antibody production and T cell
immune responses. 42
5. Bivalent inactivated vaccines effectively protect against EV71 C4a and CVA16 infections. 48
6. Bivalent vaccination prevents tissue damage caused by viral infection. 53
Part II. Effect of curdlan as mucosal adjuvant in mucosal vaccine 63
1. Curdlan increases systemic and mucosal antigen-specific antibody production. 63
2. The intranasal route by mixing OVA with curdlan increases antigen-specific Th1 and Th17
immune responses. 66
3. Curdlan can enhance VP1-specific Th17 cell immunity. 69
4. Intranasal combination of VP1 and curdlan protects against EV71 C4a infection. 72
5. Immunization with a mixture of VP1 and curdlan protects Mongolian gerbils against EV71 C4a infection. 74
Discussion 79
Conclusion 83
Reference 85

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