Search

Michiaki Takahashi developed the live attenuated varicella vaccine in 1974 . This was the first, and is still the only, herpesvirus vaccine. Early studies showed promise, but the vaccine was rigorously tested on immunosuppressed patients because of their high risk of fatal varicella; vaccination proved to be lifesaving. Subsequently, the vaccine was found to be safe and effective in healthy children. Eventually, varicella vaccine became a component of measles mumps rubella vaccine, 2 doses of which are administered in the USA to ~90% of children. The incidence of varicella has dropped dramatically in the USA since vaccine-licensure in 1995. Varicella vaccine is also associated with a decreased incidence of zoster and is protective for susceptible adults. Today, immunocompromised individuals are protected against varicella due to vaccine-induced herd immunity. Latent infection with varicella zoster virus occurs after vaccination; however, the vaccine strain is impaired for its ability to reactivate.

After 25 years of varicella vaccination in the United States, classic varicella and its complications have become an uncommon occurrence. The clinical manifestation of varicella among vaccinated persons is usually modified, with fewer skin lesions, mostly maculopapular, and milder presentation. However, the potential for severe manifestations from varicella still exists among both vaccinated and unvaccinated persons, and thus healthcare providers should keep varicella in the differential diagnosis of a maculopapular or vesicular rash. The prompt recognition and diagnosis of varicella is important because when confirmed, clinical and public health measures need to be taken swiftly.

Universal varicella vaccination might reduce opportunities for varicella-zoster virus (VZV) exposure and protective immunological boosting, thus increasing herpes zoster incidence in latently infected adults. We assessed humoral and cell-mediated immunity (CMI), as markers of VZV exposure, in adults aged ≥50 years.We repurposed data from placebo recipients in a large multinational clinical trial (ZOE-50). Countries were clustered based on their varicella vaccination program characteristics, as having high, moderate, or low VZV circulation. Anti-VZV antibody geometric mean concentrations, median frequencies of VZV-specific CD4 T cells, and percentages of individuals with increases in VZV-specific CD4 T-cell frequencies were compared across countries and clusters. Sensitivity analyses using a variable number of time points and different thresholds were performed for CMI data.VZV-specific humoral immunity from 17 countries (12 high, 2 moderate, 3 low circulation) varied significantly between countries (P .0001) but not by VZV circulation. No significant differences were identified in VZV-specific CMI between participants from 2 high versus 1 low circulation country. In 3/5 sensitivity analyses, increases in CMI were more frequent in high VZV circulation countries (.03 ≤ P .05).We found no consistent evidence of reduced VZV exposure among older adults in countries with universal varicella vaccination.NCT01165177.

Background Infants exposed to varicella zoster virus (VZV) in utero ≤5 days before or ≤48 hours after delivery and preterm infants are at high risk for varicella complications. An expanded-access program assessed varicella outcomes after administration of varicella zoster immune globulin (human) (VARIZIG) in a real-world setting. Methods In this open-label, expanded-access program, high-risk infants received ≤125 IU/10 kg of VARIZIG (NCT00338442). VZV outcomes and safety were assessed. Results There were 43 newborns exposed to VZV in utero and 80 preterm infants exposed to VZV; >80% received VARIZIG within 96 hours of reported exposure. When varicella outcomes were available, varicella occurred in 7 of 38 (18%) in utero–exposed newborns and zero of 65 preterm infants. Varicella-related complications were reported in 3 in utero–exposed newborns (3 with >100 lesions, 1 each with encephalitis and pneumonia). Adverse events were reported for 16% of in utero–exposed newborns and 25% of preterm infants, but few were considered related to VARIZIG. There were no deaths attributable to varicella or VARIZIG. Conclusions Varicella incidence and morbidity were low in in utero–exposed infants and zero in preterm infants who received prophylactic VARIZIG. There were few VARIZIG-related safety concerns., Infants born prematurely or to women who develop varicella zoster virus ≤5 days before or ≤48 hours after delivery and who were treated with varicella zoster immune globulin (VARIZIG) had a low incidence of varicella and varicella-related morbidity, regardless of administration

Varicella poses an occupational risk and a nosocomial risk for susceptible healthcare personnel and patients, respectively. Patients with varicella are thought to be infectious from 1 to 2 days before rash onset until all lesions are crusted, typically 4–7 days after onset of rash. We searched Medline, Embase, Cochrane Library and CINAHL databases to assess evidence of varicella-zoster virus (VZV) transmission before varicella rash onset. Few articles (7) contributed epidemiologic evidence; no formal studies were found. Published articles reported infectiousness at variable intervals before rash onset, between

Freedom, Measles, and Freedom from Measles False rumors about purported dangers of vaccination continue to circulate. People who reject the scientific facts about vaccines and pathogens in favor of...

