Live Attenuated Varicella-zoster Virus Research Articles

A PHASE I–II STUDY OF LIVE ATTENUATED VARICELLA-ZOSTER VIRUS VACCINE TO BOOST IMMUNITY IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED CHILDREN WITH PREVIOUS VARICELLA

Herpes zoster, may be severe and recurrent in HIV-infected children. We determined the safety and immunogenicity of live attenuated varicella-zoster virus (VZV) vaccine in 46 HIV-infected children who had experienced varicella. There were no serious adverse events. Two years after vaccination 82% of subjects remained VZV-antibody positive and 60% had VZV-specific cell-mediated immunity. No child developed herpes zoster.

Estimating the number needed to vaccinate to prevent herpes zoster-related disease, health care resource use and mortality.

A clinical trial has shown that a live-attenuated varicella-zoster virus vaccine is effective against herpes zoster (HZ) and post-herpetic neuralgia (PHN). The aim of the study was to estimate the number needed to vaccinate (NNV) to prevent HZ-related outcomes. A cohort model of HZ associated disease, health care resource use and mortality was developed. Canadian population-based data were used to estimate age-specific incidence, hospitalization, quality-adjusted life-year (QALY) lost and mortality. NNV was calculated as the number of individuals needed to be vaccinated to prevent a specific HZ-related outcome during their lifetime. Different ages at vaccination were examined and probabilistic sensitivity analysis was performed. For 65 year olds, the NNV (HZ vaccine efficacy=63%, PHN vaccine efficacy=67%, no waning) to prevent a case of HZ, a case of PHN, a HZ death, a life-year lost and a QALY lost is estimated to be 11 (90% Crl: 10-13), 43 (90% Crl: 33-53), 23,319 (90% Crl: 15,312-33,139), 3762 (90% Crl: 1650-4629) and 165 (90% Crl: 105-197), respectively. Results were most sensitive to the duration of vaccine protection and the age at vaccination. The predicted NNV to prevent HZ and PHN are low even though vaccine efficacy is between 50-70%, which reflects the high incidence of these diseases among older adults. Results clearly show that the main benefit of HZ vaccination is prevention of morbidity caused by pain (as measured by QALYs lost) rather than mortality.

The potential cost-effectiveness of vaccination against herpes zoster and post-herpetic neuralgia

A clinical trial has shown that a live-attenuated varicella-zoster virus vaccine is effective against herpes zoster (HZ) and post-herpetic neuralgia (PHN). The aim of this study was to examine the cost-effectiveness of vaccination against HZ and PHN in Canada. A cohort model was developed to estimate the burden of HZ and the cost-effectiveness of HZ vaccination, using Canadian population-based data. Different ages at vaccination were examined and probabilistic sensitivity analysis was performed. The economic evaluation was conducted from the ministry of health perspective and 5% discounting was used for costs and benefits. In Canada (population=30 million), we estimate that each year there are 130,000 new cases of HZ, 17,000 cases of PHN and 20 deaths. Most of the pain and suffering is borne by adults over the age of 60 years and is due to PHN. Vaccinating 65-year-olds (HZ efficacy=63%, PHN efficacy=67%, no waning, cost/course=$150) is estimated to cost $33,000 per QALY-gained (90%CrI: 19,000-63,000). Assuming the cost per course of HZ vaccination is $150, probabilistic sensitivity analysis suggest that vaccinating between 65 and 75 years of age will likely yield cost-effectiveness ratios below $40,000 per Quality-Adjusted Life-Year (QALY) gained, while vaccinating adults older than 75 years will yield ratios less than $70,000 per QALY-gained. These results are most sensitive to the duration of vaccine protection and the cost of vaccination. In conclusion, results suggest that vaccinating adults between the ages of 65 and 75 years is likely to be cost-effective and thus to be a judicious use of scarce health care resources.

Evaluation of the cost-effectiveness in the United States of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults

