Use of a current varicella vaccine as a live polyvalent vaccine vector

Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The varicella vaccine was developed to control VZV infection in children. The currently available Oka vaccine strain is the only live varicella vaccine approved by the World Health Organization. We previously cloned the complete genome of the Oka vaccine strain into a bacterial artificial chromosome vector and then successfully reconstituted the virus. We then used this system to generate a recombinant Oka vaccine virus expressing mumps virus gene(s). The new recombinant vaccine may be an effective polyvalent live vaccine that provides protection against both varicella and mumps viruses. In this review, we discussed about possibility of polyvalent live vaccine(s) using varicella vaccine based on our recent studies.     

The postmarketing safety profile of varicella vaccine

The postmarketing safety profile of varicella vaccine was evaluated by analyzing selected adverse experience reports temporally associated with the administration of the vaccine. There were 7963 reports voluntarily submitted to Merck for an overall reporting rate of 5.0 per 10000 doses of vaccine distributed. A varicella zoster virus (VZV) identification program detected the presence of the Oka vaccine strain in three individuals with an immune deficiency - two with pneumonia and one with hepatitis - and in three instances of secondary transmission from vaccinees with vesicular lesions to susceptible household contacts. The Oka vaccine strain was present in 23 patients and wild-type VZV was present in 15 patients with herpes zoster. Vesicular rashes that occurred within 2 weeks of vaccination were more likely to contain the presence of wild-type VZV, while vesicular rashes that occurred more than 2 weeks post-vaccination were more likely to contain the Oka vaccine strain. Eleven patients were hospitalized with complications of breakthrough varicella infection.     

Transmission of varicella vaccine virus to a non-family member in China

A 23-year-old teacher presented to hospital with a mild case of varicella. VZV vaccine strain vOka that resembles Varilrix but not Varivax or Biken strains was isolated from the skin lesion of the patient and was identified by single nucleotide polymorphism (SNP) analysis. The teacher denied having varicella vaccine before. Retrospective analysis suggests the transmission came from a pupil who developed zoster 13 months after varicella vaccine Varilrix. This is the first report in China in which an adult with varicella was attributable to vaccine virus and the 6th report of transmission of vaccine virus to a susceptible adult around the world.     

Summary of the multidisciplinary guideline 'Varicella'

The multidisciplinary guideline 'Varicella' provides guidelines for diagnosis, therapy, and prevention of chickenpox. At the first pregnancy check, patients should be questioned about previous chickenpox; in case of a negative or doubtful history varicella zoster virus (VZV) serology is indicated. VZV antibody determination is also indicated in patients considered for immunosuppressive therapy and for healthcare workers with a negative VZV history who are in contact with immunocompromised patients. Administration of VZV immunoglobulin within 96 hours following VZV contact can mitigate the infection in pregnant women and patients with T-cell deficiency. VZV immunoglobulin treatment should be considered for newborn infants of mothers who developed chickenpox in the period from five days before to two days after delivery. Antivirals can reduce the severity of infection and are safe during pregnancy. Varicella vaccine protects against chickenpox, but is contraindicated in immunocompromised patients and pregnant women.     

水痘疫苗及其免疫策略

水痘是由水痘-带状疱疹病毒(VZV)引起的儿童期高度传染性疾病。世界各地都有发生。VZV初次感染后可在体内建立潜伏感染,以后可被激活引起带状疱疹。1974年研制成功的水痘减毒活疫苗对预防和控制水痘有着重要作用。该文介绍了水痘疫苗的由来、安全性、免疫效果和免疫策略等。     

Case report: occupationally related recurrent varicella (chickenpox) in a hospital nurse

Commonly accepted outcomes of varicella-zoster virus (VZV) infections include chickenpox (primary) and shingles (recurrence or latency), as well lifetime immunity against chickenpox. We report the case of a registered nurse who worked in a neurologic surgery ward in a general hospital in Taipei, Taiwan. While working there for approximately 1 year, she developed recurrent chickenpox after caring for a paraparesis patient, who had herpes zoster during hospitalization in August 2002. The varicella incubation period was 10 days, which matched the range (10-21 days). Recently negative specific serum IgM and positive specific serum IgG indicated a past VZV infection. The nurse did not get herpes zoster from the second episode of varicella on 9 August 2002 to 4 April 2005 and is now convalescing. We conclude that occupational VZV hazards exist in the health care environment and suggest testing for VZV antibody and a VZV vaccination program for susceptible health care workers. Key words: chickenpox, indirect fluroscent antibody, occupational exposure, polymerase chain reaction, shingles, Taiwan, varicella-zoster virus.     

