Abstract:Epstein-Barr virus (EBV) is associated with a range of epithelial and B cell malignancies as well as autoimmune disorders, for which there are still no specific treatments or effective vaccines. Here, we isolate EBV gH/gL-specific antibodies from an EBV-infected individual. One antibody, 1D8, efficiently neutralizes EBV infection of two major target cell types, B cells and epithelial cells. In humanized mice, 1D8 provides protection against a high-dose EBV challenge by substantially reducing viral loads and as… Show more
“…Immunocompromised mice engrafted with human hematopoietic stem cells develop human B cells that can become infected by EBV and are used as an in vivo model of EBV infection (Fujiwara and Nakamura, 2020; Münz, 2017). This model has been used to evaluate the ability of monoclonal, or polyclonal antibodies elicited by either vaccination or infection to protect against controlled viral challenge (Cui et al, 2021; Kim et al, 2021; Singh et al ., 2020; Zhu et al ., 2021). Having established that gH/gL nanoparticles display superior immunogenicity, we sought to assess whether the antibodies they elicit confer protection against EBV challenge in this model.…”
Section: Resultsmentioning
confidence: 99%
“…Thus, relative to monomeric gH/gL, the gH/gL 60-mer may have elicited high titers of less potent anti-gH/gL antibodies like CL40 and CL59. Alternatively, the immunogens may have elicited antibodies targeting other potently neutralizing epitopes on gH/gL such as the one defined by the recently identified 1D8 mAb or other yet to be identified epitopes (Zhu et al ., 2021). Gaining a better understanding of the epitopes on gH/gL that are targeted by neutralizing and non-neutralizing antibodies elicited by natural infection or immunization through the isolation and characterization of monoclonal antibodies would enable rational gH/gL vaccine design that could further enhance neutralizing titers when combined with multimeric antigen display.…”
Section: Discussionmentioning
confidence: 99%
“…The 769B10 mAb also neutralizes EBV infection of both cell types and binds to an epitope that overlaps with AMMO1, confirming this is a critical site of vulnerability on EBV (Bu et al ., 2019). Passive transfer of AMMO1 severely limits viral infection following high-dose experimental EBV challenge in humanized mice and protects rhesus macaques against oral challenge with RhLCV if present at adequate levels at the time of challenge (Singh et al, 2020; Zhu et al ., 2021). These studies provide proof of concept that anti-gH/gL antibodies can protect against EBV infection and indicate that a gH/gL-based vaccine capable of eliciting AMMO1-like antibodies could prevent oral transmission of the virus.…”
Section: Introductionmentioning
confidence: 99%
“…Anti-gH/gL antibodies account for most serum antibodies that neutralize EBV infection of epithelial cells, but only a small fraction of antibodies that neutralize infection of B cells (Bu et al ., 2019). Only a handful of anti-gH/gL monoclonal antibodies (mAbs) have been identified, all of which neutralize EBV infection of epithelial cells with comparable potency, but most have weak, or no neutralizing activity against EBV infection of B cells (Chesnokova and Hutt-Fletcher, 2011; Li et al, 1995; Molesworth et al ., 2000; Sathiyamoorthy et al, 2016; Sathiyamoorthy et al, 2017; Snijder et al, 2018; Zhu et al, 2021). We previously described the isolation and characterization AMMO1, an anti-gH/gL monoclonal antibody (mAb) which potently neutralizes EBV infection of epithelial cells and B cells in vitro by binding to a discontinuous epitope on gH/gL (Snijder et al ., 2018).…”
Epstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 140,000 deaths per year. EBV is also the etiological agent of infectious mononucleosis and is associated with multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine could alleviate significant morbidity and mortality. EBV is orally transmitted and has tropism for both epithelial cells and B cells which are present in the oral cavity. Therefore, a prophylactic vaccine would need to prevent infection of both cell types. Passive transfer neutralizing monoclonal antibodies targeting the viral gH/gL glycoprotein complex prevent experimental EBV infection in humanized mice and rhesus macaques, suggesting that gH/gL is an attractive vaccine candidate. Here, we produced and evaluated the immunogenicity of several nanoparticle immunogens displaying gH/gL with distinct valencies and geometries. After one or two immunizations, all nanoparticles elicited superior binding and neutralizing titers relative to monomeric gH/gL. Antibodies elicited by a computationally designed self-assembling nanoparticle that displays 60 copies of the gH/gL protein conferred protection against a lethal dose of EBV in a humanized mouse challenge model, whereas antibodies elicited by monomeric gH/gL did not. Taken together, these data motivate further development of gH/gL nanoparticle vaccine candidates for EBV.
