Evaluation of monovalent and bivalent vaccines against lethalEnterovirus71 andCoxsackievirusA16 infection in newborn mice

Abstract

Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) have caused severe epidemics of hand, foot and mouth disease (HFMD) in the Asia Pacific in recent years, particularly in infants and young children. This disease has become a serious public health problem, as no vaccines or antiviral drugs have been approved for EV71 and CA16 infections. In this study, we compared four monovalent vaccines, including formalin-inactivated EV71 virus (iEV71), EV71 virus-like particles (VLPs) (vEV71), formalin-inactivated CVA16 virus (iCVA16) and CVA16 VLPs (vCVA16), along with two bivalent vaccines, including equivalent doses of formalin-inactivated EV71CCVA16 virus (iEV71CiCVA16) and EV71CCVA16 VLPs (vEV71CvCVA16). The IgG titers and neutralization antibodies titers demonstrated that there are no immune interference exists between the two immunogens of EV71 and CVA16. IgG subclass isotyping revealed that IgG1 and IgG2b were induced primarily in all vaccine groups. Furthermore, cross-neutralization antibodies were elicited in mouse sera against other sub-genotypes of EV71 and CVA16. In vivo challenge experiments showed that the immune sera from vaccinated animals could confer passive protection to newborn mice against lethal challenge with 14 LD 50 of EV71 and 50 LD 50 of CVA16. Our results indicated that bivalent vaccination is promising for HFMD vaccine development. With the advantage of having a better safety profile than inactivated virus vaccines, VLPs should be used to combine both EV71 and CVA16 antigens as a candidate vaccine for prevention of HFMD virus transmission.

Is a multivalent hand, foot, and mouth disease vaccine feasible?

“…Passive transfer of immune sera conferred protection in newborn mice against lethal challenge with both viruses although bivalent VLPs vaccines were more potent than individual VLPs formulations. 174 Multivalent HFMD vaccines: the ultimate need, the ultimate goal…”

“…In this regard, the introduction of a protective bivalent EV-A71/CV-A16 vaccine on the market should markedly reduce the number of HFMD cases. [170][171][172][173][174] CV-A16 strains of the B genotype that have elicited both homologous and heterologous protection against genotypes A and B in pre-clinical studies are potential candidates for a multivalent HFMD vaccine. [166][167][168] The selection of CV-A6, CV-A10, CV-B3, CV-B5 and E-30 vaccine strains will have to be based on comprehensive epidemiological information to identify the most prevalent circulating genotype(s) for each enterovirus serotype.…”

“…Although inactivated poliovirus and EV-A71 vaccines have been successfully developed and inactivated CV-A16 candidate vaccines are very promising, there is some indication that VLP-based bivalent vaccines are more immunogenic than a combination of inactivated EV-A71/CV-A16 vaccines. 174 It is not clear at the present time whether the production yields for EV-A71 and other HFMDassociated viruses will be sufficient to meet global needs. The selection process for an ideal vaccine strains needs to be addressed in the light of comprehensive epidemiological surveys, the optimal technology to efficiently produce potent and safe immunogens must be defined for each serotype, and clinical trials will have to be conducted for each individual vaccine before combining them.…”

Immunogenicity and protective efficacy of an EV71 virus-like particle vaccine against lethal challenge in newborn mice

“…After purification by ultracentrifugation, the EV71 VLP or formalin-inactivated vaccine was used to immunize mice at a dose of 10 mg (VP1), which induced similar neutralization antibody titer and prevented EV71 infection in newborn mice. 18 Three inactivated EV71 vaccine candidates have been studied in detail on their immunogenicity and protective efficacy including ED 50 in newborn mice before entering the clinical trials. 19,20 ED 50 is a measure method to evaluate the potency of a preparation.…”

Human picornaviruses associated with neurological diseases and their neutralization by antibodies

“…Although studies of EV-A71 have already resulted in two CFDA-approved HFMD vaccines, multivalent HFMD vaccines to control different EV-A71 genotypes and also co-circulating CV-A16 are the next goal. The proof-of-concept studies for such vaccines are promising [148,178], but further work is needed to identify the optimal combination of antigens for balanced, broadly protective immunity. Targeting multiple viruses with a single vaccine also requires delivery systems for the effective presentation of multiple epitopes.…”