寨卡病毒及其疫苗研究

寨卡病毒与黄热病毒、登革热病毒、日本脑炎病毒、西尼罗病毒等都属于蚊媒传播的黄病毒属病毒。寨卡病毒分离于1947年,但由于分布区域有限,所致寨卡热症状较轻,很长一段时间并没有引起太多的关注。最近一些年,特别是2015年后,巴西的寨卡疫情暴发及其与新生儿小头畸形的关联,引起了全球越来越多的关注。疫苗是应对寨卡疫情的重要手段,目前全球有30余个机构在进行寨卡病毒疫苗的研发。本文综述了寨卡病毒的生物学、流行病学、临床特征以及当前不同类型寨卡病毒疫苗研发现状,同时对其他几种黄病毒属病毒批准和临床阶段疫苗情况进行了概述,以为相关研究人员提供参考。     

An Ecological Assessment of the Pandemic Threat of Zika Virus

The current outbreak of Zika virus poses a severe threat to human health. While the range of the virus has been cataloged growing slowly over the last 50 years, the recent explosive expansion in the Americas indicates that the full potential distribution of Zika remains uncertain. Moreover, many studies rely on its similarity to dengue fever, a phylogenetically closely related disease of unknown ecological comparability. Here we compile a comprehensive spatially-explicit occurrence dataset from Zika viral surveillance and serological surveys based in its native range, and construct ecological niche models to test basic hypotheses about its spread and potential establishment. The hypothesis that the outbreak of cases in Mexico and North America are anomalous and outside the native ecological niche of the disease, and may be linked to either genetic shifts between strains, or El Nino or similar climatic events, remains plausible at this time. Comparison of the Zika niche against the known distribution of dengue fever suggests that Zika is more constrained by the seasonality of precipitation and diurnal temperature fluctuations, likely confining autochthonous non-sexual transmission to the tropics without significant evolutionary change. Projecting the range of the diseases in conjunction with three major vector species (Aedes africanus, Ae. aegypti, and Ae. albopictus) that transmit the pathogens, under climate change, suggests that Zika has potential for northward expansion; but, based on current knowledge, our models indicate Zika is unlikely to fill the full range its vectors occupy, and public fear of a vector-borne Zika epidemic in the mainland United States is potentially informed by biased or limited scientific knowledge. With recent sexual transmission of the virus globally, we caution that our results only apply to the vector-borne transmission route of the pathogen, and while the threat of a mosquito-carried Zika pandemic may be overstated in the media, other transmission modes of the virus may emerge and facilitate naturalization worldwide.     

寨卡病毒引发小头症?关系越确定,防治越迫切!

自2015年初至今,寨卡病毒(Zika virus,ZIKV)以巴西为首先后在数十个国家和地区暴发流行。几乎同时,与日俱增的小头症患儿使全球对此陷入警惕状态。目前,全球正在积极探索ZIKV感染所引发的各种神经系统疾病。在越来越多证据表明在细胞水平和动物模型中ZIKV能直接损伤胚胎脑部发育的同时,ZIKV感染者的防治需求也越来越迫切。本文从ZIKV的流行病学、与小头畸形因果关系的研究进展及其预防疫苗和治疗药物的研究现状等方面进行概述。     

Serological Cross Reactivity between Zika and Dengue Viruses in Experimentally Infected Monkeys

正Dear Editor,Zika virus(ZIKV),a pathogen within the genus Flavivirus,family Flaviviridae brought an international public health emergency due to its association with neonatal microcephaly case(Platt and Miner 2017).Currently the most reliable diagnostic test is PCR detection of ZIKV RNA from body fluid samples.Unfortunately,the short viremia window and asymptomatic/mild infections greatly reduce the success rate of PCRs(de Vasconcelos et al.2018).     

Zika virus inhibits type‐I interferon production and downstream signaling

Zika virus is an emerging mosquito‐borne pathogen that is associated with Guillain–Barré syndrome in adults and microcephaly and other neurological defects in newborns. Despite being declared an international emergency by the World Health Organization, comparatively little is known about its biology. Here, we investigate the strategies employed by the virus to suppress the host antiviral response. We observe that once established, Zika virus infection is impervious to interferon treatment suggesting that the virus deploys effective countermeasures to host cell defences. This is confirmed by experiments showing that Zika virus infection impairs the induction of type‐I interferon as well as downstream interferon‐stimulated genes. Multiple viral proteins affect these processes. Virus‐mediated degradation of STAT2 acts to reduce type‐I and type‐III interferon‐mediated signaling. Further, the NS5 of Zika virus binds to STAT2, and its expression is correlated with STAT2 degradation by the proteasome. Together, our findings provide key insights into how Zika virus blocks cellular defense systems. This in turn is important for understanding pathogenesis and may aid in designing antiviral therapies.     

