带状疱疹疫苗的研究进展及应用

带状疱疹是由潜伏在体内的水痘-带状疱疹病毒再激活引起的一种急性皮肤病,主要发生于老年人和免疫力低下人群。带状疱疹是一种自限性疾病,临床主要表现为带状、成片的皮疹,而其后遗神经痛为该病中最复杂且最常见的一种不良并发症。带状疱疹的发病机制较为复杂,推测与机体的特异性T细胞免疫水平降低有关。本文就带状疱疹与T细胞之间的关系,最新疫苗研究进展进行综述,为疫苗的研发及带状疱疹的预防提供参考。     

Characterization of an anti‐varicella‐zoster virus compound that targets the portal protein encoded by ORF54

An anti‐varicella‐zoster virus compound, a 5‐chlorobenzo[b]thiophen derivative (45B5), was characterized. Its 50% effective concentration against the cell‐free vaccine Oka strain and 50% cytotoxic concentration in human fibroblasts were 16.9 µM and more than 100 µM, respectively. Treatment with 45B5 decreased viral DNA synthesis and IE62 expression weakly but significantly. All 45B5‐resistant viral clones isolated were found to have at least one mutation in ORF54 that encodes the portal protein. There were no effects on interaction between the portal and scaffold proteins. Thus, 45B5 may inhibit nuclear delivery of viral DNA.

     

Immune response to the mumps component of the MMR vaccine in the routine of immunisation services in the Brazilian National Immunisation Program

A non-controlled longitudinal study was conducted to evaluate the combined vaccineagainst measles, mumps and rubella (MMR) immunogenicity in 150 children vaccinated inthe routine of three health units in the city of Rio de Janeiro, Brazil, 2008-2009,without other vaccines administered during the period from 30 days before to 30 daysafter vaccination. A previous study conducted in Brazil in 2007, in 1,769 childrenranging from 12-15 months of age vaccinated against yellow fever and MMRsimultaneously or at intervals of 30 days or more between doses, had shown lowseroconversion for mumps regardless of the interval between administration of the twovaccines. The current study showed 89.5% (95% confidence interval: 83.3; 94.0)seroconversion rate for mumps. All children seroconverted for measles and rubella.After revaccination, high antibody titres and seroconversion rates were achievedagainst mumps. The results of this study and others suggest that two MMR doses conferoptimal immunoresponses for all three antigens and the possible need for additionaldoses should be studied taking into account not only serological, but alsoepidemiological data, as there is no serological correlate of protection formumps.     

Varicella zoster virus vaccines: potential complications and possible improvements

Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine(v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia(PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.     

猪流行性腹泻病毒免疫及疫苗研制

猪流行性腹泻(Porcine epidemic diarrhea,PED)是严重危害我国和世界养猪业的重要动物疫病,其致病原为猪流行性腹泻病毒(Porcine epidemic diarrhea virus,PEDV),属冠状病毒科α冠状病毒属.文中综述分为5个部分.前两部分在介绍该病病原及其流行病学的基础上先概括了初...     

Contriving a chimeric polyvalent vaccine to prevent infections caused by herpes simplex virus (type-1 and type-2): an exploratory immunoinformatic approach

Abstract

Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) cause a variety of infections including oral-facial infections, genital herpes, herpes keratitis, cutaneous infection and so on. To date, FDA-approved licensed HSV vaccine is not available yet. Hence, the study was conducted to identify and characterize an effective epitope based polyvalent vaccine against both types of Herpes Simplex Virus. The selected proteins were retrieved from ViralZone and assessed to design highly antigenic epitopes by binding analyses of the peptides with MHC class-I and class-II molecules, antigenicity screening, transmembrane topology screening, allergenicity and toxicity assessment, population coverage analysis and molecular docking approach. The final vaccine was constructed by the combination of top CTL, HTL and BCL epitopes from each protein along with suitable adjuvant and linkers. Physicochemical and secondary structure analysis, disulfide engineering, molecular dynamic simulation and codon adaptation were further employed to develop a unique multi-epitope peptide vaccine. Docking analysis of the refined vaccine structure with different MHC molecules and human immune TLR-2 receptor demonstrated higher interaction. Complexed structure of the modeled vaccine and TLR-2 showed minimal deformability at molecular level. Moreover, translational potency and microbial expression of the modeled vaccine was analyzed with pET28a(+) vector for E. coli strain K12 and the vaccine constructs had no similarity with entire human proteome. The study enabled design of a novel chimeric polyvalent vaccine to confer broad range immunity against both HSV serotypes. However, further wet lab based research using model animals are highly recommended to experimentally validate our findings.