贵州省20例水痘患者水痘-带状疱疹病毒基因型分析

目的 了解贵州省20例水痘患者流行的水痘-带状疱疹病毒(VZV)主要基因型别,为水痘疫情的防控提供科学依据。 方法 收集20份临床诊断水痘患者血清标本、咽拭子或水疱液标本,分别用ELISA法检测VZV IgM抗体、实时荧光定量PCR检测VZV特异性核酸、普通PCR扩增VZV开放阅读框(ORF)22核酸片段,用BioEdit和MEGA 4软件分析测序结果,并与Genbank上VZV参考株序列比较,进行生物信息学分析。 结果 20份临床诊断病例VZV IgM抗体检测均为阳性,其中7份咽拭子或水疱液标本实时荧光定量PCR检测为阳性,3例标本的PCR产物在约447bp处有明显目的条带,测序证实为水痘-带状疱疹病毒。ORF22基因的单核苷酸多态性(SNP)分析显示,GZVZV001和GZVZV007核酸片段完全一致,GZVZV002序列在37922位点出现R碱基取代G碱基。3株分离株序列与J基因型参考株p-OKa序列比较,一致性为99%~100%,与E基因型参考株DUMAS序列比较,在6个关键位点上有4个碱基不一致,与M1基因型参考株CA123比较,6个关键位点上有3个碱基不一致。提示3株分离株为VZV J基因型。 结论 贵州省目前VZV流行的野毒株型别中存在J基因型,加强VZV疫苗的接种能有效防止水痘的爆发流行。     

Humoral immunoresponse to varicella-zoster virus pernasally coadministered with Escherichia coli enterotoxin in mice

It is evaluated whether Escherichia coli enterotoxin is useful for induction of immunity to varicella-zoster virus (VZV) as a mucosal adjuvant in mice. When a commercially available live varicella vaccine (Oka strain) and toxin were administered simultaneously via a nasal route three times at 2 or 6 month intervals, an antibody neutralizing VZV was detected in half or all of the mice vaccinated, respectively. The antibody specific to the vaccine strain of VZV reacted to five proteins, molecular weights of which were 110 K, 100 K, 62 K, 54 K and 46 K. These proteins were composed of glycosylated products of all kinds of glycoproteins. These results suggest that although a nasal administration of the vaccine without the adjuvant has little immunogenicity in mice, the simultaneous administration of the live vaccine and the toxin over a long period induces a specific humoral immunity to VZV.     

国产和进口水痘疫苗免疫效果对比研究

[目的 ]　比较国产和进口水痘疫苗免疫效果 ,了解宝山区儿童水痘—带状疱疹病毒 (VZV)自然感染情况。　[方法 ]　随机选择 2 6 5名无水痘病史的 0～ 7岁儿童调查血清抗VZV -IgG阳性率 ;选择 84名 1～ 2岁VZV易感儿童随机分成两组 ,分别接种国产和进口水痘疫苗 ,免疫后 6周采血 ,用酶联免疫吸附试验检测抗VZV -IgG。　 [结果 ]　 1～ 7岁儿童抗VZV -IgG阳性率分别为 2 .0 0 %、11.11%、2 0 .0 0 %、17.6 5 %、30 .77%、40 .0 0 %、32 .14 % ;免前抗VZV -IgG阴性儿童 ,分别接种国产和进口水痘疫苗后 ,抗体阳转率分别为 90 .70 % ( 39/43)和 95 .12 % ( 39/41) ,两者差别无显著性 ;两种疫苗的抗VZV-IgG几何平均滴度倒数 (GMRT)分别为 2 0 4.848( 95 %CI190 .73～ 2 6 0 4.79)和 482 .6 9( 95 %CI93.30～ 2 497.5 ) ,进口疫苗GMRT略高于国产疫苗。　 [结论 ]　宝山区婴幼儿 6个月内部分存在VZV -IgG母体免疫 ,7个月后母体免疫消失 ;国产水痘疫苗免疫效果良好 ,本区 1～ 7岁儿童是易感人群 ,尤其是 1～ 4岁易感儿童适宜接种     