Context A live-attenuated varicella–zoster virus vaccine, demonstrated to reduce the incidence of herpes zoster (HZ) and postherpetic neuralgia (PHN) and the morbidity associated with incident HZ and its sequelae, has recently been approved for use in the United States (U.S.). Objective To examine the potential value of zoster vaccine for society and payers. Design, setting and population An age-specific decision analytic model was designed to estimate the lifetime costs and outcomes associated with HZ, PHN and other HZ-related complications for vaccinated and non-vaccinated cohorts aged ≥60 years. Clinical trial data, published literature and other primary studies were used to inform the model. Robustness of results to key model parameters was explored through a series of one-way, multivariate and probabilistic sensitivity analyses. Both societal and payer perspectives were considered. Main outcome measure Incremental cost per quality-adjusted life year (QALY) gained. Results For a representative cohort of 1,000,000 U.S. vaccine recipients aged ≥60 years, use of the zoster vaccine was projected to eliminate 75,548–88,928 HZ cases and over 20,000 PHN cases. Over 300,000 outpatient visits, 375,000 prescriptions, 9700 ER visits and 10,000 hospitalizations were projected to be eliminated with the vaccine translating into savings of US$ 82 million to US$ 103 million in healthcare costs associated with the diagnosis and treatment of HZ, PHN and other HZ-related complications. Cost-effectiveness ratios range from US$ 16,229 to US$ 27,609 per QALY gained, depending on the input data source and analytic perspective. Results were most sensitive to PHN costs, duration of vaccine efficacy, vaccine efficacy against PHN and HZ, QALY loss associated with pain states and complication costs. Conclusions The zoster vaccine at a price of US$ 150 is likely to be cost-effective for a cohort of immunocompetent U.S. vaccine recipients aged ≥60 years using commonly cited thresholds for judging cost-effectiveness. Conclusions are robust over plausible ranges of input parameter values and a broad range of scenarios and age cohorts.

Safety of vaccinating sibling donors with live-attenuated varicella zoster vaccine before hematopoietic stem cell transplantation

Reactivation of varicella zoster virus (VZV), clinically manifested as herpes zoster (HZ) is a common complication after hematopoietic stem cell transplantation (HSCT). The optimum prophylaxis for this disease has not been defined. In this study, we examined the effects of vaccinating donors with a live-attenuated vaccine with particular reference to their immune responses and the outcome of HSCT patients. Forty prospective HLA-matched sibling donors were vaccinated before HSCT. There were humoral immune responses in both sero-positive (P<0.01) and sero-negative (P=0.058) donors. Cellular immune response was assayed in 26 donors. Significant correlation was observed between cellular immune responses as enumerated by thymidine incorporation and interferon gamma secretion (P<0.001) and the latter was used in subsequent analyses. Significant response was observed in sero-negative (6/26) and a group of sero-positive (13/26) donors while 7/26 sero-positive donors showed no response. Thirty-four HSCT were performed. These patients have a lower, albeit insignificant, risk of HZ compared with historical controls and only 3/34 patients developed single dermatomal HZ at 6, 9 and 28 months after HSCT. No patients developed VZV-related mortality. Vaccinating donors with live-attenuated VZV vaccine was safe, but whether it confers a significant protection to the patients would require further study.

Varicella vaccination in HIV-1-infected children after immune reconstitution

HIV-1-infected children have an increased risk of severe chickenpox. However, vaccination is not recommended in severely immunocompromised children. Can the live-attenuated varicella zoster virus (VZV) Oka strain be safely and effectively given to HIV-1-infected children despite previously low CD4 T-cell counts? VZV vaccine was administered twice to 15 VZV-seronegative HIV-1-infected children when total lymphocyte counts were greater than 700 lymphocytes/microl, and six HIV-negative VZV-seronegative siblings. Weekly clinical follow-up and sampling were performed. None of the children developed any clinical symptom or serious adverse reaction after immunization. Only nine (60%) of the HIV-1-infected children had VZV-specific antibodies after two immunizations, whereas 100% of the siblings seroconverted. Age at baseline was negatively correlated with the VZV IgG titre at 6 weeks after the second vaccination in HIV-1-infected children. VZV-specific antibody titres after two immunizations were at a similar level to those found after wild-type infection in non-vaccinated HIV-1-infected patients, but significantly lower than in HIV-negative siblings. Importantly, VZV-specific T-cell responses increased after vaccination and were comparable in both groups over time. Documented wild-type VZV contact in three vaccinated patients did not result in breakthrough infections. VZV vaccination of previously immunocompromised HIV-1-infected children was safe. Vaccination induced specific immune responses in some of the vaccinated HIV-1-infected children, suggesting that previously immunocompromised individuals are protected against severe forms of varicella.

The optimization and validation of the glycoprotein ELISA assay for quantitative varicella-zoster virus (VZV) antibody detection

Varicella is a highly contagious viral disease found throughout the world. A live-attenuated Varicella-Zoster virus (VZV) vaccine (Oka/Merck strain), VARIVAXtrade mark, was licensed in the United States (US) in 1995 and was made a part of the US recommended childhood vaccination schedule in 1996. The immune response to VZV-containing vaccines has been measured using an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to glycoproteins from VZV. A correlate for protective immunity has been established between anti-VZV glycoprotein antibody levels and protection against breakthrough varicella in children, and this correlate is used as the primary immunogenicity endpoint in clinical trials with VZV-containing vaccines. The performance of the "first generation" validated version of the assay was recently reevaluated in order to identify areas for improvement. Specific format and reagent changes were implemented, with the goal of improving assay consistency by maintaining tighter control over assay processes and reagents. An extensive validation of the "second generation" gpELISA was undertaken in order to characterize the updated assay. In this article, we describe the gpELISA method, detail the procedures used to evaluate assay performance, and present the operating characteristics of the second generation gpELISA.

