The immunogenicity and protection effect of an inactivated coxsackievirus A6, A10, and A16 vaccine against hand, foot, and mouth disease.

Coxsackievirus belongs to the Enterovirus genus of the Picornaviridae family and is one of the major pathogens associated with human hand, foot, and mouth disease (HFMD). Historically, outbreaks of HFMD have mainly been caused by enterovirus 71 and coxsackievirus A16. Recently, coxsackieviruses A6 and A10 have been associated with increased occurrences of sporadic HFMD cases and outbreak events globally. In this study, the immunogenicity of coxsackieviruses A6, A10, and A16 (CA6, CA10, and CA16), which were inactivated by formalin or ß-propiolactone (BPL) under different conditions, was evaluated as multivalent vaccine candidates. CA6 induced similar immune responses with both inactivation methods, and the immune efficacy of CA10 and CA16 was better following inactivation with BPL than with formalin. There was no sufficient cross-reactivity or cross-protectivity against heterologous strains in groups vaccinated with the BPL-inactivated (BI) monovalent vaccine. Sufficient neutralizing antibody and cell-mediated immune responses were induced in the BI-trivalent vaccinated group. These findings suggest that BI-CA6, CA10, and CA16 are potential multivalent vaccine candidates and that a multivalent vaccine is needed to control HFMD. The coxsackievirus multivalent vaccine could be useful for the development of effective HFMD vaccines.

Enhanced neutralizing antibody response induced by inactivated enterovirus 71 in cynomolgus monkeys.

Enterovirus 71 (EV71) is a major etiological agent of various public health issues, particularly in the Asia-Pacific region. EV71 causes hand-foot-and-mouth disease (HFMD) and is associated with serious neurological disorders in young children. A formalin-inactivated EV71 candidate vaccine (KCDC-HFMDV1-EV71) based on the C4 subgenotype was previously developed and confirmed to be a potential candidate vaccine for prevention of EV71 infection in mice. In this study, an inactivated EV71 vaccine was used for analysis of long-term immunogenicity and efficacy in cynomolgus monkeys, a common nonhuman primate model. The vaccine was immunized three times at 0, 4, and 8 weeks with either 20-µg doses of EV71 candidate vaccine formulated with aluminum hydroxide gel adjuvant or phosphate-buffered saline as a control. The group immunized with the inactivated EV71 showed significantly increased EV71-specific antibody and serum neutralizing antibody titers at 3 weeks after vaccination and maintained these elevated titers until the end of the experiment (54 weeks after vaccination). The sera from vaccinated cynomolgus monkeys showed a crossreactive neutralizing antibody response to the heterologous subtype of EV71 (B1-4, C1, and C2). These findings suggest that the inactivated EV71 candidate vaccine may be a potential vaccine candidate and valuable tool for the control of HFMD.

An inactivated hand-foot-and-mouth disease vaccine using the enterovirus 71 (C4a) strain isolated from a Korean patient induces a strong immunogenic response in mice.

Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD) frequently occurring in children. HFMD induced by EV71 can cause serious health problems and has been reported worldwide, particularly in the Asia-Pacific region. In this study, we assessed the immunogenicity of a formalin-inactivated HFMD vaccine using an EV71 strain (FI-EV71 C4a) isolated from a Korean patient. The vaccine candidate was evaluated in mice to determine the vaccination doses and vaccine schedules. BALB/c mice were intramuscularly administered 5, 10, or 20 µg FI-EV71 vaccine, followed by a booster 2 weeks later. EV71-specific antibodies and neutralizing antibodies were induced and maintained until the end of the experimental period in all vaccinated groups. To determine the effectiveness of adjuvant for the EV71 vaccine, three adjuvants, i.e., aluminium hydroxide gel, monophosphoryl lipid A, and polyinosinic-polycytidylic acid, were administered separately with the FI-EV71 vaccine to mice via the intramuscular route. Mice administered the FI-EV71 vaccine formulated with all three adjuvants induced a significantly increased antibody response compared with that of the single adjuvant groups. The vaccinated group with triple adjuvants exhibited more rapid induction of EV71-specific and neutralizing antibodies than the other groups. These results suggested that the role of adjuvant in inactivated vaccine was important for eliciting effective immune responses against EV71. In conclusion, our results showed that FI-EV71 was a potential candidate vaccine for prevention of EV71 infection.