The Status and Prospects of Epstein–Barr Virus Prophylactic Vaccine Development

Sun, Cong; Chen, Xinchun; Kang, Yinfeng; Zeng, Mu‐Sheng

doi:10.3389/fimmu.2021.677027

Cited by 24 publications

(18 citation statements)

References 170 publications

(197 reference statements)

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“…Thus, future studies should focus on identifying the required components of a multivalent EBV vaccine that can generate effective neutralizing activity both in vitro and in vivo . Indeed, ModernaTX Inc. has recently started recruiting participants for a Phase I clinical trial that will explore the safety and immunogenicity of their mRNA-based EBV vaccine, mRNA-1189, which targets multiple EBV glycoproteins ( 125 – 127 ).…”

Section: Discussionmentioning

confidence: 99%

Four Decades of Prophylactic EBV Vaccine Research: A Systematic Review and Historical Perspective

et al. 2022

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BackgroundEpstein-Barr virus (EBV) is the causal agent of infectious mononucleosis and has been associated with various cancers and autoimmune diseases. Despite decades of research efforts to combat this major global health burden, there is no approved prophylactic vaccine against EBV. To facilitate the rational design and assessment of an effective vaccine, we systematically reviewed pre-clinical and clinical prophylactic EBV vaccine studies to determine the antigens, delivery platforms, and animal models used in these studies.MethodsWe searched Cochrane Library, ClinicalTrials.gov, Embase, PubMed, Scopus, Web of Science, WHO’s Global Index Medicus, and Google Scholar from inception to June 20, 2020, for EBV prophylactic vaccine studies focused on humoral immunity.ResultsThe search yielded 5,614 unique studies. 36 pre-clinical and 4 clinical studies were included in the analysis after screening against the exclusion criteria. In pre-clinical studies, gp350 was the most commonly used immunogen (33 studies), vaccines were most commonly delivered as monomeric proteins (12 studies), and mice were the most used animal model to test immunogenicity (15 studies). According to an adaptation of the CAMARADES checklist, 4 pre-clinical studies were rated as very high, 5 as high, 13 as moderate quality, 11 as poor, and 3 as very poor. In clinical studies, gp350 was the sole vaccine antigen, delivered in a vaccinia platform (1 study) or as a monomeric protein (3 studies). The present study was registered in PROSPERO (CRD42020198440).ConclusionsFour major obstacles have prevented the development of an effective prophylactic EBV vaccine: undefined correlates of immune protection, lack of knowledge regarding the ideal EBV antigen(s) for vaccination, lack of an appropriate animal model to test vaccine efficacy, and lack of knowledge regarding the ideal vaccine delivery platform. Our analysis supports a multivalent antigenic approach including two or more of the five main glycoproteins involved in viral entry (gp350, gB, gH/gL, gp42) and a multimeric approach to present these antigens. We anticipate that the application of two underused challenge models, rhesus macaques susceptible to rhesus lymphocryptovirus (an EBV homolog) and common marmosets, will permit the establishment of in vivo correlates of immune protection and attainment of more generalizable data.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=198440, identifier PROSPERO I.D. CRD4202019844.

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Section: Discussionmentioning

confidence: 99%

Four Decades of Prophylactic EBV Vaccine Research: A Systematic Review and Historical Perspective

et al. 2022

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“…Several EBV NAbs have shown protection in mice and non-human primates ( 57 , 67 , 68 ), while no gB NAbs has been evaluated for protection efficiency in vivo . Most animal models for EBV infection are mainly based on infection of B lymphocytes, and associated with the formation of lymphomas ( 12 , 23 , 44 , 57 , 69 ). Hence, NAbs that effectively inhibit B-cell infection are believed to perform better with in vivo models ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, EBV is also related to a number of non-malignant diseases such as infectious mononucleosis (IM), chronic active EBV infection (CAEBV), multiple sclerosis (MS), and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) ( 9 – 11 ). However, there are no available prophylactic vaccines or therapeutics for EBV ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Glycoprotein B Antibodies Completely Neutralize EBV Infection of B Cells

et al. 2022

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The Epstein–Barr virus (EBV) is the first reported oncogenic herpesvirus that establishes persistent infection in B lymphocytes in 95% of adults worldwide. Glycoprotein B (gB) plays a predominant role in the fusion of the viral envelope with the host cell membrane. Hence, it is of great significance to isolate gB-specific fusion-inhibiting neutralizing antibodies (NAbs). AMMO5 is the only gB NAb but fails to antagonize B-cell infection. It is essential to isolate potent NAbs that can completely block EBV infection of B cells. Using hybridoma technology and neutralization assay, we isolate two gB NAbs 8A9 and 8C12 that are capable of completely neutralizing B-cell infection in vitro. In addition, 8A9 shows cross-reactivity with rhesus lymphocryptovirus (rhLCV) gB. Competitive binding experiments demonstrate that 8A9 and 8C12 recognize novel epitopes that are different from the AMMO5 epitope. The epitopes of 8A9 and 8C12 are mapped to gB D-II, and the AMMO5 epitope is located precisely at gB aa 410–419. We find that 8A9 and 8C12 significantly inhibit gB-derived membrane fusion using a virus-free fusion assay. In summary, this study identifies two gB-specific NAbs that potently block EBV infection of B cells. Our work highlights the importance of gB D-II as a predominant neutralizing epitope, and aids in the rational design of therapeutics or vaccines based on gB.

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“…Silver nanoparticles and dendrimers have intrinsic biomimetic properties, acquiring anti-viral effects in host cells. Sometimes, NPs are covered by stable structures (polietilenglicol) (PEG), increasing optimized drug dosing, improving delivery and therapeutic retention times ( Figure 4 A) [ 95 , 98 , 99 ]. Some of these NPs are designed to move to the blood–brain barrier (BBB).…”

Section: Nanosystems: From Liposomes To Nanoparticles (Nps)mentioning

confidence: 99%

Nanotechnology Frontiers in γ-Herpesviruses Treatments

Granato

2021

IJMS

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Epstein–Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients (PTDLs). KSHV, an etiologic agent of Kaposi’s sarcoma (KS), displays primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Many therapeutics, such as bortezomib, CHOP cocktail medications, and natural compounds (e.g., quercetin or curcumin), are administrated to patients affected by γ-herpesvirus infections. These drugs induce apoptosis and autophagy, inhibiting the proliferative and cell cycle progression in these malignancies. In the last decade, many studies conducted by scientists and clinicians have indicated that nanotechnology and nanomedicine could improve the outcome of several treatments in γ-herpesvirus-associated diseases. Some drugs are entrapped in nanoparticles (NPs) expressed on the surface area of polyethylene glycol (PEG). These NPs move to specific tissues and exert their properties, releasing therapeutics in the cell target. To treat EBV- and KSHV-associated diseases, many studies have been performed in vivo and in vitro using virus-like particles (VPLs) engineered to maximize antigen and epitope presentations during immune response. NPs are designed to improve therapeutic delivery, avoiding dissolving the drugs in toxic solvents. They reduce the dose-limiting toxicity and reach specific tissue areas. Several attempts are ongoing to synthesize and produce EBV vaccines using nanosystems.

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The Status and Prospects of Epstein–Barr Virus Prophylactic Vaccine Development

Cited by 24 publications

References 170 publications

Four Decades of Prophylactic EBV Vaccine Research: A Systematic Review and Historical Perspective

Four Decades of Prophylactic EBV Vaccine Research: A Systematic Review and Historical Perspective

Glycoprotein B Antibodies Completely Neutralize EBV Infection of B Cells

Nanotechnology Frontiers in γ-Herpesviruses Treatments

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