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Primary varicella-zoster virus (VZV) infection causes varicella, which remains a prominent public health concern in children. Current varicella vaccines adopt the live-attenuated Oka strain, vOka, which retains the ability to infect neurons, establish latency and reactivate, leading to vaccine-associated zoster in some vaccinees. Therefore, it is necessary to develop a safer next-generation varicella vaccine to help reduce vaccine hesitancy. This paper reviews the discovery and identification of the skin- and neuro-tropic factor, the open reading frame 7 (ORF7) of VZV, as well as the development of a skin- and neuro-attenuated live varicella vaccine comprising an ORF7-deficient mutant, v7D. This work could provide insights into the research of novel virus vaccines based on functional genomics and reverse genetics. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) is a highly contagious disease that mainly affects infants and children. Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major pathogens of HFMD. Two EV71 vaccines were recently licensed in China and the administration of the EV71 vaccines is believed to significantly reduce the number of HFMD-related severe or fatal cases. However, a monovalent EV71 vaccine cannot cross-protect against CA16 infection, this may result in that it cannot effectively control the overall HFMD epidemic. In this study, a chimeric EV71, whose VP1/210–225 epitope was replaced by that of CA16, was constructed using a reverse genetics technique to produce a candidate EV71/CA16 bivalent vaccine strain. The chimeric EV71 was infectious and showed similar growth characteristics as its parental strain. The replacement of the VP1/210–225 epitope did not significantly affect the antigenicity and immunogenicity of EV71. More importantly, the chimeric EV71 could induce protective immunity against both EV71 and CA16, and protect neonatal mice against either EV71 or CA16 lethal infections, the chimeric EV71 constructed in this study was shown to be a feasible and promising candidate bivalent vaccine against both EV71 and CA16. The construction of a chimeric enterovirus also provides an alternative platform for broad-spectrum HFMD vaccines development. [ABSTRACT FROM AUTHOR]

Coxsackievirus A6 (CA6) can induce atypical hand, foot, and mouth disease, which is characterized by severe rash, onychomadesis and a higher rate of infection in adults. Increasing epidemiological data indicated that outbreaks of CA6-associated hand, foot, and mouth disease have markedly increased worldwide in recent years. However, the current body of knowledge on the infection, pathogenic mechanism, and immunogenicity of CA6 is still very limited. In this study, we established the first neonatal mouse model for the evaluation of antibodies and vaccines against CA6. The CA6 strain CA6/141 could infect a one-day-old BALB/c mouse through intraperitoneal and intracerebral routes. The infected mice developed clinical symptoms, such as inactivity, wasting, hind-limb paralysis and even death. Pathological examination indicated that CA6 showed special tropism to skeletal muscles and skin, but not to nervous system or cardiac muscles. Infections with CA6 could induce vesicles in the dermis without a rash in mice, and the CA6 antigen was mainly localized in hair follicles. The strong tropism of CA6 to the skin may be related to its severe clinical features in infants. This mouse model was further applied to evaluate the efficacy of a therapeutic antibody and an experimental vaccine against CA6. A potential mAb 1D5 could fully protect mice from a lethal CA6 infection and also showed good therapeutic effects in the CA6-infected mice. In addition, an inactivated CA6 vaccine was evaluated through maternal immunization and showed 100% protection of neonatal mice from lethal CA6 challenge. Collectively, these results indicate that this infection model will be a useful tool in future studies on vaccines and antiviral reagents against CA6. [ABSTRACT FROM AUTHOR]

Coxsackievirus A16 (CA16) is one of the major causative agents of hand, foot, and mouth disease (HFMD). No CA16 vaccine candidates have progressed to clinical trials so far. Immunogenicity studies indicated that different CA16 particles have much influence on the efficacy of a candidate vaccine. However, there are still no relevant reports on the methods of detecting different CA16 particles. In this study, we screened several monoclonal antibodies (mAbs) specific for different CA16 particles, and several sandwich enzyme-linked immunoassays (ELISAs) were developed to measure the different types of CA16 viral particles. The mAbs that could only bind denatured or empty capsids could not neutralize CA16. In contrast, the mAbs that could bind mature full particles or all types of particles showed obvious neutralizing activity. The thermal stability of different CA16 particles was evaluated using these sandwich ELISAs. The mature full particles were found to be more thermolabile than the other types of particles and could be stabilized by high concentrations of cations. These methods can be used to assist in the potency control of CA16 vaccines and will promote the development of a CA16 vaccine. [ABSTRACT FROM AUTHOR]

Abstract: In recent year, Enterovirus 71 (EV71)-associated hand, foot and mouth disease (HFMD) has become an important public health issue in China. EV71 has been classified into genotypes A, B1–B5 and C1–C5. With such genetic diversity, whether the convalescent or recovery antibody responses can cross-protect infections from other genotypes remains a question. Understanding of the antigenicity of such diverse genetic EV71 isolates is crucial for the EV71 vaccine development. Here, a total of 186 clones anti-EV71 MAbs was generated and characterized with Western blot and cell-based neutralization assay. Forty neutralizing anti-EV71 MAbs were further used to analyze the antigenic properties of 18 recent EV71 isolates representing seven genotypes in neutralization assay. We found that most neutralizing anti-EV71 MAbs are specific to conformational epitopes. We also classified the 40 neutralizing anti-EV71 MAbs into two classes according to their reactivity patterns with 18 EV71 isolates. Class I MAb can neutralize all isolates, suggesting conserved epitopes are present among EV71. Class II MAb includes four subclasses (IIa–IId) and neutralizes only subgroups of EV71 strains. Conversely, 18 EV71 strains were grouped into antigenic types 1 and four antigenic subtypes (2.1–2.4). These results suggest that the current genotyping of EV71 does not reflect their antigenicity which may be important in the selection of EV71 vaccine strains. This panel of neutralizing anti-EV71 MAbs may be useful for the recognition of emerging antigenic variants of EV71 and vaccine development. [Copyright &y& Elsevier]

Abstract: The candidate particulate hepatitis E vaccine, HEV 239, has been shown to be an efficacious vaccine in primates, and clinical study to date shows it to be safe and immunogenic for humans. The antigenicity of HEV 239 is virtually identical to its N-terminal 26 amino acids truncated protein, E2, which is not particulate but soluble. However, HEV 239 is over 200 times more immunogenic than E2. In present study, several events underlying this dramatic immunogenicity difference have been addressed. (1) HEV 239 can efficiently evoke a vigorous and predominant T cell response while E2 cannot induce detectable T cell response; (2) the dominant T cell epitopes in HEV 239 are identified, and both are also contained integrally in E2; (3) priming mice with Th epitope peptide can partially rescue the weak immunogenicity of E2 in alum adjuvant and (4) HEV 239 but not E2 can induce significant antibody response in athymic mice, which indicates that HEV 239 can directly activate B cell more efficiently. These results contribute to a better understanding of the mechanisms involved in the significant high immunogenicity of particulate antigen and may provide knowledge for the rational design and development of future vaccines. [Copyright &y& Elsevier]