Characterization of a Discontinuous Neutralizing Epitope on Glycoprotein B of Human Cytomegalovirus

Spindler, Nadja; Rücker, Pia; Pötzsch, Sonja; Diestel, Uschi; Sticht, Heinrich; Martin‐Parras, Luis; Winkler, Thomas; Mach, Michael

doi:10.1128/jvi.00434-13

Cited by 35 publications

(35 citation statements)

References 53 publications

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“…AD-3 is located within the cytosolic domain and is a known target of exclusively non-neutralizing antibodies (33-35). Finally, AD-4 (Domain AI) and AD-5 (Domain I) are conformational, globular protein domains that were recently identified and characterized as the targets of neutralizing antibodies (23, 36-38). The antigen used for the gB/MF59 vaccine clinical trials (14, 15, 20) consisted of the full protein with two modifications to facilitate manufacture: (1) deletion of the transmembrane domain (75 amino acids) and (2) mutation of the furin protease cleavage site (39).…”

Section: Introductionmentioning

confidence: 99%

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Nelson

Huffman

Rosa

et al. 2018

Preprint

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word count: 242 (250 max) 24Significance word count: 120 (120 max) 25Manuscript character count: 48,559 (49,000 max) 26 peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/246884 doi: bioRxiv preprint first posted online 2 Abstract: 27Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently 28 causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal 29 acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. 30The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful 31HCMV vaccine tested to-date, demonstrating approximately 50% efficacy in preventing HCMV 32 acquisition in phase II trials. However, the mechanism of vaccine protection remains unknown. 33Plasma from 33 gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope

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Section: Introductionmentioning

confidence: 99%

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Nelson

Huffman

Rosa

et al. 2018

Preprint

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“…The major targets of neutralizing antibodies are located within AD-4 and AD-5 of gB, and antibodies to both regions have comparable activities on fibroblasts and epithelial/endothelial cells (27). Further characterization of critical binding residues within AD-4 recently identified an important epitope for gB-directed neutralization (39). In contrast, information on neutralizing epitopes within AD-5 is limited.…”

mentioning

confidence: 98%

“…Recombination of vBAC4-luc to introduce alanine exchanges in gB at the positions of interest and reconstitution of recombinant TB40/E viruses were performed as described previously (39). Viral DNA was isolated from infected cells by use of proteinase K, and the correctness of reconstituted viruses was confirmed by nucleotide sequence analysis.…”

Section: Bac Mutagenesis and Reconstitution Of Bac-derived Virusesmentioning

confidence: 99%

Identification of a Neutralizing Epitope within Antigenic Domain 5 of Glycoprotein B of Human Cytomegalovirus

Wiegers

Sticht

Winkler

et al. 2015

J Virol

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Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infected in utero. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus-neutralizing antibodies. We have begun to define target structures within gB that are recognized by virus-neutralizing antibodies. Antigenic domain 5 (AD-5) of gB has been identified as an important target for neutralizing antibodies in studies using human monoclonal antibodies (MAbs). Anti-AD-5 MAbs share a target site on gB, despite originating from different, healthy, HCMV-infected donors. Mutational analysis of AD-5 identified tyrosine 280 in combination with other surface-exposed residues (the YNND epitope) as critical for antibody binding. The YNND epitope is strictly conserved among different HCMV strains. Recombinant viruses carrying YNND mutations in AD-5 were resistant to virus-neutralizing MAbs. Competition enzyme-linked immunosorbent assays (ELISAs) with human HCMV-convalescent-phase sera from unselected donors confirmed the conserved antibody response for the YNND epitope in HCMV-infected individuals and, because a significant fraction of the gB AD-5 response was directed against the YNND epitope, further argued that this epitope is a major target of anti-AD-5 antibody responses. In addition, affinity-purified polyclonal anti-AD-5 antibodies prepared from individual sera showed reactivity to AD-5 and neutralization activity toward gB mutant viruses that were similar to those of AD-5-specific MAbs. Taken together, our data indicate that the YNND epitope represents an important target for anti-gB antibody responses as well as for anti-AD-5 virus-neutralizing antibodies. IMPORTANCEHCMV is a major global health concern, and a vaccine to prevent HCMV disease is a widely recognized medical need. Glycoprotein B of HCMV is an important target for neutralizing antibodies and hence an interesting molecule for intervention strategies, e.g., vaccination. Mapping the target structures of neutralizing antibodies induced by naturally occurring HCMV infection can aid in defining the properties required for a protective capacity of vaccine antigens. The data presented here extend our knowledge of neutralizing epitopes within gB to include AD-5. Collectively, our data will contribute to optimal vaccine design and development of antibody-based therapies.H uman cytomegalovirus (HCMV) is an important, ubiquitously distributed human pathogen that is found throughout all geographic locations and socioeconomic groups. Initial infection with HCMV is followed by a lifelong persistence characterized by periodic reactivation episodes. While most infections occur subclinically in the immunocompetent host, HCMV can cause severe disease and death in immunocompromised patients and newborns infected in utero. HCMV is the most frequent viral cause of congenital infection and affects 0.5 to 2% of all live births worldwide (1). It is the lead...

