Cytomegalovirus Hyperimmune Globulin Research Articles

Immunomodulatory Effect of COVID-19 on HLA-Antibody Profile in Renal Transplant Recipients.

Background/Objectives: The novel coronavirus disease 2019 (COVID-19) has led to significant morbidity and mortality among kidney transplant recipients. SARS-CoV-2 has been hypothesized to cause an unusual immunological dysregulation triggering alloimmunity and leading to graft rejection. Methods: This prospective observational cohort study assessed 321 kidney transplant recipients who had COVID-19 infection. After the infection, patients' sera were tested for the presence of anti-HLA de novo DSA and non-DSA specificities. Logistic regression analysis and a stepwise multivariable logistic regression analysis were used to analyze the independent risk factors associated with the development of antibodies, adjusting for known confounders. The variables evaluated were acute COVID-19 characteristics (i.e., presentation, and need for hospitalization), demographic characteristics (i.e., age, gender, and primary renal disease), clinical characteristics (i.e., various comorbidities), and post-COVID-19 sequelae. Results: Anti-HLA de novo DSA developed in 18.7% of patients, while anti-HLA class I and class II non-DSA antibodies developed de novo in 84 (26.3%) and 83 (25.9%) patients, respectively. The development of DSA, HLA-DQ, and HLA-DR antibodies was predicted by the history of graft rejection. Obesity appeared to be protective against the emergence of de novo DSA. De novo DSA and HLA-DR antibody formation was positively linked with intravenous immunoglobulin use, CMV-hyperimmune globulin use, and decreased doses of immunosuppression during acute infection. Better allograft function during the acute disease was a protective factor against the formation of HLA-DQ and HLA-DR antibodies. Positive predictors of de novo DSA development were graft biopsy and the reactivation of EBV after infection. Conclusions: These findings suggest that the SARS-CoV-2 virus has an immunomodulatory effect and may be associated with an increased mortality in this population.

CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44-88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56-96), and OS from HSCT at 1 year was 80% (95% CI: 50-93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.

Polymorphic Forms of Human Cytomegalovirus Glycoprotein O Protect against Neutralization of Fibroblast Entry by Antibodies Targeting Epitopes Defined by Glycoproteins H and L.

Human cytomegalovirus (CMV) utilizes different glycoproteins to enter into fibroblast and epithelial cells. A trimer of glycoproteins H, L, and O (gH/gL/gO) is required for entry into all cells, whereas a pentamer of gH/gL/UL128/UL130/UL131A is selectively required for infection of epithelial, endothelial, and some myeloid-lineage cells, but not of fibroblasts. Both complexes are of considerable interest for vaccine and immunotherapeutic development but present a conundrum: gH/gL-specific antibodies have moderate potency yet neutralize CMV entry into all cell types, whereas pentamer-specific antibodies are more potent but do not block fibroblast infection. Which cell types and neutralizing activities are important for protective efficacy in vivo remain unclear. Here, we present evidence that certain CMV strains have evolved polymorphisms in gO to evade trimer-specific neutralizing antibodies. Using luciferase-tagged variants of strain TB40/E in which the native gO is replaced by gOs from other strains, we tested the effects of gO polymorphisms on neutralization by monoclonal antibodies (mAbs) targeting four independent epitopes in gH/gL that are common to both trimer and pentamer. Neutralization of fibroblast entry by three mAbs displayed a range of potencies that depended on the gO type, a fourth mAb failed to neutralize fibroblast entry regardless of the gO type, while neutralization of epithelial cell entry by all four mAbs was potent and independent of the gO type. Thus, specific polymorphisms in gO protect the virus from mAb neutralization in the context of fibroblast but not epithelial cell entry. No influence of gO type was observed for protection against CMV hyperimmune globulin or CMV-seropositive human sera, suggesting that antibodies targeting protected gH/gL epitopes represent a minority of the polyclonal neutralizing repertoire induced by natural infection.

