Lawrence D. Gelb

Persistence of the Efficacy of Zoster Vaccine in the Shingles Prevention Study and the Short-Term Persistence Substudy

BACKGROUND The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point.

Long-Term Persistence of Zoster Vaccine Efficacy

BACKGROUND The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. METHODS Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. RESULTS The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. CONCLUSIONS Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

Safety of Herpes Zoster Vaccine in the Shingles Prevention Study: A Randomized Trial

BACKGROUND The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. OBJECTIVE To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults. DESIGN Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501) SETTING 22 U.S. academic centers. PARTICIPANTS 38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. INTERVENTION Single dose of herpes zoster vaccine or placebo. MEASUREMENTS Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. RESULTS After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. LIMITATIONS Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. CONCLUSION Herpes zoster vaccine is well tolerated in older, immunocompetent adults. PRIMARY FUNDING SOURCE Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research.

A Real-Time PCR Assay to Identify and Discriminate Among Wild-Type and Vaccine Strains of Varicella-Zoster Virus and Herpes Simplex Virus in Clinical Specimens, and Comparison With the Clinical Diagnoses

A real‐time PCR assay was developed to identify varicella‐zoster virus (VZV) and herpes simplex virus (HSV) DNA in clinical specimens from subjects with suspected herpes zoster (HZ; shingles). Three sets of primers and probes were used in separate PCR reactions to detect and discriminate among wild‐type VZV (VZV‐WT), Oka vaccine strain VZV (VZV‐Oka), and HSV DNA, and the reaction for each virus DNA was multiplexed with primers and probe specific for the human β‐globin gene to assess specimen adequacy. Discrimination of all VZV‐WT strains, including Japanese isolates and the Oka parent strain, from VZV‐Oka was based upon a single nucleotide polymorphism at position 106262 in ORF 62, resulting in preferential amplification by the homologous primer pair. The assay was highly sensitive and specific for the target virus DNA, and no cross‐reactions were detected with any other infectious agent. With the PCR assay as the gold standard, the sensitivity of virus culture was 53% for VZV and 77% for HSV. There was 92% agreement between the clinical diagnosis of HZ by the Clinical Evaluation Committee and the PCR assay results. J. Med. Virol. 81:1310–1322, 2009. Published 2009 Wiley‐Liss, Inc.

Varicella-Zoster Virus Transformation of Hamster Embryo Cells

Varicella-zoster virus infection of primary hamster embryo cells resulted in oncogenic transformation. These transformed cells exhibited virus-specific antigens by immunofluorescence and developed surface Fc receptors. They induced aggressive fibrosarcomas when injected into inbred hamsters. The tumour-bearing hamsters develop antibodies to varicella-zoster antigens.

Preventing herpes zoster through vaccination.

TOPIC The role of the zoster vaccine in the prevention of herpes zoster and its sequelae, including postherpetic neuralgia (PHN) and herpes zoster ophthalmicus. CLINICAL RELEVANCE Wide administration of the herpes zoster vaccine in accordance with the recommendations of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) will lead to a decline in the incidence and morbidity of herpes zoster and its complications, including PHN. METHODS The key study leading to the approval of the zoster vaccine for use, the Centers for Disease Control and Prevention ACIPs recommendations for appropriate use of the zoster vaccine, and predictions regarding the cost efficacy of a zoster vaccination program are reviewed. RESULTS The Shingles Prevention Study established that the zoster vaccine was safe, well tolerated, and effective in reducing the burden of illness due to herpes zoster and the incidence of PHN. The ACIP recommended that the zoster vaccine be given to adults 60 and older for the prevention of herpes zoster. Cost-efficacy analyses suggest that the greatest gain in quality-adjusted life-years can be gained by vaccinating individuals at the younger end of the ACIP-recommended age range. CONCLUSION The zoster vaccine promises to reduce the morbidity and mortality of herpes zoster. Administering the vaccine at the younger end of the age range may offer a greater cost benefit.

Varicella-zoster virus DNA from persistently infected cells contains novel tandem duplications.