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“…22 Although the gH pentamer has attracted recent interest, gB has long been known to drive a broad neutralizing antibody response in humans recognizing well-defined linear as well as conformational epitopes, 81,130 spawning strategies to better harness the response to gB. [131][132][133] Despite positive results in clinical trials, 120 there remains the question of whether gBinduced antibodies are able to efficiently neutralize the virus in all biologically relevant cell types. Recently, two preclinical vaccine strategies, each devoid of the gH pentamer, reported the induction of antibodies in mice that can prevent epithelial cell infection.…”

Section: Vaccine Experiences-subunit Dna and Non-live CMV Vaccinmentioning

confidence: 99%

The immunological underpinnings of vaccinations to prevent cytomegalovirus disease

McCormick

Mocarski

2014

Cell Mol Immunol

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A universal cytomegalovirus (CMV) vaccination promises to reduce the burden of the developmental damage that afflicts up to 0.5% of live births worldwide. An effective vaccination that prevents transplacental transmission would reduce CMV congenital disease and CMV-associated still births and leave populations less susceptible to opportunistic CMV disease. Thus, a vaccination against this virus has long been recognized for the potential of enormous health-care savings because congenital damage is life-long and existing anti-viral options are limited. Vaccine researchers, industry leaders, and regulatory representatives have discussed the challenges posed by clinical efficacy trials that would lead to a universal CMV vaccine, reviewing the links between infection and disease, and identifying settings where disrupting viral transmission might provide a surrogate endpoint for disease prevention. Reducing the complexity of such trials would facilitate vaccine development. Children and adolescents are the targets for universal vaccination, with the expectation of protecting the offspring of immunized women. Given that a majority of females worldwide experience CMV infection during childhood, a universal vaccine must boost natural immunity and reduce transmission due to reactivation and re-infection as well as primary infection during pregnancy. Although current vaccine strategies recognize the value of humoral and cellular immunity, the precise mechanisms that act at the placental interface remain elusive. Immunity resulting from natural infection appears to limit rather than prevent reactivation of latent viruses and susceptibility to re-infection, leaving a challenge for universal vaccination to improve upon natural immunity levels. Despite these hurdles, early phase clinical trials have achieved primary end points in CMV seronegative subjects. Efficacy studies must be expanded to mixed populations of CMV-naive and naturally infected subjects to understand the overall efficacy and potential. Together with CMV vaccine candidates currently in clinical development, additional promising preclinical strategies continue to come forward; however, these face limitations due to the insufficient understanding of host defense mechanisms that prevent transmission, as well as the age-old challenges of reaching the appropriate threshold of immunogenicity, efficacy, durability and potency. This review focuses on the current understanding of natural and CMV vaccine-induced protective immunity.

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Characterization of a Discontinuous Neutralizing Epitope on Glycoprotein B of Human Cytomegalovirus

Cited by 35 publications

References 53 publications

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Identification of a Neutralizing Epitope within Antigenic Domain 5 of Glycoprotein B of Human Cytomegalovirus

The immunological underpinnings of vaccinations to prevent cytomegalovirus disease

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