IntroductionAfter infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV1 may lead to neurodegeneration and Alzheimer’s disease (AD) pathology. HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid beta-protein (Aβ) aggregation and HSV1 DNA is common in amyloid plaques. Anti-HSV drugs reduce Aβ and phosphorylated tau accumulation in cell-culture models. Cognitive impairment is greater in patients with HSV seropositive, and antiviral drugs show robust efficacy against peripheral HSV infection. Recent studies of electronic health records databases demonstrate that HSV infections increase dementia risk, and that antiviral medication treatment reduces this risk. The generic antiviral drug valacyclovir was superior to placebo in improving memory in a schizophrenia pilot trial but has not been tested in AD.Methods and analysisIn patients with mild AD who test positive for HSV1 or HSV2 serum antibodies, valacyclovir, repurposed as an anti-AD drug, will be compared with placebo (lactose pills) in 130 patients (65 valacyclovir and 65 placebo) in a randomised, double-blind, 78-week phase II proof-of-concept trial. Patients on valacyclovir, dose-titrated from 2 g to a targeted oral dose of 4 g daily, compared with placebo, are hypothesised to show smaller cognitive and functional decline, and, using18F-Florbetapir positron emission tomography (PET) and18F-MK-6240 PET imaging, to show less amyloid and tau accumulation, respectively. In the lumbar puncture subsample, cerebrospinal fluid acyclovir will be assayed to assess central nervous system valacyclovir penetration.Ethics and disseminationThe trial is being overseen by the New York State Psychiatric Institute Institutional Review Board (protocol 7537), the National Institute on Ageing, and the Data Safety Monitoring Board. Written informed consent is obtained for all subjects. Results will be disseminated via publication, clinicaltrials.gov, media and conferences.Trial registration numberClinicalTrials.gov identifier (NCT03282916) Pre-results.

Varicella zoster virus (VZV) is the cause of chickenpox (varicella) and shingles (zoster), and was once responsible for over 4 million infections in the United States annually. The development of a live attenuated VZV vaccine was initially viewed with extreme skepticism. Nonetheless, a VZV vaccine was developed in the 1970s by Takahashi and his colleagues in Japan and was eventually licensed in the US. It is now known to be one of the safest and most effective vaccines available and is administered worldwide. Here are described important factors that contributed to the successful research and licensure of the highly successful VZV vaccine.

Zoster vaccine is a single dose live, attenuated vaccine (ZVL) indicated for individuals ≥50 years-old for the prevention of herpes zoster (HZ). Safety data from clinical trials and post-licensure studies provided reassurance that ZVL is generally safe and well tolerated. The objective of this review was to provide worldwide post-marketing safety information following 10 years of use and34 million doses distributed.All post-marketing adverse experience (AE) reports received worldwide between 02-May-2006 and 01-May-2016 from healthcare professionals following vaccination with ZVL and submitted to the MSD AE global safety database, were analyzed.A total of 23,556 AE reports, 93% non-serious, were reported. Local injection site reactions (ISRs), with a median time-to-onset of 2 days, were the most frequently reported AEs followed by HZ. The majority of HZ reports were reported within 2 weeks of vaccination and considered, based on time-to-onset, pathogenesis of HZ, and data from clinical trials, to be caused by wild-type varicella-zoster virus (VZV). HZ confirmed by PCR analysis to be VZV Oka/Merck vaccine-strain was identified in an immunocompetent individual 8 months postvaccination and in 4 immunocompromised individuals. Disseminated HZ was reported very rarely (1%) with 38% occurring in immunocompromised individuals. All reports of disseminated HZ confirmed by PCR as VZV Oka/Merck vaccine-strain were in individuals with immunosuppressive conditions and/or therapy at the time of vaccination.The safety profile of ZVL, following 10 years of post-marketing use, was favorable and consistent with that observed in clinical trials and post-licensure studies.