A persistent infection with varicella-zoster virus was established in the Mewo human melanoma cell line. This persistently infected cell line went through periodic crises of virus-induced cell killing and then recovery. Analyses of viral DNA derived from the persistently infected cultures revealed that novel viral nucleic acid rearrangements had been generated. These viral DNA sequences were derived from a specific region of the inverted repeat sequence of the genome flanking the short unique genome segment. The novel DNA was of various lengths, each generated by tandem duplication of an approximately 2760 base pair sub-sequence of the normal viral inverted repeat. These novel sequences were inserted into an otherwise apparently normal genome.

Varicella-Zoster Virus Fails to Induce Immunoglobulin G Fc Receptors in Infected Human Cells

Abstract Varicella-zoster virus infection of human fibroblasts and human brain cells produces characteristic cytopathogenic effects and virus-specific antigens. Receptors for the Fc portion of immunoglobulin G, which have been noted on cells infected with other human herpesviruses, could not be detected either by hemadsorption of sensitized sheep erythrocytes or by binding of radiolabeled IgG. Herpes simplex virus-infected cells were positive under the same conditions.

LIVE ATTENUATED VARICELLA VACCINE: USE IN HEALTHY ADULTS

We administered live attenuated varicella vaccine to 187 healthy adults seronegative to varicella-zoster virus (VZV); 176 have been followed at least 2 mos. 121/176 (69%) received 2 doses about 3 months apart. Side effects after 1 dose were: local reactions in 18 (10%), rash in 12 (7%), & fever in 4(2%). Side effects were less frequent after the 2nd dose. Vaccine associated rash was mild (mean 14 lesions, range 1-100). Vaccine type virus was isolated from 1 adult with a total of 8 lesions, 1 mo. after vaccination; there was no spread of vaccine virus to others. Seroconversions to VZV, measured by fluorescent antibody to membrane antigen (FAMA) were: after 1 dose 136/169 (80%), & after 2 doses 114/121 (94%). 22 seroconverted only after the 2nd dose; 7 (6%) failed to seroconvert after 2 doses. Positive antibody responses have been detected after 1 yr in 44/67 (66%), after 2-3 yr.in 19/28 (68%), & after 4-6 yr in 10/13 (77%). Ten have had a household exposure to varicella after as long as 7 years (mean 3 yrs); 6 (60%) developed at least some evidence of clinical varicella with 1-40 lesions (mean 16) but no toxicity. Seropositives (5/10) rarely developed clinical symptoms; 1 had 1 vesicle. There were a total of 10 cases of mild varicella in adult vaccinees with 1-58 lesions, (mean 10), 4-72 months after immunization. Wild type virus was isolated from 2 MDs, but there was no spread. Clinical infection was likely to occur in those seronegative at exposure (7/8, 88%) but the illness was still very mild. Varicella vaccine has the potential to control but not prevent nosocomial varicella. Varicella vaccine is less protective for healthy adults than for healthy children, but it modifies the illness even if VZV antibodies are no longer detectable.

VARICELLA VACCINE: PROTECTIVE EFFICACY IN CHILDREN WITH LEUKEMIA

Varicella may be severe in children with leukemia, with 10% mortality. We therefore evaluated the efficacy of live attenuated varicella vaccine in children with acute lymphocytic leukemia (ALL) in remission. We immunized 53 children with ALL off chemotherapy and 138 with ALL with chemotherapy suspended for 2 weeks, with 1000 pfu of varicella-zoster (VZ) (Oka) vaccine. After 1 dose of vaccine 82% seroconverted; 95% seroconverted after 2 doses, as detected by the fluorescent antibody to membrane antigen (FAMA) assay.The only significant side effect was rash, which occurred in 4% off chemotherapy, and in 36% with chemotherapy suspended. Rashes were not severe, but spread of VZ virus occurred to 4/129 (3%) of susceptible siblings. There was no increase in ALL relapse or incidence of zoster in vaccinees compared to a control ALL group after natural varicella. There were 22 household exposures to VZ virus in vaccinees, after which the incidence of mild varicella (average # of vesicles 50) was 18%, significantly lower than the usual 80-90% attack rate. Mild varicella occurred even in vaccinees with VZ antibody at exposure. This vaccine was 80% effective in preventing clinical varicella and 100% effective in preventing severe varicella in children with ALL, even those on chemotherapy.