Coxsackievirus 16 (CA16) is one of the major pathogens associated with hand, foot, and mouth disease (HFMD) in infants and young children. In recent years, CA16 and human enterovirus 71 (EV71) have often circulated alternatively or together in the Western Pacific region, which has become an important public health problem in this region. HFMD caused by CA16 infection is generally thought to be mild and self-limiting. However, recently several severe and fatal cases involving CA16 have been reported. Studies have shown that co-infection with CA16 and EV71 can cause serious complications in the central nervous system (CNS) and increase the chance of genetic recombination, which may be responsible for the large HFMD outbreak in Mainland China in 2008. For these reasons, recent studies have focused on the virological characteristics of CA16 and the development of CA16-related diagnostic reagents and vaccines.

https://www.tandfonline.com/doi/pdf/10.4161/hv.27087

Coxsackievirus A16: epidemiology, diagnosis, and vaccine.

Enterovirus A infections are the primary cause of hand, foot and mouth disease (HFMD) in infants and young children. Although enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are the predominant causes of HFMD epidemics worldwide, EV-A71 has emerged as a major neurovirulent virus responsible for severe neurological complications and fatal outcomes. HFMD is a serious health threat and economic burden across the Asia-Pacific region. Inactivated EV-A71 vaccines have elicited protection against EV-A71 but not against CV-A16 infections in large efficacy trials. The current development of a bivalent inactivated EV-A71/CV-A16 vaccine is the next step toward that of multivalent HFMD vaccines. These vaccines should ultimately include other prevalent pathogenic coxsackieviruses A (CV-A6 and CV-A10), coxsackieviruses B (B3 and B5) and echovirus 30 that often co-circulate during HFMD epidemics and can cause severe HFMD, aseptic meningitis and acute viral myocarditis. The prospect and challenges for the development of such multivalent vaccines are discussed.

https://www.tandfonline.com/doi/pdf/10.1080/21645515.2015.1049780

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

Hand-foot-and-mouth disease (HFMD) has been recognized as an important global public health issue, which is predominantly caused by enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16). There is no available vaccine against HFMD. An ideal HFMD vaccine should be bivalent against both EV-A71 and CVA16. Here, a novel strategy to produce bivalent HFMD vaccine based on chimeric EV-A71 virus-like particles (ChiEV-A71 VLPs) was proposed and illustrated. The neutralizing epitope SP70 within the capsid protein VP1 of EV-A71 was replaced with that of CVA16 in ChiEV-A71 VLPs. Structural modeling revealed that the replaced CVA16-SP70 epitope is well exposed on the surface of ChiEV-A71 VLPs. These VLPs produced in Saccharomyces cerevisiae exhibited similarity in both protein composition and morphology as naive EV-A71 VLPs. Immunization with ChiEV-A71 VLPs in mice elicited robust Th1/Th2 dependent immune responses against EV-A71 and CVA16. Furthermore, passive immunization with anti-ChiEV-A71 VLPs sera conferred full protection against lethal challenge of both EV-A71 and CVA16 infection in neonatal mice. These results suggested that this chimeric vaccine, ChiEV-A71 might have the potential to be further developed as a bivalent HFMD vaccine in the near future. Such chimeric enterovirus VLPs provide an alternative platform for bivalent HFMD vaccine development.

/pdf/novel-recombinant-chimeric-virus-like-particle-is-1tfo7gjlsx.pdf

Novel Recombinant Chimeric Virus-Like Particle Is Immunogenic and Protective Against Both Enterovirus 71 and Coxsackievirus A16 in Mice