Superiority of varicella skin test antigen over purified varicella-zoster virus glycoproteins in monitoring booster response to Oka varicella vaccine

Varicella skin test antigen has been developed based on the induction of delayed-type hypersensitivity (DTH) to varicella-zoster virus (VZV). The booster immune response to Oka varicella vaccine was assessed by cutaneous reactivity to purified VZV glycoprotein complexes, gB, gE:gI, gH:gL, and varicella skin test antigen. Skin tests with these antigens significantly augmented antibody production to glycoproteins and VZV antigen resulting in no further augmentation by the subsequent vaccination. All glycoprotein complexes induced the cutaneous reaction similarly to varicella skin test antigen. Cutaneous reaction to glycoproteins and varicella skin test antigen was boosted after vaccination. However, the magnitude of cutaneous reaction to each glycoprotein complex before and after vaccination was rich in variety. These results indicated that skin test with varicella skin test antigen is a more suitable indicator in monitoring cell-mediated immunity to VZV than that using purified glycoproteins.     

An analysis of infection control of varicella-zoster virus infections in Addenbrooke's Hospital Cambridge over a 5-year period, 1987-92.

This prospective study analyses infections with varicella-zoster virus (VZV) in Addenbrooke''s Hospital, Cambridge during 1987-92 and examines the spread of infection. In total, 93 patients and staff experienced VZV infection. Twenty-one patients had varicella and 49 experienced zoster. None of 101 patients and 1 of 625 staff members in contact with varicella cases acquired infection. By contrast, 2 of 227 patients, and 5 of 1039 staff in contact with zoster cases acquired varicella. One out of 28 (3.6%) VZV antibody-negative patients and staff in contact with varicella acquired infection, compared with 5 out of 29 (17.2%) VZV antibody-negative patients and staff in contact with zoster. Thus, zoster was found to be a more frequent cause of nosocomial infection than varicella. Fourteen members of staff had VZV infection during the study period. One of 99 patients and none of 389 staff members in contact with these cases developed varicella. The cost of dealing with infection control for VZV infections in our hospital is estimated to be Pounds 714 per patient case and a total of Pounds 13,204 per year.     

Varicella seroepidemiology in United States air force recruits: A retrospective cohort study comparing immunogenicity of varicella vaccination and natural infection

Background/ObjectivesInfection with varicella zoster virus (VZV) produces lifelong immunity, but duration of post-vaccination immunity has not been established. The purpose of this study is to determine if a difference exists in the long-term seropositivity of anti-VZV antibodies in a cohort of young adults who were vaccinated against varicella as compared to a similar cohort with a history of chickenpox disease, and to determine which variables best predict waning seropositivity following varicella vaccination.MethodsThis retrospective cohort study captures immunization and serology data from approximately 10,000 recruits who entered basic military training between January 1, 2008, and December 31, 2015, and who have childhood immunization records in the Air Force Aeromedical Services Information Management System. Varicella vaccine immunogenicity was determined relative to the immunogenicity of chickenpox disease, as measured by multiplex flow immunoassay. Among vaccine recipients, waning seroimmunity was modeled and adjusted for several important covariates.ResultsBasic military trainees who received varicella vaccine in childhood were 24% less likely to be seropositive to VZV than trainees who were exempt from vaccine due to a history of chickenpox disease. There was no significant difference in seropositivity between male and female trainees. The odds of a vaccinated trainee being seropositive to VZV decreased by 8% with each year elapsed since vaccination. Seroprevalence declined below estimated herd immunity thresholds in vaccinated trainees born after 1994, and in the cohort as a whole for trainees born after 1995.ConclusionDespite prior vaccination, seroimmunity in a large cohort of young adults unexposed to wild-type VZV failed to meet the estimated threshold for herd immunity. If vaccination in accordance with the current US VZV vaccination schedule is inadequate to maintain herd immunity, young adults not previously exposed to wild-type VZV may be at increased risk for varicella outbreaks.     