Communicated by Ramaswamy H. Sarma     

Evaluation of the European tick‐borne encephalitis vaccine against Omsk hemorrhagic fever virus

This study focused on the antigenic cross‐reactivity between tick‐borne encephalitis virus (TBEV) and Omsk hemorrhagic fever virus (OHFV) to assess the efficacy of the commercial TBE vaccine against OHFV infection. Neutralization tests performed on sera from OHFV‐ and TBEV‐infected mice showed that neutralizing antibodies are cross‐protective. The geometric mean titers of antibodies against TBEV and OHFV from TBEV‐infected mice were similar. However, the titers of anti‐TBEV antibodies in OHFV‐infected mice were significantly lower than those of anti‐OHFV antibodies in the same animals. In mouse vaccination and challenge tests, the TBE vaccine provided 100% protection against OHFV infection. Eighty‐six percent of vaccinees seroconverted against OHFV following complete vaccination, and the geometric mean titers of neutralizing antibodies against OHFV were comparable to those against TBEV. These data suggest that the TBE vaccine can prevent OHFV infection.     

Outbreak of mumps virus genotype G infection in tribal individuals during 2016–17 in India

Tribal individuals presented with fever and uni‐ or bi‐lateral parotitis in Galonda and Silli villages (Dadra and Nagar Haveli, India) between 2 October 2016 and 19 March 2017. Consequently, the magnitude and epidemiological characteristics of the outbreak were investigated. Overall, 139 cases of suspected mumps were identified in both the above villages. Most of the suspected cases were 5–15 years old, the exceptions being three adults who had no noticeable complications. Specimens were collected from 42 of the suspected cases and their close contacts (n = 39) for laboratory investigation. Mumps infection was laboratory‐confirmed in 73.8% and 20.5% of the suspected cases and contacts, respectively. Mumps was confirmed in seven adults aged 17–42 years, including three suspected cases and four contacts. To the best of our knowledge, this is the first report of a complete virus genome circulating among tribal individuals. Sequencing and phylogenetic studies revealed circulation of mumps virus genotype G in these tribal villages with 99% identity to a mumps virus detected in the UK (1996) and Canada (2009). Comparison with Indian mumps viruses revealed 99% and 98% identity to previously reported isolates from Pune during 2012 and 1986, respectively. Although the outbreak was large, no major complications were reported in the tribal villages. Detection of asymptomatic mumps in numerous close contacts indicates the importance of laboratory investigations in an outbreak setting.

     

Detection of measles,mumps and rubella viruses by immuno‐colorimetric assay and its application in focus reduction neutralization tests

Measles, mumps and rubella are vaccine‐preventable diseases; however limited epidemiological data are available from low‐income or developing countries. Thus, it is important to investigate the transmission of these viruses in different geographical regions. In this context, a cell culture‐based rapid and reliable immuno‐colorimetric assay (ICA) was established and its utility studied. Twenty‐three measles, six mumps and six rubella virus isolates and three vaccine strains were studied. Detection by ICA was compared with plaque and RT‐PCR assays. In addition, ICA was used to detect viruses in throat swabs (n = 24) collected from patients with suspected measles or mumps. Similarly, ICA was used in a focus reduction neutralization test (FRNT) and the results compared with those obtained by a commercial IgG enzyme immuno assay. Measles and mumps virus were detected 2 days post‐infection in Vero or Vero‐human signaling lymphocytic activation molecule cells, whereas rubella virus was detected 3 days post‐infection in Vero cells. The blue stained viral foci were visible by the naked eye or through a magnifying glass. In conclusion, ICA was successfully used on 35 virus isolates, three vaccine strains and clinical specimens collected from suspected cases of measles and mumps. Furthermore, an application of ICA in a neutralization test (i.e., FRNT) was documented; this may be useful for sero‐epidemiological, cross‐neutralization and pre/post‐vaccine studies.     

