A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection
The New England journal of medicine. 2021;385(5):436-444
BACKGROUND Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection. METHODS In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed. RESULTS From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo. CONCLUSIONS Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial
The Lancet. Respiratory medicine. 2019
BACKGROUND Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial. METHODS This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013-14 to 2017-18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0.25 g/kg bodyweight, 24.75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov, NCT02287467. FINDINGS 313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1.25 (95% CI 0.79-1.97; p=0.33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0.94 (0.55-1.59) and was 3.19 (1.21-8.42) for those with influenza B (interaction p=0.023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1.06, 95% CI 0.70-1.60; p=0.79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment. INTERPRETATION When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted. FUNDING NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.
Hospitalised adults with laboratory-confirmed influenza A or B infection (n= 308).
Single 500-mL infusion of high-titre hIVIG (0.25 g/kg bodyweight, 24.75 g maximum (hIVIG group, n=156).
Saline placebo (placebo group, n=152).
hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1.25). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0.94 and was 3.19 for those with influenza B. Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1.06). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment.
Valganciclovir (VGCV) followed by cytomegalovirus (CMV) hyperimmune globulin compared to VGCV for 200 days in abdominal organ transplant recipients at high risk for CMV infection: A prospective, randomized pilot study
Transplant Infectious Disease : an Official Journal of the Transplantation Society. 2017;19((6))
BACKGROUND With the advent of effective antivirals against cytomegalovirus (CMV), use of CMV hyperimmune globulin has decreased. Although antiviral prophylaxis in patients at high risk for CMV is effective, many patients still have late infection, never developing antibodies sufficient to achieve immunity. Utilizing a combination of antiviral and CMV immunoglobulin G may allow patients to achieve immunity and decrease late CMV infections. METHODS This was a prospective randomized, open-label, pilot study comparing valganciclovir (VGCV) prophylaxis for 200 days vs VGCV for 100 days followed by CMV HIG in abdominal transplant recipients at high risk for CMV. The primary outcome was a comparison of late CMV disease. RESULTS Forty patients were randomized to VGCV for 200 days (n = 20) or VGCV for 100 days followed by 3 doses of monthly CMV HIG (n = 20). Numerically, more overall CMV infections occurred in the CMV HIG group (45 vs 20%, P = 0.09). No differences in overall CMV infections or late CMV disease were seen between groups (20% vs 15%, P = 1.00 and 0 vs 0, P = 1.00). All CMV disease occurred within 200 days, with 63% occurring while patients were on VGCV. No differences were found in toxicities, graft function, or rejection between groups. Patients with CMV infection at any time had a higher body weight than those who did not have an infection (82 vs 95 kg, P = .049). CONCLUSION Use of CMV HIG sequentially with prophylaxis may be an effective and affordable prophylactic regimen in abdominal transplant recipients at high risk for CMV, and warrants larger prospective study. Increased monitoring for patients with obesity may be warranted. This article is protected by copyright. All rights reserved.
INSIGHT FLU005: An anti-influenza virus hyperimmune intravenous immunoglobulin pilot study
Journal of Infectious Diseases. 2016;213((4)):574-8.
UNLABELLED Hemagglutination inhibition (HAI) antibody responses to anti-influenza virus hyperimmune intravenous immunoglobulin (hIVIG) were characterized. Thirty-one patients with influenza during the 2013-2014 season were randomly assigned to receive 0.25 g/kg of hIVIG (n = 16) or placebo (n = 15). For hIVIG recipients, the ratio of geometric mean titers (1 hour after infusion/before infusion) was 4.00 (95% confidence interval [CI], 2.61-6.13) for 2009 pandemic influenza A(H1N1) and 1.76 (95% CI, 1.33-2.32) for influenza A(H3N2) and influenza B. Among patients with 2009 pandemic influenza A(H1N1), ratios for hIVIG (n = 9) versus placebo (n = 8) were higher 1 hour after infusion (3.9 [95% CI, 2.3-6.7]) and sustained through day 3 (2.0 [95% CI, 1.0-4.0]). hIVIG administration significantly increases HAI titer levels among patients with influenza, supporting the need to perform a clinical outcomes study. CLINICAL TRIALS REGISTRATION NCT02008578.Copyright © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail email@example.com.