“…Immunocompromised mice engrafted with human hematopoietic stem cells develop human B cells that can become infected by EBV and are used as an in vivo model of EBV infection (Fujiwara and Nakamura, 2020; Münz, 2017). This model has been used to evaluate the ability of monoclonal, or polyclonal antibodies elicited by either vaccination or infection to protect against controlled viral challenge (Cui et al, 2021; Kim et al, 2021; Singh et al ., 2020; Zhu et al ., 2021). Having established that gH/gL nanoparticles display superior immunogenicity, we sought to assess whether the antibodies they elicit confer protection against EBV challenge in this model.…”
Section: Resultsmentioning
confidence: 99%
“…Thus, relative to monomeric gH/gL, the gH/gL 60-mer may have elicited high titers of less potent anti-gH/gL antibodies like CL40 and CL59. Alternatively, the immunogens may have elicited antibodies targeting other potently neutralizing epitopes on gH/gL such as the one defined by the recently identified 1D8 mAb or other yet to be identified epitopes (Zhu et al ., 2021). Gaining a better understanding of the epitopes on gH/gL that are targeted by neutralizing and non-neutralizing antibodies elicited by natural infection or immunization through the isolation and characterization of monoclonal antibodies would enable rational gH/gL vaccine design that could further enhance neutralizing titers when combined with multimeric antigen display.…”
Section: Discussionmentioning
confidence: 99%
“…The 769B10 mAb also neutralizes EBV infection of both cell types and binds to an epitope that overlaps with AMMO1, confirming this is a critical site of vulnerability on EBV (Bu et al ., 2019). Passive transfer of AMMO1 severely limits viral infection following high-dose experimental EBV challenge in humanized mice and protects rhesus macaques against oral challenge with RhLCV if present at adequate levels at the time of challenge (Singh et al, 2020; Zhu et al ., 2021). These studies provide proof of concept that anti-gH/gL antibodies can protect against EBV infection and indicate that a gH/gL-based vaccine capable of eliciting AMMO1-like antibodies could prevent oral transmission of the virus.…”
Section: Introductionmentioning
confidence: 99%
“…Anti-gH/gL antibodies account for most serum antibodies that neutralize EBV infection of epithelial cells, but only a small fraction of antibodies that neutralize infection of B cells (Bu et al ., 2019). Only a handful of anti-gH/gL monoclonal antibodies (mAbs) have been identified, all of which neutralize EBV infection of epithelial cells with comparable potency, but most have weak, or no neutralizing activity against EBV infection of B cells (Chesnokova and Hutt-Fletcher, 2011; Li et al, 1995; Molesworth et al ., 2000; Sathiyamoorthy et al, 2016; Sathiyamoorthy et al, 2017; Snijder et al, 2018; Zhu et al, 2021). We previously described the isolation and characterization AMMO1, an anti-gH/gL monoclonal antibody (mAb) which potently neutralizes EBV infection of epithelial cells and B cells in vitro by binding to a discontinuous epitope on gH/gL (Snijder et al ., 2018).…”
Epstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 140,000 deaths per year. EBV is also the etiological agent of infectious mononucleosis and is associated with multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine could alleviate significant morbidity and mortality. EBV is orally transmitted and has tropism for both epithelial cells and B cells which are present in the oral cavity. Therefore, a prophylactic vaccine would need to prevent infection of both cell types. Passive transfer neutralizing monoclonal antibodies targeting the viral gH/gL glycoprotein complex prevent experimental EBV infection in humanized mice and rhesus macaques, suggesting that gH/gL is an attractive vaccine candidate. Here, we produced and evaluated the immunogenicity of several nanoparticle immunogens displaying gH/gL with distinct valencies and geometries. After one or two immunizations, all nanoparticles elicited superior binding and neutralizing titers relative to monomeric gH/gL. Antibodies elicited by a computationally designed self-assembling nanoparticle that displays 60 copies of the gH/gL protein conferred protection against a lethal dose of EBV in a humanized mouse challenge model, whereas antibodies elicited by monomeric gH/gL did not. Taken together, these data motivate further development of gH/gL nanoparticle vaccine candidates for EBV.
“…The failure of an EBV gp350 vaccine to achieve sterilizing immunity in a clinical trial ( 12 ) suggests that a second component is advisable in a next-generation vaccine. Monoclonal antibodies (mAbs) to the gH/gL complex protect against EBV infection in humanized mice ( 32 , 33 ). Anti-gH/gL mAbs, such as AMMO1, have been shown to induce sterilizing immunity in NHPs challenged with the rhesus homolog of EBV and are more potent in inhibiting EBV infection than anti-gp350 mAbs, such as 72A1 ( 32 ).…”
Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several human cancers and, more recently, multiple sclerosis. Despite its prevalence and health impact, there are currently no vaccines or treatments. Four viral glycoproteins (gp), gp350 and gH/gL/gp42, mediate entry into the major sites of viral replication, B cells, and epithelial cells. Here, we designed a nanoparticle vaccine displaying these proteins and showed that it elicits potent neutralizing antibodies that protect against infection in vivo. We designed single-chain gH/gL and gH/gL/gp42 proteins that were each fused to bacterial ferritin to form a self-assembling nanoparticle. Structural analysis revealed that single-chain gH/gL and gH/gL/gp42 adopted a similar conformation to the wild-type proteins, and the protein spikes were observed by electron microscopy. Single-chain gH/gL or gH/gL/gp42 nanoparticle vaccines were constructed to ensure product homogeneity needed for clinical development. These vaccines elicited neutralizing antibodies in mice, ferrets, and nonhuman primates that inhibited EBV entry into both B cells and epithelial cells. When mixed with a previously reported gp350 nanoparticle vaccine, gp350D
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, no immune competition was observed. To confirm its efficacy in vivo, humanized mice were challenged with EBV after passive transfer of IgG from mice vaccinated with control, gH/gL/gp42+gp350D
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, or gH/gL+gp350D
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nanoparticles. Although all control animals were infected, only one mouse in each vaccine group that received immune IgG had detectable transient viremia. Furthermore, no EBV lymphomas were detected in immune animals. This bivalent EBV nanoparticle vaccine represents a promising candidate to prevent EBV infection and EBV-related malignancies in humans.
Epstein-Barr virus (EBV) infection is prevalent in global population and associated with multiple malignancies and autoimmune diseases. During the infection, EBV-harbored or infected cell-expressing antigen could elicit a variety of antibodies with significant role in viral host response and pathogenesis. These antibodies have been extensively evaluated and found to be valuable in predicting disease diagnosis and prognosis, exploring disease mechanisms, and developing antiviral agents. In this review, we discuss the versatile roles of EBV antibodies as important biomarkers for EBV-related diseases, potential driving factors of autoimmunity, and promising therapeutic agents for viral infection and pathogenesis.
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