Exploring dengue proteome to design an effective epitope-based vaccine against dengue virus

Dengue, a mosquito-borne disease, is caused by four known dengue serotypes. This infection causes a range of symptoms from a mild fever to a sever homorganic fever and death. It is a serious public health problem in subtropical and tropical countries. There is no specific vaccine currently available for clinical use and study on this issue is ongoing. In this study, bioinformatics approaches were used to predict antigenic, immunogenic, non-allergenic, and conserved B and T-cell epitopes as promising targets to design an effective peptide-based vaccine against dengue virus. Molecular docking analysis indicated the deep binding of the identified epitopes in the binding groove of the most popular human MHC I allele (human leukocyte antigens [HLA] A*0201). The final vaccine construct was created by conjugating the B and T-cell identified epitopes using proper linkers and adding an appropriate adjuvant at the N-terminal. The characteristics of the new subunit vaccine demonstrated that the epitope-based vaccine was antigenic, non-toxic, stable, and soluble. Other physicochemical properties of the new designed construct including isoelectric point value, aliphatic index, and grand average of hydropathicity were biologically considerable. Molecular docking of the engineered vaccine with Toll-like receptor 2 (TLR2) model revealed the hydrophobic interaction between the adjuvant and the ligand binding regions in the hydrophobic channel of TLR2. The study results indicated the high potential capability of the new multi-epitope vaccine to induce cellular and humoral immune responses against the dengue virus. Further experimental tests are required to investigate the immune protection capacity of the new vaccine construct in animal models.

Communicated by Ramaswamy H. Sarma     

Immunogenicity of recombinant measles vaccine expressing fusion protein of respiratory syncytial virus in cynomolgus monkeys

Respiratory syncytial virus (RSV) is a common cause of respiratory infections in infants. Effective vaccines are currently being sought, but no vaccine is thus far available. In our previous study, recombinant AIK‐C measles vaccine expressing the RSV fusion protein (MVAIK/RSV/F) was developed and protective immunity against RSV demonstrated in cotton rats. In the present study, the immunogenicity and protective effects were investigated in three cynomolgus monkeys immunized with MVAIK/RSV/F. Neutralizing test antibodies against RSV were detected and no infectious virus was recovered from the lungs of monkeys immunized with MVAIK/RSV/F after challenge. MVAIK/RSV/F has the potential to inhibit RSV infection.

     

风疹减毒活疫苗主种子批毒种(松叶株)的安全性和免疫原性检测

评价兰州生物制品研究所用风疹病毒松叶株主种子批毒种制备的冻干风疹减毒活疫苗的安全性和免疫原性。采用自身对照、开放性的免疫原性临床观察试验,对100名8～10月龄筛选后符合条件的健康易感儿童,皮下接种1剂风疹减毒活疫苗,观察其免疫后的局部和全身反应并采集每个受试者免前和免后35d的血清标本,检测风疹HI抗体,计算阳转率和几何平均滴度。试验中所有受试者在系统观察期内均未观察到注射部位局部的不良反应;总的发热率为5%,且均为轻度发热;有1例在观察期内出现腹泻和咳嗽并持续5d,发生率为1%,属中度全身反应;血清风疹病毒抗体(HI)阳转率为100%,GMT为1:638.7±1.7。该疫苗与国内、外其它种类的风疹疫苗一样具有良好的安全性和免疫原性。     

Epstein—Barr病毒相关疾病的免疫治疗与疫苗发展策略

简要介绍了EB病毒的感染类型及机体对不同类型EB病毒感染的免疫反应,并对EB病毒相关疾病的免疫治疗手段和疫苗发展策略进行了评述。     

Intrinsic disorder mediates hepatitis C virus core–host cell protein interactions

Viral proteins bind to numerous cellular and viral proteins throughout the infection cycle. However, the mechanisms by which viral proteins interact with such large numbers of factors remain unknown. Cellular proteins that interact with multiple, distinct partners often do so through short sequences known as molecular recognition features (MoRFs) embedded within intrinsically disordered regions (IDRs). In this study, we report the first evidence that MoRFs in viral proteins play a similar role in targeting the host cell. Using a combination of evolutionary modeling, protein–protein interaction analyses and forward genetic screening, we systematically investigated two computationally predicted MoRFs within the N‐terminal IDR of the hepatitis C virus (HCV) Core protein. Sequence analysis of the MoRFs showed their conservation across all HCV genotypes and the canine and equine Hepaciviruses. Phylogenetic modeling indicated that the Core MoRFs are under stronger purifying selection than the surrounding sequence, suggesting that these modules have a biological function. Using the yeast two‐hybrid assay, we identified three cellular binding partners for each HCV Core MoRF, including two previously characterized cellular targets of HCV Core (DDX3X and NPM1). Random and site‐directed mutagenesis demonstrated that the predicted MoRF regions were required for binding to the cellular proteins, but that different residues within each MoRF were critical for binding to different partners. This study demonstrated that viruses may use intrinsic disorder to target multiple cellular proteins with the same amino acid sequence and provides a framework for characterizing the binding partners of other disordered regions in viral and cellular proteomes.     

