The differences in short- and long-term varicella-zoster virus (VZV) immunoglobulin G levels following varicella vaccination of healthcare workers measured by VZV fluorescent-antibody-to-membrane-antigen assay (FAMA), VZV time-resolved fluorescence immunoassay and a VZV purified glycoprotein enzyme immunoassay.

Healthcare 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.

The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. Varicella Vaccine Collaborative Study Group.

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.

Antibodies to varicella-zoster virus glycoproteins I, II, and III in leukemic and healthy children.

A dot ELISA was used to analyze the antibody response to varicella-zoster virus glycoproteins I, II, and III in leukemic and healthy children who either developed natural varicella or received the live attenuated varicella vaccine. Both groups of children showed an antibody response to these viral glycoproteins. The antibody response to all three glycoproteins showed excellent persistence over the 3-year period of study. None of the glycoproteins provoked an antibody response that could be shown to correlate with protection from breakthrough varicella after household exposure to chickenpox or from zoster in leukemic vaccinees.

Live attenuated varicella vaccine: protection in healthy adults compared with leukemic children. National Institute of Allergy and Infectious Diseases Varicella Vaccine Collaborative Study Group.

Protection against varicella infection was assessed in leukemic children and healthy young adults who were immunized with live attenuated varicella vaccine. Attack rates of breakthrough infection following household exposure to varicella in 102 children and 26 adults were similar whether one or two doses of vaccine had been given. The mild breakthrough illness was also similar after one or more doses. Specific antibody titers were similar 1 year after immunization whether individuals had received one or two doses. Humoral and cell-mediated immunity to varicella-zoster virus (VZV) was lower in these vaccinees than in persons who had experienced natural varicella infection. Protection after natural infection in adult family members exposed to varicella was superior to that in vaccinees; none developed varicella infection. These observations suggest that immunization induces less protection than does natural disease in leukemic children and young adults. This may be partly due to the nature of the vaccine virus, but because responses of adults were similar to those of leukemic children, it suggests also that both of these groups have impaired immune responses to VZV. Boosting of humoral immunity after exposure to VZV was common and was observed in healthy adults with past natural infection and in vaccinated adults and leukemic children.

Live attenuated varicella vaccine: evidence that the virus is attenuated and the importance of skin lesions in transmission of varicella-zoster virus. National Institute of Allergy and Infectious Diseases Varicella Vaccine Collaborative Study Group.

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.

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.

Western blot analysis of antibody to varicella-zoster virus.

We used western blot (WB) to compare the IgG response to varicella-zoster virus (VZV) after chickenpox (CP), zoster, and administration of a live attenuated varicella vaccine (LAVV). After CP, 13 of 14 normal children had antibody to glycoprotein (gp) I (99 and 92 kilodaltons [kDa]), 11 had antibody to gpII (133 kDa), and 10 had antibody to gpIII (119 kDa). Bands at 150 and 35 kDa were also seen in 13 and 11 sera, respectively. Bands to gpI, gpII, and p35 were more intense after zoster than CP. After one dose of LAVV, eight of eight normal children had gpI antibody. In leukemic children, gpI antibody appeared in 18 (56%) after one dose and in 25 (89%) after two doses. Upon household exposure, leukemic vaccinees who developed CP were less likely than those protected to have prior gpIII and p35 antibodies. As seen after zoster, WBs after breakthrough CP showed intense responses to VZV antigens. Thus, WB helps distinguish secondary from primary antibody responses to VZV.

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.

Molecular epidemiology of live, attenuated varicella virus vaccine in children with leukemia and in normal adults.

Restriction endonuclease analysis of varicella-zoster virus (VZV) DNA has been used in unraveling the complex epidemiology of VZV infections in individuals immunized with a live, attenuated varicella virus vaccine. Early rashes appearing within the first six weeks after vaccination are invariably due to vaccine virus. True breakthrough infections with wild-type VZV also occur in vaccinees. Five cases of zoster have been seen in leukemic children vaccinated while in remission. One case appeared 22 months after vaccination in the same general area as the inoculation. The virus isolated was vaccine derived. A second case of zoster appeared in a dermatome unrelated to the sites of vaccination approximately 19 months after apparently natural varicella. This virus was wild type. Vaccine virus can therefore establish latency and can later reactivate as herpes zoster.

Live attenuated varicella vaccine use in immunocompromised children and adults.

Live attenuated varicella vaccine has been administered to 307 children with leukemia in remission and to 86 healthy adults. The vaccine was well tolerated and immunogenic. The major side effect in leukemic children receiving maintenance chemotherapy was development of a vaccine-associated rash. Vaccinees in whom a rash developed were potentially somewhat infectious to others about 1 month after immunization. Vaccination was not associated with an increase in the incidence of herpes zoster or in relapse of leukemia. Vaccination provided excellent protection against severe varicella. It was associated with a significant decrease in the attack rate of chickenpox following an intimate exposure to varicella-zoster virus, conferring about 80% protection in leukemic children. The cases of breakthrough varicella that occurred were mild. Thus, the vaccine may either prevent or modify varicella in high-risk individuals. It may also have use for prevention of nosocomial varicella.

Live attenuated varicella vaccine. Efficacy for children with leukemia in remission.

One hundred ninety-one varicella-susceptible children with leukemia in remission were immunized with live attenuated varicella vaccine. There was serological evidence of an immune response in approximately 80% after one dose and in more than 90% after two doses. The major side effect was mild to moderate rash, seen especially in children with maintenance chemotherapy suspended for one week before and one week after vaccination. Children with rash had higher antibody titers than those without rash, but those with rash were also at risk (10%) to transmit vaccine virus to others. Twenty-two vaccinees subsequently had household exposures to varicella or zoster. The attack rate of clinical varicella in these vaccinees was 18%, significantly lower than the attack rate of approximately 90% in varicella-susceptible persons with household exposures. All cases of clinical illness were extremely mild, with an average of about 50 vesicles. The mild character of the illness was clearly different than varicella in unimmunized children receiving chemotherapy for leukemia. Varicella vaccine was approximately 80% effective in preventing clinical varicella in children with leukemia and completely effective in preventing severe varicella in this high-risk group.

Clinical reinfection with varicella-zoster virus.

Eight patients became clinically reinfected with varicella-zoster virus despite the presence of specific antibody in the blood three days to six months before the onset of illness. One patient had had varicella previously; a second had been immunized with live, attenuated varicella vaccine 10 months earlier. While it was suspected that these patients experienced a reactivation of latent virus that caused atypical disseminated zoster rather than varicella, detailed study of the vaccinated child suggests that this was not the case; by restriction-endonuclease techniques, this vaccinee was shown to have been infected with wild-type varicella-zoster virus despite the presence of specific antibody and cellular immunity to the virus. All cases clinically resembled chickenpox. Thus, not only subclinical varicella (manifested by a rise in antibody titer after close exposure) but also clinical reinfection with the virus can occur. Clinical reinfection probably develops more frequently in immunocompromised than in immunocompetent individuals. Reinfections are usually mild.