ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection

Semmes, Eleanor C; Miller, Itzayana G; Rodgers, Nicole; Phan, Caroline T; Hurst, Jillian H.; Walsh, Kyle M.; Stanton, Richard J.; Pollara, Justin; Permar, Sallie R.

doi:10.1101/2023.03.15.23287332

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…Although no consistent benefit of post-exposure HIG therapy has been demonstrated for cCMV infections across various human clinical trials, it appears that treatment dosage and pharmacokinetics are important parameters of efficacy and protection ( 14–18 ). In line with these observations, we recently demonstrated that not neutralization, but IgG-Fc-gamma (Fcγ)-mediated anti-viral mechanisms by non-neutralizing IgG, specifically maternal plasma levels of antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), correlate with a reduced risk of congenital infection ( 19, 20 ). Intriguingly, both ADCP and ADCC are mediated by Fcγ receptors (FcγRs) expressed by nearly all immune cells including neutrophils, macrophages and NK cells.…”

Section: Introductionmentioning

confidence: 72%

Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity

Otero,

Petkova,

Ebermann

et al. 2024

Preprint

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Human cytomegalovirus (HCMV) encodes four viral Fc-gamma receptors (vFcγRs) that counteract antibody-mediated activationin vitro, but their role in infection and pathogenesis is unknown. To examine thein vivofunction of vFcγRs in animal hosts closely related to humans, we identified and characterized vFcγRs encoded by rhesus CMV (RhCMV). We demonstrate that Rh05, Rh152/151 and Rh173 represent the complete set of RhCMV vFcγRs, each displaying functional similarities to their respective HCMV orthologs with respect to antagonizing host FcγR activationin vitro. When RhCMV-naïve rhesus macaques were infected with vFcγR-deleted RhCMV, peak plasma viremia levels and anti-RhCMV antibody responses were comparable to wildtype infections. However, the duration of plasma viremia was significantly shortened in immunocompetent, but not in CD4+ T cell-depleted animals. Since vFcγRs were not required for superinfection, we conclude that vFcγRs delay control by virus-specific adaptive immune responses, particularly antibodies, during primary infection.

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Section: Introductionmentioning

confidence: 72%

Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity

Otero,

Petkova,

Ebermann

et al. 2024

Preprint

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“…Fc-mediated effector responses, and ADCC in particular, have been thought to play a major role in control of infections that utilize cell-to-cell spread as a primary mode of dissemination, such as herpes simplex virus (HSV) and cytomegalovirus (CMV). Both of these viruses can cause severe disease in infected neonates, but maternal antiviral ADCC-mediating antibodies have been associated with protection from disseminated HSV infection and from vertical CMV transmission in clinical observational studies [ 6 , 31 ].…”

Section: Mechanisms Of Nnab-mediated Protectionmentioning

confidence: 99%

“…Clinical trials for vaccines targeting influenza virus [ 2 ] and HIV [ 3 ] found that protection was associated with nNAbs. Similarly, partial vaccine-mediated protection against human cytomegalovirus (HCMV) [ 4 ] and reduced risk of in utero HCMV transmission [ 5 , 6 ] has been associated with nNAbs.…”

Section: Introductionmentioning

confidence: 99%

Protective mechanisms of nonneutralizing antiviral antibodies

Chandler,

Yang,

Otero

et al. 2023

PLoS Pathog

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Antibodies that can bind to viruses but are unable to block infection in cell culture are known as “nonneutralizing antibodies.” Such antibodies are nearly universally elicited following viral infection and have been characterized in viral infections such as influenza, rotavirus, cytomegalovirus, HIV, and SARS-CoV-2. It has been widely assumed that these nonneutralizing antibodies do not function in a protective way in vivo and therefore are not desirable targets of antiviral interventions; however, increasing evidence now shows this not to be true. Several virus-specific nonneutralizing antibody responses have been correlated with protection in human studies and also shown to significantly reduce virus replication in animal models. The mechanisms by which many of these antibodies function is only now coming to light. While nonneutralizing antibodies cannot prevent viruses entering their host cell, nonneutralizing antibodies work in the extracellular space to recruit effector proteins or cells that can destroy the antibody-virus complex. Other nonneutralizing antibodies exert their effects inside cells, either by blocking the virus life cycle directly or by recruiting the intracellular Fc receptor TRIM21. In this review, we will discuss the multitude of ways in which nonneutralizing antibodies function against a range of viral infections.

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Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses than that of the Partially Effective gB/MF59 Vaccine

Hu,

Karthigeyan,

Herbek

et al. 2023

Preprint

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BackgroundThe MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated ~50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting efforts to improve this vaccine design might yield a vaccine suitable for licensure. A vaccine candidate employing nucleoside-modified mRNAs encoding HCMV gB and pentameric complex (PC) encapsulated in lipid nanoparticle, mRNA-1647, is currently in late-stage efficacy trials. Yet, its immunogenicity has not been compared to the partially-effective gB/MF59 vaccine.MethodsWe assessed neutralizing and Fc-mediated IgG effector antibody responses induced by mRNA-1647, a vaccine comprising an equal mass of 6 mRNAs encoding gB and PC antigens, in both HCMV seropositive and seronegative vaccinees from a first-in-human clinical trial through 1-year following 3rdvaccination using a systems serology approach. Further, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative female adolescent gB/MF59 vaccine recipients.ResultsmRNA-1647 vaccination boosted pre-existing HCMV-specific IgG responses in seropositive vaccinees, including neutralizing and Fc-mediated effector antibody responses. In seronegative vaccinees, mRNA-1647 induced durable and functional HCMV-specific IgG responses. Elicited gB-specific IgG responses were lower than the PC-specific IgG responses. Additionally, gB-specific IgG and antibody-dependent cellular phagocytosis (ADCP) responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited robust neutralization and high antibody-dependent cellular cytotoxicity (ADCC) responses.ConclusionsmRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses. mRNA-1647-elicited gB-specific IgG responses were lower than PC-specific IgG responses and lower than those elicited by the partially effective gB/MF59. However, higher neutralization and ADCC responses were elicited by mRNA-1647 than gB/MF59.Clinical Trials RegistrationClinicalTrials.gov(NCT03382405, mRNA-1647) and (NCT00133497, gB/MF59).SummarymRNA-1647 HCMV vaccine elicited polyfunctional and durable antibody responses in humans. While the mRNA-1647-elicited glycoprotein B (gB)-specific IgG responses were lower than that of the moderately-effective gB/MF59 vaccine, the pentameric complex (PC)-specific IgG responses were strong.

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ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection

Cited by 3 publications

References 51 publications

Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity

Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity

Protective mechanisms of nonneutralizing antiviral antibodies

Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses than that of the Partially Effective gB/MF59 Vaccine

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