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.

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.

Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. The Cardiac Study Group.

OBJECTIVE: To examine the effectiveness of respiratory syncytial virus immune globulin administered intravenously (RSV-IGIV) in reducing hospitalization for treatment of RSV in children with congenital heart disease (CHD). METHODS: Children younger than 4 years of age were randomly assigned to a treatment group receiving RSV-IGIV, 750 mg/kg, monthly or to a control group not receiving infusions. Surveillance for respiratory tract infections was carried out and management decisions were made by physicians blinded to treatment group. RESULTS: Hospitalization for treatment of an RSV infection occurred in 32 of 214 (15%) of control children and 21 of 202 (10%) of the children receiving RSV-IGIV, a 31% reduction (P = .16). However, in infants younger than 6 months of age at study entry, 20 of 82 (24%) in the control group and 10 of 96 (10%) in the RSV-IGIV group had RSV hospitalizations (58% reduction, P = .01). The incidence of hospitalization for any respiratory tract symptomatology was lower in the RSV-IGIV group (34 of 202, 17%) than in the control group (57 of 214, 27%; P = .02). There was a significantly higher frequency of unanticipated cyanotic episodes and of poor outcomes after surgery among children with cyanotic CHD in the RSV-IGIV group (22 of 78, 28%) than in the control group (4 of 47, 8.5%; P = .009). CONCLUSION: RSV-IGIV should not be used for prophylaxis of RSV disease in children with cyanotic CHD. RSV-IGIV did not reduce RSV hospitalization in all children with CHD, but it was effective in preventing RSV hospitalization in infants younger than 6 months of age. Further studies in these children are indicated.

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.

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.

Effect of passage history on dengue-2 virus replication in subpopulations of human leukocytes.

Three passage levels of dengue-2 virus strain PR-159, obtained during the course of deriving the attenuated S-1 vaccine, were tested for their ability to replicate in subpopulations of human peripheral blood leukocytes: (i) 6th primary African green monkey kidney (PGMK) cell passage (parent virus); (ii) 19th PGMK cell passage of a small-plaque-forming clone derived from the parent virus (S-1 PGMK virus); and (iii) virus derived by four additional passages of the S-1 PGMK virus in diploid fetal rhesus lung cells (S-1 vaccine virus). Replication of these PR-159 viruses and another strain of dengue-2 virus adapted to Raji cells (16681-Raji virus) was measured in adherent and nonadherent mononuclear cells. All viruses except the S-1 PGMK virus replicated in monocytes. Occasional replication of the S-1 PGMK virus was associated with reversion to parent virus. The addition to the monocyte cultures of low concentrations of homologous dengue-2 antibody or non-neutralizing heterologous antibody increased the yield of the parent virus as much as 400-fold. This phenomenon of immune enhancement usually enabled the S-1 PGMK virus to replicate slowly in monocytes, but the progeny virus produced large plaques similar to the parent virus. Replication of the S-1 vaccine virus in cultured monocytes did not result in the appearance of large plaques. We could not recover S-1 vaccine virus from monocytes harvested from infected volunteers in the same manner that monocytes from natural human infections yield wild virus. The three passage levels of PR-159 virus were tested for replication in lymphocytes in comparison with the 16681-Raji virus. Only the 16681-Raji virus replicated in human lymphocytes cultured with or without enhancing antibody.

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).

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.

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.

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.

Serologic responses and systemic reactions in adults after vaccination with bivalent A/Victoria/75-A/New Jersey/76 and monovalent B/Hong Kong/72 influenza vaccines.

Bivalent A/Victoria/75-A/New Jersey/76 and monovalent B/Hong Kong/72 influenza vaccines were given alone or together to adutls, and systemic reactions and antibody responses were determined. The rates of systemic reactivity observed varied among vaccine groups. Disrupted vaccines and whole-virus vaccines containing type B antigen only did not cause significant reactivity. Systemic reactions were observed after administration of the bivalent A whole-virus vaccines, and this reactivity was increased if the B vaccine was also administered. Reactions to the more reactive vaccines were less frequent in older subjects or in younger individuals with evidence of previous exposure to influenza antigens in the vaccine. Antibody responses in this study indicated that individuals older than 25 years responded better to A/New Jersey antigens than did younger subjects. The A/Victoria antigen produced lower antibody levels in older individuals than in younger subjects. The B/Hong Kong antibody responses were similar in all vaccine groups.

Swine influenza A at Fort Dix, New Jersey (January-February 1976). I. Case finding and clinical study of cases.

After the isolation of A/New Jersey/76 (Hsw1N1) influenza virus from five soldiers at Fort Dix, New Jersey, case finding was initiated by obtaining specimens for viral isolation from 95 patients with acute respiratory disease and determining antibody to influenza A/Mayo Clinic/103/74 (Hsw1N1) antigen in paired sera from 74 soldiers who had been hospitalized with acute respiratory disease. Influenza A/New Jersey virus was not isolated, but serologic studies identified eight additional soldiers as A/New Jersey influenza patients. Development of heterotypic antibody to A/Mayo Clinic antigen following infection and/or immunization with influenza A (H3N2) strains was studied and was found to occur infrequently. One of the 13 identified patients had died, and postmortem findings were consistent with viral pneumonia. Four of the 12 surviving patients had radiologic evidence of pneumonia, but clinical syndromes in all 12 were similar to those described for other influenza A infections.