Varicella and zoster continue to cause significant morbidity and even mortality in children and adults. Complications include bacterial superinfection, central nervous system manifestations such as meningitis, encephalitis, and cerebellar ataxia, and pain syndromes especially post herpetic neuralgia. Many developed countries but not all, are now administering live attenuated varicella vaccine routinely, with a decrease in the incidence of disease, providing personal and herd immunity. There is some controversy, however, in some countries concerning whether a decrease in the circulation of wild type virus will result in loss of immunity to VZV in persons who have already had varicella. This manuscript reviews the complications of varicella and zoster in detail, the reasons for development of vaccines against these diseases, complications of vaccinations, and mechanisms by which immunity to this virus develops and is maintained. There are strong indications that the best way to control disease and spread of this virus is by vaccination against both.

The adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50 to 85 years old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su), gE-specific CD4+ and CD8+ T cell responses were 10-fold or more higher in HZ/su compared with ZV recipients. Comparing the vaccines, T cell memory responses, including gE-IL-2+ and VZV-IL-2+ spot-forming cells (SFCs), were higher in HZ/su recipients and cytotoxic and effector responses were lower. At 1 year after vaccination, all gE-Th1 and VZV-IL-2+ SFCs remained higher in HZ/su compared with ZV recipients. Mediation analyses showed that IL-2+ PMR were necessary for the persistence of Th1 responses to either vaccine and VZV-IL-2+ PMR explained 73% of the total effect of HZ/su on persistence. This emphasizes the biological importance of the memory responses, which were clearly superior in HZ/su compared with ZV participants.

CONTEXT:Live vaccines usually provide robust immunity but can transmit the vaccine virus.OBJECTIVE:To assess the characteristics of secondary transmission of the vaccine-strain varicella-zoster virus (Oka strain; vOka) on the basis of the published experience with use of live varicella and zoster vaccines.DATA SOURCES:Systematic review of Medline, Embase, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and Scopus databases for articles published through 2018.STUDY SELECTION:Articles that reported original data on vOka transmission from persons who received vaccines containing the live attenuated varicella-zoster virus.DATA EXTRACTION:We abstracted data to describe vOka transmission by index patient’s immune status, type (varicella or herpes zoster) and severity of illness, and whether transmission was laboratory confirmed.RESULTS:Twenty articles were included. We identified 13 patients with vOka varicella after transmission from 11 immunocompetent varicella vaccine recipients. In all instances, the vaccine recipient had a rash: 6 varicella-like and 5 herpes zoster. Transmission occurred mostly to household contacts. One additional case was not considered direct transmission from a vaccine recipient, but the mechanism was uncertain. Transmission from vaccinated immunocompromised children also occurred only if the vaccine recipient developed a rash postvaccination. Secondary cases of varicella caused by vOka were mild.LIMITATIONS:It is likely that other vOka transmission cases remain unpublished.CONCLUSIONS:Healthy, vaccinated persons have minimal risk for transmitting vOka to contacts and only if a rash is present. Our findings support the existing recommendations for routine varicella vaccination and the guidance that persons with vaccine-related rash avoid contact with susceptible persons at high risk for severe varicella complications.

The live-attenuated varicella vaccine, a routine immunization in the United States since 1995, is both safe and effective. Like wild-type varicella-zoster virus, however, vaccine Oka (vOka) varicella can establish latency and reactivate as herpes zoster, rarely leading to serious disease, particularly among immunocompromised hosts. All but one previously reported cases of reactivated vOka resulting in meningitis have been described in young children who received a single dose of varicella vaccine; less is known about vOka reactivation in older children after the 2-dose vaccine series. We present 2 adolescents with reactivated vOka meningitis, 1 immunocompetent and 1 immunocompromised, both of whom received 2 doses of varicella vaccine many years before as children. Pediatricians should be aware of the potential of vOka varicella to reactivate and cause clinically significant central nervous system disease in vaccinated children and adolescents.

