Anne A. Gershon

The incidence of zoster after immunization with live attenuated varicella vaccine : a study in children with leukemia

BACKGROUND The Oka strain of live attenuated varicella vaccine is immunogenic and highly protective, but there has been concern about the risk of zoster after immunization. METHODS We examined the incidence of zoster, risk factors for it, and measures of immune response in children with leukemia who received the vaccine and in appropriate controls. RESULTS After a mean follow-up of 4.1 years, zoster was documented in 13 of the 548 vaccinated children with leukemia (2.4 percent). In a subgroup of 96 vaccinated children matched prospectively with 96 children with leukemia who had had natural varicella infections, there were 4 cases of zoster among the vaccinated children and 15 among the controls, for crude incidence rates of 0.80 and 2.46 cases per 100 person-years, respectively (P = 0.01). Of the total of 13 vaccinated children who had zoster, 11 had a skin rash due to varicella-zoster virus, either from the vaccine itself or from breakthrough varicella after household exposure in the period between immunization and the documentation of zoster. In the 268 children who had any type of rash caused by varicella-zoster virus after vaccination, as compared with those who did not have a rash, the relative risk of subsequent zoster was 5.75. For the 21 vaccinated children who received bone marrow transplants, as compared with those who did not, the relative risk of zoster was 7.5. Cell-mediated immunity as assessed by lymphocyte stimulation was lower in 4 children in whom zoster later developed than in 29 controls who had been vaccinated but who did not have zoster (mean stimulation index, 5.1 vs. 23.8; P = 0.0001). CONCLUSIONS In children with leukemia who receive the live attenuated varicella vaccine, the subsequent incidence of zoster is lower than in children who have natural varicella infections.

The effectiveness of the varicella vaccine in clinical practice.

BACKGROUND A live attenuated varicella vaccine was approved for use in the United States in March 1995 and is recommended for all susceptible persons 12 months of age or older. METHODS To assess the effectiveness of the varicella vaccine, we conducted a case-control study with two controls per child with chickenpox, matched according to both age and pediatric practice. Children with potential cases of chickenpox were identified by active surveillance of pediatric practices in the New Haven, Connecticut, area. Research assistants visited the children on day 3, 4, or 5 of the illness, assessed the severity of the illness, and collected samples from lesions to test for varicella-zoster virus by polymerase chain reaction (PCR). RESULTS From March 1997 through November 2000, data collection was completed for 330 potential cases, of which 243 (74 percent) were in children who had positive PCR tests for varicella-zoster virus. Of the 56 vaccinated children with chickenpox, 86 percent had mild disease, whereas only 48 percent of the 187 unvaccinated children with chickenpox had mild disease (P<0.001). Among the 202 children with PCR-confirmed varicella-zoster virus and their 389 matched controls, 23 percent of the children with chickenpox and 61 percent of the matched controls had received the vaccine (vaccine effectiveness, 85 percent; 95 percent confidence interval, 78 to 90 percent; P<0.001). Against moderately severe and severe disease the vaccine was 97 percent effective (95 percent confidence interval, 93 to 99 percent). The effectiveness of the vaccine was virtually unchanged (87 percent) after adjustment for potential confounders by means of conditional logistic regression. CONCLUSIONS Varicella vaccine is highly effective as used in clinical practice.

A Controlled Trial of Acyclovir for Chickenpox in Normal Children

BACKGROUND Chickenpox, the primary infection caused by the varicella-zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications. METHODS To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multicenter, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered by the oral route in a dose of 20 mg per kilogram of body weight four times daily for five days. RESULTS The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs 347; P less than 0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P less than 0.001). In over 95 percent of the recipients of acyclovir no new lesions formed after day 3, whereas new lesions were forming in 20 percent of the placebo recipients on day 6 or later. The recipients of acyclovir also had accelerated progression to the crusted and healed stages, less itching, and fewer residual lesions after 28 days. In the children treated with acyclovir the duration of fever and constitutional symptoms was limited to three to four days, whereas in 20 percent of the children given placebo illness lasted more than four days. There was no significant difference between groups in the distribution of 11 disease complications (10 bacterial skin infections and 1 case of transient cerebellar ataxia). Acyclovir was well tolerated, and there was no significant difference between groups in the titers of antibodies against varicella-zoster virus. CONCLUSIONS Acyclovir is a safe treatment that reduces the duration and severity of chickenpox in normal children when therapy is initiated during the first 24 hours of rash. Whether treatment with acyclovir can reduce the rare, serious complications of chickenpox remains uncertain.

Varicella-Zoster Virus–Specific Immune Responses in Elderly Recipients of a Herpes Zoster Vaccine

BACKGROUND A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. METHODS The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. RESULTS VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old. CONCLUSIONS The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

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.

Varicella-Zoster Virus–Specific Immune Responses to Herpes Zoster in Elderly Participants in a Trial of a Clinically Effective Zoster Vaccine

BACKGROUND The objectives of this study were to evaluate the association between varicella-zoster virus (VZV)-specific humoral and cell-mediated immunity (CMI) to herpes zoster (HZ) and protection against HZ morbidity and to compare immune responses to HZ and zoster vaccine. METHODS In 981 elderly persons who developed HZ during a zoster vaccine efficacy trial (321 vaccinees and 660 placebo recipients) and 1362 without HZ (682 vaccinees and 680 placebo recipients), CMI was measured by VZV responder cell frequency and interferon-gamma enzyme-linked immunospot, and antibodies were measured by VZV enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA). RESULTS Robust VZV CMI at HZ onset correlated with reduced HZ morbidity, whereas VZV gpELISA titers did not. Three weeks after HZ onset, gpELISA titers were highest in those with more severe HZ and were slightly increased in placebo recipients (compared with zoster vaccine recipients) and in older individuals. VZV CMI responses to HZ were similar in zoster vaccine and placebo recipients and were not affected by demographic characteristics or antiviral therapy, except for responder cell frequency at HZ onset, which decreased with age. When responses to zoster vaccine and HZ could be compared, VZV CMI values were similar, but antibody titers were lower. CONCLUSIONS Higher VZV CMI at HZ onset was associated with reduced HZ severity and less postherpetic neuralgia. Higher antibody titers were associated with increased HZ severity and occurrence of postherpetic neuralgia. HZ and zoster vaccine generated comparable VZV CMI.

