Study of integrated protective immunity induced in rhesus macaques by the intradermal administration of a bivalent EV71-CA16 inactivated vaccine.

Enterovirus type 71 (EV71) and coxsackievirus A 16 (CA16) are recognized as the major pathogens responsible for human hand-foot-mouth disease. To develop a bivalent EV71-CA16 vaccine, rhesus macaques immunized with two doses of this vaccine via the intradermal route were challenged with EV71 or CA16, and their clinical symptoms, viral shedding, neutralizing antibodies, IFN-γ-specific ELISpots, and tissue viral load were examined longitudinally. Specific immunity against EV71 and CA16 was observed in the macaques, which exhibited controlled proliferation of the EV71 and CA16 viruses and upregulated expression of immune-related genes compared with the controls.

Erratum: Author Correction: Role of innate lymphoid cells and dendritic cells in intradermal immunization of the enterovirus antigen.

[This corrects the article DOI: 10.1038/s41541-019-0108-6.].

Role of innate lymphoid cells and dendritic cells in intradermal immunization of the enterovirus antigen.

Enterovirus type 71 (EV71) and coxsackievirus A 16 (CA16) are the major pathogens of human hand, foot, and mouth disease (HFMD). In our previous study, intramuscular immunization with the inactivated EV71 vaccine elicited effective immunity, while immunization with the inactivated CA16 vaccine did not. In this report, we focused on innate immune responses elicited by inactivated EV71 and CA16 antigens administered intradermally or intramuscularly.

Pathologic and immunologic characteristics of coxsackievirus A16 infection in rhesus macaques.

Coxsackievirus A16 (CV-A16) causes human hand, foot and mouth disease, but its pathogenesis is unclear. In rhesus macaques, CV-A16 infection causes characteristic vesicles in the oral mucosa and limbs as well as viremia and positive viral loads in the tissues, suggesting that these animals reflect the pathologic process of the infection. An immunologic analysis indicated a defective immune response, which included undetectable neutralizing antibodies and IFN-γ-specific memory T-cells in macaques infected with CV-A16.

The Structure, Pathogenicity and Immunogenicity of Two Virion Fractions Harvested from Cell Cultures Infected with the CA16 Virus.

Objectives: To investigate the biological characteristics of the two types of virion fractions of Coxsackievirus A 16 (CA16), which include the real virion fraction and pseudo-virion fraction in their structure, pathogenicity and immunogenicity.

Methods: We obtained the two CA16 virion fractions by density gradient centrifugation. The morphology of virion fractions was analyzed by electron microscopy, while the antigenic characteristics and immunogenicity of two virion fractions were determined by ELISA, SDS-PAGE, Western blot, qRT-PCR, and the mouse model of immune response.

Similar protective immunity induced by an inactivated enterovirus 71 (EV71) vaccine in neonatal rhesus macaques and children.

During the development of enterovirus 71 (EV71) inactivated vaccine for preventing human hand, foot and mouth diseases (HFMD) by EV71 infection, an effective animal model is presumed to be significant and necessary. Our previous study demonstrated that the vesicles in oral regions and limbs potentially associated with viremia, which are the typical manifestations of HFMD, and remarkable pathologic changes were identified in various tissues of neonatal rhesus macaque during EV71 infection. Although an immune response in terms of neutralizing antibody and T cell memory was observed in animals infected by the virus or stimulated by viral antigen, whether such a response could be considered as an indicator to justify the immune response in individuals vaccinated or infected in a pandemic needs to be investigated.

Immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy Chinese children: a report of further observations.

Background: To investigate the long-term effects on immunity of an inactivated enterovirus 71 (EV71) vaccine and its protective efficacy.

Methods: A sub-cohort of 1,100 volunteers from Guangxi Province in China was eligible for enrolment and randomly administered either the EV71 vaccine or a placebo on days 0 and 28 in a phase III clinical trial and then observed for the following 2 years with approval by an independent ethics committee of Guangxi Zhuang Autonomous Region, China. Serum samples from the 350 participants who provided a full series of blood samples (at all the sampling points) within the 2-year period were collected.

HSV-1 nucleocapsid egress mediated by UL31 in association with UL34 is impeded by cellular transmembrane protein 140.

