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.

Varicella zoster virus in human and rat tissue specimens.

The limited supple of appropriate tissues for study has been an impediment to investigations of varicella zoster virus (VZV) latency. Human dorsal root ganglia (DRG) harboring latent virus are not plentiful and are not amenable to manipulation for studying the events surrounding the establishment, maintenance, and cessation of latency. An alternative to studies in human DRG is the rat model of latency, which appears to provide a reliable method of investigating VZV latency. Other alternatives include studies in other human tissues involved in VZV pathogenesis. In order to improve our understanding of the establishment and cessation of latency, we performed comparative immunohistochemical analysis of chickenpox and zoster skin lesions. This analysis revealed that during primary infection and reactivation productive VZV infection occurs in a variety of cell types and that the major VZV DNA binding protein, ORF29p, is present in peripheral axons early during the course of chickenpox. VZV latency was studied in the rat model by in situ hybridization and compared with similar studies performed in human DRG containing latent virus, confirming that VZV DNA persists in the same sites in DRG of the two species.

Varicella-zoster virus proteins in skin lesions: implications for a novel role of ORF29p in chickenpox.

Skin biopsy samples from varicella-zoster virus (VZV)-infected patients examined by immunohistochemistry demonstrated VZV replication in nonepithelial cell types. ORF29p, a nonstructural nuclear protein, was found in nerves of two of six patients with chickenpox. In tissue culture, ORF29p was secreted by VZV-infected fibroblasts. Extracellular ORF29p can be taken up through endocytosis by human neurons, implying a novel role for this protein in pathogenesis.

Aberrant intracellular localization of Varicella-Zoster virus regulatory proteins during latency.

Varicella-Zoster virus (VZV) is a herpesvirus that becomes latent in sensory neurons after primary infection (chickenpox) and subsequently may reactivate to cause zoster. The mechanism by which this virus maintains latency, and the factors involved, are poorly understood. Here we demonstrate, by immunohistochemical analysis of ganglia obtained at autopsy from seropositive patients without clinical symptoms of VZV infection that viral regulatory proteins are present in latently infected neurons. These proteins, which localize to the nucleus of cells during lytic infection, predominantly are detected in the cytoplasm of latently infected neurons. The restriction of regulatory proteins from the nucleus of latently infected neurons might interrupt the cascade of virus gene expression that leads to a productive infection. Our findings raise the possibility that VZV has developed a novel mechanism for maintenance of latency that contrasts with the transcriptional repression that is associated with latency of herpes simplex virus, the prototypic alpha herpesvirus.

Reactivated and latent varicella-zoster virus in human dorsal root ganglia.

Ganglia obtained at autopsy were examined by in situ hybridization from one patient with zoster (also called herpes zoster or shingles), two varicella-zoster virus (VZV)-seropositive patients with clinical evidence of zoster, one VZV-seronegative child, and one fetus. Ganglia positive for VZV had a hybridization signal in both neuronal and nonneuronal satellite cells. Ganglia obtained from the fetus and from the seronegative infant were consistently negative for VZV. Two striking observations were evident regarding the presence of VZV DNA in ganglia obtained from the individual with zoster at the time of death. First, ganglia innervating the sites of reactivation and ganglia innervating adjacent sites yielded strongly positive signals in neurons and satellite cells, whereas ganglia from distant sites were rarely positive. Second, VZV DNA was found in both the nuclei and the cytoplasm of neurons innervating areas of zoster. However, in neurons innervating zoster-free areas, VZV DNA was found only in the nucleus of neurons and their supporting satellite cells. Immunohistochemistry with a fluorescent monoclonal antibody to the VZV glycoprotein gpI, a late virus protein, revealed a positive signal in the cytoplasm of ganglia with clinical evidence of reactivation. These results illustrate that both neuronal and satellite cells become latently infected following primary VZV infection. The presence of VZV DNA and gpI in the cytoplasm of neurons demonstrates productive infection following reactivation at the site of latency.

Nucleotide sequence and genetic analysis of the neuD and neuB genes in region 2 of the polysialic acid gene cluster of Escherichia coli K1.