Exploring the Zika Genome to Design a Potential Multiepitope Vaccine Using an Immunoinformatics Approach

International Journal of Peptide Research and Therapeutics - Zika is one of the most dreaded viruses which has left mankind crippled for over years. Current no vaccines for Zika are available in...     

寨卡病毒非结构蛋白研究进展

自2015年巴西确诊首个寨卡病毒感染病例以来,该病毒在全球范围内迅速蔓延,引发了大规模疫情。寨卡病毒感染不仅会导致新生儿小头畸形,还会引起格林-巴利综合征,后者是一种严重的神经系统疾病,可以导致患者瘫痪乃至死亡。但是目前并没有特异性的疫苗或药物可以用于阻断寨卡病毒的感染。近几年来,寨卡病毒在复制传播过程中多个关键蛋白的结构逐步得到解析,在一定程度上为其致病机制的阐释提供了理论基础,并对特异性药物设计具有一定指导意义。主要对寨卡病毒多个非结构蛋白的三维空间结构研究进展及其抑制剂研发的主要方向进行了综述,以期为药物靶点的分析筛选及抗病毒药物的开发设计提供参考。     

A conceptual model for optimizing vaccine coverage to reduce vector-borne infections in the presence of antibody-dependent enhancement

Background

Many vector-borne diseases co-circulate, as the viruses from the same family are also transmitted by the same vector species. For example, Zika and dengue viruses belong to the same Flavivirus family and are primarily transmitted by a common mosquito species Aedes aegypti. Zika outbreaks have also commonly occurred in dengue-endemic areas, and co-circulation and co-infection of both viruses have been reported. As recent immunological cross-reactivity studies have confirmed that convalescent plasma following dengue infection can enhance Zika infection, and as global efforts of developing dengue and Zika vaccines are intensified, it is important to examine whether and how vaccination against one disease in a large population may affect infection dynamics of another disease due to antibody-dependent enhancement.

Methods

Through a conceptual co-infection dynamics model parametrized by reported dengue and Zika epidemic and immunological cross-reactivity characteristics, we evaluate impact of a hypothetical dengue vaccination program on Zika infection dynamics in a single season when only one particular dengue serotype is involved.

Results

We show that an appropriately designed and optimized dengue vaccination program can not only help control the dengue spread but also, counter-intuitively, reduce Zika infections. We identify optimal dengue vaccination coverages for controlling dengue and simultaneously reducing Zika infections, as well as the critical coverages exceeding which dengue vaccination will increase Zika infections.

Conclusion

This study based on a conceptual model shows the promise of an integrative vector-borne disease control strategy involving optimal vaccination programs, in regions where different viruses or different serotypes of the same virus co-circulate, and convalescent plasma following infection from one virus (serotype) can enhance infection against another virus (serotype). The conceptual model provides a first step towards well-designed regional and global vector-borne disease immunization programs.

     

Molecular evolution of Zika virus as it crossed the Pacific to the Americas

Zika virus was previously considered to cause only a benign infection in humans. Studies of recent outbreaks of Zika virus in the Pacific, South America, Mexico and the Caribbean have associated the virus with severe neuropathology. Viral evolution may be one factor contributing to an apparent change in Zika disease as it spread from Southeast Asia across the Pacific to the Americas. To address this possibility, we have employed computational tools to compare the phylogeny, geography, immunology and RNA structure of Zika virus isolates from Africa, Asia, the Pacific and the Americas. In doing so, we compare and contrast methods and results for tree search and rooting of Zika virus phylogenies. In some phylogenetic analyses we find support for the hypothesis that there is a deep common ancestor between African and Asian clades (the “Asia/Africa” hypothesis). In other phylogenetic analyses, we find that Asian lineages are descendent from African lineages (the “out of Africa” hypothesis). In addition, we identify and evaluate key mutations in viral envelope protein coding and untranslated terminal RNA regions. We find stepwise mutations that have altered both immunological motif sets and regulatory sequence elements. Both of these sets of changes distinguish viruses found in Africa from those in the emergent Asia–Pacific–Americas lineage. These findings support the working hypothesis that mutations acquired by Zika virus in the Pacific and Americas contribute to changes in pathology. These results can inform experiments required to elucidate the role of viral genetic evolution in changes in neuropathology, including microcephaly and other neurological and skeletomuscular issues in infants, and Guillain‐Barré syndrome in adults.     

