Antibody responses to early antigens of varicella-zoster virus (VZV) during varicella and zoster

The antibody responses to membrane and early antigens and thymidine kinase of varicella-zoster virus (VZV) were studied in sera during both varicella and zoster by a test with fluorescent antibody to membrane antigen (FAMA), staining the biochemically transformed cells by the immunofluorescent technique and neutralization of virus-specific thymidine kinase activity, respectively. Similar increases in FAMA antibody titers were demonstrated in sera from patients with varicella and zoster. IgM was detected in both groups, but appeared earlier during varicella than during zoster. Furthermore, the antibody titers to early antigens and virus-specific thymidine kinase were higher in patients with zoster than in those with varicella. These data suggest that different types of antibody responses occur during varicella and zoster.     

Varicella-zoster virus (VZV)

Varicella-zoster virus (VZV) causes varicella in primary infection and zoster after reactivation from latency. Both herpes simplex virus (HSV) and VZV are classified into the same alpha-herpesvirus subfamily. Although most VZV genes have their HSV homologs, VZV has many unique biological characteristics. In this review, we summarized recent studies on 1) animal models for VZV infection and outcomes from studies using the models, including 2) viral dissemination processes from respiratory mucosa, T cells, to skin, 3) cellular receptors for VZV entry, 4) functions of viral genes required uniquely for in vivo growth and for establishment of latency, 5) host immune responses and viral immune evasion mechanisms, and 6) varicella vaccine and anti-VZV drugs.     

Simian varicella virus antibody response in experimental infection of African green monkeys

Abstract: The humoral immune response to simian varicella virus (SVV) was investigated following primary and secondary experimental infection of African green monkeys. Neutralization and immunoprecipitation assays were used to determine antibody titers to SVV throughout the course of infection. The immune response to specific viral polypeptides was analyzed by immunoprecipitation analysis. The results demonstrate that the simian varicella model offers a useful approach to investigate immune mechanisms in human varicella zoster virus (VZV) infections.     

Anticomplement immunofluorescence for the titration of antibody to varicella-zoster virus

Anticomplement immunofluorescence (ACIF) was tested for its use for the titration of antibody against varicella-zoster virus (VZV). ACIF antibody responses of patients with VZV infection were specific for VZV antigen and heterotypic responses to herpes simplex virus type-1 and cytomegalovirus antigens were not observed. Comparative studies of ACIF, membrane immunofluorescence (MIF) and indirect immunofluorescence (IF), using acetone-fixed antigen, were carried out with nonimmune sera and convalescent sera of patients who had recovered from varicella, herpes zoster and Rumsey Hunt disease. Nonspecific staining occurred with some nonimmune sera at a 1:4 dilution in the MIF and IF tests, after freezing and thawing of the serum, but not in the ACIF test. The antibody titers in convalescent sera agreed well in these three methods and the highest titer was obtained by MIF. The titers in ACIF and IF were similar but the ACIF antibody decreased earlier than the IF antibody during convalescence. On the other hand there was a discrepancy between the titers of ACIF and those of MIF and IF antibody in the sera of healthy adults, all sera with titers higher than 10 in the MIF and IF tests had titers below 10 in the ACIF test. The average titer of ACIF antibody declined to less than 10 with increasing age (13 to more than 20 years), whereas the MIF antibody increased during the same period of life.     

A five-year immunological follow-up study of the institutionalized handicapped children vaccinated with live varicella vaccine or infected with natural varicella

Twenty-two institutionalized handicapped children who were susceptible to varicella were vaccinated with live varicella vaccine of the Oka strain and their immune status was followed for 5 years under conditions without exposure to natural varicella. Simultaneously, 7 children infected with natural varicella were followed. Of the 22 vaccinees, 16 showed sero-positive conversion by the fluorescent antibody to membrane antigen (FAMA) test, the other 6 remaining seronegative during 5 years of observation period. All the 16 cases showing seroconversion had detectable antibody for 5 years after vaccination, and 14 of them gave a positive reaction in the varicella skin test. All the 7 cases after natural varicella gave positive reactions in both the FAMA and skin test. These results suggest that immunity conferred by the vaccination would persist long even in the absence of exposure to natural varicella, though further follow-up studies are needed.     