The K1 capsular polysaccharide, a polymer of sialic acid, is an important virulence determinant of extraintestinal pathogenic Escherichia coli. The genes responsible for the synthesis and expression of the polysialic acid capsule of E. coli K1 are located on the 17-kb kps gene cluster, which is functionally divided into three regions. Central region 2 encodes proteins necessary for the synthesis, activation, and polymerization of sialic acid, while flanking regions 1 and 3 are involved in polymer transport to the cell surface. In this study, we identified two genes at the proximal end of region 2, neuD and neuB, which encode proteins with predicted sizes of 22.7 and 38.7 kDa, respectively. Several observations suggest that the neuB gene encodes sialic acid synthase. EV24, a neuB chromosomal mutant that expresses a capsule when provided exogenous sialic acid, could be complemented in trans by the cloned neuB gene. In addition, NeuB has significant sequence similarity to the product of the cpsB gene of Neisseria meningitidis group B, which is postulated to encode sialic acid synthase. We also present data indicating that neuD has an essential role in K1 polymer production. Cells harboring pSR426, which contains all of region 2 but lacks region 1 and 3 genes, produce an intracellular polymer. In contrast, no polymer accumulated in cells carrying a derivative of pSR426 lacking a functional neuD gene. Unlike strains with mutations in neuB, however, neuD mutants are not complemented by exogenous sialic acid, suggesting that NeuD is not involved in sialic acid synthesis. Additionally, cells harboring a mutation in neuD accumulated sialic acid and CMP-sialic acid. We also found no significant differences between the endogenous and exogenous sialyltransferase activities of a neuD mutant and the wild-type organism. NeuD shows significant similarity to a family of bacterial acetyltransferases, leading to the theory that NeuD is an acetyltransferase which may exert its influences through modification of other region 2 proteins.

Comparison of a three-component acellular pertussis vaccine with a whole-cell pertussis vaccine in 4- through 6-year-old children. Elmwood Pediatric Associates, Pennridge Pediatric Associates.

OBJECTIVE: To compare the safety and immunogenicity of a three-component acellular pertussis (DTaP) vaccine containing pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin with whole-cell pertussis (DTwP) vaccine in 4- through 6-year-old children. PARTICIPANTS: One hundred seventy-two healthy 4- through 6-year-old children previously immunized with the DTwP vaccine at or near 2, 4, 6, and 18 months of age. INTERVENTIONS: Prevaccination serum samples were obtained on all study participants. One hundred twelve children received 0.5 mL of the DTaP vaccine intramuscularly. Fifty-three children received 0.5 mL of a commercially available DTwP vaccine intramuscularly. Approximately 30 days following vaccination, additional serum samples were obtained. MEASUREMENTS: Parents monitored adverse reactions for 7 days following immunization. Significantly fewer children in the DTaP group reported temperatures of greater than 38.1 degrees C and an area of redness of more than 10 mm and moderate-to-severe pain at the injection site. RESULTS: Antibody responses to PT, FHA, pertactin, and diphtheria and tetanus toxoids were measured by enzyme-linked immunosorbent assay. Among subjects who were seronegative prior to vaccination, response was defined as the detection of antibody levels following vaccination; among children with detectable antibody levels prior to vaccination, in terms of the rise in antibody titers. Data using a twofold and a fourfold rise in antibody titers as criteria to define response were evaluated. Children in the DTaP group had significantly greater increases in geometric mean titers of antibodies against PT, FHA, and pertactin. Over 90% of the DTaP group responded to PT, FHA, and pertactin according to the criteria of both the twofold and the fourfold rise in antibody titers. Significantly fewer of the DTwP group responded to PT, FHA, and pertactin with at least a fourfold rise in antibody titers. When analyzing subjects with at least a twofold increase in antibody titers, a statistically significant difference remained in regard to anti-FHA antibodies. All study subjects had protective antibody titers against diphtheria and tetanus toxoids following vaccination. The geometric mean titer of antibodies against tetanus was significantly greater in the DTwP group than in the DTaP group. CONCLUSION: The three-component DTaP vaccine administered as a booster immunization in 4-through 6-year-old children produced less fever and less redness and pain at the injection site than the DTwP vaccine and was as immunogenic as the DTaP vaccine.

The epidemiology of pediatric HIV-1 infection.

While the incidence of HIV infection has leveled off in older homosexual men, infection in women, children, and adolescents is rising. Unless effective intervention measures are implemented, the number of pediatric patients with HIV and related illnesses will continue to increase. Interventions aimed at curtailing perinatal transmission potentially will have the greatest impact on decreasing the incidence of pediatric AIDS. Studies evaluating strategies aimed at this are currently underway. Educational initiatives targeting adolescents also may lower the number of pediatric patients with HIV infection. As treatments improve, the majority of HIV-infected children will survive for years and perhaps decades. The number of children with HIV infection in the upcoming decades will have a profound impact on our communities and our practice of pediatric medicine.