Sharon Steinberg

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.

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.

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.

Disseminated Varicella Infection Due to the Vaccine Strain of Varicella-Zoster Virus, in a Patient with a Novel Deficiency in Natural Killer T Cells

An 11-year-old girl presented with a papulovesicular rash and severe respiratory distress 5 weeks after receiving varicella vaccine. Restriction fragment length-polymorphism analysis of virus isolated from an endotracheal-tube aspirate and from bronchoalveolar lavage revealed that this patients illness was due to the Oka vaccine strain of varicella. An extensive immunologic analysis failed to identify a known diagnostic entity to explain her susceptibility to this attenuated vaccine strain. Analysis of her lymphocytes on separate occasions, months after recovery from her illness, revealed a profound deficiency of natural killer T (NKT) cells and of NKT-cell activity, suggesting that NKT cells contribute to host defense against varicella virus.

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.

Live attenuated varicella vaccine: Evidence that the virus is attenuated and the importance of skin lesions in transmission of varicella-zoster virus

To examine whether the live varicella vaccine virus is attenuated, we analyzed varicella vaccine-induced contact cases of clinical chickenpox in healthy siblings of immunized children with leukemia. A rash developed approximately 1 month later in 156 children with leukemia who had been vaccinated. Vaccine-type virus was isolated from 25 of these children. Of 88 known susceptible healthy siblings who were exposed to a vaccine with a rash and from whom follow-up information was available, there was evidence of infection in 15 (17%). Of 15 siblings with seroconversion, 11 (73%) also acquired a mild rash with an average of 38 lesions and no accompanying systemic symptoms. Vaccine-type virus was isolated from four of the contact siblings. Tertiary transmission was documented once. Contact siblings with seroconversion were protected during future household exposure to chickenpox, which occurred in four instances. There was a direct relationship between transmission from vaccinees to varicella-susceptible close contacts and the presence and number of skin lesions in children with leukemia after vaccination. We conclude that in the transmission of varicella, the virus probably originates from skin lesions of infected persons and reaches the respiratory tract of those with secondary cases by the airborne route. On the basis of the mildness of the contact illness, the higher-than-normal rate of subclinical primary infection with varicella-zoster virus in contacts, and the lower-than-normal rate of spread of the vaccine virus to susceptible children in the household, we further conclude that the vaccine virus is attenuated. There was no evidence of reversion of the vaccine virus to virulence.

The risk of zoster after varicella vaccination in children with leukemia

We examined the incidence of zoster in 346 children with underlying acute lymphoblastic leukemia who were immunized with live attenuated varicella vaccine while in remission. We also compared a subset of 84 of these children with a matched group of 84 children with leukemia who had had natural infection with varicella. Of the 346 vaccinated children, 5 (1.45 percent) became infected with zoster after 10,878 months of observation, for an incidence of 0.552 case per 100 person-years. Among the matched pairs of subjects, zoster occurred in 3 (3.6 percent) of the 84 vaccinated subjects during 2936 months of observation--an incidence of 1.23 cases per 100 person-years--and in 11 (13.1 percent) of the subjects with natural infection during 4245 months--an incidence of 3.11 cases of zoster per 100 person-years. Although the incidence of zoster was more than twice as high in the control children as in the vaccinated children (3.11 vs. 1.23 cases per 100 person-years), a Kaplan-Meier product-limit analysis revealed no significant differences in incidence between the two groups. Children from both groups in whom leukemia recurred were more likely to contract zoster than those who did not have a recurrence (7 of 35 vs. 7 of 133, P less than 0.025). Zoster was not a marker for impending relapse. No case of zoster was severe or disseminated. We conclude that the incidence of zoster following immunization with live attenuated varicella vaccine is no greater than that following natural varicella infection.

Effectiveness of 2 Doses of Varicella Vaccine in Children

BACKGROUND Because of ongoing outbreaks of varicella, a second dose of varicella vaccine was added to the routine immunization schedule for children in June 2006 by the Centers for Disease Control and Prevention. METHODS We assessed the effectiveness of 2 doses of varicella vaccine in a case-control study by identifying children ≥4 years of age with varicella confirmed by polymerase chain reaction assay and up to 2 controls matched by age and pediatric practice. Effectiveness was calculated using exact conditional logistic regression. RESULTS From July 2006 to January 2010, of the 71 case subjects and 140 matched controls enrolled, no cases (0%) vs 22 controls (15.7%) had received 2 doses of varicella vaccine, 66 cases (93.0%) vs 117 controls (83.6%) had received 1 dose, and 5 cases (7.0%) vs 1 control (0.7%) did not receive varicella vaccine (P < .001). The effectiveness of 2 doses of the vaccine was 98.3% (95% confidence level [CI]: 83.5%-100%; P < .001). The matched odds ratio for 2 doses vs 1 dose of the vaccine was 0.053 (95% CI: 0.002-0.320; P < .001). CONCLUSION The effectiveness of 2 doses of varicella vaccine in the first 2.5 years after recommendation of a routine second dose of the vaccine for children is excellent. Odds of developing varicella were 95% lower for children who received 2 doses compared with 1 dose of varicella vaccine.