Zoster immune globulin. A further assessment.

Abstract The prophylactic efficacy of zoster immune globulin was evaluated in 21 immunocompromised children (under therapy for leukemia or other malignant processes) who had household exposures to varicella. In six of the children who had serum antibody to antigen on the membrane of cells infected with Varicella Zoster virus, evidence of varicella did not develop. The remaining 15 children who did not have detectable Varicella Zoster antibody became infected. Varicella was severe in one, mild in nine and subclinical in five children. All 15 children, had persistence of Varicella Zoster antibody for months to years after infection. Administration of zoster immune globulin appeared to be an effective method to modify varicella in immunocompromised patients. (N Engl J Med 290:243–245, 1974)

The Safety Profile of Varicella Vaccine: A 10-Year Review

Varivax (varicella virus vaccine live [Oka/Merck]; Merck), a live attenuated varicella vaccine, is indicated for vaccination against varicella in appropriate individuals > or =12 months of age. The 10-year safety profile for Varivax is described using data submitted to Merck from routine global postmarketing surveillance, combined with information from a Varicella Zoster Virus Identification Program, which uses polymerase chain reaction (PCR) analysis to identify the presence and strain of VZV in selected specimens. There were 16,683 reports worldwide voluntarily submitted to Merck, for an overall reporting rate of 3.4 reports/10,000 doses of vaccine distributed. PCR analysis of vesicular rashes that occurred within the first 2 weeks after vaccination was more likely to identify wild-type varicella-zoster virus (VZV), whereas the presence of Oka VZV was generally associated with vesicular rashes that occurred 15-42 days after vaccination. Reports of breakthrough varicella that occurred >42 days after vaccination were associated with wild-type VZV. Among 697 herpes zoster reports, PCR analysis identified Oka VZV in 57 reports and wild-type VZV in 38 reports. There were no primary neurologic adverse events associated with Oka VZV. Secondary transmission of Oka VZV from vaccine recipients with postvaccination vesicular rashes was identified in 3 susceptible household contacts. Disseminated Oka VZV was identified in 6 immunocompromised patients and 1 patient with Down syndrome. This review has shown that the vaccine is generally safe and well tolerated.

Advances in the understanding of the pathogenesis and epidemiology of herpes zoster.

The primary varicella zoster virus (VZV) infection results in chickenpox (varicella), which is transmitted via the airborne route. VZV is highly infectious, but in the USA the incidence of varicella has been reduced by 76-87% as a result of the varicella vaccine. The virus establishes latency in the dorsal root ganglia during varicella and, when reactivated, travels along the sensory nerve axons to cause shingles (herpes zoster [HZ]). There are over 1 million cases of HZ in the USA each year, with an estimated lifetime attack rate of 30%. The incidence of HZ, which causes significant morbidity, increases with age and reaches approximately 10 cases per 1,000 patient-years by age 80. Cell-mediated immunity (CMI) is known to decline with age as part of immunosenescence, and decreased CMI is associated with reactivation of VZV. This article provides an overview of our emerging understanding of the epidemiology and pathogenesis of varicella and HZ, in addition to exploring the current theories on latency and reactivation. Understanding the risk factors for developing HZ and the complications associated with infection, particularly in older people, is important for prompt diagnosis and management of HZ in primary care, and they are therefore also reviewed.

Persistence of Immunity to Varicella in Children with Leukemia Immunized with Live Attenuated Varicella Vaccine

To determine the safety and efficacy of varicella vaccine, we studied 437 children in remission from leukemia who were immunized with live attenuated varicella virus. Three hundred one of the patients received two doses of vaccine and 136 received a single dose of vaccine from 1 of 10 lots from two manufacturers. The patients have been followed for an average of three years (range, one to six). Seroconversion occurred in 88 percent of the 437 children after the first dose of vaccine and in 98 percent after one or two doses. The proportions of patients who were seronegative after one, three, and five years were 20, 25, and 30 percent, respectively, with little change over time in the geometric mean titers of specific antibody (6.3, 6.5, and 5.7, respectively). Chickenpox has been documented in 36 vaccinated patients (8 percent) who had 3 to 640 vesicles (mean, 100), mild illness, and no complications. Of the 83 vaccinated patients exposed to varicella within their families, 11 had chickenpox; the attack rate was 14 percent (8 percent among seropositive patients, 29 percent among seronegative patients). There was no relation between the time since vaccination and either the attack rate or the severity of the breakthrough illness. Two doses of vaccine appeared to be no more effective than a single dose. Of the 372 patients receiving maintenance chemotherapy when immunized, 149 (40 percent) had a rash, which was treated with acyclovir in 16 children (4 percent) and became a severe febrile illness in 4. These reactions were not fatal and were all associated with vaccine lots, the use of which has since been discontinued. We conclude that in children in remission from leukemia, varicella vaccine is safe and induces an immunity to chickenpox that persists for more than three years.