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.

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.

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.

Cellular immunity to varicella-zoster virus in patients with major depression.

The incidence of herpes zoster increases markedly with advancing age, and this appears to be causally related to an age-dependent decline in varicella-zoster virus (VZV)-specific cellular immunity. Psychologic stress has also been linked to the occurrence of herpes zoster, but the mechanism involved has not been investigated. This study examined the relationship between major depression and VZV-specific cellular immunity by comparing VZV-specific responder cell frequency (RCF) in adults with major depression (n = 11) to that in age- and sex-matched nondepressed controls (n = 11) and in a larger group of nondepressed adults who were > or = 60 years old. VZV-specific RCF in depressed patients was markedly reduced compared with the RCF in matched controls (t = 2.7, P < .02). In fact, the levels of VZV-specific RCF in the depressed patients were comparable in magnitude to the low levels found in adults > or = 60 years of age. These data indicate that major depression is associated with a marked decline in VZV-specific cellular immunity.

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.

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.

Twenty-one base pair repeat elements influence the ability of a Gal4-Tax fusion protein to transactivate the HTLV-I long terminal repeat.

The Tax1 protein of the human T-cell leukemia virus (HTLV-I) is a 40-kDa positive transactivator of viral gene expression. Tax1 does not bind directly to DNA, but associates indirectly with DNA via cellular transcription factors. To further investigate the activation of HTLV-I transcription by Tax1, a chimeric protein containing Tax1 fused to the DNA binding domain of Gal4 was created (Gal4-Tax). HTLV-I long terminal repeat (LTR) reporter plasmids were constructed in which specific Tax1 responsive elements were replaced with Gal4 binding sites. Cotransfection of Gal4-Tax or Tax1 with HTLV-I LTR reporter constructs containing Gal4 binding sites demonstrated that Gal4 sequences were necessary but not sufficient for maximal activation of the promoter by Gal4-Tax. Sequences surrounding the Gal4 binding sites were important in determining the level of Gal4-Tax activation. Association of Gal4-Tax with promoters which contained six Gal4 binding sites, but which lacked flanking LTR sequences, were weakly transactivated by Gal4-Tax (sevenfold). In contrast, LTR-CAT reporter constructs containing three Gal4 binding sites flanked by two 21 base pair repeat elements demonstrated a ninefold greater response to Gal4-Tax. These results suggest that cellular transcription factors, which bind the 21 base pair repeat elements, influence the ability of Tax1 to function as a transactivator. Furthermore, this effect is not fully explained by the ability of these factors to physically direct Tax1 to the LTR.

Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial.

Two hundred fifty patients were entered into a multicenter trial to evaluate the efficacy and toxicity of orally administered acyclovir for treatment of recurrent genital herpes. The study consisted of part A, in which patients entered the study within 48 hours of the onset of lesions, and part B, in which patients self-initiated therapy as soon as possible after the onset of a recurrent episode. In both parts, patients received either acyclovir (200 mg) or placebo, five times daily for five days. In both parts, the duration of virus shedding and the time to crusting and healing of lesions were shorter among acyclovir recipients than among placebo recipients. In part B, fewer acyclovir recipients formed new lesions during the study medication period than did placebo recipients. When parts A and B were compared directly, the duration of virus shedding and the times required for crusting and healing of lesions were significantly shorter among acyclovir recipients in part B than among acyclovir recipients in part A. No significant differences in the duration of itching and pain or in the times of subsequent recurrence were noted between acyclovir and placebo groups in either part A or part B. No significant toxic or adverse reactions were seen in acyclovir recipients. Oral acyclovir shortens the duration of virus shedding and the duration of lesions in patients with recurrent genital herpes. These effects are more pronounced when therapy is self-initiated by patients early in the course of a recurrent episode.

Rapid viral diagnosis.

The advent of antiviral chemotherapy provides a strong impetus to develop methods to diagnose viral infections rapidly and accurately. Several other potential contributions of rapid viral diagnoses to patient management also exist. Virus isolation remains the "gold standard" of viral diagnosis against which most newly developed diagnostic approaches--including serologic testing, viral-enzyme detection, microscopic techniques, radioimmunoassays, and enzyme immunoassays--must be compared. Since, as currently performed, enzyme immunoassays such as enzyme-linked immunosorbent assays have reached the limit of their sensitivity, fully satisfactory rapid viral diagnosis will require new approaches. Two such potentially useful approaches are the detection of viral antigen with a method that permits visual localization of virus-specific immunoenzymatic staining and the detection of viral nucleic acids in clinical specimens by hybridization with nucleic-acid probes.

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.

Enzyme immunofiltration technique for rapid diagnosis of herpes simplex virus eye infections in a rabbit model.

A rapid enzyme immunofiltration assay for herpes simplex virus (HSV) has been developed which is sensitive enough to detect viral antigens in eye swabs from rabbits with primary herpes keratitis. This assay employs a specially designed filter manifold to immobilize whole cells and cell debris dissociated from the swabs. Viral antigens trapped on the filters are then detected in an indirect immunoassay utilizing staphylococcal protein A conjugated with horseradish peroxidase. The assay required only 2.5 h to perform and could be read visually. Reconstruction experiments indicated that antigen from as few as 49 HSV-infected cells could be detected. Calcium alginate swabs were shown to recover more viral antigen than dacron swabs. The enzyme immunofiltration assay detected HSV antigens on 95% of the eye swabs from which infectious virus was recovered. In addition, HSV antigen was also detected in several swabs from infected eyes which did not yield infectious virus, presumably because the virus was neutralized by native antibody present in the lacrimal fluid. This enzyme immunofiltration assay technique lends itself to the elution of native antibody bound to the viral antigens, and this may be especially applicable in the diagnosis of recurrent HSV keratitis, where antiviral antibody in the lacrimal fluid may interfere with virus isolation and fluorescent-antibody or other virus detection assays.