Perspectives on optimal control of varicella and herpes zoster by mass routine varicella vaccination

Herpes zoster arises from reactivation of the varicella–zoster virus (VZV), causing varicella in children. As reactivation occurs when cell-mediated immunity (CMI) declines, and there is evidence that re-exposure to VZV boosts CMI, mass varicella immunization might increase the zoster burden, at least for some decades. Fear of this natural zoster boom is the main reason for the paralysis of varicella immunization in Europe. We apply optimal control to a realistically parametrized age-structured model for VZV transmission and reactivation to investigate whether feasible varicella immunization paths that are optimal in controlling both varicella and zoster exist. We analyse the optimality system numerically focusing on the role of the cost functional, of the relative zoster–varicella cost and of the planning horizon length. We show that optimal programmes will mostly be unfeasible for public health owing to their complex temporal profiles. This complexity is the consequence of the intrinsically antagonistic nature of varicella immunization programmes when aiming to control both varicella and zoster. However, we show that gradually increasing—hence feasible—vaccination schedules can perform better than routine programmes with constant vaccine uptake. Finally, we show the optimal profiles of feasible programmes targeting mitigation of the post-immunization natural zoster boom with priority.     

The impact of demographic changes on the epidemiology of herpes zoster: Spain as a case study

Varicella zoster virus (VZV) causes varicella upon first exposure and may reactivate later in life into herpes zoster (HZ), with a risk that is thought to be reduced by re-exposures to VZV. Given the decades-long time scales of reactivation and its dependence on the accumulation of re-exposure episodes, adopting a long-term perspective may be useful to correctly interpret current epidemiological trends of VZV. In this study, we investigate the possible impact of demographic changes on varicella and HZ in Spain, using an age-structured mathematical model informed with historical demographic data and calibrated against age-specific profiles of varicella seroprevalence and HZ incidence data. The model qualitatively reproduces the remarkable growth of HZ incidence observed in Spain between 1997 and 2004, before the introduction of varicella vaccination programmes. We demonstrate that this growth may be partially ascribed to the reduction of varicella circulation that followed the overall decline of the birth rate in the twentieth century. Model predictions further suggest that, even under the most optimistic projections, HZ incidence will continue its rise until at least 2040. Considering the effect of demographic changes can help interpreting variations in epidemiological trends of HZ, contributing to a more accurate evaluation of vaccination programmes against VZV.     

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.     

Immune response induced by live attenuated varicella vaccine and short term follow-up on immunity of the vaccinated children

Live attenuated varicella vaccine (Oka strain, 500 to 750 PFU) was inoculated into 234 children with various underlying diseases. Varicella-zoster virus (VZV) specific immune adherence hemagglutination antibody developed in 95% of initially seronegative subjects. VZV specific cellular immune responses were detected in 91% of subjects within 6 weeks after vaccination. A preliminary survey of 46 vaccinated normal-risk subjects during the first and the third year revealed excellent protection with the exception of one case who had not shown any antibody response at the fourth week.     

Herpes Zoster Risk Reduction through Exposure to Chickenpox Patients: A Systematic Multidisciplinary Review

Varicella-zoster virus (VZV) causes chickenpox and may subsequently reactivate to cause herpes zoster later in life. The exogenous boosting hypothesis states that re-exposure to circulating VZV can inhibit VZV reactivation and consequently also herpes zoster in VZV-immune individuals. Using this hypothesis, mathematical models predicted widespread chickenpox vaccination to increase herpes zoster incidence over more than 30 years. Some countries have postponed universal chickenpox vaccination, at least partially based on this prediction. After a systematic search and selection procedure, we analyzed different types of exogenous boosting studies. We graded 13 observational studies on herpes zoster incidence after widespread chickenpox vaccination, 4 longitudinal studies on VZV immunity after re-exposure, 9 epidemiological risk factor studies, 7 mathematical modeling studies as well as 7 other studies. We conclude that exogenous boosting exists, although not for all persons, nor in all situations. Its magnitude is yet to be determined adequately in any study field.     

