The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type b polysaccharide and Neisseria meningitidis outer-membrane protein complex

BACKGROUND AND METHODS. Several conjugate vaccines against Haemophilus influenzae type b have been developed in the search for one that induces protection even in young infants. We evaluated the safety and efficacy of a conjugate vaccine that links the H. influenzae type b capsular polysaccharide to the outer-membrane protein complex (OMPC) of Neisseria meningitidis serogroup B. We conducted a double-blind, placebo, controlled trial in Navajo infants, who are at high risk for systemic infections caused by H. influenzae type b. The infants were randomly assigned to receive the first dose of vaccine or placebo at 42 to 90 days of age and the second at 70 to 146 days of age. RESULTS. Of the infants in the trial, 2588 were assigned to receive the vaccine and 2602 to receive placebo. The mean follow-up was 269 days in the vaccine group and 267 days in the placebo group. Before the age of 18 months, there was 1 systemic H. influenzae type b infection in the vaccine group, as compared with 22 in the placebo group (P less than 0.001; point estimate of efficacy, 95 percent; 95 percent confidence interval, 72 to 99 percent). Of the 22 H. influenzae type b infections in the placebo group, 13 were meningitis. Among the children who received both doses, there was 1 H. influenzae type b infection in the vaccine group (n = 2056) and 14 in the placebo group (n = 2105) (P less than 0.001; point estimate of efficacy, 93 percent; 95 percent confidence interval, 53 to 98 percent). The single infection in the vaccine group occurred at 15 1/2 months of age in an infant with osteomyelitis. Between the first and second doses there were no H. influenzae type b infections in the vaccine group and eight in the placebo group (P less than 0.005; point estimate of efficacy, 100 percent; 95 percent confidence interval, 41 to 100 percent). CONCLUSIONS. The H. influenzae type b OMPC vaccine, administered at 2 and 4 months of age, is safe and induces a high rate of protection against invasive disease caused by H. influenzae type b in infants under the age of 18 months. Protection begins after the first dose.     

A novel glycoprotein for detection of herpes simplex virus type 1-specific antibodies

A novel herpes simplex virus type 1 (HSV-1)-specific glycoprotein reactive with monoclonal antibody H1379 was purified by affinity chromatography. This glycoprotein, provisionally designated as gG-1, forms two sets of bands with molecular weights of 40-44,000 and 60-88,000. When used in an immunodot enzymatic assay, gG-1 reacted strongly with rabbit antisera to HSV-1, but not with sera hyperimmune to HSV-2. Specificity of the assay was further established by the lack of reactivity of convalescent sera collected from 20 patients with primary genital HSV-2 infections, and from 100 sero-negative individuals. In contrast, antibodies to gG-1 were detected in 9 of 10 patients with primary HSV-1 infection, and in 63/67 patients with culture-positive, recurrent oral or genital HSV-1 infection. Reproducibility of the gG-1 immunodot assay for HSV-1 antibody detection was 96%. Serological assay with purified gG-1, done in parallel with the assay using purified gG-2 described in an earlier report, provides simple and reliable methods to detect type-specific HSV-1 and HSV-2 antibodies for seroepidemiological studies.     

Invasion profiles of Brazilian field isolates of Plasmodium falciparum: phenotypic and genotypic analyses

The invasion of red blood cells (RBCs) by Plasmodium falciparum is dependent on multiple molecular interactions between erythrocyte receptors and parasite ligands. Invasion studies using culture-adapted parasite strains have indicated significant receptor heterogeneity. It is not known whether this heterogeneity reflects the parasite invasion arsenal in the field. We have studied the invasion phenotypes of 14 distinct field isolates from the Legal Amazon areas of Brazil by using erythrocyte invasion assays to investigate invasion into normal, enzyme-treated, and clinical-mutant RBCs. Analysis of these isolates revealed four distinct invasion profiles. Using En(a-) cells to get an unequivocal estimate of the use of glycophorin A (GPA) as a receptor, we found that the 175-kDa erythrocyte-binding antigen (EBA-175)/GPA pathway was used by a minority of the parasite isolates studied. Although polymorphism of region II domains at specific amino acid positions in both EBA-140 and EBA-181 was found in these field isolates, this did not correlate with invasion profiles and thus receptor selectivity. These studies have further confirmed the existence of a significant diversity of invasion pathways in nature and suggest that additional parasite ligands will have to be targeted to devise global vaccines that will work in the field.     

A sensitive assay for detecting low-affinity interactions at the cell surface reveals no additional ligands for the adhesion pair rat CD2 and CD48

The ligand for the T cell antigen CD2 is CD48 in rodents, but CD58 in humans. The extracelluar parts of these three antigens are structurally related in that all contain two immunoglobulin superfamily (IgSF) domains. There have been reports of alternative ligands for CD2 in the human, but not so far in rodents. We describe the analysis of ligands for rat CD2 and CD48 using fluorescent beads capable of displaying a high ligand density and detecting low-affinity interactions like that of CD2 with CD48 (Kd = 60 ? 90 μM). Monovalent chimeric proteins containing the two IgSF domains of rat CD48 or CD2 and domains 3 and 4 of rat CD4 (CD4d3+4) were anchored to fluorescent covaspheres^TM via a CD4 monoclonal antibody (mAb) with the CD48 or CD2 domains available for ligand binding. Multivalent CD48-CD4d3 + 4 covaspheres^TM gave strong specific binding to rat CD2 expressed on the surface of transfected Jurkat cells. CD48-CD4d3+4 was compared with CD48-IgG and CD48-IgM as tools for detecting binding at the cell surface. Soluble divalent CD48-IgG and decavalent CD48-IgM bound to soluble CD2 with a K_off of around 10^?3 s^?1 as determined using a BIAcore^TM biosensor. However, binding to cells by CD48-IgG and CD48-IgM was only detectable when they were immobilized on covaspheres^TM and represented no increase in sensitivity over CD48-CD4 covaspheres^TM when tested for binding to cells expressing high and low levels of CD2. CD48-CD4d3 + 4 covaspheres^TM only bound to rat cells expressing CD2. In the reverse orientation, binding of CD2-CD4d3 + 4 covaspheres^TM was dependent on expression of CD48. Pre-incubation of cells with CD2 or CD48 mAb abolished all binding of CD48-CD4d3 + 4 or CD2-CD4d3 + 4, respectively. The data provide no evidence for an alternative ligand for rat CD2 or CD48.     

Frequent attenders in secondary care: a 3-year follow-up study of patients with medically unexplained symptoms

BACKGROUND: There are few longitudinal studies of patients with medically unexplained symptoms. The aim of this study was to investigate outcome in frequent attenders in secondary care who present repeatedly with medically unexplained symptoms. METHOD: Forty-eight patients presenting with medically unexplained symptoms, from a sample of 61, participated in a 3-year follow-up study. Psychiatric morbidity, functional impairment and use of services were evaluated. RESULTS: At follow-up there was a high prevalence of psychiatric morbidity with 69% having at least one psychiatric diagnosis. The sample continued to be high users of a range of health services and substantial functional impairment was reported. CONCLUSION: In this group of frequent attenders with medically unexplained symptoms outcome as measured by psychiatric morbidity, service use and functional impairment remained poor after 3 years.     

Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo

Dectin-2 is a recently described dendritic-cell-associated receptor, suggested to be involved in the initiation and maintenance of UV-induced tolerance. To understand the physiological relevance of the proposed functions of this C-type lectin-like receptor, we have generated monoclonal antibodies against its extracellular domain and performed a detailed study of its expression. In naive mice, Dectin-2 has a novel distribution pattern compared with other myeloid markers, but is predominantly expressed by a wide variety of tissue macrophages. Its expression was limited on dendritic cells and notably absent from brain microglia and choroid plexus or meningeal macrophages. On peripheral blood monocytes, Dectin-2 expression was very low on the surface but was transiently and markedly up-regulated on induction of inflammation in vivo using a variety of stimuli. This change in Dectin-2 expression occurs on 'inflammatory' monocytes after arrival at the inflammatory lesion as demonstrated by adoptive cell-transfer studies, and is independent of whether the macrophages elicited by the stimuli ultimately expressed Dectin-2. These observations show Dectin-2 expression to be characteristic of monocyte activation/maturation at an inflammatory lesion and provide a new perspective on the interpretation of Dectin-2 function in vivo.     

Immunohistochemical renin study of DES-induced renal tumor in the Syrian hamster

Diethylstilbestrol (DES) treatment of a male Syrian hamster resulted in the development of a renal tumor and its widely scattered scrosal metastases. Cells in both the primary tumor and metastatic nodules contained secretory granules. The tumors were transplanted serially into DES-supported and non-DES-supported host hamsters until DES-independent tumors developed. Rabbit antiserum to mouse salivary renin and rabbit antiserum to rat kidney resin were reacted with sections of the primary tumor, metastatic nodules, and all transport tumors. The sections were stained by the PAP and Vector-ABC-AP procedures. Renin-positive material was observed in all tumors. Plasma renin activity (PRA) was determined for the host hamsters carrying the renal tumor transplants and compared to the PRA values that had been determined for normal non-DES-treated male and female hamsters. It was found that the average PRA values of host hamsters carrying the tumor transplants were significantly higher than the normal PRA ralues.