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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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          Most cited references 43

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          Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects

          Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4 + and/or CD8 + T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4 + and CD8 + memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8 + T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.
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            Infection in solid-organ transplant recipients.

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              Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection.

              We reviewed studies that reported results of systematic cytomegalovirus (CMV) screening on fetuses and/or live-born infants. The overall birth prevalence of congenital CMV infection was 0.64%, but varied considerably among different study populations. About 11% of live-born infants with congenital CMV infection were symptomatic, but the inter-study differences in definitions of symptomatic cases limit the interpretation of these data. Non-white race, low socioeconomic status (SES), premature birth, and neonatal intensive care unit admittance were risk factors for congenital CMV infection. Birth prevalence increased with maternal CMV seroprevalence. Maternal seroprevalence accounted for 29% of the variance in birth prevalence between study populations. Maternal seroprevalence and birth prevalence were both higher in study populations that were ascertained at birth rather than in the prenatal period. Thus, timing of ascertainment should be considered when interpreting birth prevalence estimates. Birth prevalence was inversely correlated with mean maternal age, but this relationship was not significant when controlling for maternal seroprevalence. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy was 32% and 1.4%, respectively. Possible maternal primary infections (i.e. seropositive mother with CMV IgM) resulted in congenital infections about 20% of the time, but are likely to represent a mixture of primary and recurrent infections. In summary, CMV is a common congenital infection worldwide that can lead to permanent disabilities. There is an urgent need for interventions that can reduce the substantial burden of this often overlooked disease.
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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
                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
                Article
                38
                10.1038/s41541-017-0038-0
                5730571
                © 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/.

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