建立膜抗原荧光抗体试验评价北京株冻干水痘疫苗免疫效果

为了建立用于水痘疫苗接种后血清中特异性抗体检测的膜抗原荧光抗体(FAMA)法,并对接种水痘疫苗后儿童血清中水痘特异性抗体进行检测,评价北京株水痘疫苗的免疫效果。以水痘带状疱疹病毒(VZV)感染细胞作为抗原制备成固定抗原玻片,以异硫氰酸荧光素(FITC)标记的羊抗人IgG作为二抗建立FAMA法,并对该法的敏感性、特异性进行验证。运用此法对不同剂量北京株水痘疫苗接种后儿童血清中特异性抗体进行检测,分析儿童血清中水痘特异性抗体水平以及免后抗体阳转率,并与Oka株水痘疫苗进行比较。结果显示,FAMA法敏感性可达0.0196IU/ml,特异性好。应用此法检测300名观察者免前免后双份血清样本中抗VZVIgG,易感者中北京株水痘疫苗原苗(39810PFU/0.5ml)、2000PFU/0.5ml、500PFU/0.5ml接种组儿童血清免后抗体阳转率分别为100%、98.77%、85.42%,抗体几何平均滴度(GMT)分别为36.4、34.3、18.6,原苗与2000PFU间的抗体阳转率和GMT均无显著性差异(P>0.05),但原苗与500PFU、2000PFU与500PFU间的抗体阳转率和GMT均有显著性差异(P<0.05)。对照国产、进口Oka株水痘疫苗接种后抗体阳转率分别为95.35%、96.97%,抗体GMT分别为13.3、16.0,不同剂量北京株疫苗抗体阳转率与国产、进口Oka株疫苗相比,差别无显著性(P>0.05),但北京株疫苗原?     

Modeling the effects of varicella vaccination programs on the incidence of chickenpox and shingles

Two possible dangers of an extensive varicella vaccination program are more varicella (chickenpox) cases in adults, when the complication rates are higher, and an increase in cases of zoster (shingles). Here an age-structured epidemiologic—demographic model with vaccination is developed for varicella and zoster. Parameters are estimated from epidemiological data. This mathematical and computer simulation model is used to evaluate the effects of varicella vaccination programs. Although the age distribution of varicella cases does shift in the simulations, this does not seem to be a danger because many of the adult cases occur after vaccine-induced immunity wanes, so they are mild varicella cases with fewer complications. In the simulations, zoster incidence increases in the first three decades after initiation of a vaccination program, because people who had varicella in childhood age without boosting, but then it decreases. Thus the simulations validate the second danger of more zoster cases.     

Clinical application of a live varicella vaccine (Oka strain) in a hospital

A total of 239 children, including 22 high-risk children and 55 non-high risk diseased children have been immunized with a live varicella vaccine (Oka strain) since June, 1978. No clinical reaction attributable to the vaccine has been observed. Of these children, 87 received emergency vaccination. Of 47 children receiving emergency vaccination because they had been in contact with varicella patients either in hospital, school or a playground, only 5 developed varicella and their symptoms were mild. Of 40 children receiving emergency vaccination because of exposure to varicella in their home, 10 developed mild varicella and 30 were protected. Clinical symptoms of varicella when seen seemed to be due to incomplete protection because the vaccine was given too late rather than to clinical reactions to the vaccine. During follow-up period of 6 to 66 months after vaccination, 8 children showed very mild rashes without fever as the result of exogenous varicella infection.     