Frequently asked questions about varicella vaccine

Each year in Australia severe varicella and zoster infections cause a number of deaths and thousands of hospitalisations. A live attenuated varicella zoster virus vaccine has been available in Australia since 2000. This vaccine is recommended for all non-immune children over 12 months of age and all susceptible adults. There have been theoretical concerns about the vaccine leading to increased cases of zoster and varicella in adults because of a combination of waning vaccineinduced immunity and reduced immunological boosting from exposure to circulating virus. However, clinicians are encouraged to consider its use in all non-immune people apart from immunocompromised patients and pregnant women.

Immunogenicity of a two-dose regime of varicella vaccine in children with cancers.

Live-attenuated varicella vaccine is effective and safe in immunocompetent children. In this study, we assess the immunogenicity and adverse events following varicella vaccination in immunosuppressed cancer children. Varicella-zoster virus (VZV)-seronegative cancer children received two doses of live-attenuated VZV vaccine (Varilrix) in a span of 3 months. Patients with acute lymphoblastic leukaemia (ALL) were in the maintenance phase of chemotherapy, whereas those with solid tumours joined the study around 3-6 months from treatment discontinuation. VZV-specific cellular and humoral immune responses were measured before and after VZV vaccination. The median (range) age of the 17 patients was 4.4 yr (2.0-14.5). Thirteen had ALL, one had myelodysplastic syndrome and three had solid tumours. Following vaccination, the VZV-specific stimulation index (SI) increased from 1.7 (0.9-2.9) to 17.9 (5.9-36.0) (P < 0.001). Similarly, SI to phytohaemagglutinin mitogen increased from 1136 (499-1930) to 1714 (848-2518) (P = 0.028). There were also significant increases in CD4+ cells and CD4:CD8 ratio as well as a reduction in CD16/56+ cells in peripheral blood lymphocytes. Seroconversion rate to VZV was 19% after one dose and increased to 94% after the second dose of VZV vaccine. Serum VZV-specific IgG concentrations also increased significantly following two doses when compared with one dose of VZV vaccine (P = 0.0004). One subject developed possibly vaccine-related chickenpox with self-limiting hepatitis at 5 wk following vaccination. None of the patients developed herpes-zoster at a median (range) follow-up of 27.5 months (24.0-30.0). Non-immune cancer children can be effectively vaccinated against chickenpox at the defined period. However, the safety of chickenpox vaccine in these immunosuppressed children needs to be further studied.

Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-dose VZV vaccine.

The safety and immunogenecity of a booster dose of live attenuated varicella-zoster virus (VZV) vaccine was evaluated in 196 healthy subjects, >or=60 years old, who had already received a VZV vaccine >5 years before. This repeat booster dose was well tolerated. Cell-mediated immunity (CMI) to VZV was measured by an interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell (ELISPOT) assay and a limiting dilution responder cell frequency (RCF) assay. Prevaccination responses decreased as a function of increasing age but were detectable in all subjects by use of the IFN-gamma ELISPOT assay. In most subjects, VZV-specific CMI was increased at 6 weeks postvaccination. The magnitude of the vaccine-induced IFN-gamma ELISPOT response was inversely related to prevaccination values. Although there was a significant correlation between the IFN-gamma ELISPOT and RCF assays, the ELISPOT assay had greater sensitivity and a wider dynamic range. A live attenuated VZV vaccine is safe and immunogenic in an elderly population, and the vaccine-induced immunity may be monitored by the IFN-gamma ELISPOT assay.

Antibody Response in Seropositive Multiple Sclerosis Patients Vaccinated with Attenuated Live Varicella Zoster Virus

To determine the safety and effectiveness of live attenuated varicella zoster virus (VZV) vaccine (OKA/Merck) on 50 patients with chronic progressive multiple sclerosis (MS), based on the hypothesis that VZV might be the antigen or antigen mimic of MS plus the fact that repeated high antigen doses have produced 'antigen paralysis' in experimental allergic encephalomyelitis mice. Fifty patients were randomly selected without controls. They were assessed clinically at entry and on four other occasions over 14 months. Enhanced cranial magnetic resonance imaging (MRI) was performed at entry and at six and 12 months post entry. All were vaccinated after initial assessment and again six weeks later. All clinical and laboratory assessments were performed at the Health Sciences Centre, Winnipeg, in the out-patient department. All MRI examinations were performed at the St Boniface General Hospital, Winnipeg, Manitoba. Both are tertiary care hospitals. Fifty randomly selected patients with chronic progressive MS, age 18 to 60 years, and a disability status scale of 2.0 or greater were included. Forty-five patients completed the study. Two vaccinations with attenuated live VZV six weeks apart. All patients were VZV seropositive at entry and all showed an increased antibody level following vaccination. No one was harmed by the vaccine. There may have been some changes in the MS of 15 patients. It may be reasonable and safe to challenge the process of MS using large doses of the immunogenic proteins of the VZV to induce 'immune paralysis'.