Amniocentesis to diagnose congenital cytomegalovirus infection following maternal primary infection

BACKGROUNDCongenital cytomegalovirus infection following maternal primary cytomegalovirus infection affects approximately 0.4% of newborns in the United States but may be hard to diagnose prenatally. OBJECTIVETo evaluate the current sensitivity and specificity of amniocentesis in detecting congenital cytomegalovirus infection. STUDY DESIGNSecondary analysis of a multicenter randomized placebo-controlled trial designed to evaluate whether cytomegalovirus hyperimmune globulin reduces congenital cytomegalovirus infection in neonates of individuals diagnosed with primary cytomegalovirus infection before 24 weeks of gestation. At randomization, subjects had no clinical evidence of fetal infection. Eligible subjects were randomized to monthly infusions of cytomegalovirus hyperimmune globulin or placebo until delivery. Although not required by the trial protocol, amniocentesis following randomization was permitted. The fetuses and neonates were tested for the presence of cytomegalovirus at delivery. Comparisons were made between those with and without amniocentesis and between those with cytomegalovirus-positive and negative results, using chi-square or Fisher exact test for categorical variables and the Wilcoxon rank sum test or t test for continuous variables. A P value of <.05 was considered significant. RESULTSFrom 2012 to 2018, 397 subjects were included, of whom 55 (14%) underwent amniocentesis. Cytomegalovirus results were available for 53 fetuses and neonates. Fourteen amniocenteses were positive (25%). Gestational age at amniocentesis was similar between those with and without cytomegalovirus present, as was the interval between maternal diagnosis and amniocentesis. The prevalence of fetal or neonatal infection was 26% (14/53). The neonates of all 12 subjects with a positive amniocentesis and available results had cytomegalovirus infection confirmed at delivery, as did 2 neonates from the group of 41 subjects with a negative amniocentesis, with a sensitivity of 86% (95% confidence interval, 57–98), specificity of 100% (95% confidence interval, 91–100), positive predictive value of 100% (95% confidence interval, 74–100), and negative predictive value of 95% (95% confidence interval, 83–99). Amniocentesis-positive pregnancies were delivered at an earlier gestational age (37.4 vs 39.6 weeks; P<.001) and had lower birthweights (2583±749 vs 3428±608 g, P=.004) than amniocentesis-negative pregnancies. CONCLUSIONAmniocentesis results are an accurate predictor of congenital cytomegalovirus infection.

Describing the Impact of Maternal Hyperimmune Globulin and Valacyclovir on the Outcomes of Cytomegalovirus Infection in Pregnancy: A Systematic Review.

Cytomegalovirus (CMV) is the leading infectious cause of congenital neurological disabilities. Valacyclovir and CMV hyperimmune globulin (HIG) may reduce vertical transmission and sequelae in neonates. A systematic review on valacyclovir and CMV HIG in preventing vertical transmission or reducing sequelae in neonates was conducted to 3 September 2021. Valacyclovir as a preventive strategy was supported by a well-conducted randomized controlled trial. Evidence supporting valacyclovir as a treatment strategy was limited to observational studies at moderate risk of bias. CMV HIG was not supported as a preventive strategy in 2 randomized controlled trials, which contrasted with observational studies. Evidence favoring CMV HIG as a treatment strategy was limited to observational studies at moderate risk of bias. The role of valacyclovir and CMV HIG in CMV infection in pregnancy is still being defined. Valacyclovir to prevent vertical transmission has the highest quality evidence in favor of use.

Impact Of Recipient CMV Serological Status On Outcomes After Heart Transplantation In Contemporary Prophylactic Treatment Era

Background Cytomegalovirus (CMV) infection can limit the long term success of heart transplantation (HT) by promoting cardiac allograft vasculopathy (CAV). Moreover, prophylactic treatment of HT recipients with ganciclovir and/or CMV hyperimmune globulin reduces the incidence of CAV. We aimed to determine the prognostic impact of CMV serostatus of the donor and recipient and its effect on survival, graft failure and drug treated rejection in the contemporary prophylactic treatment era. Methods We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor CMV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of CMV serostatus on survival. Results Out of 34,279 HT recipients, 46.3 % had dissimilar (8028 with -/+ and 7840 with +/-) and 53.7% had similar (n=5417 with -/- and 12,994 with+/+) CMV serostatus. Compared to dual negative CMV serostatus, recipients with other CMV serostatuses had significantly higher 1-, 3- and 5-year mortality (Figure & Table 1). Surprisingly, while CMV +/- had an increased prevalence of graft failure, CMV -/+ had a decreased prevalence of graft failure when compared to the dual negative serotype. There was no significant difference for drug treated rejection between groups (Table 2). Conclusion Recipient and donor CMV seronegative status is associated with best post-HT survival and decreased graft failure. Despite prophylactic treatment CMV positive serostatus impacts post HT outcomes. This observation warrants further investigation into developing strategies to improve outcomes in this large HT cohort. Cytomegalovirus (CMV) infection can limit the long term success of heart transplantation (HT) by promoting cardiac allograft vasculopathy (CAV). Moreover, prophylactic treatment of HT recipients with ganciclovir and/or CMV hyperimmune globulin reduces the incidence of CAV. We aimed to determine the prognostic impact of CMV serostatus of the donor and recipient and its effect on survival, graft failure and drug treated rejection in the contemporary prophylactic treatment era. We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor CMV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of CMV serostatus on survival. Out of 34,279 HT recipients, 46.3 % had dissimilar (8028 with -/+ and 7840 with +/-) and 53.7% had similar (n=5417 with -/- and 12,994 with+/+) CMV serostatus. Compared to dual negative CMV serostatus, recipients with other CMV serostatuses had significantly higher 1-, 3- and 5-year mortality (Figure & Table 1). Surprisingly, while CMV +/- had an increased prevalence of graft failure, CMV -/+ had a decreased prevalence of graft failure when compared to the dual negative serotype. There was no significant difference for drug treated rejection between groups (Table 2). Recipient and donor CMV seronegative status is associated with best post-HT survival and decreased graft failure. Despite prophylactic treatment CMV positive serostatus impacts post HT outcomes. This observation warrants further investigation into developing strategies to improve outcomes in this large HT cohort.

