A Self-assembled Nanoparticle Vaccine Elicits Effective Neutralizing Antibody Response Against EBV Infection

Overview

Journal Front Immunol

Date 2025 Jan 20

PMID 39830517

Authors

Ping Li

Ziyi Jiang

Jingjing Shi

Haochuan Sha

Zihang Yu

Yan Zhao

Sanyang Han

Lan Ma

Affiliations

Soon will be listed here.

Abstract

Background: Epstein-Barr virus (EBV) is a significant global public health concern because of its association with various malignancies and autoimmune diseases. Over 90% of the global population is chronically infected with EBV, impacting numerous cancer-related cases annually. However, none of the effective prophylactic vaccines against EBV is approved at present.

Methods: In this study, we developed a novel vaccine candidate based on epitope peptides from the receptor-binding domain of EBV-encoded gp350 glycoprotein to prevent EBV infection. These epitope peptides detected a binding capability with host cells were then fused by flexibility linkers and expressed in to reduce the unnecessary glycan modifications to simulate their free-glycan status. The fused recombinant protein (L350) was displayed on the surface of ferritin-based nanoparticle. The immunogenicity of the L350-ferritin nanoparticle was evaluated in Balb/c mice, and the neutralizing titers of sera from immunized mice were detected by means of an infection blocking assay in an cell model.

Results: All the five epitope peptides could bind to AKATA cells, and their fused recombinant protein (L350) was successfully presented on the surface of self-assembled ferritin nanoparticles. Sera from the L350-ferritin nanoparticle-immunized mice showed high titers of both L350 protein-specific and gp350D protein-specific antibodies, and sera from gp350D protein-immunized mice could also recognize L350 protein well. Most importantly, the L350-ferritin nanoparticle induced efficient neutralizing antibodies to block EBV-GFP infection in AKATA cells and also constructed a strong antigen-specific B-cell memory in immunized mice. Moreover, histopathological changes of main tissues from all vaccinated mice were not observed.

Conclusion: These data indicate that the L350-ferritin nanoparticle vaccine candidate has considerable potential application in preventing EBV infection and provides a promising basis for developing prophylactic EBV vaccines.

References

Tanner J, Whang Y, Sample J, Sears A, Kieff E . Soluble gp350/220 and deletion mutant glycoproteins block Epstein-Barr virus adsorption to lymphocytes. J Virol. 1988; 62(12):4452-64. PMC: 253554. DOI: 10.1128/JVI.62.12.4452-4464.1988. View

Ortega-Rivera O, Shukla S, Shin M, Chen A, Beiss V, Moreno-Gonzalez M . Cowpea Mosaic Virus Nanoparticle Vaccine Candidates Displaying Peptide Epitopes Can Neutralize the Severe Acute Respiratory Syndrome Coronavirus. ACS Infect Dis. 2021; 7(11):3096-3110. DOI: 10.1021/acsinfecdis.1c00410. View

Zhang H, Tian J, Qi X, Xiang T, He G, Zhang H . Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation. PLoS Pathog. 2018; 14(7):e1007208. PMC: 6082576. DOI: 10.1371/journal.ppat.1007208. View

Brauninger A, Schmitz R, Bechtel D, Renne C, Hansmann M, Kuppers R . Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer. 2005; 118(8):1853-61. DOI: 10.1002/ijc.21716. View

Joyce M, Chen W, Sankhala R, Hajduczki A, Thomas P, Choe M . SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity. Cell Rep. 2021; 37(12):110143. PMC: 8651551. DOI: 10.1016/j.celrep.2021.110143. View

Mizokami H, Okabe A, Choudhary R, Mima M, Saeda K, Fukuyo M . Enhancer infestation drives tumorigenic activation of inactive B compartment in Epstein-Barr virus-positive nasopharyngeal carcinoma. EBioMedicine. 2024; 102:105057. PMC: 10951899. DOI: 10.1016/j.ebiom.2024.105057. View

Tanner J, Hu J, Alfieri C . Construction and Characterization of a Humanized Anti-Epstein-Barr Virus gp350 Antibody with Neutralizing Activity in Cell Culture. Cancers (Basel). 2018; 10(4). PMC: 5923367. DOI: 10.3390/cancers10040112. View

Kanekiyo M, Joyce M, Gillespie R, Gallagher J, Andrews S, Yassine H . Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses. Nat Immunol. 2019; 20(3):362-372. PMC: 6380945. DOI: 10.1038/s41590-018-0305-x. View

Ma X, Zou F, Yu F, Li R, Yuan Y, Zhang Y . Nanoparticle Vaccines Based on the Receptor Binding Domain (RBD) and Heptad Repeat (HR) of SARS-CoV-2 Elicit Robust Protective Immune Responses. Immunity. 2020; 53(6):1315-1330.e9. PMC: 7687490. DOI: 10.1016/j.immuni.2020.11.015. View

10.