* Abbreviation: VZV — : varicella zoster virus The live attenuated varicella vaccine remains the only vaccine in use against a virus that has a latent form and therefore causes 2 illnesses: varicella and zoster (also known as shingles).1 Zoster occurs after latent infection with varicella zoster virus (VZV) reactivates, after either chickenpox or vaccination. Viral latency lasts a lifetime. In countries where the vaccine is not used, varicella is mainly a disease of children, and zoster is a disease of adults. Because of declining cell-mediated immunity in older individuals, the incidence of zoster increases sharply after age 50. However, zoster may occur at any age in individuals who have previously been infected with VZV, and children vaccinated against chickenpox are at risk. In addition to waning cellular immunity with age, other factors that may precipitate zoster include immunosuppression, other viral infections, and stress.1 The varicella vaccine was developed in Japan in 1974, after Takahashi et al2 successfully attenuated VZV that was obtained from an otherwise healthy child with chickenpox. When the varicella vaccine was initially tested in the United States in the late 1970s, children with leukemia were frequently on their way to being cured of … Address correspondence to Anne A. Gershon, MD, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032. E-mail: aag1{at}cumc.columbia.edu

Varicella-zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian varicella virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.

SUMMARYHealthcare workers (HCWs) reporting no history of varicella frequently receive varicella vaccination (vOka) if they test varicella-zoster virus (VZV) immunoglobulin G (IgG) negative. In this study, the utilities of VZV-IgG time-resolved fluorescence immunoassay (VZV-TRFIA) and a commercial VZV-IgG purified glycoprotein enzyme immunoassay (gpEIA) currently used in England for confirming VZV immunity have been compared to the fluorescent-antibody-to-membrane-antigen assay (FAMA). A total of 110 HCWs received two doses of vOka vaccine spaced 6 weeks apart and sera collected pre-vaccination (n= 100), at 6 weeks post-completion of vaccination (n= 86) and at 12–18 months follow-up (n= 73) were analysed. Pre-vaccination, by FAMA, 61·0% sera were VZV IgG negative, and compared to FAMA the sensitivities of VZV-TRFIA and gpEIA were 74·4% [95% confidence interval (CI) 57·9–87·0] and 46·2% (95% CI 30·1–62·8), respectively. Post-completion of vaccination the seroconversion rate by FAMA was 93·7% compared to rates of 95·8% and 70·8% determined by VZV-TRFIA and gpEIA, respectively. At 12–18 months follow-up seropositivity rates by FAMA, VZV-TRFIA and gpEIA were 78·1%, 74·0% and 47·9%, respectively. Compared to FAMA the sensitivities of VZV-TRFIA and gpEIA for measuring VZV IgG following vaccination were 96·4% (95% CI 91·7–98·8) and 74·6% (95% CI 66·5–81·6), respectively. Using both FAMA and VZV-TRFIA to identify healthy adult VZV susceptibles and measure seroconversion showed that vOka vaccination of HCWs is highly immunogenic.