DNA sequence analysis of varicella-zoster virus gene 62 from subclinical infections in healthy children immunized with the Oka varicella vaccine

A live attenuated varicella vaccine, the Oka vaccine strain (vOka), is routinely administered to children in Japan and other countries, including the United States. vOka consists of a mixture of genotypically distinct variants, but little is known about the growth potential of each variants in vivo. We isolated varicella-zoster virus (VZV) DNA sequences from the peripheral blood mononuclear cells (PBMCs) of asymptomatic healthy children immunized with the Oka varicella vaccine. VZV gene 62 DNA fragments were detected in 5 of 166 (3.0%) PBMC samples by nested PCR within 5 weeks of the vaccination. Sequence analysis of VZV DNA from these five PBMC samples indicated that multiple viral clones in the vaccine could infect vaccinees and replicate in vivo. We also provide evidence that a nonsynonymous substitution at position 105356 may affect viral replication in vivo.     

人群水痘—带状疱疹病毒流行率及发病状况分析

为了解本辖区现阶段健康人群水痘 -带状疱疹病毒 (VZV)流行情况 ,采用酶联免疫吸附实验 (ELISA)分别对本地以及外来人员共 40 7名 1～ 50岁健康人群VZV的血清流行病学情况进行检测 ,同时根据 2 0 0 2始纳入国家传染病管理信息系统报告的天河区水痘发病状况进行统计分析。结果显示 :人群中血清抗VZV -IgG阳性率平均为 61 7% ,年龄别流行率 1～ 2岁、3～ 6岁、7～ 1 2岁、1 3～ 1 9岁、2 0～ 2 9岁、30～ 39岁、40～ 50岁组分别为 1 4 1 %、2 4 3 %、62 0 %、85 7%、95 2 %、92 9%、1 0 0 % ,说明血清年龄别流行率以1～ 6岁组最低 ,以后随年龄增长而上升。同时对天河区 2 0 0 2～ 2 0 0 3年收到报告的 1 883例水痘病例分析表明 ,1 0岁以下儿童的发病占总病例的 79 1 % ,与所检测的人群VZV流行率相一致 ,表明婴儿、幼儿、学前班儿童、小学低年级学生为高度易感人群 ,是水痘疫苗的主要免疫对象     

Recombinant varicella vaccines induce neutralizing antibodies and cellular immune responses to SIV and reduce viral loads in immunized rhesus macaques

The development of an effective AIDS vaccine remains one of the highest priorities in HIV research. The live, attenuated varicella-zoster virus (VZV) Oka vaccine, safe and effective for prevention of chickenpox and zoster, also has potential as a recombinant vaccine against other pathogens, including human immunodeficiency virus (HIV). The simian varicella model, utilizing simian varicella virus (SVV), offers an approach to evaluate recombinant varicella vaccine candidates. Recombinant SVV (rSVV) vaccine viruses expressing simian immunodeficiency virus (SIV) env and gag antigens were constructed. The hypothesis tested was that a live, attenuated rSVV-SIV vaccine will induce immune responses against SIV in the rhesus macaques and provide protection against SIV challenge. The results demonstrated that rSVV-SIV vaccination induced low levels of neutralizing antibodies and cellular immune responses to SIV in immunized rhesus macaques and significantly reduced viral loads following intravenous challenge with pathogenic SIVmac251-CX-1.     

水痘病毒血清流行病学研究

用酶联免疫吸附试验检测了１９９８年杭州、台州２地区１３６３名０￣６３岁健康人群血清水痘带状疱疹病毒（ＶＺＶ）抗体。结果显示：ＶＺＶ抗体总阳性率为５８．４７％；男、女阳性率，不同地区阳性率，２月份、５月份、１１月份抗体阳性率均无显著性差异；〈３个月婴儿阳性率只有８．３３％；８￣１２岁，１３￣３０岁，２０岁以上阳性率分别为６３．４５％、８３．２３％和９２．５５％。表明婴儿、幼儿、学前班儿童、小学低年级     