A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus
The New England Journal of Medicine. 2014;370(14):1316-26
BACKGROUND Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%. METHODS We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis. RESULTS A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%). CONCLUSIONS In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection
BACKGROUND Experience from influenza pandemics suggested that convalescent plasma treatment given within 4 to 5 days of symptom onset might be beneficial. However, robust treatment data are lacking. METHODS This is a multicenter, prospective, double-blind, randomized controlled trial. Convalescent plasma from patients who recovered from the 2009 pandemic influenza A(H1N1) (A[H1N1]) infection was fractionated to hyperimmune IV immunoglobulin (H-IVIG) by CSL Biotherapies (now BioCSL). Patients with severe A(H1N1) infection on standard antiviral treatment requiring intensive care and ventilatory support were randomized to receive H-IVIG or normal IV immunoglobulin manufactured before 2009 as control. Clinical outcome and adverse effects were compared. RESULTS Between 2010 and 2011, 35 patients were randomized to receive H-IVIG (17 patients) or IV immunoglobulin (18 patients). One defaulted patient was excluded from analysis. No adverse events related to treatment were reported. Baseline demographics and viral load before treatment were similar between the two groups. Serial respiratory viral load demonstrated that H-IVIG treatment was associated with significantly lower day 5 and 7 posttreatment viral load when compared with the control (P = .04 and P = .02, respectively). The initial serum cytokine level was significantly higher in the H-IVIG group but fell to a similar level 3 days after treatment. Subgroup multivariate analysis of the 22 patients who received treatment within 5 days of symptom onset demonstrated that H-IVIG treatment was the only factor that independently reduced mortality (OR, 0.14; 95% CI, 0.02-0.92; P = .04). CONCLUSIONS Treatment of severe A(H1N1) infection with H-IVIG within 5 days of symptom onset was associated with a lower viral load and reduced mortality. TRIAL REGISTRY ClinialTrials.gov; No.: NCT01617317; URL: www.clinicaltrials.gov.
Respiratory syncytial virus immune globulin
Respiratory syncytial virus (RSV) immune globulin is a purified human hyperimmune globulin that provides passive immunity against complicated RSV disease in select groups of infants and young children. According to microneutralisation assay results, its RSV-neutralising antibody concentration was significantly greater than that of nonspecific immune globulin, thereby suggesting the potential for more reliable protection against RSV infection. In 2 randomised double-blind trials, prophylaxis with RSV immune globulin significantly reduced (vs no immune globulin) the incidence and severity of RSV disease in infants and young children with bronchopulmonary dysplasia, prematurity or bronchopulmonary dysplasia due to prematurity, or congenital heart disease (in 1 study). Treatment with RSV immune globulin did not significantly reduce the duration of hospitalisation and intensive care in children hospitalised with RSV infection in 2 randomised double-blind trials; however, a trend towards a significant treatment benefit was apparent in children with severe disease in 1 of these studies.
Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. The Federal Hyperimmune Immunoglobulin Trial Study Group
Journal of Infectious Diseases. 1996;174((3):):537-43.
To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).
Intravenous immunoglobulin in the treatment of paediatric cerebral malaria
Clinical & Experimental Immunology. 1992;90((3):):357-62.
Hyperimmune globulin can inhibit and reverse the cytoadherence between Plasmodium falciparum-infected erythrocytes and melanoma cells in vitro. Cytoadherence is believed to mediate disease in cerebral malaria. Therefore we studied the efficacy of i.v. immunoglobulin, purified from the plasma of local semi-immune blood donors, as an adjunct to standard treatment for cerebral malaria in Malawian children. The immunoglobulin preparation (IFAT antimalarial antibody titre 1:5120) recognized erythrocyte-associated antigens of each of 22 Malawian P. falciparum isolates studied, and reversed binding of Malawian isolates to melanoma cells. Immunoglobulin did not reverse binding to human monocytes or to cells of the human histiocytic lymphoma cell line U937. Thirty-one children with P. falciparum parasitaemia and unrousable coma were enrolled. All were treated with i.v. quinine dihydrochloride; in addition patients were randomized to receive either immunoglobulin (400 mg/kg by i.v. infusion over 3 h) or placebo (albumen and sucrose by similar infusion) in a double blind trial with sequential analysis. Of 16 patients receiving immunoglobulin, five (31%) died and five survivors had neurological sequelae. Of 15 patients receiving placebo, one (7%) died and two had sequelae. Parasite clearance, fever clearance and coma resolution times in survivors were similar in the two groups. Although the difference in outcome between the two groups was not significant, the trial was stopped because immunoglobulin was demonstrated not to be superior to placebo.