Varicella zoster virus encephalitis during treatment with anti-tumor necrosis factor-alpha agent in a psoriatic arthritis patient

The introduction of targeted immunotherapies has greatly improved the therapeutic options of several inflammatory diseases such as psoriatic arthritis. However treatment-related opportunistic infections and viral reactivations may still occur. We describe a case of varicella zoster virus (VZV) encephalitis due to the reactivation of latent VZV infection during a long therapy with the anti-tumor necrosis factor-alpha (TNF-alpha) drug Adalimumab. The low incidence of VZV encephalitis in patients treated with biological agents does not justify VZV serological screening in these subjects, but careful monitoring of the patients is recommended to recognize early signs and symptoms of herpes zoster to start prompt antiviral therapy to prevent associated complications.     

Quantifying the re-exposure process to an infectious agent. Measles and Varicella as examples

Background and objectives

For viral infections conferring what is usually considered as permanent immunity, re-exposure to the pathogen due to contacts with infectious individuals might be critical for immunity boosting. A major example is represented by the varicella-zoster virus (VZV) where re-exposure is thought to lead to boosting of cell mediated immunity (CMI), which plays a protective role against the development of herpes zoster (HZ). Similar concerns have recently been raised also in relation to measles. However, while the first effective exposure, i.e. infection, has been the object of many studies, both theoretical and epidemiological, there has been no corresponding investigation of the re-exposure process.

Methodology and data

By combining basic concepts from deterministic and stochastic modelling of infection, we develop a basic model for quantifying the timing and number of re-exposures and, consequently, the potential for immune boosting at any given age. The model is then applied to measles, mumps and rubella (MMR) in the UK, and to varicella in Italy, using literature estimates of the pre-vaccination forces of infection.

Results

We supply analytical expressions for the expected number of lifetime re-exposures and for underlying age-patterns, including the average age at which the last re-exposure occurs. Based on updated estimates of the force of VZV infection, we show that the expected number of boosting opportunities of CMI might be in the range 2–3, which is consistent with recent findings about the development of herpes zoster. We also show that the estimate of the age at which the last re-exposure to VZV occurs is highly sensitive to the underlying form of age dependence of the force of infection.

Conclusions

Our results contribute to the study of the potential immunity boosting effect of re-exposures to an infective agent by quantifying the re-exposure process.     

Successful infection of the common marmoset (Callithrix jacchus) with human varicella-zoster virus.

The common marmoset, Callithrix jacchus, can be infected with human varicella-zoster virus (VZV), both wild-type strain KMcC and attenuated vaccine strain Oka/Merck. Infection was accomplished with either whole-cell-associated or cell extract VZV by combined oral-nasal-conjunctival application and was characterized by substantial and persistent anti-VZV antibody responses. The infectivity of VZV for marmosets was destroyed by treatment of inocula with heat or UV light. Diluted inocula with as few as 40 PFU/ml were infectious for marmosets. The lungs were demonstrated to be a major site of viral replication; both the presence of viral antigens and signs of pneumonia were demonstrated in lung tissues. Four serial passages of VZV KMcC were carried out in C. jacchus by a process of in vitro isolation and culturing of VZV from infected lung tissue and reapplication of the cultured isolates to fresh animals. The isolated viruses were identified as VZV both serologically and by restriction endonuclease analyses. The C. jacchus infectivity model should prove useful for determining the efficacy of subunit and live recombinant VZV vaccines as well as for the study of zoster.     