Maternal Facial Nerve Palsy and a Perinatal Infection.

Maternal Facial Nerve Palsy and a Perinatal Infection.

Management of ganciclovir resistance cytomegalovirus infection with CMV hyperimmune globulin and leflunomide in seven cardiothoracic transplant recipients and literature review.

Cytomegalovirus (CMV) disease caused by genetically resistant CMV poses a major challenge in solid organ transplant recipients, and the development of resistance is associated with increased morbidity and mortality. Antiviral resistance affects 5%-12% of patients following ganciclovir (GCV) therapy, but is more common in individuals with specific underlying risk factors. These include the CMV D+R- serostatus, type of transplanted organ, dose and duration of (Val)GCV ([V]GCV) prophylaxis, peak viral loads, and the intensity of immunosuppressive therapy. Guideline recommendations for the management of GCV resistance (GanR) in solid organ transplant recipients are based on expert opinion as there is a lack of data from controlled trials. Second-line options to treat GanR include foscarnet (FOS) and cidofovir (CDV), but these drugs are often poorly tolerated due to high rates of toxicity, such as renal dysfunction and neutropenia. Here, we report seven cardiothoracic transplant recipients with GCV resistance CMV infection from our centre treated with CMV immunoglobulin (CMVIG) +/- leflunomide (LEF) and reviewed the literature on the use of these agents in this therapeutic setting.

A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection

BackgroundPrimary 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.MethodsIn 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.ResultsFrom 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.ConclusionsAmong 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.)

Comparative neutralizing potencies of antibodies suggest conservation as well as mechanistic differences in human cytomegalovirus entry into epithelial and endothelial cells

Antibody neutralization of cytomegalovirus (CMV) entry into diverse cell types is a key consideration for development of vaccines and immunotherapeutics. CMV entry into fibroblasts differs significantly from entry into epithelial or endothelial cells: fibroblast entry is mediated by gB and gH/gL/gO, whereas both epithelial and endothelial cell entry require an additional pentameric complex (PC) comprised of gH/gL/UL128/UL130/UL131A. Because PC-specific antibodies in CMV-seropositive human sera do not affect fibroblast entry but potently block entry into epithelial or endothelial cells, substantially higher neutralizing potencies for CMV-positive sera are observed when assayed using epithelial cells as targets than when using fibroblasts. That certain sera exhibit similar discordances between neutralizing potencies measured using epithelial vs. endothelial cells (Gerna G. et al.J Gen Virol, 89:853–865, 2008) suggested that additional mechanistic differences may also exist between epithelial and endothelial cell entry. To further explore this issue, neutralizing potencies using epithelial and endothelial cells were simultaneously determined for eight CMV-positive human sera, CMV-hyperimmune globulin, and a panel of monoclonal or anti-peptide antibodies targeting specific epitopes in gB, gH, gH/gL, or the PC. No significant differences were observed between epithelial and endothelial neutralizing potencies of epitope-specific antibodies, CMV-hyperimmune globulin, or seven of the eight human sera. However, one human serum exhibited a six-fold higher potency for neutralizing entry into epithelial cells vs. endothelial cells. These results suggest that epitopes exist that are important for epithelial entry but are less critical, or perhaps dispensable, for endothelial cell entry. Their existence should be considered when developing monoclonal antibody therapies or subunit vaccines representing limited epitopes.