UL7, a tegument protein of Herpes Simplex Virus type I (HSV-1), is highly conserved in viral infection and proliferation and has an unknown mechanism of action. A HSV-1 UL7 mutant (UL7-MU) was constructed using the CRISPR-cas9 system. The replication rate and plaque morphology were used to analyze the biological characteristics of the wild-type (WT), UL7-MU and MU-complemented P1 viruses. The virulence of the viruses was evaluated in mice. Real-time RT-qPCR and ChIP assays were used to determine the expression levels of relevant genes. The replication capacity of a recombinant virus (UL7-MU strain) was 10-fold lower than that of the WT strain. The neurovirulence and pathologic effect of the UL7-MU strain were attenuated in infected mice compared with the WT strain. In the latency model, the expression of latency-associated transcript (LAT) in the central nervous system (CNS) and trigeminal nerve was lower in UL7-MU-infected mice than in WT strain-infected mice. The transcription level of the immediate-early gene α-4 in UL7-MU-infected cells was reduced by approximately 2-fold compared with the clear transcriptional peak identified in WT strain-infected Vero cells within 7 h post-infection (p.i.). By modulating the transcription of the α-4 gene, UL7 may be involved in transcriptional regulation through its interaction with the transcript complex structure of the viral genome during HSV-1 infection.

/pdf/the-mutated-tegument-protein-ul7-attenuates-the-virulence-of-4sva6r75r0.pdf

The mutated tegument protein UL7 attenuates the virulence of herpes simplex virus 1 by reducing the modulation of α-4 gene transcription.

Hand, foot, and mouth disease (HFMD), caused by enteroviruses, is a syndrome characterized by fever with vesicular eruptions mainly on the skin of the hands, feet, and oral cavity. HFMD primarily affects infants and young children. Although infection is usually self-limited, severe neurological complications in the central nervous system can present in some cases, which can lead to death. Widespread infection of HFMD across the Asia-Pacific region over the past two decades has made HFMD a major public health challenge, ranking first among the category C notifiable communicable diseases in China every year since 2008. This review summarizes our understanding of HFMD, focusing on the etiology and pathogenesis of the disease, as well as on progress toward antivirals and vaccines. The review also discusses the implications of these studies as they relate to the control and prevention of the disease.

/pdf/etiology-pathogenesis-antivirals-and-vaccines-of-hand-foot-nx6ldu3jxd.pdf

Etiology, pathogenesis, antivirals and vaccines of hand, foot, and mouth disease

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. The results showed that the neutralizing antibody was developed in a dose-dependent manner, and was sustained for 70 days with an average GMT (geometric mean titer) level of 80 to 90 in immunized mouse and for 56 days with GMT of higher than 300 in monkeys. The neutralizing antibody had a cross-neutralizing activity against different viral strains (genotype A and B), and the specific IFN-γ-secreting cell response was activated by these virus strains in an ELISPOT assay. This study provides evidence for the potential use of inactivated CA16 as a candidate for use in vaccines.

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

The herpes simplex virus type 1 (HSV-1) tegument proteins have important functions in the viral replication process. In order to investigate the role of the HSV-1 tegument protein VP22 in viral replication, its transcriptional regulation of viral promoters was investigated using the chloramphenicol acetyltransferase (CAT) assay. The results indicate that VP22 exerts a dose-dependent transcriptional inhibitory effect on the HSV-1 α4, TK, and gC gene promoters. VP22 had the capacity to repress transcriptional activation of promoters via different viral transcription regulatory factors such as VP16 and ICP0, as evidenced by the specific repression of the TK and gC gene promoters by ICP0. In addition, VP22 was capable of inhibiting the promotion of ICP0 transcriptional activation in the presence of HAT PCAF, which is even more remarkable than the VP22 repression of ICP0 transcriptional activation. Finally, the transcriptional inhibitory effect of VP22 on other viral promoters was demonstrated by the analysis of β-galactosidase activities in internal controls.

Functional analysis of transcriptional regulation of herpes simplex virus type 1 tegument protein VP22

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. This observation, along with biological analysis, indicated that the differences in the strains’ biological characteristics, such as proliferation kinetics and immunogenicity, correlate with differences in their pathogenicity toward neonatal mice. Furthermore, these differences are thought to be associated with the sequence of the 5′ non-coding region of the viral genome and the VP1 structural region sequence. The results suggest that the biological and genetic characteristics of the CA16 viral strains are relevant to their pathogenicity.

/pdf/a-comparative-study-of-the-characteristics-of-two-coxsackie-2dfz6d467h.pdf

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

CoxA16 virus strain and human CoxA16 inactivated vaccine

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

Functional analysis of transcriptional regulation of herpes simplex virus type 1 tegument protein VP22

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

CoxA16 virus strain and human CoxA16 inactivated vaccine