Background Routine vaccination with varicella-zoster (VZV) vaccine has resulted in significant declines in the incidence of VZV cases, hospitalizations, and deaths across pediatric age. This vaccine is safe and effective and adverse events are monitored closely. Methods We describe a case of vOka meningoencephalitis in a twelve-year-old vaccinated boy who presented with altered mental status and a vesicular facial rash. Results A twelve-year-old healthy, fully-vaccinated boy presented to urgent care clnic with left-sided frontotemporal headache, left-sided eye pain, and photosensitivity. Over several days, a left-sided facial rash progressed to include papular and vesicular lesions over the cheek, as well as over the left side of the chin and at the midline of the lower lip. He was somnolent, sleeping 18- 20 hours a day. The child was evaluated by a pediatric neurologist who noted a left-sided ptosis and left lateral rectus palsy; he was admitted for further workup. Cerebrospinal fluid (CSF) analysis showed WBC of 33 cells/ml3 with 92% lymphocytes; glucose of 44mg/dL (serum glucose 84mg/dL), and protein of 50mg/dL (range: 15-45). Nasopharyngeal multiplex polymerase chain reaction (PCR) (BioFire Diagnostics, Salt Lake City, Utah) was positive for rhinovirus/enterovirus. Testing of facial vesicles for varicella-zoster virus (VZV) and herpes simplex virus (HSV) was negative by DFA and culture, and enteroviral throat and rectal PCRs were negative. However, CSF PCR for VZV was found to be positive. In light of this finding, the viral isolate was sent to Dr. Anne Gershon’s research lab at Columbia University Medical Center for typing and was determined to be vOka. Quantitative and functional immune studies were performed, and were normal. The patient initially received 7 days of intravenous acyclovir, during which time his rash resolved and mental status returned to baseline. He completed a total of 14 days of acyclovir and has had no recurrences. Conclusion This case represents only the tenth case of Oka-strain meningitis in an immunocompetent child reported to date, and one of very few cases in immunocompetent adolescents. While rare, vOka meningitis is an entity of which primary care pediatricians and infectious diseases specialists should be aware, even in older children. Disclosures All Authors: No reported disclosures

Background A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. Methods An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo–0%Endo, 75%Exo–25%Endo, 50%Exo–50%Endo, 25%Exo–75%Endo, 0%Exo–100%Endo. Results HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. Conclusions Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence. Electronic supplementary material The online version of this article (10.1186/s12879-019-3759-z) contains supplementary material, which is available to authorized users.

Introduction Despite vaccination, there were more than 100,000 annual cases of varicella in the United States in 2013–2014. Individuals at highest risk of developing severe or complicated varicella include immunocompromised people, preterm infants, and pregnant women. Varicella zoster immune globulin (human) (VARIZIG) is recommended by the CDC for postexposure prophylaxis to prevent or attenuate varicella-zoster virus infection in high-risk individuals. Contemporary information on administration of VARIZIG is limited. Methods This open-label, expanded-access program provided VARIZIG to physician-identified, high-risk participants exposed to varicella. Participants included immunocompromised children/adults, infants (preterm, newborns whose mothers had varicella onset within 5 days before or 2 days after delivery, and those aged 100 pox, pneumonia, or encephalitis) were assessed up to 42 days after administration. Results The varicella outcome population (n = 507) included 263 immunocompromised participants (32 adults, 231 children), 137 pregnant women, 105 infants, and 2 healthy adults with no history of varicella. Varicella incidence was 4.5% in immunocompromised participants, 7.3% in pregnant women, and 11.5% in infants. The incidence of varicella was similar when comparing VARIZIG administration ≤ 96 hours vs > 96 hours (up to 10 days) postexposure in the entire population (6.2% vs. 9.4%, respectively), and also in each subgroup. Of 34 participants with varicella, 5 developed > 100 pox and 1 developed pneumonia and encephalitis. There were no product-related deaths and only 1 serious adverse event (serum sickness) considered probably related to VARIZIG. Conclusion Postexposure administration of VARIZIG was associated with low rates of varicella in high-risk participants, regardless of when administered within 10 days postexposure. VARIZIG was well-tolerated and safe in high-risk participants.

Introduction Live attenuated zoster vaccine (Zostavax) was used to test the hypothesis that constitutive level of interleukin 10 (IL-10), which may be high in elderly subjects, impairs vaccine efficacy. If constitutive IL-10 impairs vaccine efficacy, the effectiveness of viral vaccines might be improved by transient inhibition of IL-10 before vaccination. Methods Zostavax was given to 26 patients (age, 60–80 years). IL-10 and immunity to varicella zoster virus (VZV) were measured at baseline and after vaccination. Fluorescent antibody to membrane antigen (FAMA) assays and glycoprotein enzyme-linked immunosorbent assays (gpELISAs) were used to assess humoral immunity; anti–varicella virus T-cell responses were studied in a subset of subjects. In a prospective animal model, T-cell responses to chimeric vaccines against lymphocytic choriomeningitis virus (LCMV) were assessed in mice that express or lack IL-10. Results FAMA assays revealed significant boosting (by 4-fold) of humoral immunity, which occurred only in subjects (10 of 26) with a low constitutive IL-10 level (ie, Conclusions A high constitutive IL-10 level adversely affects vaccine efficacy.

