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      Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination

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          Abstract

          Human cytomegalovirus (HCMV) is the leading cause of in utero viral infection in the United States. Since congenital HCMV infection can lead to birth defects in newborns, developing a prophylactic vaccine is a high priority. One of the early experimental vaccines, composed of a recombinant glycoprotein B (gB) formulated with MF59 adjuvant, has demonstrated approximately 50% efficacy against HCMV infection in seronegative women. Using immune sera from two gB/MF59 Phase 1 studies in humans we showed that complement can enhance the in vitro HCMV neutralizing potency of antibodies induced by the gB/MF59 vaccination. To characterize this complement-dependent antiviral activity, we analyzed three rabbit non-neutralizing gB monoclonal antibodies (mAbs) with different biochemical profiles including epitope specificity. Two of the three mAbs, r272.7 and r210.4, exhibited neutralizing activity when complement was added to the assays, and this complement-dependent antiviral activity was not related to the antibody’s affinity to gB but appeared to be associated with their epitope specificities. Moreover, neutralization could only be demonstrated when complement was present at or before viral entry, suggesting that IgG Fc-mediated function was not the basis for this antiviral activity. Lastly, we demonstrated that gB/MF59 immune sera contained antibodies that can cross-compete with r272.7 for gB binding and that the titers of these antibodies correlated with complement-dependent neutralization titers. These results suggested that gB antibodies with certain biochemical properties have neutralizing potency when complement is present and that this complement-dependent antiviral activity may be a part of immune components which conferred protection against HCMV infection by gB/MF59 vaccination.

          Fetal infection: Complementing menting vaccine performance

          Enhancing a cytomegalovirus vaccine candidate with immune system proteins could be a step closer to protection against pre-birth infections. Cytomegalovirus is the leading cause of in utero infections in the United States; however, the leading vaccine candidate against the virus is, at best, 50% effective. A US group of scientists led by Merck’s Tong-Ming Fu found that adding a set of innate, antipathogenic proteins called ‘complement’ to the candidate increased the protective effects of immunization in humans, and in vitro with a selection of otherwise non-protective antibodies. The team also found that complement augmented the vaccine through a non-standard mechanism, which was dependent on the specific profile of the antibodies fighting the infection. This article describes an interesting mechanism of vaccine protection that warrants further investigation.

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          Vaccine prevention of maternal cytomegalovirus infection.

          Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.) 2009 Massachusetts Medical Society
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            Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex.

            Human cytomegalovirus (HCMV) is a widely circulating pathogen that causes severe disease in immunocompromised patients and infected fetuses. By immortalizing memory B cells from HCMV-immune donors, we isolated a panel of human monoclonal antibodies that neutralized at extremely low concentrations (90% inhibitory concentration [IC(90)] values ranging from 5 to 200 pM) HCMV infection of endothelial, epithelial, and myeloid cells. With the single exception of an antibody that bound to a conserved epitope in the UL128 gene product, all other antibodies bound to conformational epitopes that required expression of two or more proteins of the gH/gL/UL128-131A complex. Antibodies against gB, gH, or gM/gN were also isolated and, albeit less potent, were able to neutralize infection of both endothelial-epithelial cells and fibroblasts. This study describes unusually potent neutralizing antibodies against HCMV that might be used for passive immunotherapy and identifies, through the use of such antibodies, novel antigenic targets in HCMV for the design of immunogens capable of eliciting previously unknown neutralizing antibody responses.
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              Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee.

              Cytomegalovirus (CMV) infection is the most common intrauterine infection in the United States, and it exacts a heavy toll when it infects children and immunocompromised individuals. A CMV vaccine was assigned the highest priority by the Institute of Medicine in its 1999 assessment of targets for vaccine development. The priority was based on the cost and human suffering that would be alleviated by reducing the disease burden of congenital CMV infection. The National Vaccine Advisory Committee and invited experts examined the prospects for a CMV vaccine and the actions needed to bring about successful vaccine development at a National Vaccine Program Office workshop in October 2000. This article summarizes information about the changing epidemiology of CMV and immune responses to infection and immunity, and it reviews the current status of several vaccine candidates. Support of government agencies for CMV vaccine research and development is critical to address this need.
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                Author and article information

                Contributors
                tong-ming_fu@merck.com
                Journal
                NPJ Vaccines
                NPJ Vaccines
                NPJ Vaccines
                Nature Publishing Group UK (London )
                2059-0105
                14 December 2017
                14 December 2017
                2017
                : 2
                : 36
                Affiliations
                [1 ]ISNI 0000 0001 2260 0793, GRID grid.417993.1, Department of Vaccines Research, , MRL, Merck & Co., Inc, ; Kenilworth, NJ USA
                [2 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, , University of Texas Health Science Center at Houston, ; Houston, TX 77030 USA
                [3 ]ISNI 0000 0004 0458 8737, GRID grid.224260.0, Virginia Commonwealth University, ; Richmond, VA USA
                [4 ]ISNI 0000 0000 8692 8176, GRID grid.469131.8, Rutgers New Jersey Medical School, ; Newark, NJ USA
                [5 ]CMV Research Foundation, Richmond, VA USA
                Author information
                http://orcid.org/0000-0003-1420-2271
                Article
                38
                10.1038/s41541-017-0038-0
                5730571
                29263890
                442484dc-e03c-4500-b525-2c6cd150c50d
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 August 2017
                : 21 October 2017
                : 23 November 2017
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                © The Author(s) 2017

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