Sun C, Yuan R, Xie C, Sun J, Fang X, Hu Y . Induction of Broadly Cross-Reactive Antibody Responses to SARS-CoV-2 Variants by S1 Nanoparticle Vaccines. J Virol. 2022; 96(13):e0038322. PMC: 9278117. DOI: 10.1128/jvi.00383-22. View

11.

Kanekiyo M, Wei C, Yassine H, McTamney P, Boyington J, Whittle J . Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature. 2013; 499(7456):102-6. PMC: 8312026. DOI: 10.1038/nature12202. View

12.

Haque T, Johannessen I, Dombagoda D, Sengupta C, Burns D, Bird P . A mouse monoclonal antibody against Epstein-Barr virus envelope glycoprotein 350 prevents infection both in vitro and in vivo. J Infect Dis. 2006; 194(5):584-7. DOI: 10.1086/505912. View

13.

Urquiza M, Lopez R, Patino H, Rosas J, Patarroyo M . Identification of three gp350/220 regions involved in Epstein-Barr virus invasion of host cells. J Biol Chem. 2005; 280(42):35598-605. DOI: 10.1074/jbc.M504544200. View

14.

Hesse C, Kollenda S, Rotan O, Pastille E, Adamczyk A, Wenzek C . A Tumor-Peptide-Based Nanoparticle Vaccine Elicits Efficient Tumor Growth Control in Antitumor Immunotherapy. Mol Cancer Ther. 2019; 18(6):1069-1080. DOI: 10.1158/1535-7163.MCT-18-0764. View

15.

Chen R, Zhang X, Yuan Y, Deng X, Wu B, Xi Z . Development of Receptor Binding Domain (RBD)-Conjugated Nanoparticle Vaccines with Broad Neutralization against SARS-CoV-2 Delta and Other Variants. Adv Sci (Weinh). 2022; 9(11):e2105378. PMC: 9008796. DOI: 10.1002/advs.202105378. View

16.

Hoffman G, Lazarowitz S, Hayward S . Monoclonal antibody against a 250,000-dalton glycoprotein of Epstein-Barr virus identifies a membrane antigen and a neutralizing antigen. Proc Natl Acad Sci U S A. 1980; 77(5):2979-83. PMC: 349530. DOI: 10.1073/pnas.77.5.2979. View

17.

Wu T, Mann R, CHARACHE P, Hayward S, Staal S, Lambe B . Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin's disease. Int J Cancer. 1990; 46(5):801-4. DOI: 10.1002/ijc.2910460509. View

18.

Wang W, Liu Z, Zhou X, Guo Z, Zhang J, Zhu P . Ferritin nanoparticle-based SpyTag/SpyCatcher-enabled click vaccine for tumor immunotherapy. Nanomedicine. 2018; 16:69-78. DOI: 10.1016/j.nano.2018.11.009. View

19.

Bu W, Joyce M, Nguyen H, Banh D, Aguilar F, Tariq Z . Immunization with Components of the Viral Fusion Apparatus Elicits Antibodies That Neutralize Epstein-Barr Virus in B Cells and Epithelial Cells. Immunity. 2019; 50(5):1305-1316.e6. PMC: 6660903. DOI: 10.1016/j.immuni.2019.03.010. View

20.

Zhao B, Zhang X, Krummenacher C, Song S, Gao L, Zhang H . Immunization With Fc-Based Recombinant Epstein-Barr Virus gp350 Elicits Potent Neutralizing Humoral Immune Response in a BALB/c Mice Model. Front Immunol. 2018; 9:932. PMC: 5938345. DOI: 10.3389/fimmu.2018.00932. View