During HSV-1 infection, the viral UL31 protein forms a complex with the UL34 protein at the cellular nuclear membrane, where both proteins play important roles in the envelopment of viral nucleocapsids and their egress into the cytoplasm. To characterize the mechanism of HSV-1 nucleocapsid egress, we screened host proteins to identify proteins that interacted with UL31 via yeast two-hybrid analysis. Transmembrane protein 140 (TMEM140), was identified and confirmed to bind to and co-localize with UL31 during viral infection.

Comparative study of the immunogenicity in mice and monkeys of an inactivated CA16 vaccine made from a human diploid cell line.

The coxsackie A16 virus (CA16), along with enterovirus 71 (EV71), is a primary pathogen that causes hand, foot, and mouth disease (HFMD). To control HFMD, CA16, and EV71 vaccines are needed. In this study, an experimental inactivated CA16 vaccine was prepared using human diploid cells, and the vaccine's immunogenicity was analyzed in mice and rhesus monkeys.

An inactivated enterovirus 71 vaccine in healthy children.

Background: Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease in children and may be fatal. A vaccine against EV71 is needed.

Methods: We conducted a randomized, double-blind, placebo-controlled phase 3 trial involving healthy children 6 to 71 months of age in Guangxi Zhuang Autonomous Region, China.

The gene expression profile of peripheral blood mononuclear cells from EV71-infected rhesus infants and the significance in viral pathogenesis.

Enterovirus 71 (EV71) is the major pathogen responsible for fatal hand, foot and mouth disease (HFMD). Our previous work reported on an EV71-infected rhesus monkey infant model that presented with histo-pathologic changes of the central nervous system (CNS) and lungs. This study is focused on the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) from EV71-infected rhesus monkey infants.

EV71-infected CD14(+) cells modulate the immune activity of T lymphocytes in rhesus monkeys.

Preliminary studies of the major pathogen enterovirus 71 (EV71), a member of the Picornaviridae family, have suggested that EV71 may be a major cause of fatal hand, foot and mouth disease cases. Currently, the role of the pathological changes induced by EV71 infection in the immunopathogenic response remains unclear. Our study focused on the interaction between this virus and immunocytes and indicated that this virus has the ability to replicate in CD14(+) cells.

Study of the integrated immune response induced by an inactivated EV71 vaccine.

Unlabelled: Enterovirus 71 (EV71), a major causative agent of hand-foot-and-mouth disease (HFMD), causes outbreaks among children in the Asia-Pacific region. A vaccine is urgently needed. Based on successful pre-clinical work, phase I and II clinical trials of an inactivated EV71 vaccine, which included the participants of 288 and 660 respectively, have been conducted.

The effect of enterovirus 71 immunization on neuropathogenesis and protein expression profiles in the thalamus of infected rhesus neonates.

Enterovirus 71 (EV71) is a major pathogen that causes hand-foot-mouth disease (HFMD). Our previous studies have demonstrated that the complete process of pathogenesis, which may include tissue damage induced by host inflammatory responses and direct tissue damage caused by viral infection, can be observed in the central nervous system (CNS) of animals infected in the laboratory with EV71. Based on these observations, the neuropathogenesis and protein expression profiles in the thalamic tissues of EV71-infected animals were further analyzed in the present study.

Analysis of the Th1/Th2 reaction in the immune response induced by EV71 inactivated vaccine in neonatal rhesus monkeys.

Although clinical trials for the enterovirus type 71 (EV71) inactivated vaccine have been progressing, the potential mechanism of EV71 infection and its associated pathogenesis are not well-characterized in terms of comprehensive analysis of the induced immune response, which is generally recognized as an important indicator of the safety of vaccines. To investigate the Th1/Th2 response following viral challenge in neonatal rhesus monkeys immunized with different doses of EV71 inactivated vaccines, the variety of different Th1 and Th2 cytokines in the organs or tissues of the monkeys were identified. The results suggest that depending on the viral challenge, the Th1/Th2 reaction induced by different doses of EV71 inactivated vaccine varies.

A comparative study of the characteristics of two Coxsackie A virus type 16 strains (genotype B).

Coxsackie A virus is one of the major pathogens associated with hand, foot and mouth disease (HFMD). The etiological characteristics of Coxsackie A virus type 16 (CA16) are thought to correlate with the pathological process of its infection. Two CA16 strains that were isolated from a severe HFMD patient presented with different plaque forms.