scholarly journals Design of stable Enterovirus 71 virus like particles (VLPs) as a potential approach to vaccine development

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Agnieszka Martyna ◽  
Helen Fox ◽  
Andrew Macadam
Keyword(s):  
Vaccine Development ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Systemic Complications ◽  
Polio Virus ◽  
Virus Like Particles ◽  
Alternative Approach ◽  
Causative Agents ◽  
Inactivated Vaccines ◽  
Single Construct

We have previously described the design of stable and immunogenic polio virus-like particles (VLPs) (Fox, et al. 2017) as an alternative approach to vaccine production. Unlike current polio vaccines, recombinantly-expressed VLP vaccines are non-infectious so would pose no risk of accidental escape from production plants, threatening eradication. To do this we devised a pipeline for the identification of stabilising mutations which could then be combined in a single construct to produce suitable particles; this strategy may have applications for other enterovirus vaccines. Enterovirus 71 (EV71) is one of causative agents of hand, foot and mouth disease which is usually mild but in some cases neurological and systemic complications may occur. Recently there have been several outbreaks with significant mortality in South East Asia as well as increasing numbers of reports of outbreaks in Europe. VLP vaccines might be a useful alternative to inactivated vaccines currently in use or development. EV71, like poliovirus, produces empty particles that are antigenically different from the virion. If, like poliovirus, these empty particles are less immunogenic than the virion, it would be necessary to stabilise them in the native conformation. We are attempting to do this (1) by incorporating modifications that proved successful in the context of poliovirus and (2) by identifying new candidate mutations using an analogous pipeline. Here we will report the characterisation of a range of different modifications that have stabilising and de-stabilising effects on EV71 particles as well as unexpected effects on morphogenesis.

scholarly journals Peptidyl Aldehyde NK-1.8k Suppresses Enterovirus 71 and Enterovirus 68 Infection by Targeting Protease 3C

2015 ◽  
Vol 59 (5) ◽  
pp. 2636-2646 ◽  
Author(s):  
Yaxin Wang ◽  
Ben Yang ◽  
Yangyang Zhai ◽  
Zheng Yin ◽  
Yuna Sun ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Binding Pocket ◽  
The United States ◽  
Single Amino Acid ◽  
Global Public Health ◽  
Causative Agents ◽  
Low Cytotoxicity ◽  
Neurological Infections

ABSTRACTEnterovirus (EV) is one of the major causative agents of hand, foot, and mouth disease in the Pacific-Asia region. In particular, EV71 causes severe central nervous system infections, and the fatality rates from EV71 infection are high. Moreover, an outbreak of respiratory illnesses caused by an emerging EV, EV68, recently occurred among over 1,000 young children in the United States and was also associated with neurological infections. Although enterovirus has emerged as a considerable global public health threat, no antiviral drug for clinical use is available. In the present work, we screened our compound library for agents targeting viral protease and identified a peptidyl aldehyde, NK-1.8k, that inhibits the proliferation of different EV71 strains and one EV68 strain and that had a 50% effective concentration of 90 nM. Low cytotoxicity (50% cytotoxic concentration, >200 μM) indicated a high selective index of over 2,000. We further characterized a single amino acid substitution inside protease 3C (3Cpro), N69S, which conferred EV71 resistance to NK-1.8k, possibly by increasing the flexibility of the substrate binding pocket of 3Cpro. The combination of NK-1.8k and an EV71 RNA-dependent RNA polymerase inhibitor or entry inhibitor exhibited a strong synergistic anti-EV71 effect. Our findings suggest that NK-1.8k could potentially be developed for anti-EV therapy.

scholarly journals Human enterovirus 71 and hand, foot and mouth disease

2010 ◽  
Vol 138 (8) ◽  
pp. 1071-1089 ◽  
Author(s):  
S. S. Y. WONG ◽  
C. C. Y. YIP ◽  
S. K. P. LAU ◽  
K. Y. YUEN
Keyword(s):  
Vaccine Development ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Human Enterovirus ◽  
Human Enterovirus 71 ◽  
Asian Pacific Region ◽  
Route Of Transmission ◽  
Foot And Mouth

