Immunization with Epstein-Barr Virus Core Fusion Machinery Envelope Proteins Elicit High Titers of Neutralizing Activities and Protect Humanized Mice from Lethal Dose EBV Challenge

Overview

Journal Vaccines (Basel)

Date 2021 Apr 3

PMID 33808755

Citations 14

Authors

Xinle Cui

Zhouhong Cao

Yuriko Ishikawa

Sara Cui

Ken-Ichi Imadome

Clifford M Snapper

Affiliations

Soon will be listed here.

Abstract

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. EBV core fusion machinery envelope proteins gH/gL and gB coordinately mediate EBV fusion and entry into its target cells, B lymphocytes and epithelial cells, suggesting these proteins could induce antibodies that prevent EBV infection. We previously reported that the immunization of rabbits with recombinant EBV gH/gL or trimeric gB each induced markedly higher serum EBV-neutralizing titers for B lymphocytes than that of the leading EBV vaccine candidate gp350. In this study, we demonstrated that immunization of rabbits with EBV core fusion machinery proteins induced high titer EBV neutralizing antibodies for both B lymphocytes and epithelial cells, and EBV gH/gL in combination with EBV trimeric gB elicited strong synergistic EBV neutralizing activities. Furthermore, the immune sera from rabbits immunized with EBV gH/gL or trimeric gB demonstrated strong passive immune protection of humanized mice from lethal dose EBV challenge, partially or completely prevented death respectively, and markedly decreased the EBV load in peripheral blood of humanized mice. These data strongly suggest the combination of EBV core fusion machinery envelope proteins gH/gL and trimeric gB is a promising EBV prophylactic vaccine.

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References

Cohen J . Vaccine Development for Epstein-Barr Virus. Adv Exp Med Biol. 2018; 1045:477-493. PMC: 6328312. DOI: 10.1007/978-981-10-7230-7_22. View

Cui X, Cao Z, Chen Q, Arjunaraja S, Snow A, Snapper C . Rabbits immunized with Epstein-Barr virus gH/gL or gB recombinant proteins elicit higher serum virus neutralizing activity than gp350. Vaccine. 2016; 34(34):4050-5. DOI: 10.1016/j.vaccine.2016.06.021. View

Cui X, Cao Z, Wang S, Flora M, Adler S, McVoy M . Immunization of Rabbits with Recombinant Human Cytomegalovirus Trimeric versus Monomeric gH/gL Protein Elicits Markedly Higher Titers of Antibody and Neutralization Activity. Int J Mol Sci. 2019; 20(13). PMC: 6651862. DOI: 10.3390/ijms20133158. View

Heslop H, Slobod K, Pule M, Hale G, Rousseau A, Smith C . Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2009; 115(5):925-35. PMC: 2817637. DOI: 10.1182/blood-2009-08-239186. View

Cui X, Snapper C . Development of novel vaccines against human cytomegalovirus. Hum Vaccin Immunother. 2019; 15(11):2673-2683. PMC: 6930071. DOI: 10.1080/21645515.2019.1593729. View

Kimura H, Morita M, Yabuta Y, Kuzushima K, Kato K, Kojima S . Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol. 1998; 37(1):132-6. PMC: 84187. DOI: 10.1128/JCM.37.1.132-136.1999. View

Rowe M, Young L, Cadwallader K, Petti L, Kieff E, Rickinson A . Distinction between Epstein-Barr virus type A (EBNA 2A) and type B (EBNA 2B) isolates extends to the EBNA 3 family of nuclear proteins. J Virol. 1989; 63(3):1031-9. PMC: 247795. DOI: 10.1128/JVI.63.3.1031-1039.1989. View

Mackett M, Cox C, Pepper S, Lees J, Naylor B, Wedderburn N . Immunisation of common marmosets with vaccinia virus expressing Epstein-Barr virus (EBV) gp340 and challenge with EBV. J Med Virol. 1996; 50(3):263-71. DOI: 10.1002/(SICI)1096-9071(199611)50:3<263::AID-JMV9>3.0.CO;2-7. View

Al-Mansour Z, Nelson B, Evens A . Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013; 8(3):173-83. PMC: 4831913. DOI: 10.1007/s11899-013-0162-5. View

10.

Rooney C, Smith C, Ng C, Loftin S, Sixbey J, Gan Y . Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood. 1998; 92(5):1549-55. View

11.

Finerty S, Tarlton J, Mackett M, Conway M, Arrand J, Watkins P . Protective immunization against Epstein-Barr virus-induced disease in cottontop tamarins using the virus envelope glycoprotein gp340 produced from a bovine papillomavirus expression vector. J Gen Virol. 1992; 73 ( Pt 2):449-53. DOI: 10.1099/0022-1317-73-2-449. View

12.

Song S, Kim W, Ko Y, Kim K, Lee M, Park K . Aggressive natural killer cell leukemia: clinical features and treatment outcome. Haematologica. 2002; 87(12):1343-5. View

13.

Lee J, Kim S, Han S, An J, Lee E, Kim Y . Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol. 2009; 24(3):354-65. DOI: 10.1111/j.1440-1746.2009.05775.x. View

14.

Shannon-Lowe C, Rickinson A . The Global Landscape of EBV-Associated Tumors. Front Oncol. 2019; 9:713. PMC: 6691157. DOI: 10.3389/fonc.2019.00713. View

15.

Delecluse H, Hilsendegen T, Pich D, Zeidler R, Hammerschmidt W . Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A. 1998; 95(14):8245-50. PMC: 20961. DOI: 10.1073/pnas.95.14.8245. View

16.

Chiuppesi F, Nguyen J, Park S, Contreras H, Kha M, Meng Z . Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice. J Virol. 2018; 92(19). PMC: 6146800. DOI: 10.1128/JVI.01012-18. View

17.

Sokal E, Hoppenbrouwers K, Vandermeulen C, Moutschen M, Leonard P, Moreels A . Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2008; 196(12):1749-53. DOI: 10.1086/523813. View

18.

Hjerrild K, Jin J, Wright K, Brown R, Marshall J, Labbe G . Production of full-length soluble Plasmodium falciparum RH5 protein vaccine using a Drosophila melanogaster Schneider 2 stable cell line system. