The serum opacity reaction of Streptococcus pyogenes. The demonstration of multiple, strain-specific lipoproteinase antigens.

Investigation into the antigenicity of streptococcal lipoproteinase has revealed the existence of multiple, immunologically distinct enzymes. Each lipoproteinase identified was found to be strain specific in that it was found only in strains of a particular T-agglutination pattern. In some T patterns, all streptococci of that T pattern which were examined shared a common lipoproteinase antigen. In other T patterns, strains which produced antigenically different lipoproteinases were identified. Evidence that the lipoproteinase antigen is distinct from other well-established cellular antigens of Group A streptococci has been presented. The production of this strain-specific enzyme by strains currently difficult to type by the standard M precipitin method may facilitate more precise identification of these strains and a better assessment of their role in the pathogenesis of Group A streptococcal infections and their sequelae.

M antigens among group A streptococci isolated from skin lesions.

Three new provisional types of Group A streptococci have been identified among strains isolated from skin infections of American Indian children. A previously established type, Type 41, was also recognized among the pyoderma strains. Most of the skin streptococci with T-agglutination pattern 3/13/B3264 could be identified as Type 41 or as one of two new provisional types, Schoenborn (Type 52) and Hanson (proposed Type 53). Strains of the third new provisional type, Kingbird (proposed Type 54), agglutinated as 15/17/19/23/47, a T pattern not associated with skin infections in studies of other populations. Approximately half of the pyoderma strains examined were found to produce an M antigen; the proportion of M-typable strains from skin infections was found to be similar to that currently found in throat cultures of children with pharyngitis. The demonstration of M antigens in streptococci from skin lesions provides evidence of their potential virulence and should facilitate their classification in subsequent epidemiological studies.

Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. The MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. DESIGN: A Phase I/II multicenter, open label, escalating dose clinical trial. PATIENT POPULATION AND DOSING REGIMEN: Children (n=65) born prematurely at < or =35 weeks of gestation who were < or =6 months of age (n=41) and children with bronchopulmonary dysplasia who were < or =24 months of age (n=24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n=11), 10 mg/kg (n=6) and 15 mg/kg (n=48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. RESULTS: The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 microg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 microg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of approximately 70 microg/ml. These concentrations were similar to previously published trough concentrations after i.v. administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. CONCLUSIONS: MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 microg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with i.v. administration of MEDI-493.

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN: Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION: Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS: MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS: MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation - a compassionate use experience.

Respiratory syncytial virus (RSV) pneumonia in BMT recipients carries a mortality rate of approximately 50-70% despite ribavirin (Virazole) treatment. In both immunocompetent and immunocompromised animal models, RSV neutralizing antibodies rapidly reduce pulmonary virus load after a single dose. RSV-IGIV (RespiGam) is an IgG immune globulin with high concentrations of RSV neutralizing antibody (>19 200 MU/ml). From June 1991 to February 1996, a compassionate-use protocol using RSV-IGIV for treatment of RSV infections was conducted. Eleven children at multiple centers, mean age 3.3 years (4 months to 9 years), were undergoing BMT and met the protocol criteria. They received a single 1500 mg/kg dose of RSV-IGIV infused over 12 h at a median of 5 days (1-37 days) after RSV symptom onset. Ten of these patients received prior or concurrent aerosolized ribavirin. Serum RSV neutralizing titers were measured in five patients and showed a 3- to 30-fold increase 24 h after RSV-IGIV infusion. Adverse events were mild. One of 11 (9.1%) patients died from their RSV illness (91% RSV survival). In comparison to previously published reports, RSV-IGIV treatment of RSV pneumonia in BMT patients may increase survival above that in such patients treated with ribavirin alone. Bone Marrow Transplantation (2000) 25, 161-165.

Experimental infection of vertebrates of the Pocomoke Cypress Swamp, Maryland with Keystone and Jamestown Canyon viruses.

Experimental studies were conducted to assess the susceptibility of white-tailed deer (Odocoileus virginianus), gray squirrels (Sciurus carolinensis), and cottontail rabbits (Sylvilagus floridanus) to Jamestown Canyon (JC) and/or Keystone (KEY) virus infection. Viremia occurred in 5 of 6 deer inoculated with JC virus; however, all deer developed KEY virus neutralizing antibody. Based on the observation that antibody elicited by primary infection of deer with either KEY or JC virus exhibited partial heterologous neutralization in vitro, cross-challenge experiments were performed in these animals. Keystone virus failed to infect deer 30 days post primary JC virus infection; however, deer became infected when challenged with KEY virus 80 days after the initial JC virus infection as indicated by a substantial increase in antibody titer. Similarly, JC virus failed to produce viremia in immune animals infected with KEY virus 80 days previously, although 2 of the 3 animals challenged had serological evidence of infection. Three field-collected cottontail rabbits with no evidence of KEY antibody were readily susceptible to KEY virus infection and developed viremias of 1-4 days' duration; rabbits with KEY virus antibody did not develop viremia upon KEY virus challenge. Eight antibody-negative field-collected gray squirrels became viremic following injection with KEY virus; however, a comparable group of squirrels did not become viremic when injected with JC virus.

Control of adenovirus acute respiratory disease in U.S. Army trainees.

Although limited almost exclusively to military trainees, acute respiratory disease (ARD) caused by adenovirus types 4 and 7 had been the leading cause of hospitalization in U.S. Army personnel. This decrease which resembles influenza in clinical manifestations led to hospitalization of as many as 50% of military trainees in midwinter and imposed a heavy burden on military hospitals and training programs. In studies undertaken from 1965 to 1970, live adenovirus type 4 and subsequently type 7 vaccines were found to be safe and immunogenic and to confer protection against type specific adenovirus ARD. For the past 5 yr. military trainees have been immunized with both adenovirus vaccines during periods of expected adenovirus disease. Since 1966, use of adenovirus vaccines has been monitored through the adenovirus surveillance program which yields weekly data on incidence and etiology of ARD in basic combat trainees. Since 1973, stable adenovirus vaccines have resulted in excellent control of adenovirus ARD. Potential problems with this immunization program are discussed.

Swine influenza A at Fort Dix, New Jersey (January-February 1976). IV. Summary and speculation.

Influenza A/New Jersey/76 virus was detected at Fort Dix from January 19 through February 9, 1976 and infected at least 230 military personnel. Thirteen hospital admissions for acute respiratory disease were associated with influenza A/New Jersey infection, and additional members of index training companies may have been hospitalized with influenza A/New Jersey. This virus was likely introduced into the reception center by an incoming trainee. Although our studies could not eliminate the possibility that influenza A/New jersey strains are inherently less transmissible in humans than H3N2 viruses, the simultaneous transmission of influenza A/Victoria/75 virus and the unusual environment in basic combat training may explain why influenza A/New Jersey did not spread significantly outside of this training population.

Simultaneous administration of live, enteric-coated adenovirus types 4, 7 and 21 vaccines: safety and immunogenicity.

The safety of and the immune response to simultaneous administration of live, enteric-coated adenovirus type 4 (ADV-4), type 7 (ADV-7), and type 21 (ADV-21) vaccines were studied. Volunteers (476 men), randomly assigned to four study groups, received three vaccines (ADV-4, ADV-7, and ADV-21), two vaccines (ADV-4 and ADV-7), one vaccine (ADV-21), or no vaccine (placebo). Subjects were observed for three weeks, and no side effects due to vaccination occured. The percentages of susceptible subjects (those entering the study with a neutralizing antibody titer of less than 1:2 to each vaccine virus received) who seroconverted to ADV-4 were similar in both groups that received ADV-4 vaccine (78% of 77 subjects and 74% of 76). However, in the group that received three vaccines, only 62% of 77 subjects seroconverted to ADV-7, compared with 79% of 76 in the group that received two vaccines (P less than 0.05). Only 58% of 77 subjects in the three-vaccine group seroconverted to ADV-21, compared with 69% of 59 in the group that received one vaccine (P greater than 0.1).

Subtypes of hepatitis B surface antigen in Southeast Asia.