49: Amniocentesis to diagnosis congenital cytomegalovirus infection following maternal primary cytomegalovirus infection in early pregnancy

Cytomegalovirus (CMV) infection is the most common congenital infection in the U.S. Our objective was to evaluate amniocentesis (AMNIO) in detecting congenital CMV infection (cCMV). Secondary analysis of a multicenter RCT designed to evaluate if CMV hyperimmune globulin (HIG) reduces cCMV in the offspring of women diagnosed with primary CMV infection prior to 24 weeks’ gestation and having no evidence of fetal infection (ultrasound findings or amniocentesis with CMV infection) at randomization. Eligible subjects were randomized to monthly infusions of HIG or placebo until delivery; those who underwent elective amniocentesis following randomization are included in this analysis. The fetus/neonate was tested for the presence of CMV at delivery or death. Comparisons were made between those with or without CMV at AMNIO, using chi-square test or Fisher’s exact test for categorical variables and the Wilcoxon rank test for continuous variables. A P-value of < 0.05 was considered significant. 399 women were randomized, and 55 (14%) women had AMNIO; 53 offspring had CMV results. Twelve AMNIOs were positive (12%) - one only by culture (8%), 7 only by PCR (58%) and four by culture and PCR (33%). The prevalence of fetal/neonatal infection was 26% (14/53). All 12 AMNIO-POS had cCMV infection confirmed at delivery, as well as 2 of the 41 AMNIO-NEG women (AMNIOs performed at 18.1 and 21 wks), for a sensitivity of 86%, specificity of 100%, positive predictive value of 100% and negative predictive value of 95%. (Table 1) Compared with AMNIO-NEG women, AMNIO-POS women had a lower avidity index at diagnosis and were more likely to undergo termination (Table 2). The gestational age (GA) at time of AMNIO was similar, as was the interval between maternal diagnosis and AMNIO. AMNIO-POS pregnancies delivered at an earlier GA and had a lower birthweight. AMNIO results are an accurate predictor of cCMV infection, particularly using PCR, even when performed at an early GA. Positive results are associated with increased termination rates and poor neonatal outcomes in continuing pregnancies.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

2: The effect of treatment of maternal CMV infection on the development of placental syndrome

Cytomegalovirus (CMV) is known to infect trophoblasts and result in placental dysfunction. Our objective was to evaluate whether treatment of maternal CMV infection prevents “placental syndrome”, a composite of adverse pregnancy outcomes that involve placental dysfunction. Secondary analysis of a multicenter randomized placebo-controlled trial of CMV hyperimmune globulin (HIG) to prevent congenital CMV infection. Women were eligible for the trial if they had primary CMV infection—positive IgM antibody and positive low avidity (< 50%) IgG antibody before 24 weeks, or IgG seroconversion before 28 weeks—as analyzed in a single reference laboratory, and were carrying a singleton fetus without ultrasound abnormalities suspicious for congenital CMV infection. Trained research nurses abstracted the outcomes which were prespecified according to standard criteria. Placental syndrome was defined as any preeclampsia, gestational hypertension (GHTN), small for gestational age (SGA; birthweight < 10%ile), placental abruption, preterm delivery (PTD before 37 weeks), or perinatal death. We also evaluated the effect of treatment on severe placental syndrome defined as any of the following: preeclampsia or GHTN requiring delivery < 37 weeks, birthweight < 5%ile, PTD < 34 weeks, or perinatal death. P < 0.05 was used to denote statistical significance. The primary analysis showed that HIG did not prevent congenital infection. Of 399 women randomized, 390 had informative data for this analysis. Baseline characteristics were balanced between the treatment groups. Placental syndrome was significantly more common in the HIG group (Table). Each of the individual components of the placental syndrome, as well as severe placental syndrome and its components, occurred more often in the HIG group, but the differences were not statistically significance (Table). In this largest randomized trial to date, treatment of maternal CMV with hyperimmune globulin not only did not prevent congenital infection, but also increased the frequency of placental syndrome.

Randomized trial to prevent congenital cytomegalovirus

Primary CMV infection during pregnancy carries a high risk of transmission to the fetus with the potential for severe sequelae including fetal death, premature birth, hearing loss and developmental delay. There is no universally accepted method of preventing congenital CMV. Our objective was to evaluate whether CMV hyperimmune globulin (HIG) administered to women with primary CMV during pregnancy reduces congenital infection.