SUMMARYHand, foot and mouth disease (HFMD) is generally a benign febrile exanthematous childhood disease caused by human enteroviruses. The route of transmission is postulated to be faeco-oral in developing areas but attributed more to respiratory droplet in developed areas. Transmission is facilitated by the prolonged environmental survival of these viruses and their greater resistance to biocides. Serious outbreaks with neurological and cardiopulmonary complications caused by human enterovirus 71 (HEV-71) seem to be commoner in the Asian Pacific region than elsewhere in the world. This geographical predilection is unexplained but could be related to the frequency of intra- and inter-typic genetic recombinations of the virus, the host populations' genetic predisposition, environmental hygiene, and standard of healthcare. Vaccine development could be hampered by the general mildness of the illness and rapid genetic evolution of the virus. Antivirals are not readily available; the role of intravenous immunoglobulin in the treatment of serious complications should be investigated. Monitoring of this disease and its epidemiology in the densely populated Asia Pacific epicentre is important for the detection of emerging epidemics due to enteroviruses.

scholarly journals A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus

2015 ◽  
Vol 60 (2) ◽  
pp. 913-924 ◽  
Author(s):  
Yu Guo ◽  
Yaxin Wang ◽  
Lin Cao ◽  
Peng Wang ◽  
Jie Qing ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Asia Pacific ◽  
Human Hand ◽  
Content Type ◽  
Viral Proteases ◽  
Causative Agents ◽  
Multiple Strains

ABSTRACTEnterovirus 71 (EV71) (Picornaviridaefamily) and hepatitis C virus (HCV) (Flaviviridaefamily) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1-acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1-acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2Apro) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2Aprois the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2Apro, confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti-EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections.

scholarly journals Structures of Coxsackievirus A16 Capsids with Native Antigenicity: Implications for Particle Expansion, Receptor Binding, and Immunogenicity

2015 ◽  
Vol 89 (20) ◽  
pp. 10500-10511 ◽  
Author(s):  
Jingshan Ren ◽  
Xiangxi Wang ◽  
Ling Zhu ◽  
Zhongyu Hu ◽  
Qiang Gao ◽  
...  
Keyword(s):  
High Resolution ◽  
Insect Cells ◽  
Vaccine Development ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Vaccine Antigen ◽  
Coxsackievirus A16 ◽  
Structure Based Drug Design ◽  
Foot And Mouth

ABSTRACTEnterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the primary causes of the epidemics of hand-foot-and-mouth disease (HFMD) that affect more than a million children in China each year and lead to hundreds of deaths. Although there has been progress with vaccines for EV71, the development of a CVA16 vaccine has proved more challenging, and the EV71 vaccine does not give useful cross-protection, despite the capsid proteins of the two viruses sharing about 80% sequence identity. The structural details of the expanded forms of the capsids, which possess nonnative antigenicity, are now well understood, but high resolution information for the native antigenic form of CVA16 has been missing. Here, we remedy this with high resolution X-ray structures of both mature and natural empty CVA16 particles and also of empty recombinant viruslike particles of CVA16 produced in insect cells, a potential vaccine antigen. All three structures are unexpanded native particles and antigenically identical. The recombinant particles have recruited a lipid moiety to stabilize the native antigenic state that is different from the one used in a natural virus infection. As expected, the mature CVA16 virus is similar to EV71; however, structural and immunogenic comparisons highlight differences that may have implications for vaccine production.IMPORTANCEHand-foot-and-mouth disease is a serious public health threat to children in Asian-Pacific countries, resulting in millions of cases. EV71 and CVA16 are the two dominant causative agents of the disease that, while usually mild, can cause severe neurological complications, leading to hundreds of deaths. EV71 vaccines do not provide protection against CVA16. A CVA16 vaccine or bivalent EV71/CVA16 vaccine is therefore urgently needed. We report atomic structures for the mature CVA16 virus, a natural empty particle, and a recombinant CVA16 virus-like particle that does not contain the viral genome. All three particles have similar structures and identical antigenicity. The recombinant particles, produced in insect cells (a system suitable for making vaccine antigen), are stabilized by recruiting from the insect cells a small molecule that is different from that used by the virus in a normal infection. We present structural and immunogenic comparisons with EV71 to facilitate structure-based drug design and vaccine development.

scholarly journals Insights into innate and adaptive immune responses in vaccine development against EV-A71

2019 ◽  
Vol 7 ◽  
pp. 251513551988899 ◽  
Author(s):  
Hui Xuan Lim ◽  
Chit Laa Poh
Keyword(s):  
T Cell ◽  
Cellular Immunity ◽  
Vaccine Development ◽  
Foot And Mouth Disease ◽  
T Cell Immunity ◽  
Effective Vaccine ◽  
Cell Immunity ◽  
Causative Agents ◽  
Us Fda

