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.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Screening for depression in the older adult: criterion validity of the 10-item Center for Epidemiological Studies Depression Scale (CES-D)

BACKGROUND: The Center for Epidemiological Studies Depression Scale (CES-D) has been widely used in studies of late-life depression. While the CES-D is convenient to use in most settings, it can present problems for elderly respondents who may find the response format confusing, the questions emotionally stressful, and the time to complete burdensome. A briefer 10-item version has been proposed, but there are few data on its properties as a screening instrument. METHODS: The 10-item CES-D was administered in 2 studies. In study 1, a stratified sample of middle-aged depressed patients (n = 40) and comparison controls (n = 43) were administered the CES-D to determine an optimal cutoff score. In study 2, the accuracy of the CES-D optimal cutoff score was tested in a sample of adults older than 60 years (n = 68). Major depression diagnoses were derived from the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, with consensus diagnoses using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. RESULTS: Reliability statistics with the 10-item CES-D were found to be comparable to those reported for the original CES-D. Using an optimal cutoff score of 4 in study 1, the sensitivity of the 10-item CES-D was 97%; specificity, 84%; and positive predictive value, 85%. In the study 2 sample of older adults, the sensitivity of the CES-D was 100%; specificity, 93%; and positive predictive value, 38%. CONCLUSION: The 10-item CES-D has excellent properties for use as a screening instrument for the identification of major depression in older adults.

Immunization to reduce the frequency and severity of herpes zoster and its complications.

Herpes zoster (HZ) is a localized disease that results from reactivation of an endogenous varicella-zoster virus (VZV) infection that has persisted in latent form within sensory ganglia following an earlier attack of varicella. The incidence and the severity of HZ and its complications increase with advancing age, and this is temporally associated with an age-related decline in cell-mediated immunity (CMI) to VZV. Information on the cellular site and mechanism of VZV latency and on the events that follow reactivation appears to explain many of the clinical features of HZ and to provide a pathophysiologic basis for the presumption that immunity to VZV plays a critical role in limiting the frequency and consequences of VZV reactivation. The close temporal correlation between the decline in VZV-specific CMI and the increased frequency and severity of HZ and its complications in older individuals suggests that HZ may actually develop because VZV-specific CMI falls below some critical threshold. The development of a live attenuated varicella vaccine provides a means of stimulating VZV-specific CMI and thus of determining its role in the pathogenesis of HZ. Levin and his colleagues have demonstrated that waning VZV-specific CMI in elderly persons can be stimulated by varicella vaccine to levels typical of those observed in younger persons, in whom the incidence and severity of HZ are much reduced. Thus the stage is set for a large placebo-controlled clinical trial that will test directly the hypothesis that restoration of waning CMI to VZV will reduce the frequency and severity of HZ and its complications in the elderly.

Immobilization of viral antigens on filter paper for a [125I]staphylococcal protein A immunoassay: a rapid and sensitive technique for detection of herpes simplex virus antigens and antiviral antibodies.

A new technique is described for the rapid detection and quantitation of herpes simplex virus (HSV) antigens and antiviral antibodies. It involves immobilization of HSV antigens on filter paper discs and subsequent analysis by 125I-labeled staphylococcal protein A (SPA) radioimmunoassay. A specially designed 96-well filtration device is employed which serves both as an incubation chamber and as a filtration manifold. It is rapid, simple, sensitive and specific, and requires only small volumes of antiserum and few target cells. The results may be readily and objectively quantitated. This technique permits the simultaneous assay of a large number of specimens in less than 1 h. Its sensitivity is considerably greater than that of other currently used immunologic techniques, and it is amenable to automation. These characteristics suggest that this [125I]SPA immunofiltration technique may be applicable to the rapid diagnosis of viral infections.

Fatal disseminated adenovirus infection in a renal transplant recipient.

A 61 year old woman died of diffuse interstitial adenovirus pneumonia 55 days after receiving a cadaveric renal allograft. The adenovirus was serologically distinct from the 33 known human adenovirus serotypes and appears to represent a new human adenovirus. Pathologic and virological findings indicate that the pneumonia was only one manifestation of a disseminated infection, the source of which may have been a latent adenovirus infection preexisting in the donor kidney. The establishment of the etiologic diagnosis in this case, which was complicated by the presence of oculocutaneous and esophageal herpes simplex virus infection as well as focal pulmonary aspergillosis, required coordinated histopathologic and virological investigation. Our findings demonstrate that severe viral infections in transplant recipients are not caused exclusively by members of the herpesvirus group.

Controlled trial of oral acyclovir in the therapy of recurrent herpes simplex genitalis. A preliminary report.