Evaluation in mice of the immunogenicity and protective efficacy of a tetravalent subunit vaccine candidate against dengue virus

A dengue vaccine must induce protective immunity against the four serotypes of the virus. Our group has developed chimeric proteins consisting of the protein P64k from Neisseria meningitidis and the domain III from the four viral envelope proteins. In this study, the immunogenicity of a tetravalent vaccine formulation using aluminum hydroxide as adjuvant was evaluated in mice. After three doses, neutralizing antibody titers were detected against the four viral serotypes, the lowest seroconversion rate being against dengue virus serotype 4. One month after the last dose, immunized animals were challenged with infective virus, and partial but statistically significant protection was found to have been achieved. Based on these results, further studies in mice and non‐human primates using this tetravalent formulation in a prime‐boost strategy with attenuated viruses are strongly recommended.     

抗白念珠菌感染的疫苗及抗体研究进展

白念珠菌是与人类共生的条件致病真菌,能引起免疫力低下患者皮肤黏膜和全身系统性持续感染.系统性念珠菌病是引起免疫力低下患者死亡的主要原因之一.由于临床缺乏念珠菌病的早期诊疗手段、可用的抗真菌药物种类有限且毒副作用大、耐药菌株越来越普遍、新药研发难度大等因素,抗真菌治疗依然面临着严峻挑战.目前有较多研究者致力于阐明白念珠菌感染的宿主免疫应答机制,并试图研发抗白念珠菌感染的免疫治疗方法,使免疫治疗有望成为预防和治疗真菌感染的有效手段.该文将几种抗白念珠菌感染的疫苗和抗体研究进展作简要概述,旨在为新型抗白念珠菌感染疫苗及抗体的研究提供参考.     

Cytokine GM-CSF genetic adjuvant facilitates prophylactic DNA vaccine against pseudorabies virus through enhanced immune responses

Granulocyte/macrophage colony-stimulatory factor (GM-CSF) is an attractive adjuvant for a DNA vaccine on account of its ability to recruit antigen-presenting cells (APCs) to the site of antigen synthesis as well as its ability to stimulate the maturation of dendritic cells (DCs). This study evaluated the utility of GM-CSF cDNA as a DNA vaccine adjuvant for glycoprotein B (gB) of pseudorabies virus (PrV) in a murine model. The co-injection of GM-CSF DNA enhanced the levels of serum PrV-specific IgG with a 1.5-to 2-fold increase. Moreover, GM-CSF co-injection inhibited the production of IgG2a isotype. However, it enhanced production of an IgG1 isotype resulting in humoral responses biased to the Th2-type against PrV antigen. In contrast, the co-administration of GM-CSF DNA enhanced the T cell-mediated immunity biased to the Th1-type, as judged by the significantly higher level of cytokine IL-2 and IFN-gamma production but not IL-4. When challenged with a lethal dose of PrV, the GM-CSF co-injection enhanced the resistance against a PrV infection. This suggests that co-inoculation with a vector expressing GM-CSF enhanced the protective immunity against a PrV infection. This immunity was caused by the induction of increased humoral and cellular immunity in response to PrV antigen.     

Fish DNA vaccine against infectious hematopoietic necrosis virus: efficacy of various routes of immunisation

The DNA vaccine, pIHNVw-G, contains the gene for the glycoprotein (G) of the rhabdovirus infectious hematopoietic necrosis virus (IHNV), a major pathogen of salmon and trout. The relative efficacy of various routes of immunisation with pIHNVw-G was evaluated using 1.8 g rainbow trout fry vaccinated via intramuscular injection, scarification of the skin, intraperitoneal injection, intrabuccal administration, cutaneous particle bombardment using a gene gun, or immersion in water containing DNA vaccine-coated beads. Twenty-seven days after vaccination neutralising antibody titres were determined, and 2 days later groups of vaccinated and control unvaccinated fish were subjected to an IHNV immersion challenge. Results of the virus challenge showed that the intramuscular injection and the gene gun immunisation induced protective immunity in fry, while intraperitoneal injection provided partial protection. Neutralising antibodies were not detected in sera of vaccinated fish regardless of the route of immunisation used, suggesting that cell mediated immunity may be at least partially responsible for the observed protection.