Enterovirus A71 (EV-A71) is one of the major causative agents of hand, foot and mouth disease (HFMD) in the world, infecting mostly infants and young children (<5 years of age) in Asia. Approximately 2 million cases of HFMD were reported in China each year, of which approximately 45–50% were due to EV-A71. Most of the HFMD infections caused by EV-A71 usually result in mild symptoms with rashes and ulcers in the mouth. However, virulent strains of EV-A71 can infect the central nervous system and cause severe neurologic diseases, leading to reduced cognitive ability, acute flaccid paralysis and death. The lack of understanding of cellular immunity for long-term protection from the HFMD disease represents a major obstacle for vaccine development. In particular, the role of innate and T cell immunity during HFMD infection remains unclear and there is evidence suggesting the importance of CD4+ and CD8+ T cells for protective immunity. Currently, no US FDA-approved vaccine is available for EV-A71. Although the inactivated vaccines produced in China are highly effective (vaccine efficacy >95%), they lack the cellular immunity required for long-term protection. In this review, we discuss the findings that support the protective roles of innate and T cell immunity against EV-A71 infection, which will provide the knowledge needed for the urgent development of efficacious vaccines that will confer long-term protection.

scholarly journals Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Yaxin Wang ◽  
Lin Cao ◽  
Yangyang Zhai ◽  
Zheng Yin ◽  
Yuna Sun ◽  
...  
Keyword(s):  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Serine Residue ◽  
3C Protease ◽  
The Pacific ◽  
Causative Agents ◽  
Pacific Asia ◽  
Protease Assay ◽  
Shed Light

ABSTRACT Hand-foot-and-mouth disease (HFMD), caused by enterovirus, is a threat to public health worldwide. To date, enterovirus 71 (EV71) has been one of the major causative agents of HFMD in the Pacific-Asia region, and outbreaks with EV71 cause millions of infections. However, no drug is currently available for clinical therapeutics. In our previous works, we developed a set of protease inhibitors (PIs) targeting the EV71 3C protease (3Cpro). Among these are NK-1.8k and NK-1.9k, which have various active groups and high potencies and selectivities. In the study described here, we determined the structures of the PI NK-1.8k in complex with wild-type (WT) and drug-resistant EV71 3Cpro. Comparison of these structures with the structure of unliganded EV71 3Cpro and its complex with AG7088 indicated that the mutation of N69 to a serine residue destabilized the S2 pocket. Thus, the mutation influenced the cleavage activity of EV71 3Cpro and the inhibitory activity of NK-1.8k in an in vitro protease assay and highlighted that site 69 is an additional key site for PI design. More information for the optimization of the P1′ to P4 groups of PIs was also obtained from these structures. Together with the results of our previous works, these in-depth results elucidate the inhibitory mechanism of PIs and shed light to develop PIs for the clinical treatment of infections caused by EV71 and other enteroviruses.

scholarly journals Platforms for Production of Protein-Based Vaccines: From Classical to Next-Generation Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1072
Author(s):  
Raquel Cid ◽  
Jorge Bolívar
Keyword(s):  
Infectious Diseases ◽  
Mammalian Cells ◽  
Vaccine Development ◽  
Low Cost ◽  
Cost Effective ◽  
Insect Larvae ◽  
Subunit Vaccines ◽  
Effective Strategies ◽  
Alternative Systems ◽  
Inactivated Vaccines

To date, vaccination has become one of the most effective strategies to control and reduce infectious diseases, preventing millions of deaths worldwide. The earliest vaccines were developed as live-attenuated or inactivated pathogens, and, although they still represent the most extended human vaccine types, they also face some issues, such as the potential to revert to a pathogenic form of live-attenuated formulations or the weaker immune response associated with inactivated vaccines. Advances in genetic engineering have enabled improvements in vaccine design and strategies, such as recombinant subunit vaccines, have emerged, expanding the number of diseases that can be prevented. Moreover, antigen display systems such as VLPs or those designed by nanotechnology have improved the efficacy of subunit vaccines. Platforms for the production of recombinant vaccines have also evolved from the first hosts, Escherichia coli and Saccharomyces cerevisiae, to insect or mammalian cells. Traditional bacterial and yeast systems have been improved by engineering and new systems based on plants or insect larvae have emerged as alternative, low-cost platforms. Vaccine development is still time-consuming and costly, and alternative systems that can offer cost-effective and faster processes are demanding to address infectious diseases that still do not have a treatment and to face possible future pandemics.

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