A randomized, placebo-controlled, double-blind study was performed to evaluate the efficacy and toxicity of orally administered acyclovir in the treatment of patients with recurrent herpes simplex genitalis (HSG). A total of 107 patients from centers in Burlington, Vermont, and San Diego, California, were entered into the study within 48 hours of the onset of lesions. Patients who received acyclovir shed virus for 1.8 +/- 0.6 days (mean +/- SEM) compared with 2.8 +/- 1.2 days for those who received placebo. The duration of shedding from genital lesions of patients in the acyclovir-treated group was significantly less than from lesions of patients who received placebo (p = 0.016 by a logrank test). An analysis of the toxicity of the drug was performed in 52 of the study participants. Acyclovir was well-tolerated and no alterations were observed in measurements of bone marrow, liver, or kidney function. Orally administered acyclovir is a promising antiviral compound for the treatment of recurrent HSG.

Hospital management of patients and personnel exposed to communicable diseases.

Patients and personnel who are exposed to certain communicable diseases in a hospital setting often require therapeutic or epidemic control measures which may differ from measures employed following community exposure. This paper offers guidelines for reducing the hospital spread of communicable diseases by preventive measures (admission screening procedures, immunizations for personnel), and post-exposure management of patients and personnel. It is intended as a companion to the "Hospital Isolation and Precaution Guidelines" for patients with clinically manifest infections which appeared previously.

Assessment of pain in herpes zoster: lessons learned from antiviral trials.

Pain typically accompanies acute herpes zoster and, in a proportion of patients, it persists well beyond rash healing. Pain must therefore be analyzed in trials of antiviral agents in herpes zoster, but different methods have been used to analyze pain in recent published trials. These reports are reviewed and their methodological strengths and weaknesses examined. Based on this review, recommendations for the design and analysis of future trials of antiviral agents in herpes zoster are proposed. The principal recommendation is that antiviral efficacy should be evaluated both by distinguishing post-herpetic neuralgia from acute pain and by considering pain as a continuum. The primary endpoint should address both the prevalence and duration of post-herpetic neuralgia and should be examined in those patients who have post-herpetic neuralgia. Adopting the proposed recommendations in design and analysis of future trials should facilitate comparison across trials of the efficacy of antiviral agents in the treatment of herpes zoster.

Detection of herpes simplex virus in clinical specimens by DNA hybridization.

An assay to detect herpes simplex virus (HSV) DNA in clinical specimens has been developed. It utilizes nucleic acid hybridization with a 32P-labeled DNA probe prepared from a fragment of HSV DNA cloned in a plasmid vector. This assay can detect 5 X 10(4) plaque-forming units of cell-free HSV and as few as four virus-infected cells. The assay has a sensitivity of 78% and a specificity of 100% compared to virus culture for the detection of HSV in swab specimens from genital lesions. No hybridization is observed with uninfected, varicella-zoster virus infected, or cytomegalovirus infected cells, and specimens from herpes zoster lesions are uniformly negative. While hybridization with a 32P-labeled probe is not optimally suited for routine diagnostic use, this report establishes the feasibility of using nucleic acid hybridization to detect HSV in clinical specimens.

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.

Molecular mechanisms of the antiviral action of interferon: effects of interferon on the transcription of viral messenger RNA.

Evidence from a number of virus-cell systems, discussed above and in other papers in this section, shows that the resistance to virus infection induced by interferon is characterized by inhibition of both primary transcription and translation. This may be because interferon induces two (or more) distinct "antiviral proteins" which inhibit, respectively, the transcription and the translation of virus genetic information. Although both may be present in interferon treated cells, the one which is manifest in any given experimental system may depend on whether transcription or translation is the primary event in the replication of the particular virus, and upon the accessibility of the viral nucleic acid. Alternatively, inhibition of transcription and translation may be mediated by a single antiviral protein which is able to distinguish viral from cellular nucleotide sequences in both DNA and RNA. The interferon-induced ribosome-associated inhibitors of viral mRNA translation (see related papers in this section) are prime candidates for such an antiviral protein.

Interferon and transcription of early virus-specific RNA in cells infected with simian virus 40.

Treatment with interferon reduced the content of early virus-specific RNA, as well as the content of an early viral protein (T antigen), in monkey cells acutely infected with simian virus 40 (SV40). This unexpected finding suggests either that the action of interferon involves inhibition of the transcription of early SV40 messenger RNA, or that the SV40 genome contains a "proto-early" gene whose product is required for the transcription of the remaining early genes.

Antibody to varicella-zoster virus-induced membrane antigen: immunofluorescence assay using monodisperse glutaraldehyde-fixed target cells.

A sensitive and reproducible technique was developed for the detection of antibody to varicella-zoster virus-induced membrane antigen (VZMA) by immunofluorescence. Controlled trypsinization and glutaraldehyde fixation were employed to prepare a monodisperse suspension of noninfectious VZMA-positive target cells that can be stored indefinitely at -72 degrees C. A microtiter immunofluorescence assay utilizing these target cells was shown to provide a sensitive and specific means for the detection and quantitation of antibody to varicella-zoster virus. The properties of the target cell preparation and the characteristics of the assay make practical the rapid assessment of immunity to the varicella-zoster virus.

New human adenovirus (candidate adenovirus type 35) causing fatal disseminated infection in a renal transplant recipient.