Combination of ELISA screening and seroneutralisation tests to expedite Zika virus seroprevalence studies

Here we propose a strategy allowing implementing efficient and practicable large-scale seroepidemiological studies for Zika Virus (ZIKV). It combines screening by a commercial NS1 protein-based Zika IgG ELISA, and confirmation by a cytopathic effect-based virus neutralization test (CPE-based VNT). In post-epidemic samples from Martinique Island blood donors (a population with a dengue seroprevalence above 90%), this strategy allowed reaching specificity and sensitivity values over 98%. The CPE-based VNT consists of recording CPE directly under the optical microscope, which is easy to identify with ZIKV strain H/PF/2013 at day 5 pi. Overall, considered that CPE-based VNT is cost effective and widely automatable, the NS1 protein-based Zika IgG ELISA+CPE-based VNT combination strategy represents a convenient tool to expedite ZIKV seroprevalence studies.     

Development of Vaccine Prototype Against Zika Virus Disease of Peptide-Loaded PLGA Nanoparticles and Evaluation of Cytotoxicity

Zika virus has recently evolved from an obscure mosquito-borne pathogen to an international public health concern. People with Zika virus disease can have indications including mild fever, skin rash, conjunctivitis, muscle pain, malaise or headache. Effective vaccines are needed for controlling and preventing the disease. In the current study, we aim to design the substructure for vaccine against Zika virus by forming antigenic peptide epitope of the disease. Zika peptide loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles have been fabricated in the present work as a potential artificial vaccine. UV and FT-IR Spectrophotometers and ZetaSizer were used for studying the nanoparticles, and Scanning Electron Microscope was used for morphological examination. The nanoparticles (NPs) yield, encapsulation efficiency, the peptide loading capacity were determined and in vitro release of the peptide was studied. Cytotoxic effects of the various concentrations of Zika peptide, blank PLGA nanoparticles and Zika peptide loaded PLGA nanoparticles on ECV304 human epithelial cells were determined via MTT assay. The present paper could be considered as one of the important steps in the use of nanoparticles for constructing the new generation of vaccination systems.

     

Inhibitors of the Zika virus protease NS2B-NS3

In recent years, the Zika virus has emerged from a neglected flavivirus to a health-threatening pathogen that causes epidemic outbreaks associated with neurological disorders and congenital malformations. In addition to vaccine development, the discovery of specific antiviral agents has been pursued intensely. The Zika virus protease NS2B-NS3 catalyses the processing of the viral precursor polyprotein as an essential step during viral replication. Since the epidemic Zika virus outbreak in the Americas, several inhibitors of this protease have been reported. Substrate-derived peptides revealed important structural information about the active site, whilst more drug-like small molecules have been discovered as allosteric inhibitors.     

Zika,contraception and the non‐identity problem

The 2016 outbreak of the Zika arbovirus was associated with large numbers of cases of the newly‐recognised Congenital Zika Syndrome (CZS). This novel teratogenic epidemic raises significant ethical and practical issues. Many of these arise from strategies used to avoid cases of CZS, with contraception in particular being one proposed strategy that is atypical in epidemic control. Using contraception to reduce the burden of CZS has an ethical complication: interventions that impact the timing of conception alter which people will exist in the future. This so‐called ‘non‐identity problem’ potentially has significant social justice implications for evaluating contraception, that may affect our prioritisation of interventions to tackle Zika. This paper combines ethical analysis of the non‐identity problem with empirical data from a novel survey about the general public's moral intuitions. The ethical analysis examines different perspectives on the non‐identity problem, and their implications for using contraception in response to Zika. The empirical section reports the results of an online survey of 93 members of the US general public exploring their intuitions about the non‐identity problem in the context of the Zika epidemic. Respondents indicated a general preference for a person‐affecting intervention (mosquito control) over an impersonal intervention (contraception). However, their responses did not appear to be strongly influenced by the non‐identity problem. Despite its potential philosophical significance, we conclude from both theoretical considerations and analysis of the attitudes of the community that the non‐identity problem should not affect how we prioritise contraception relative to other interventions to avoid CZS.     

寨卡疫苗研究进展

寨卡病毒系由伊蚊传播的黄病毒,超过20亿人在其流行区域生活。近几年,在中南美洲乃至世界范围内爆发的寨卡疫情已对全球公共卫生事业构成严重威胁。已有研究证实寨卡病毒感染为格林巴利综合征的病因之一;孕妇感染寨卡病毒后,可造成新生儿小头症。早日研制出安全有效的寨卡疫苗之重要性不言而喻。全球率先报道的寨卡疫苗为一款DNA疫苗,其在设计、制备和生产方面均较其他类型疫苗更加简易,且可避免可复制型疫苗因毒力回复而造成对孕妇和胎儿的健康威胁,在寨卡疫苗的研究中具有显著优势。其他传统类型疫苗和基于抗体的新型疫苗等均有研究机构开展研究,并已取得阶段性进展,本文将扼要综述寨卡疫苗的研究现状与进展。     

The fertility-inhibiting effect of mosquitoes: Socio-economic differences in response to the Zika crisis in Colombia

We estimated the impact of the Zika virus outbreak on birth rates and demand for health care services in Colombia. Our analysis exploits the variation in the level of natural protection against mosquito-transmitted diseases across the country. This characteristic induced exogenous variation in Zika incidence, which allows us to construct a control group of municipalities with similar historical fertility trends but with differential exposure to the Zika crisis. We implemented a difference-in-differences model after matching, as well as synthetic control. We found a decrease in birth rates of approx. 10% in the last two quarters of 2019. The impact of the virus was similar irrespective of the women’s education level, and we found no discernible impact on teenage pregnancy.     