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.

The binding of staphylococcal protein A by the sera of different animal species.

The capacity of purified immunoglobulin or serum to bind (125I)-labeled staphylococcal protein A (SPA) was measured by means of an immunofiltration assay that facilitated the examination of large numbers of sera and required only a minute quantity of each. Sera from 80 species, including humans, laboratory animals, domestic animals, and a variety of African mammals were examined. A wide interspecies variation in the SPA-binding capacity of serum immunoglobulins was confirmed. Only small variations were observed among individuals within the same species with one notable exception. A greater than 10,000-fold variation in SPA-binding capacity was observed among sera from nine goats. Interspecies differences in serum SPA-binding capacity correlated well with taxonomic differences, and the serum SPA-binding capacity correlated well with taxonomic differences, and the serum SPA-binding capacities of African mammals corresponded closely to those of their more common relatives. The sensitivity of antibody detection by indirect (125I)SPA immunoassay was shown to be determined mostly by the SPA-binding capacity of the serum examined. The titer of antibody to influenza A/Texas/1/77(H3N2) virus in sera from several different species, when measured by (125I)SPA immunofiltration assay, was directly proportional to the SPA-binding capacity of the serum and was not proportional to the hemagglutination inhibition titer. An (125I)SPA immunofiltration assay for antibody to Lassa virus in the serum of Mastomys natalensis (which binds SPA only one-thousandth as well as human serum) was at least as sensitive as the standard fluorescent antibody assay.

Rapid serological technique for typing herpes simplex viruses.

A rapid technique is described which can accurately identify a herpes simplex virus (HSV) isolate as type 1 or type 2. Filter paper disks were used to immobilize viral antigens, which were then identified by means of an (125)I-labeled staphylococcal protein A immunoassay. The assay was performed in a specially designed 96-well filtration device which served as both an incubation chamber and a filter manifold. By using this system and cross-absorbed antisera to HSV types 1 and 2, 69 coded clinical isolates of HSV were correctly and unequivocally typed. HSV was also clearly distinguished from varicella-zoster virus and cytomegalovirus. This assay can be rapidly executed (less than 2 h) and yielded an objective endpoint; it required only minute quantities of typing sera and can be easily performed with the cells from a single infected roller tube culture. Thus, it can be used to type initial clinical isolates of HSV, yielding results within hours after the first appearance of cytopathic effects in the culture used for primary virus isolation. Moreover, it is particularly well suited to the simultaneous analysis of many specimens and is amenable to automation. These characteristics suggest that this (125)I-labeled staphylococcal protein A immunofiltration technique will be applicable to the rapid identification of other herpesviruses, as well as other clinical isolates.

A rapid enzyme immunofiltration technique using monoclonal antibodies to serotype herpes simplex virus.

A rapid enzyme immunofiltration technique using monoclonal antibodies to serotype herpes simplex virus is described. It requires only a single tube culture showing viral cytopathology and can accommodate multiple specimens in a single assay. The monoclonal antibodies confer absolute specificity and the use of horseradish peroxidase-conjugated staphylococcal protein A or antiglobulin permits easy visual interpretation of the results following the 2-3 hour assay. Although it is possible that an occasional wild strain of HSV might escape recognition by monoclonal antibody, this potential problem has not been observed among the more than 500 clinical isolates tested to date, all of which have yielded an unequivocal result.

Psoralen inactivation of influenza and herpes simplex viruses and of virus-infected cells.

Psoralen compounds covalently bind to nucleic acids when irradiated with long-wavelength ultraviolet light. This treatment can destroy the infectivity of deoxyribonucleic acid and ribonucleic acid viruses. Two psoralen compounds, 4'-hydroxymethyltrioxsalen and 4'-aminomethyltrioxsalen, were used with long-wavelength ultraviolet light to inactivate cell-free herpes simplex and influenza viruses and to render virus-infected cells noninfectious. This method of inactivation was compared with germicidal (short-wavelength) ultraviolet light irradiation. The antigenicity of the treated, virus-infected, antigen-bearing cells was examined by immunofluorescence and radioimmunoassay and by measuring the capacity of the herpes simplex virus-infected cells to stimulate virus-specific lymphocyte proliferation. The infectivity of the virus-infected cells could be totally eliminated without altering their viral antigenicity. The use of psoralen plus long-wavelength ultraviolet light is well suited to the preparation of noninfectious virus antigens and virus antigen-bearing cells for immunological assays.

A rapid radioimmunoassay using 125I-labeled staphylococcal protein A for antibody to varicella-zoster virus.

A sensitive radioimmunoassay for serum antibody to varicella-zoster virus is described; it uses 125I-labeled staphylococcal protein A and a specially designed immunofiltration apparatus. The assay accurately distinguishes between individuals who are susceptible and those who are immune to infection with varicella-zoster virus. In addition, it can detect passive antibody in recipients of varicella-zoster immune globulin. This radioimmunoassay also detects the heterologous antibody responses that occasionally occur in patients infected with herpes simplex virus, which also have been detected by other antibody assays. The particular advantages of this assay are the use of noninfectious reagents, the speed of execution (less than 3 hr), the requirement for only small quantities of serum (30 microliters), the objectivity of end-point determination, and the capability of screening large numbers of sera. Consequently, this radioimmunoassay is especially useful for the rapid identification of susceptible individuals, which is essential for the appropriate management of patients and hospital personnel after exposure to varicella.