An antigenically distinct adenovirus is described which was isolated in March 1973 from the lungs and kidney of a 61-year-old woman who died of diffuse interstitial adenovirus pneumonia 55 days after receiving a cadaveric renal allograft. Complement fixation, hemagglutination inhibition, and serum neutralization tests on sequential serum specimens from the patient confirmed that the adenovirus infection occurred in coincidence with her clinical illness and failed to document concomitant infection by any other common respiratory agent. Pathological and virological findings indicated that the pneumonia was only one manifestation of a disseminated adenovirus infection, the source of which may have been a latent infection pre-existing in the donor kidney. The adenovirus, purified by terminal dilution and plaque procedures, has antigenic, morphological, biological, biophysical, host susceptibility, and hemagglutinating properties characteristic of adenovirus group 1A. Buoyant densities in CsCl are 1.340 g/ml for the virion, 1,300 g/ml for the group complement-fixing (hexon) antigen, and 1.290 g/ml for the major soluble complete hemagglutinin (dodecon). The virus was serologically distinct from adenoviruses 1 to 34 in reciprocal serum neutralization tests with antisera to these viruses. We propose this virus as candidate adenovirus type 35 (holden).

Rapid typing of herpes simplex virus isolates by deoxyribonucleic acid:deoxyribonucleic acid hybridization.

A method for typing clinical isolates of herpes simplex virus was developed. It utilizes hybridization between unlabeled deoxyribonucleic acid from infected cultures and tritium-labeled virus deoxyribonucleic acid, and it can be completed within a day using a single roller-tube culture of the clinical isolated. The data obtained are inherently quantitative, and the method yields unequivocal identification and typing. Thirty-nine coded clinical isolates were all correctly typed by this method.

Herpes simplex virus microneutralization: a simplification of the test.

The herpes simplex virus (HSV) microneutralization test has been simplified; its use has been demonstrated for the identification of HSV isolates as type 1 (HSV-1) or type 2 (HSV-2) and for the measurement of antibodies to HSV-1 and HSV-2. In this test, the relation between the neutralization titer and virus input is linear, and thus test results can be expressed as corrected neutralization titers, rather than as the more complex neutralizing potency values previously proposed. By means of this test, 45 of 46 clinical isolates of HSV were unequivocally identified as either HSV-1 or HSV-2. Evaluation of neutralizing antibody to HSV infection was more difficult because some neutralizing antibody to the heterotypic HSV is produced after primary infection with HSV-1 or HSV-2, because patients previously infected with one HSV type may show a variety of serological responses to subsequent heterotypic infection, and because human sera obtained early after primary HSV infection may not yet exhibit a type-specific response.

Control of simian virus 40 gene expression in adenovirus-simian virus 40 hybrid viruses. Synthesis of hybrid adenovirus 2-simian virus 40 RNA molecules in cells infected with a nondefective adenovirus 2-simian virus 40 hybrid virus.

The effect of interferon on simian virus 40 (SV40) and adenovirus 2 (Ad2) T antigen synthesis has been examined in cells infected with SV40, with Ad2, and with a nondefective Ad2-SV40 hybrid virus, Ad2(+)ND(4). The induction of SV40 T antigen by SV40 was highly sensitive to interferon, whereas the induction of Ad2 T-antigen by Ad2 was resistant. This difference in interferon sensitivity was also noted in cells simultaneously infected with both viruses. However, the induction of SV40 T antigen by Ad2(+)ND(4), which contains covalently linked SV40 and Ad2 DNAs, was as resistant to interferon as the induction of Ad2 T antigen. This change in the interferon sensitivity of SV40 T antigen synthesis suggests that the expression of at least this portion of the SV40 genetic information in Ad2(+)ND(4) is under Ad2 genetic control. When RNA extracted from Ad2(+)ND(4)-infected cells was examined by means of sequential hybridization with Ad2 DNA, elution, and rehybridization with SV40 DNA, 27% of the SV40-specific RNA was found to be linked to Ad2 RNA. No such linkage was detected in control mixtures of Ad2 and SV40 RNAs. The presence of Ad2 and SV40 nucleotide sequences in the same RNA molecule implies that, in Ad2(+)ND(4) infection, transcription is initiated in the DNA of one virus (Ad2 or SV40) and continues without interruption across the point of junction into the DNA of the other virus. Furthermore, the interferon resistance of Ad2(+)ND(4)-induced SV40 T antigen synthesis suggests that transcription of the genetic information for SV40 T antigen is initiated in a region of Ad2 DNA.

Herpes simplex virus as a source of thymidine kinase for thymidine kinase-deficient mouse cells: suppression and reactivation of the viral enzyme.

Thymidine kinase (EC 2.7.1.21)-deficient mouse cells were infected with inactivated herpes simplex virus, after which "transformed" cells that produce viral thymidine kinase were isolated. Shortly after transformation, the expression of the viral enzyme could be suppressed and reactivated with high efficiency. On continued multiplication in nonselective medium, the proportion of cells producing the viral enzyme decayed exponentially. This decay seemed to represent a change in the expression of the viral gene for thymidine kinase rather than the loss of the gene from the cells, since the viral enzyme could be apparently reactivated in every cell, albeit at a very low frequency.