Varicella zoster virus (VZV) infects and becomes latent in sensory, enteric, and other autonomic neurons during the viremia of varicella. Reactivation of VZV in neurons that project to the skin causes the rash of zoster; however, reactivation of VZV in enteric neurons can cause a painful gastrointestinal disorder ("enteric zoster") without cutaneous manifestations. Detection of VZV DNA in saliva of patients with gastrointestinal symptoms may suggest enteric zoster. This diagnosis is reinforced by observing a response to antiviral therapy and can be confirmed by detecting VZV gene products in intestinal mucosal biopsies. We developed an in vivo guinea pig model that may be useful in studies of VZV latency and reactivation. VZV-infected lymphocytes are used to induce latent infection in sensory and enteric neurons; evidence suggests that exosomes and stimulator of interferon genes (STING) may, by preventing proliferation play roles in the establishment of neuronal latency.

Background. Varicella zoster virus (VZV) establishes latency in dorsal root, cranial nerve, and enteric ganglia and can reactivate to cause zoster. Serious gastrointestinal dysfunction can result from VZV reactivation in enteric neurons (enteric zoster), but an absence of rash makes diagnosis difficult. We thus determined whether detecting VZV DNA in saliva facilitates identification of enteric zoster. Methods. Nested and real-time polymerase chain reaction were used to validate salivary VZV DNA as a surrogate marker of VZV reactivation and then to determine the utility of that marker for the identification of those individuals within a population defined by abdominal pain that might have enteric zoster. Results. Salivary VZV DNA was detected in 0 of 20 healthy negative controls, 11 of 16 positive controls with zoster or varicella (P < .0001), 2 of 2 patients with zoster sine herpete (P < .01), 6 of 11 patients with unexplained abdominal pain (P < .001), and 0 of 8 patients with unrelated gastrointestinal disorders. Salivary VZV DNA disappeared after recovery in 9 of 9 tested subjects with zoster, 2 of 2 with zoster sine herpete, and 5 of 5 with abdominal pain. One patient with abdominal pain and salivary VZV DNA had perforated gastric ulcers, necessitating a wedge gastrectomy. VZV DNA (vaccine type) was found in the resected stomach; immediate early (ORF63p) and late (gE) VZV proteins were immunocytochemically detected in gastric epithelium. After recovery, VZV DNA and proteins were not detected in gastric biopsies or saliva. Conclusions. Detection of salivary VZV DNA in patients with abdominal pain helps to identify putative enteric zoster for investigation and treatment.

Live-attenuated Varicella Zoster Virus (VZV) Vaccine was first developed in Japan and tested for safety in children who were steroid treated. It proved safe and immunogenic. This led to its testing in the United States in a population of children with acute lymphoblastic leukemia who were in remission. This study too showed that the vaccine was safe and immunogenic in this population. After the vaccine was approved for healthy children, it was tested in a population of HIV-infected children and adolescents with minimal to moderate immunosuppression (i.e., CD4 percentage of >25 and a count of >350). It also proved safe and relatively immunogenic in this population. Finally, it has been evaluated in a more immunocompromised population of HIV-infected children and adolescents (i.e., CD4 percentage >15 and a count >200). VZV vaccine also proved safe and relatively immunogenic in this population. It is suggested that two immunizations, 12 weeks apart, be the vaccination strategy for these HIV populations.

Varicella, although a frequently benign childhood disease, nevertheless represents a considerable health burden. WHO recommends including varicella vaccines in universal routine vaccination programs, and maintaining coverage80%. Many countries have successfully introduced varicella vaccination and have benefited from lower disease burden, but many others have not adopted the vaccine. Reasons include cost commitment for a 'mild childhood disease' or concerns that vaccination will shift varicella to older age groups or increase herpes zoster incidence. Areas covered: This literature review summarizes the effectiveness and epidemiological impact of varicella immunization programs. Expert commentary: Varicella vaccines are immunogenic with acceptable safety profiles. One and two dose schedules are highly effective against varicella and large reductions in disease incidence, particularly moderate-severe disease, have been widely reported. There is currently no evidence to suggest that the introduction of varicella vaccination results in a shift of varicella disease burden to older age groups. Although epidemiological studies have shown an increased incidence of herpes zoster since the vaccines were launched, there are many other contributing factors, and indeed, this secular trend was evident before their introduction. In conclusion, varicella vaccination easily fits into existing immunization programs and significantly reduces the often underestimated burden of varicella.

Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used.

Immunization with the vOka vaccine prevents varicella (chickenpox) in children and susceptible adults. The vOka vaccine strain comprises a mixture of genotypes and, despite attenuation, causes rashes in small numbers of recipients. Like wild-type virus, the vaccine establishes latency in neuronal tissue and can later reactivate to cause Herpes zoster (shingles). Using hybridization-based methodologies, we have purified and sequenced vOka directly from skin lesions. We show that alleles present in the vaccine can be recovered from the lesions and demonstrate the presence of a severe bottleneck between inoculation and lesion formation. Genotypes in any one lesion appear to be descended from one to three vaccine-genotypes with a low frequency of novel mutations. No single vOka haplotype and no novel mutations are consistently present in rashes, indicating that neither new mutations nor recombination with wild type are critical to the evolution of vOka rashes. Instead, alleles arising from attenuation (i.e., not derived from free-living virus) are present at lower frequencies in rash genotypes. We identify 11 loci at which the ancestral allele is selected for in vOka rash formation and show genotypes in rashes that have reactivated from latency cannot be distinguished from rashes occurring immediately after inoculation. We conclude that the vOka vaccine, although heterogeneous, has not evolved to form rashes through positive selection in the mode of a quasispecies, but rather alleles that were essentially neutral during the vaccine production have been selected against in the human subjects, allowing us to identify key loci for rash formation.

In the twenty-first century, there is great interest in prevention of zoster, both in healthy and immunocompromised patients. Successful prevention of clinical reactivation of varicella zoster virus (VZV) is obviously preferable to treatment after VZV has reactivated and caused disease. Despite the development of effective zoster vaccines [1, 2], however, there will continue to be a need for antiviral therapy for zoster in patients who have not received immunization or in whom a vaccine has not been entirely effective. Today, most individuals who develop zoster, particularly if they are immunocompromised or over 50 years old, are recommended to receive specific therapy mainly to decrease morbidity from VZV infection; death from zoster is uncommon or rare [3]. Therapy of zoster, even if given early after onset, unfortunately, probably does not prevent development of postherpetic neuralgia (PHN), as discussed below. On the other hand, relief of pain and promotion of healing of the rash of zoster are obviously greatly welcomed by patients, and antiviral therapy is given to most zoster patients.

Post-licensure surveillance for adverse events following immunizations (AEFI) can identify rare complications of vaccinations and rigorous vaccine adverse event causality assessments can help to identify possible causal relationships. We report the development of arm paralysis after varicella vaccination in a 1-year-old child. Paralysis was initially presumed to be due to vOka because of the temporal relationship between vaccination and onset of arm weakness; however, molecular studies identified wild-type varicella zoster virus VZV (WT-VZV) in the CSF, leading the authors to conclude that WT-VZV was the probable cause. This case illustrates the complexity of assessing AEFI causality, and the importance of careful and complete evaluations when determining the most likely cause of an AEFI.

Infection with varicella zoster virus (VZV) causes varicella (chickenpox), which can be severe in immunocompromised individuals, infants and adults. Primary infection is followed by latency in ganglionic neurons. During this period, no virus particles are produced and no obvious neuronal damage occurs. Reactivation of the virus leads to virus replication, which causes zoster (shingles) in tissues innervated by the involved neurons, inflammation and cell death - a process that can lead to persistent radicular pain (postherpetic neuralgia). The pathogenesis of postherpetic neuralgia is unknown and it is difficult to treat. Furthermore, other zoster complications can develop, including myelitis, cranial nerve palsies, meningitis, stroke (vasculopathy), retinitis, and gastroenterological infections such as ulcers, pancreatitis and hepatitis. VZV is the only human herpesvirus for which highly effective vaccines are available. After varicella or vaccination, both wild-type and vaccine-type VZV establish latency, and long-term immunity to varicella develops. However, immunity does not protect against reactivation. Thus, two vaccines are used: one to prevent varicella and one to prevent zoster. In this Primer we discuss the pathogenesis, diagnosis, treatment, and prevention of VZV infections, with an emphasis on the molecular events that regulate these diseases. For an illustrated summary of this Primer, visit: http://go.nature.com/14xVI1.