Universal varicella vaccine immunization in Japan

In 1974, Japanese scientists developed a live attenuated varicella vaccine based on the Oka strain. The efficacy of the vaccine for the prevention of varicella has been primarily demonstrated in studies conducted in the United States following the adoption of universal immunization using the Oka strain varicella vaccine in 1996. Although the vaccine was developed by Japanese scientists, until recently, the vaccine has been administered on a voluntary basis in Japan resulting in a vaccine coverage rate of approximately 40%. Therefore, Japan initiated universal immunization using the Oka strain varicella vaccine in November 2014. Given the transition from voluntary to universal immunization in Japan, it will also be important to monitor the epidemiology of varicella and herpes zoster.The efficacy and safety of co-administration of the varicella vaccine and measles, mumps, and rubella vaccine have been demonstrated in many countries; however, there was no data from Japan. In order to adopt the practice of universal immunization using the Oka strain varicella vaccine in Japan, data demonstrating the efficacy and safety of co-administration of varicella vaccine and measles and rubella (MR) vaccine were required. Additionally, we needed to elucidate the appropriate time interval between the first and second administrations of the vaccine. It is also important to differentiate between wild type and Oka vaccine type strains in herpes zoster patient with past history of varicella vaccine. Thus, there are many factors to consider regarding the adoption of universal immunization in Japan to control varicella zoster virus (VZV) infections.     

Generation of a recombinant Oka varicella vaccine expressing mumps virus hemagglutinin-neuraminidase protein as a polyvalent live vaccine

We constructed a recombinant varicella-zoster virus (VZV) Oka vaccine strain (vOka) that contained the mumps virus (MuV) hemagglutinin-neuraminidase (HN) gene, inserted into the site of the ORF 13 gene by using the bacterial artificial chromosome (BAC) system in Escherichia coli. Insertion of the HN gene into the VZV genome was confirmed by PCR and Southern blot. The infectious virus reconstituted from the vOka-HN genome (rvOka-HN) had a growth curve similar to the original recombinant vOka without the HN gene. The mumps virus HN protein expressed in rvOka-HN infected cells was expressed diffusely in the cytoplasm, and modification of the protein was similar to that seen in MuV-infected cells. Electron microscopic examination of infected cells revealed that HN was expressed on the plasma membrane of the cells but not in the viral envelope, suggesting that the tropism of rvOka-HN would be unchanged from that of the original vOka strain. Immunization of guinea pigs with rvOka-HN-induced VZV- and HN-specific antibodies. Interestingly, the induced antibodies had a strong neutralizing activity against virus-cell infections of both MuV and VZV. Therefore, the novel varicella vaccine expressing MuV HN protein is suitable as a polyvalent live attenuated vaccine against VZV and MuV infections.     

Impact and costs of varicella prevention in a university hospital.

Information regarding all patient and staff exposures to varicella-zoster virus (VZV) was prospectively accumulated from 1/1/86 to 12/31/86 at North Carolina Memorial Hospital. During this period of time 37 sources of exposure to VZV were reported: 10 outside and 27 within the hospital. Index cases for nosocomial exposure included: 12 patients with zoster, 9 patients with varicella, two staff with varicella, three visitors with varicella, and one staff with zoster. One hundred and twenty patients received nosocomial exposures; 28 had no history of VZV infection (23 per cent), of whom 11 were serosusceptible (39 per cent). Sources of nosocomial patient exposure included: other patients (85 per cent), staff (14 per cent), and a single visitor (1 per cent). More than 300 employees received nosocomial exposure; 158 had no history of VZV infection, of whom 49 were serosusceptible (31 per cent). Only a single employee and no patients developed clinical varicella as a result of nosocomial exposure. Costs associated with VZV control during 1986 totaled $55,934: $39,658 for work furloughs, $9,800 for serologies, $4,293 for patient isolation, $155 for varicella-zoster immune globulin, and $2,028 for infection control personnel time. These costs should be considered as part of any benefit-cost analysis of varicella immunization of health care personnel.     

Antibody assays suitable for assessing immune responses to live varicella vaccine.

An enzyme-linked immunosorbent assay for antibodies to varicella-zoster virus (VZV), using purified viral glycoproteins as antigen (gpELISA), was compared with other assays for measuring vaccine-induced antibody responses. The gpELISA was more sensitive than conventional assays, proved highly specific for VZV and agreed well with an assay for neutralizing antibody activity. It was successfully applied to large-scale testing of live varicella vaccine in humans.