High-Dose Cytomegalovirus (CMV) Hyperimmune Globulin and Maternal CMV DNAemia Independently Predict Infant Outcome in Pregnant Women With a Primary CMV Infection.

After primary maternal cytomegalovirus (CMV) infection during pregnancy, infants are at risk for disease. Factors predictive of infant outcome were analyzed in a database of 304 pregnant women with primary infection. These women were enrolled between 2010 and 2017 and delivered 281 infants, of whom 108 were CMV infected. Long term follow-up occurred for 173 uninfected and 106 infected infants at age 4 years (range, 1-8 years). One hundred fifty-seven women were treated with an average of 2 doses (range, 1-6 doses) of high-dose hyperimmune globulin (HIG: 200 mg/kg/infusion). We used a regression model to define predictors of fetal infection, symptoms at birth, and long-term sequelae; 31 covariates were tested. Four factors predicted fetal infection: a 1.8-fold increase (30% vs 56%) in the rate of congenital infection without HIG (adjusted odds ratio [AOR], 5.2; P < .0001), a 1.8-fold increase (32% vs 56%) associated with maternal viral DNAemia prior to HIG administration (AOR, 3.0; P = .002), abnormal ultrasounds (AOR, 59; P = .0002), and diagnosis of maternal infection by seroconversion rather than avidity (AOR, 3.3; P = .007). Lack of HIG and abnormal ultrasounds also predicted symptoms (P = .001). Long-term sequelae were predicted by not receiving HIG (AOR, 13.2; P = .001), maternal infection in early gestation (odds ratio [OR], 0.9; P = .017), and abnormal ultrasounds (OR, 7.6; P < .003). Prevalence and copy/number of DNAemia declined after HIG. Maternal viremia predicts fetal infection and neonatal outcome. This may help patient counseling. High-dose HIG may prevent fetal infection and disease and is associated with the resolution of DNAemia.

The use of CMVIg rescue therapy in cardiothoracic transplantation: A single‐center experience over 6 years (2011‐2017)

Cytomegalovirus (CMV) is the most important infectious agent in solid organ transplant recipients and has a major impact on morbidity and mortality. Most cases are well managed with antiviral agents, but CMV hyperimmune globulin (CMVIg) can be used alongside antiviral therapy for prophylaxis in high-risk thoracic organ recipients and to treat life-threatening CMV infection or disease. CMVIg may also improve antiviral host defences when genetic resistance to antivirals or unwanted side effects occur. In this single-center, retrospective study, we reviewed the CMVIg use to supplement antiviral therapy as a "rescue therapy" in cardiothoracic transplant recipients. These comprised 12 single lung, 11 double lung, and 12 heart transplant recipients. Patients received a median of 2 doses of CMVIg, most often in combination with ganciclovir or valganciclovir, and reduced immunosuppression. One week after rescue therapy was initiated, CMV DNA levels were significantly reduced, and after four weeks, CMV DNA was undetectable in 73% patients. Only one patient died as a result of CMV-related disease. No significant adverse effects were observed. We conclude that CMVIg rescue therapy is safe, well tolerated, and effective at controlling viral replication in cardiothoracic transplant recipients.

Cytomegalovirus Infection and Disease in Lung Transplant Recipients

Purpose Cytomegalovirus (CMV) infection causes significant morbidity and mortality in lung transplant recipients (LTR), the most important risk factor for which is the serostatus of donor (D) and recipient (R). Our program employs a CMV prophylaxis strategy. In 2016, our protocol for management of D+ R- changed from 3-6 months of valganciclovir (VGCV) with CMV hyperimmune globulin to 12 months of VGCV with human normal immunoglobulin. Aims: To determine the effect of changing CMV prophylaxis protocol for D+ R- on the incidence of CMV infection/disease in LTR. Methods We retrospectively reviewed laboratory results and clinical notes from all LTR transplanted between 1/01/2014 - 31/12/2017 in the National Heart and Lung Transplant Centre, Ireland. Data were collected for a minimum of ten months post-transplant, with a longer follow-up of those transplanted earlier. Results Data were available on 134 of 137 LTR, Table 1. There were fewer episodes of infection (14 v 30, p = 0.19) and less tissue invasive disease (TID) (0 v 4, p = 0.14) in the D+ R- 2016-17 group. The average time to infection/disease was longer (9 v 7.7 months) in the 2016-17 group. The incidence of CMV infection and disease was 29% in LTR transplanted in 2016-17 and 36% in 2014-15. Conclusion Recent guidelines (1) advocate a minimum of 6 months VGCV prophylaxis in D+ R- LTR. Our data demonstrates there is a trend for less adverse events such as TID with a longer duration. The average time to infection in the 2016-17 group of 9 months suggests some patients are not tolerating prophylaxis and terminating early. In conclusion, following a change in protocol less CMV infection episodes and no invasive CMV disease were reported in our cohort. Reduction in CMV disease and infection will reduce graft loss, morbidity and mortality. Innovations to improve tolerability of VGCV may further delay time to infection.