Swine influenza A at Fort Dix, New Jersey (January-February 1976). II. Transmission and morbidity in units with cases.

Epidemiologic study of 13 influenza A/New Jersey/76 (Hsw1N1) patients indicated that person-to-person transmission had occurred in several distinct military units. Soldiers in eight of these units (companies) were studied to determine whether they had experienced influenza A/New Jersey infections and associated acute respiratory disease. Titers of hemagglutination-inhibiting antibody to influenza A/Mayo Clinic/103/74 (Hsw1n1) antigen were determined. In seven of these eight companies, individuals with titers of greater than or equal to 1:20 were found. In these seven companies, members of platoons with cases (contact platoons) had antibody prevalences of 7%-56%, and members of platoons without cases had prevalences of 0-40%. Hospital admissions for acute respiratory disease were proportionately greater in trainees with A/Mayo Clinic antibody titers of greater than or equal to 1:20 than in trainees without antibody in five of six contact platoons studied.

Swine influenza A at Fort Dix, New Jersey (January-February 1976). III. Extent of spread and duration of the outbreak.

The extent and duration of transmission of influenza A/New Jersey/76 virus at Fort Dix, New Jersey, was examined with use of titers of hemagglutination-inhibiting antibody to influenza A/Mayo Clinic/74 (HswN1) antigen as an index of infection. Five hundred ninety-three soldiers (a 9.3% sample) in basic combat training (BCT) were grouped in weekly cohorts by the date on which BCT was started. Cohorts with 11 of the 12 BCT cases of A/swine influenza began training on January 12, 19, and 26, 1976, respectively; 9%-19% of the trainees in these cohorts had titers of antibody to A/Mayo Clinic antigen of greater than or equal to 1:20. In five other cohorts without cases, which began training before January 12 or after January 26, 0-5% of trainees had titers of greater than or equal to 1:20. Titers observed in persons from military units not in BCT and in the civilian population of the post were not consistent with widespread transmission of the virus. Transmission of influenza A/New Jersey virus at Fort Dix probably occurred between mid-January and mid-February with little involvement of people outside of BCT units.

Serodiagnosis of hepatitis B virus infection by antibody to core antigen.

In a military population antibody to hepatitis B core antigen (anti-HBc) was found in 39% of acute hepatitis cases negative for hepatitis B surface antigen (HBS Ag) and in 96% of HBs Ag-positive cases. Persistence of antibody to HBs Ag (anti-HBs) in convalescent-phase sera was significantly greater (P less than 0.001) in individuals with acute HBs Ag-positive hepatitis B than in patients with clinical HBs Ag-negative hepatitis B. The prevalence of anti-HBc in the absence of HBs Ag, anti-HBs, and clinical disease was 3.2% in this military population. In longitudinal studies of hepatitis B infection, the presence of anti-HBc preceded anti-HBs and improved the ability to determine the onset of sublicnical infection. Anti-HBc is a useful serologic marker for the study of the epidemiology of hepatitis B and improves the efficiency of detection of hepatitis B virus infection.

Virus-enhanced modulation of cell surface antigens: effect on immune lytic susceptibility.

Monkey kidney cells, upon progressive subculture, became refractory to complement (C)-dependent immune cytolysis by anti-cell serum. Arbovirus infection restored these cells to a state of lytic susceptibility. Similar results were also abtained with antibody-dependent cellular cytotoxicity (ADCC), which is C independent. Antibodies raised against different subcultures varied considerably in lytic efficiency, indicating changing patterns of host cell expression during continous subculture. Taken together with the fact that arbovirus infection festored the lytic efficiency of all antibody preparations to the same degree suggested some form of host cell antigen re-expression as a mechanism. The results obtained in several exploratory experiments indicated that the antigenic re-expression responsible for the restoration of lysis was probably a local or selective rather than a generalized phenomenon. Thus, the amount of host cell surface antigen, measured by the use of mouse anti-cell serum and 125I anti-mouse globulin, was identical in both uninfected lytic susceptible and refractory cells, and decreased in both functional states following infection. Further, the binding of 125I concanavalin A, used to quantify surface glycoproteins, was similar in both lytic refractory and susceptible cells, and in both cases declined folowing virus infection. This result was incompatible with gross "masking" of cell surface antigens by exuberant production of surface coat material in lytic resistant cells. Finally, brief trypsinization of lytic resistant cells yielded an 8-fold increase in immune lysis, a result further consistent with local rather than generalized surface changes. The data were discussed interms of modulation of cell surface antigens affected both by repeated subculture and arboviral infection, and as a possible in vitro correlate of altered self-reactivity.

Persistence of antibody to hepatitis B surface antigen.

Sera from military personnel found to have antibodies to hepatitis B surface antigen (anti-HBS) in an epidemiological study of a hepatitis B outbreak were tested for persistence of that antibody 1 year later. Initially, 64% of the anti-HBS-positive sera reacted in passive hemagglutination tests with erythrocytes coated with hepatitis B surface antigen of both ayw and adw subtypes; the remaining sera reacted only with adw-coated erythrocytes (19%) or ayw-coated erythrocytes (17%). After 1 year, anti-HBS was detectable by passive hemagglutination tests in 87% of individuals with initial antibody to both subtypes but in only 41% and 16% (P less than 0.001) of those initially reacting only to adw- or ayw-coated erythrocytes, respectively. Seropositivity for anti-HBS correlated best with history of contact with jaundiced people (20.3%) and duty in Asia.

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.