Viral skin infections

The new antiviral drugs famiciclovir and valacyclovir are effective for the treatment of recurrent gential herpes and herpes zostar and may be given less frequently than acyclovir. Asymptomatic shedding of herpes simplex virus type 2 may be reduced by administration of daily acyclovir. Recombinant genetic techniques that allow viral protein production in vitro are being used in herpes simplex and papilloma virus vaccine development. Administatrtion of a live attenuated varicella-zoster virus vaccine provides long-lasting measures of cellular immunity in the elderly.

Immune Responses Of Elderly Persons 4 Years After Receiving A Live Attenuated Varicella Vaccine

Annually, for 4 years after a live attenuated varicella-zoster virus (VZV) vaccine was administered to 202 elderly (55 to > 87 years old) VZV-immune persons, the immune response of vaccinees was evaluated. Anti-VZV antibody levels were enhanced by vaccination for just 1 year. However, VZV-specific proliferating T cells in peripheral blood were increased in frequency from 1 in 68,000 to 1 in 40,000 at 1 year; VZV-responding T cells were still 1 in 51,000 4 years after vaccination. The calculated half-life of this enhanced immunity was 54 months. Age had little effect on response to the vaccine, but larger doses were associated with longer duration of enhanced immunity. Immunity in approximately 10%-15% of vaccinees, independent of dose, failed to increase with the vaccine. This might complicate the use of this vaccine for prevention or attenuation of herpes zoster in the elderly.

Prevention of infections in patients with T cell defects.

Although no specific infection is limited entirely to hosts with T-lymphocyte defects, certain microbial organisms have an affinity for such individuals. Effective, safe, and feasible methods are available for the prevention of two of the major life-threatening infections in patients with T-lymphocyte defects, although none of these methods is ideal. Trimethoprim-sulfamethoxazole administered orally daily or thrice weekly is highly effective for the prevention of Pneumocystis carinii pneumonia. For patients who cannot tolerate this drug combination, monthly inhalation of aerosolized pentamidine is an alternative prophylactic approach. Additional drugs in clinical or preclinical trials offer promise for use in preventing this pneumonitis. Varicella is one of the most frequent serious viral infections in patients with cancer, especially children. Varicella-zoster immune globulin (VZIG) has proven effective in reducing the frequency of infection in exposed susceptible individuals; however, breakthrough infections are not uncommon. Of 358 children with acute lymphoblastic leukemia, 62 received VZIG following exposure to varicella, and 16 (26%) of these had breakthrough varicella. A live attenuated varicella-zoster virus vaccine offers promise, especially for the universal immunization of individuals before immunocompromise occurs.

Varicella Vaccine Reflux

In Reply.— Herpes zoster (shingles) is the dermatomal skin eruption resulting from the reactivation of varicella-zoster virus remaining latent in posterior sensory root ganglia following childhood chickenpox (the primary infection with varicella-zoster virus). Since the live attenuated varicella-zoster virus contained in the vaccine replicates in the vaccinee similar to the wild-type virus, establishment of latency is possible for the attenuated strain. Several publications have addressed latency of the attenuated virus following immunization. Two studies have examined the incidence of zoster in children with acute lymphoblastic leukemia (ALL) following immunization with live attenuated varicella-zoster virus.

Live attenuated varicella vaccine: Immunization of healthy children with the OKA strain

Ninety-one healthy children were immunized with one of three preparations of the OKA strain of live attenuated varicella zoster virus in order to gain sufficient information on safety and immunogenicity to justify vaccine studies in immunosuppressed children. The OKA-Biken vaccine was studied in a dose response trial. Two additional clinical trails were conducted with the OKA strain that was further passaged: a frozen aqueous (OKA-RIT-Aq) form and a lyophilized (OKA-RIT-Ly) form were tested. With each of these vaccines clinical reactivity was minimal and virus shedding, viremia, and transmission of the vaccine virus were absent. Excellent seroconversion rates of 100 and 94% were induced with approximately 500 pfu of OKA-Biken and OKA-RIT-Ly vaccine, respectively. A lower seroconversion rate was noted for OKA-RIT-Aq, presumably on the basis of defective individual vials. Diluted OKA-Biken vaccine induced less seroconversion but even the 5 pfu dose produced antibody responses in 81% of the vaccinees. In vitro specific cellular immune responses to varicella virus antigens were demonstrated in each group of vaccinees, including all but two of those vaccines who failed to seroconvert. The data indicate that two preparations of the OKA strain are sufficiently safe and immunogenic in healthy children to support further studies in immunocompromised children.