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Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Primary infection and reactivation of human cytomegalovirus (CMV) remain a major problem in immunocompromised patients, frequently resulting in a life threatening CMV disease. Intravenous polyvalent (hyper)-immunoglobulins (IVIG) can be administered for therapy and prophylaxis of CMV infections. However, only limited data about the efficacy and mechanism of action of IVIG products against viral infections in vitro are available so far. In this study, the effect of IVIG on CMV infection in vitro was investigated using isolates from CMV-infected patients as well as the laboratory strains AD169 and TB40. A qualitative and quantitative comparison of five different commercially available IVIG products in different human cell lines was performed concerning their ability (1) to neutralize cell-free virus, (2) to inhibit cell-to-cell spread and cell-associated transmission and (3) to influence CMV mRNA levels. All IVIG tested exhibited a high neutralization activity in epithelial and endothelial cell cultures (50% inhibition dose <0.1 mg/ml). However, qualitative differences between the products could be demonstrated in neutralization tests using human embryonal lung fibroblasts (HELF). The IVIG products also significantly differed in their ability to inhibit cell-to-cell spread within an CMV-infected HELF monolayer displaying inhibition rates that varied between 61 and 100%. No correlation between the ability to neutralize cell-free virus and to inhibit cell-to-cell spread could be observed. The incubation with IVIG influenced the amount of CMV immediate early and late mRNA, as indicated by a significant reduction in CMV mRNA in infected epithelial cells after incubation with IVIG in a dose-dependent manner. This study suggests different antiviral functions of polyvalent IVIG and confirms their potential to inhibit a CMV infection in vitro, with profound differences between the hereby used IVIG products. [ABSTRACT FROM AUTHOR]

Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. There is little evidence guiding therapeutic strategies during pregnancy when intrauterine fetal CMV infection is confirmed. We provide a systematic review of the use of ganciclovir (GCV) or VGCV during pregnancy discussing safety of its use for mother and fetus and describe two cases of intrauterine therapy of fetal CMV infection with valganciclovir (VGCV). A PubMed database search was done up to November 16, 2016 without any restrictions of publication date or journal, using the following keywords: 'valganciclovir' or 'ganciclovir' and 'pregnan*'. Furthermore, citations were searched and expert references were obtained. Reported cases were considered if therapy was in humans and initiation of treatment of the CMV infection was during pregnancy. In total, seven case reports were retrieved which described GCV or VGCV use during pregnancy for fetal or maternal CMV infection. In the four cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. Three cases of GCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection were found. We additionally present two cases of VGCV treatment in pregnancy from our center of tertiary care. VGCV seems to be a safe treatment for congenital CMV infection for the mother and the fetus. Therapeutic concentrations can be achieved in the fetus by oral intake of the mother and CMV replication can be suppressed. Larger studies are needed to evaluate this therapeutic intervention and the long-term effects. [ABSTRACT FROM AUTHOR]

Congenital human cytomegalovirus (HCMV) infection is one leading cause of childhood disabilities. Prevention of congenital HCMV disease by vaccination has consequently been identified as a priority public healthcare goal. Several vaccine candidates have been introduced in the past that aimed at the prevention of primary HCMV infection in pregnancy. None of these has provided complete protection, and no licensed vaccine is thus far available. An additional level of complexity has been reached by recent studies indicating that the burden of HCMV transmission and disease following non-primary infections in pregnancy may be higher than previously anticipated. Substantial progress in our understanding of the immunobiology of HCMV infection in pregnancy has fostered studies to test revised or novel vaccine strategies. Preventing HCMV transmission has been identified a surrogate endpoint, rendering the conduction of vaccine studies feasible with reasonable effort. Identification of the glycoprotein complex gH/gL/UL128-131 as a mediator of HCMV host cell tropism and evaluation of that complex as a major target of the neutralizing antibody response made manufacturers consider vaccine candidates that include these proteins. Detailed structural analyses of the neutralizing determinants on HCMV glycoprotein B (gB) have revived interest in using this protein in its pre-fusion conformation for vaccine purposes. Studies in pregnant women and in animal models have provided evidence that addressing the T lymphocyte response by vaccination may be crucial to prevent HCMV transmission to the offspring. CD4 T lymphocytes may be of particular importance in this respect. A simultaneous targeting of both the humoral and cellular immune response against HCMV by vaccination thus appears warranted in order to prevent congenital HCMV infection. There is, however, still need for further research to be able to define an immunological correlate of protection against HCMV transmission during pregnancy. This brief review will highlight recent developments in our understanding of the natural history and immunobiology of HCMV infection in pregnancy and their possible impact on the strategies for the development of an HCMV vaccine. [ABSTRACT FROM AUTHOR]

Co-infection with CMV in HIV-positive pregnant women is associated with perinatal mother-to-child transmission (MTCT) of both viruses. This retrospective study reports on the incidence of maternal and neonatal CMV (presence of anti-CMV IgG and IgM, CMV DNA PCR and/or CMV virus isolation) in high-risk pregnancies due to maternal HIV infection, MTCT of HIV and/or CMV. One hundred and eleven maternal samples and 75 matched neonatal samples were available for HIV and subsequent CMV testing. In this cohort of HIV-positive pregnant women, 96 (86.5 %) serum samples were anti-CMV IgG positive. In nine (9.4 %) of these, anti-CMV IgM was detected, and in none of them a maternal primary CMV infection was suspected. Fifty-seven (51.8 %) maternal serum samples were tested retrospectively by CMV DNA PCR; one sample was positive (0.9 %). All matched neonates were tested for HIV by PCR in the first month of life; HIV transmission was detected in one case. In 74 (67.2 %) of neonates, CMV testing was performed. Sixty-six of these serum samples were tested retrospectively by CMV DNA PCR. Two newborns (2.7 %) showed laboratory markers for CMV infection (one by detection of CMV DNA in plasma, and one by isolation of CMV from a urine sample). In the follow-up, neither of these two showed clinical signs for active CMV disease. We discussed these findings in the light of the national official guidelines. All CMV transmissions occurred due to maternal reinfection or endogenous reactivation. This suggests the success of highly active antiretroviral therapy in preventing MTCT of HIV and CMV disease and highlights the importance of adequate care and follow-up. [ABSTRACT FROM AUTHOR]

Vaccination has proven to be one of the best weapons protecting the mankind against infectious diseases. Along with the huge progress in microbiology, numerous highly efficacious and safe vaccines have been produced by conventional technology (cultivation), by the use of molecular biology (genetic modification), or by synthetic chemistry. Sterilising prevention is achieved by the stimulation of antibody production, while the stimulation of cell-mediated immune responses may prevent the outbreak of disease in consequence of an acute or reactivated infection. From several examples, two rules are deduced to evaluate the perspectives of future vaccine developments: They are promising, if (1) the natural infectious disease induces immunity or (2) passive immunisation (transfer of antibodies, adoptive transfer of lymphocytes) is successful in preventing infection. [ABSTRACT FROM AUTHOR]