Granulomatous arteritis characterizes the pathology of giant cell arteritis, granulomatous aortitis, and intracerebral varicella zoster virus (VZV) vasculopathy. Because intracerebral VZV vasculopathy and giant cell arteritis are strongly associated with productive VZV infection in cerebral and temporal arteries, respectively, we evaluated human aortas for VZV antigen and VZV DNA. Using 3 different anti-VZV antibodies, we identified VZV antigen in 11 of 11 aortas with pathologically verified granulomatous arteritis, in 1 of 1 cases of nongranulomatous arteritis, and in 5 of 18 control aortas (28%) obtained at autopsy. The presence of VZV antigen in granulomatous aortitis was highly significant (P = .0001) as compared to control aortas, in which VZV antigen was never associated with pathology, indicating subclinical reactivation. VZV DNA was found in most aortas containing VZV antigen. The frequent clinical, radiological, and pathological aortic involvement in patients with giant cell arteritis correlates with the significant detection of VZV in granulomatous aortitis.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) A flow cytometry-adapted fluorescent antibody to membrane antigen (FAMA) assay to detect IgG antibodies against varicella-zoster virus (VZV) was developed and tested in 62 serum samples, showing 90.32% accuracy obtained from a receiver operating characteristic (ROC) curve with a 0.9125 (95% confidence interval [CI], 0.829 to 1.00) area below the curve compared to the result with standard FAMA. Fed Univ São Paulo UNIFESP EPM, Div Pediat Infect Dis, BR-04040000 São Paulo, Brazil Columbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10027 USA Fed Univ São Paulo UNIFESP EPM, Div Pediat Infect Dis, BR-04040000 São Paulo, Brazil CAPES: 0108-08-1 Web of Science

The Oka vaccine is a live attenuated vaccine for the prevention of varicella. Although the vaccine differs from the progenitor virus by over 40 mutations, only three of these are fixed, the rest being a mixture of the wild-type and the vaccine allele. To examine the extent of this variability between two of the three commercially available vaccine preparations, we analysed the vaccine/wild-type allele frequencies present at fifteen vaccine loci in five preparations each from two different manufacturers of the vOka vaccine. Our results suggest that differences in manufacturing processes between the two companies have resulted in significant variation in the frequencies of the vaccine/wild-type alleles in their vaccines. Yet despite these differences, the allele frequencies in the vaccines from the two companies are strongly correlated. We discuss the significance of these findings and the role of evolutionary processes that influence the production of this live attenuated vaccine.

Determination of varicella zoster virus (VZV) immunity in healthcare workers without a history of chickenpox is important for identifying those in need of vOka vaccination. Post immunisation, healthcare workers in the UK who work with high risk patients are tested for seroconversion. To assess the performance of the time-resolved fluorescence immunoassay (TRFIA) for the detection of antibody in vaccinated as well as unvaccinated individuals, a cut-off was first calculated. VZV-IgG specific avidity and titres six weeks after the first dose of vaccine were used to identify subjects with pre-existing immunity among a cohort of 110 healthcare workers. Those with high avidity (≥ 60%) were considered to have previous immunity to VZV and those with low or equivocal avidity (60%) were considered naive. The former had antibody levels ≥ 400 mIU/mL and latter had levels400 mIU/mL. Comparison of the baseline values of the naive and immune groups allowed the estimation of a TRFIA cut-off value of130 mIU/mL which best discriminated between the two groups and this was confirmed by ROC analysis. Using this value, the sensitivity and specificity of TRFIA cut-off were 90% (95% CI 79-96), and 78% (95% CI 61-90) respectively in this population. A subset of samples tested by the gold standard Fluorescence Antibody to Membrane Antigen (FAMA) test showed 84% (54/64) agreement with TRFIA.