High-Dose CMV Hyperimmune Globulin (HIG) and Maternal CMV DNAemia Independently Predict Infant Outcome in Pregnant Women with a Primary Cytomegalovirus (CMV) Infection

High-Dose CMV Hyperimmune Globulin (HIG) and Maternal CMV DNAemia Independently Predict Infant Outcome in Pregnant Women with a Primary Cytomegalovirus (CMV) Infection

Prevention and treatment of fetal cytomegalovirus infection with cytomegalovirus hyperimmune globulin: a multicenter study in Madrid

Introduction: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection. Materials and methods: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009–2015, CMV-HIG (Cytotect® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy. Results: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38–40) and two children (5.5%) were premature (born at 28 and 34 weeks’ gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3–1185; p = .007). Discussion: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.

Cytomegalovirus Virions Shed in Urine Have a Reversible Block to Epithelial Cell Entry and Are Highly Resistant to Antibody Neutralization.

Cytomegalovirus (CMV) causes sensorineural hearing loss and developmental disabilities in newborns when infections are acquired in utero Pregnant women may acquire CMV from oral exposure to CMV in urine or saliva from young children. Neutralizing antibodies in maternal saliva have the potential to prevent maternal infection and, in turn, fetal infection. As CMV uses different viral glycoprotein complexes to enter different cell types, the first cells to be infected in the oral cavity could determine the type of antibodies needed to disrupt oral transmission. Antibodies targeting the pentameric complex (PC) should block CMV entry into epithelial cells but not into fibroblasts or Langerhans cells (which do not require the PC for entry), while antibodies targeting glycoprotein complexes gB or gH/gL would be needed to block entry into fibroblasts, Langerhans cells, or other cell types. To assess the potential for antibodies to disrupt oral acquisition, CMV from culture-positive urine samples (uCMV) was used to study cell tropisms and sensitivity to antibody neutralization. uCMV entered epithelial cells poorly compared with the entry into fibroblasts. CMV-hyperimmune globulin or monoclonal antibodies targeting gB, gH/gL, or the PC were incapable of blocking the entry of uCMV into either fibroblasts or epithelial cells. Both phenotypes were lost after one passage in cultured fibroblasts, suggestive of a nongenetic mechanism. These results suggest that uCMV virions have a reversible block to epithelial cell entry. Antibodies may be ineffective in preventing maternal oral CMV acquisition but may limit viral spread in blood or tissues, thereby reducing or preventing fetal infection and disease.

Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex.

ABSTRACTHuman cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross-neutralize the field strains of HCMV, remains a challenge. In this study, with a panel of neutralizing antibodies from three healthy human donors with natural HCMV infection or a vaccinated animal, we mapped eight sites on the dominant virus-neutralizing antigen—the pentameric complex of glycoprotein H (gH), gL, and pUL128, pUL130, and pUL131. By evaluating the site-specific antibodies in vaccine immune sera, we demonstrated that vaccination elicited functional antiviral antibodies to multiple neutralizing sites in rhesus macaques, with quality attributes comparable to those of CMV hyperimmune globulin. Furthermore, these immune sera showed antiviral activities against a panel of genetically distinct HCMV clinical isolates. These results highlighted the importance of understanding the quality of vaccine-induced antibody responses, which includes not only the neutralizing potency in key cell types but also the ability to protect against the genetically diverse field strains.IMPORTANCE HCMV is the leading cause of congenital viral infection, and development of a preventive vaccine is a high public health priority. To understand the strain coverage of vaccine-induced immune responses in comparison with natural immunity, we used a panel of broadly neutralizing antibodies to identify the immunogenic sites of a dominant viral antigen—the pentameric complex. We further demonstrated that following vaccination of a replication-defective virus with the restored pentameric complex, rhesus macaques can develop broadly neutralizing antibodies targeting multiple immunogenic sites of the pentameric complex. Such analyses of site-specific antibody responses are imperative to our assessment of the quality of vaccine-induced immunity in clinical studies.