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.

An investigation of enhanced secondary ion emission under Au(n)+ (n = 1-7) bombardment.

We investigate the mechanism of the nonlinear secondary ion yield enhancement using Au(n)+ (n = 1, 2, 3, 5, 7) primary ions bombarding thin films of Irganox 1010, DL-phenylalanine and polystyrene on Si, Al, and Ag substrates. The largest differences in secondary ion yields are found using Au+, Au2+, and Au3+ primary ion beams. A smaller increase in secondary ion yield is observed using Au5+ and Au7+ primary ions. The yield enhancement is found to be larger on Si than on Al, while the ion yield is smaller using an Au+ beam on Si than on Al. Using Au(n)+ ion structures obtained from Density Functional Theory, we demonstrate that the secondary yield enhancement is not simply due to an increase in energy per area deposited into the surface (energy deposition density). Instead, based on simple mechanical arguments and molecular dynamics results from Medvedeva et al, we suggest a mechanism for nonlinear secondary ion yield enhancement wherein the action of multiple concerted Au impacts leads to efficient energy transfer to substrate atoms in the near surface region and an increase in the number of secondary ions ejected from the surface. Such concerted impacts involve one, two, or three Au atoms, which explains well the large nonlinear yield enhancements observed going from Au+ to Au2+ to Au3+ primary ions. This model is also able to explain the observed substrate effect. For an Au+ ion passing through the more open Si surface, it contacts fewer substrate atoms than in the more dense Al surface. Less energy is deposited in the Si surface region by the Au+ primary ion and the secondary ion yield will be lower for adsorbates on Si than on Al. In the case of Au(n)+ the greater density of Al leads to earlier break-up of the primary ion and a consequent reduction in energy transfer to the near-surface region when compared with Si. This results in higher secondary ion yields and yield enhancements on silicon than aluminum substrates.

Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy.

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and HBeAg status was maintained in all. Four of the patients with HBeAg responses lost HBsAg at least once. In 10 (43%) of 23 patients tested, we identified HBV polymerase YMDD mutations, 3 with detectable HBV DNA (2 with ALT elevations) and 7 without virological/biochemical breakthrough. In conclusion, up to 18 months of lamivudine therapy was well tolerated, suppressed HBV replication consistently, and tripled the frequency of HBeAg losses observed during brief-duration therapy; HBeAg loss/seroconversion remained durable posttreatment. The emergence of YMDD-variant HBV was relatively common but occurred typically without reappearance of detectable HBV DNA or ALT elevation. Our observations suggest that lamivudine can be stopped after confirmed HBeAg loss or seroconversion.

Multiple recurrent branch retinal artery occlusions associated with varicella zoster virus.

PURPOSE: The authors describe an immunocompetent patient who developed multiple recurrent branch retinal artery occlusions (BRAOs) associated with the varicella zoster virus (VZV). METHODS: A 69-year-old woman with mild bilateral vitritis developed superior and inferior BRAOs in her right eye with decreased visual acuity to 20/40, and a peripheral BRAO inferotemporally in her left eye. One month later, the inferotemporal BRAO progressed proximally in her left eye with a decrease of visual acuity to 20/40. After an extensive negative systemic evaluation, she underwent a diagnostic pars plana vitrectomy of her right eye. RESULTS: Vitreous fluid was positive for VZV DNA by polymerase chain reaction (PCR). The patient was treated with intravenous acyclovir and systemic oral steroids. After remaining disease free for 3 months, the patient had two recurrences: 1) a mild vitritis and 2) development of a new superior temporal artery occlusion in the left eye. Both recurrences were treated with oral acyclovir and systemic steroids. The patient remained recurrence free for 12 months on a maintenance dose of oral acyclovir, and for 4 additional months without acyclovir. CONCLUSIONS: Varicella zoster virus can be associated with the syndrome of multiple recurrent BRAOs. The diagnosis of VZV-associated BRAO can be established by PCR of intraocular fluid.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

Restriction fragment differences between the genomes of the Oka varicella vaccine virus and American wild-type varicella-zoster virus.

The Oka vaccine strains of varicella-zoster virus (VZV) have a significantly different BgII DNA restriction pattern from that of American wild-type isolates of VZV. This difference consists primarily of an additional BgII site, which lies within the BamHI "D" fragment. In conjunction with a study of the efficacy of an experimental Merck/Oka VZV vaccine, the area of the genome from which the most marked restriction pattern alteration arises was studied more closely to determine if there are other significant differences between the Oka strains and American wild-type strains. BamHI "D" fragments from the DNA of the Oka parent strain (the progenitor of the vaccine strain), the RIT/Oka vaccine strain (a derivative of the Oka parent strain), the Merck/Oka vaccine strain, and the EF strain (an American wild type), were submitted to extensive endonuclease digestion studies to ascertain if additional unique restriction sites are present in the Oka parent or vaccine strains. The extra BgII restriction site characteristic of the Merck/Oka vaccine strain is also present in the DNA of the parent virus as well as its derivatives and was therefore not produced by the "attenuation" process. No other novel sites were found in the Oka parent or Oka-derived strains in this section of the genome. The Merck/Oka vaccine strain of VZV, despite its Japanese origin, is therefore quite similar to circulating American varicella-zoster virus strains. Varicella-zoster virus DNA, at least in the area of the BamHI D fragment, also appears to be remarkably stable from strain to strain.