The prevalences of hepatitis B surface antigen (HBs Ag) subtypes in Thais, Cambodians, and Vietnamese were compared with the prevalences in Americans residing in Southeast Asia. HBs Ag was found with approximately equal frequency in Thai (43 percent) and American (39 percent) patients with hepatitis. However, higher prevalences of HBs Ag were found in asympotomatic Thais (9.5 percent), Cambodians (11.9 percent), and Vietnamese (14.3 percent) than in asymptomatic Americans (0.7 percent). Among asymptomatic Thais, the ratio of HBs Ag/adr to HBs Ag/adw was approximately 10:1, with one exception: adw was not detected in a rural population of northern Thailand. The y determinant was not found in Thais. In contrast, both d and y determinants were found in Americans. These observations conform to a geographic pattern, with ad as the predominant combination in the Far East. In Southeast Asia determinants w and r are more useful epidemiologic markers than y and d.

Evaluation of the plasma kinin system in dengue hemorrhagic fever.

The role of the plasma kinin system in the pathogenesis of dengue hemorrhagic fever (DHF) ws explored by simultaneously measuring factor XLL (Hageman), prekallikrein, kallikrein inhibitors, bradykinin, and complement (C3) in the blood of Thai children with DHF and acute febrile illnesses other than dengue. Prekallikrein, factor XII, and C3 levels were significantly lower in DHF patients compared to fever control patients with the lowest mean levels found in dengue patients with shock. However, bradykinin concentrations were not elevated and mean activity levels of kallikrein inhibitors were not depressed in dengue patients. Two dengue patients first studies at least 2 days before onset of shock had falling C3 levels which were more closely related temporally to the onset of shock than were their rising levels of prekallikrein. The results fail to provide convincing evidence ofr activation of the plasma kinin system leading to free bradykinin or a significant role for bradykinin in the immunopathogenesis of DHF. By contrast, the results refocus attention on complement as a potentially important humoral mediator of the dengue shock syndrome.

Method for extracting viral hemagglutination-inhibiting antibodies from the nonspecific inhibitors of serum.

Various methods are used to remove nonspecific inhibitors from sera before titering viral hemagglutination-inhibiting antibodies. These methods have several undesirable features; some are tedious and time-consuming, some remove antibody along with nonspecific inhibitors, and different techniques are usually required to remove the nonspecific inhibitors for different viruses. This communication describes a single method that uses diethylaminoethyl-Sephadex to extract the immunoglobulin G antibodies for several viruses from nonspecific inhibitors. The procedure is fast, simple to perform, and removed the nonspecific inhibitors for influenza, Western equine encephalitis, dengue-2, and rubella viruses.

Kaeng Khoi virus from naturally infected bedbugs (cimicidae) and immature free-tailed bats.

Kaeng Khoi virus was recovered from bedbugs (Stricticimex parvus and Cimex insuetus) and from suckling wrinkle-lipped bats (Tadarida plicata) collected in central Thailand. The data implicate bedbugs as possible vectors of this virus.

Dengue-2 vaccine: virological, immunological, and clinical responses of six yellow fever-immune recipients.

Six male volunteers, previously immunized with yellow fever vaccine, were inoculated subcutaneously with a live, attenuated dengue-2 virus (PR-159/S-1) candidate vaccine. Five recipients developed viremia 8 or 9 days after vaccination, which lasted 1 to 10 days. The onset of viremia was followed by fever in three people, transient leukopenia in four, and an erythematous rash in one. One volunteer developed an oral temperature of 38.8 degrees C with headache, myalgia, fatigue, and photophobia suggestive of mild dengue fever. All five viremic volunteers developed fourfold or greater rises in serum neutralizing antibody. The sixth volunteer, who had a low titer of preexisting dengue-2 neutralizing antibody, had no viremia, no symptoms, and a modest rise in hemagglutination inhibiting antibody. Virus isolates obtained from plasma retained the small-plaque and temperature-sensitive growth characteristics of the vaccine virus in vitro. In this study, the vaccine virus genetically stable and immunogenic and seemed sufficiently attenuated for additional testing in humans.

Herpes simplex virus type I from a patient with radiculoneuropathy.

Herpes simplex virus type I was isolated from the CSF of a patient with atypical lumbosacral pain. The features of this case are unusual and important in light of the current understanding of herpes-simplex-virus-associated neurologic disease.