Perspectives on the Impact of Varicella Immunization on Herpes Zoster. A Model-Based Evaluation from Three European Countries

The introduction of mass vaccination against Varicella-Zoster-Virus (VZV) is being delayed in many European countries because of, among other factors, the possibility of a large increase in Herpes Zoster (HZ) incidence in the first decades after the initiation of vaccination, due to the expected decline of the boosting of Cell Mediated Immunity caused by the reduced varicella circulation. A multi-country model of VZV transmission and reactivation, is used to evaluate the possible impact of varicella vaccination on HZ epidemiology in Italy, Finland and the UK. Despite the large uncertainty surrounding HZ and vaccine-related parameters, surprisingly robust medium-term predictions are provided, indicating that an increase in HZ incidence is likely to occur in countries where the incidence rate is lower in absence of immunization, possibly due to a higher force of boosting (e.g. Finland), whereas increases in HZ incidence might be minor where the force of boosting is milder (e.g. the UK). Moreover, a convergence of HZ post vaccination incidence levels in the examined countries is predicted despite different initial degrees of success of immunization policies. Unlike previous model-based evaluations, our investigation shows that after varicella immunization an increase of HZ incidence is not a certain fact, rather depends on the presence or absence of factors promoting a strong boosting intensity and which might or not be heavily affected by changes in varicella circulation due to mass immunization. These findings might explain the opposed empirical evidences observed about the increases of HZ in sites where mass varicella vaccination is ongoing.     

Comparison of 4 serological tests--complement fixation, neutralization, fluorescent antibody to membrane antigen and immune adherence hemagglutination--for assay of antibody to varicella-zoster (V-Z) virus.

Four tests for antibody to varicella-zoster (V-Z) virus were compared; these were tests of complement fixation (CF), neutralization (NT), fluorescent antibody to membrane antigen (FAMA) and immune adherence hemagglutination (IAHA). Fifty-two sera from patients with varicella and zoster and from recipients of live varicella vaccine were examined by the 4 tests. The CF test was least sensitive, but the antibody titers by the NT, FAMA and IAHA tests were roughly comparable. The IAHA test was the simplest and fastest to perform, and appeared suitable for routine serological assay to V-Z virus. The correlation between the IAHA antibody titer and susceptibility of individuals to clinical varicella was investigated retrospectively using sera obtained during 2 outbreaks of varicella in an institution for children, where all the unvaccinated children had developed varicella symptoms. Most of the 25 pre-exposure sera from unvaccinated children examined by the IAHA test had tiers of less than 1:2. In contrast, all the 23 sera from vaccinated children who did not develop varicella had detectable antibody titers of 1:2 to 1:64. These results indicate that the IAHA titer reflects the susceptibility or resistance of individuals to clinical varicella.     

T lymphocyte cytotoxicity with natural varicella-zoster virus infection and after immunization with live attenuated varicella vaccine

Varicella-zoster virus (VZV) specific cytotoxicity was investigated during acute primary VZV infection, in naturally immune subjects and after vaccination with the live attenuated varicella vaccine by using T cell cultures (TCC) generated by stimulating PBMC with VZV Ag and autologous VZV-superinfected lymphoblastoid cell lines as targets. Lysis of VZV-infected lymphoblastoid cell lines was observed by TCC from acutely infected subjects, naturally immune subjects, and recipients of the varicella vaccine. VZV glycoprotein I induced cytotoxic T cells but killing was less efficient than killing by TCC stimulated with VZV Ag. The TCC were primarily CD4+ (mean 86.6%) T lymphocytes with 15.2% of the cells coexpressing Leu-19. TCC were predominantly restricted by HLA class II as demonstrated by lack of any blocking using class I mAb and blocking of 15 to 71% by L243, a mAb to class II. Unrestricted killing as measured by killing of K562 cells occurred in all TCC but was minimally greater than that observed against uninfected autologous targets. Phenotypes of PBMC during acute infection had an initial increase in CD4+ cells and an overall decrease in the percentage of circulating Leu-11+ (CD16). No enhanced K562 killing was demonstrated in PBMC from subjects with acute infection compared to subjects without infection. CD4+ CTL may function as an important primary host response in acute varicella. Immunization with live attenuated varicella vaccine induced VZV-specific, memory CTL responses comparable to those of naturally immune subjects. The demonstration of their persistence long after primary VZV infection may indicate a role for CTL in restriction of viral replication during episodes of VZV reactivation from latency.