Herpes zoster in an adult recipient of live attenuated varicella vaccine.

A healthy 30-y-old female physician who was immunized with two doses of live attenuated varicella vaccine developed a localized case of zoster involving the right T8-10 dermatomes 36 mo after vaccination. The virus isolated from her rash was an unusual wild-type of varicella-zoster virus. After immunization she developed detectable antibodies to varicella-zoster virus, but antibodies were no longer detectable after 20 mo. Six months before development of zoster, she was exposed to a patient with varicella; however, she did not develop a clinical illness although she again became seropositive. To date, this is the only reported case of zoster among 187 healthy adult vaccinees.

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.

Recombination in tissue culture between varicella-zoster virus strains.

Several clinical varicella-zoster virus isolates obtained during testing of a live varicella vaccine had DNA restriction fragment patterns resembling neither vaccine nor wild-type virus [Gelb et al., J Infect. Dis. 155, 633-640, 1987]. One explanation for these isolates was recombination in vivo. To determine if such recombination is likely, two strains of varicella-zoster virus, distinguishable by restriction endonuclease fragment size differences (wild-type strain EF and the OKA vaccine strain), were grown together in tissue culture. After three passages, the mixed infection virus was plaque-purified. DNA from about 13% of the plaque-purified isolates had one or more BglI fragments found in neither parental virus. Hybridization studies showed that isolates containing one of the new BglI fragments were recombinants of the two parental strains. The BglI restriction fragment pattern of these recombinants resembled those of the unusual varicella isolates from individuals either vaccinated with the live attenuated OKA varicella vaccine and later exposed to natural varicella, or simultaneously exposed to both a recent recipient of the vaccine and natural varicella.

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.

Physical maps of varicella-zoster virus DNA derived with 11 restriction enzymes.

Varicella-zoster virus DNA was digested with 11 restriction endonucleases, and the resulting fragments were separated on agarose gels. Terminal fragments were identified by lambda exonuclease digestion. Physical maps were then constructed using a combination of double restriction enzyme digestion and hybridization to cloned BamHI fragments to place the remaining fragments in order.

Restriction endonuclease analysis of varicella-zoster vaccine virus and wild-type DNAs.

The DNA from several clinical isolates of varicella-zoster virus (VZV) were compared with the DNA from the vaccine strain VZV using three restriction endonucleases: BamHI, BgII, and HpaI. When electrophoresed through an agarose gel, the vaccine DNA digestion pattern was significantly different from the digestion patterns of the wild-type DNAs. Variations in the digestion pattern of the separate clinical isolates were also observed.

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.

A partial characterization of hepatitis B e antigen.

Partially purified hepatitis B e antigen (HBeAG) was prepared by ultracentrifugation, ammonium sulfate precipitation, and molecular sieve chromatography of sera obtained from asymptomatic carriers of hepatitis B surface antigen. The antigenic specificity of the HBeAG preparations was investigated further with affinity chromatography. The results indicated that HBeAG is distinct and separable from DNA polymerase activity. Columns coupled with either goat IgG prepared from antiserum to human IgG or antibody to HBeAg bound all detectable HBeAg and bound 31% and 100% of the IgG, respectively, from a partially purified HBeAg preparation. Rate zonal sucrose sedimentation and molecular sieve and ion-exchange chromatography indicated a variability in molecular weight and charge; this finding suggested a heterogenous population of immunoreactivities containing HBeAg. Our preliminary results suggest the existence of an HBeAg-IgG complex.

Filtration and immunoprecipitation in the elimination of DNA polymerase activity associated with bacterial contamination of sera positive for hepatitis B e antigen and its corresponding antibody.

Samples of serum inoculated with Escherichia coli and serum that became contaminated with bacteria after exposure to a laboratory atmosphere demonstrated elevated DNA polymerase activity. The levels of activity were well within the range of values found in hepatitis B e antigen (HBeAg)-positive samples. The bacterial polymerase activity was markedly reduced by a single passage of serum samples through a 0.22-micron Millipore filter prior to analysis. Repeated filtration did not result in a substantial further decrease in polymerase activity. In sera that were heavily contamined with E. coli, however, filtration was not successful in reducing bacteria-associated polymerase activity to a base-line uncontaminated level. In such instances double antibody immunoprecipitation proved effective in elimination of bacterial activity. When bacterial contamination of serum samples is a possibility, specimens should be subjected to either Millipore filtration or immunoprecipitation prior to analysis, particularly when correlation of DNA polymerase activity with HBeAg and its corresponding antibody is attempted.

Discordant e antigen, DNA polymerase activity, and Dane particle responses in two patients representing an index case-contact case pair with hepatitis B virus infection.

Discordant results for e antigen, DNA polymerase activity, and Dane particle frequency were noted in the sera of two patients representing an index case-contact case pair with chronic aggressive hepatitis B. The lack of correlation between presence of e antigen and the infecting viral strain, as well as the strong relationship of e antigen to persistent and significant viremia, emphasize the role of the host's immune response in the expression of this antigen.