Co-circulation and misdiagnosis led to underestimation of the 2015–2017 Zika epidemic in the Americas

During the 2015–2017 Zika epidemic, dengue and chikungunya–two other viral diseases with the same vector as Zika–were also in circulation. Clinical presentation of these diseases can vary from person to person in terms of symptoms and severity, making it difficult to differentially diagnose them. Under these circumstances, it is possible that numerous cases of Zika could have been misdiagnosed as dengue or chikungunya, or vice versa. Given the importance of surveillance data for informing epidemiological analyses, our aim was to quantify the potential extent of misdiagnosis during this epidemic. Using basic principles of probability and empirical estimates of diagnostic sensitivity and specificity, we generated revised estimates of reported cases of Zika that accounted for the accuracy of diagnoses made on the basis of clinical presentation with or without laboratory confirmation. Applying this method to weekly reported case data from 43 countries throughout Latin America and the Caribbean, we estimated that 944,700 (95% CrI: 884,900–996,400) Zika cases occurred when assuming all confirmed cases were diagnosed using molecular methods versus 608,400 (95% CrI: 442,000–821,800) Zika cases that occurred when assuming all confirmed cases were diagnosed using serological methods. Our results imply that misdiagnosis was more common in countries with proportionally higher reported cases of dengue and chikungunya, such as Brazil. Given that Zika, dengue, and chikungunya appear likely to co-circulate in the Americas and elsewhere for years to come, our methodology has the potential to enhance the interpretation of passive surveillance data for these diseases going forward. Likewise, our methodology could also be used to help resolve transmission dynamics of other co-circulating diseases with similarities in symptomatology and potential for misdiagnosis.     

Adverse fetal and neonatal outcomes in pregnancies with confirmed Zika Virus infection in Rio de Janeiro,Brazil: A cohort study

ObjectiveTo analyze adverse fetal and neonatal outcomes of Zika virus infection by the timing of infection during pregnancy. Method: Cohort study of 190 pregnancies with 193 offspring with a positive RT-PCR test for Zika virus (March/2016 to April/2017).ResultsDeath or defects related to congenital Zika virus infection were identified in 37.3% of fetuses and newborns, and microcephaly in 21.4% of the newborns. The proportion of small for gestational age newborns was 21.9%. Maternal symptoms in the first trimester were significantly associated with the birth of newborns with microcephaly/cerebral atrophy, small for gestational age and with the deaths (one abortion, one stillbirth and the two neonatal deaths). Maternal infection during the second trimester was further associated with asymptomatic newborns at birth. The study showed that 58.5% of the offspring with microcephaly and / or cortical atrophy were small for gestational age, with an evident decrease in symptomatic offspring without microcephaly, 24.1%, and with only 9.1% in the asymptomatic group.ConclusionThis study showed that the earlier the symptoms appear during gestation, the more severe the endpoints. We found a higher percentage of small for gestational age newborns exposed to Zika virus early in gestation. We also found a group of apparently asymptomatic newborns with proven Zika infection, which highlights the importance of follow up studies in this population.     

Codon usage bias and evolutionary analyses of Zika virus genomes

Zika virus (ZIKV) is a member of the family Flaviviridae and contains a single-stranded RNA genome with positive-polarity. Like Dengue, Zika virus uses Aedes aegypti mosquito as a vector to infect human with a wide range of clinical signs, from asymptomatic to influenza-like syndrome. Despite significant progress in genomic analyses, how a viral relationship with two different hosts affect the overall fitness, constancy, and dodging of hosts immune system are elusive. Here we analyzed Zika virus codon-based evolution using eleven strains from different geographical locations. The overall codon usage was similar and slightly bias among all strains. An occurrence of A-ending in highly-preferred codons and analysis by various approaches strongly suggests that mutational bias is the main force shaping codon usage in this virus. However, natural selection and geographical realities cannot be ignored in marginal influence on codon usage. The viral genomes naturally favor Aedes aegypti over human host for tRNA pool in translation. Such findings will assist researchers in understanding elements contribute to viral adaptation and evolutionary setup with hosts.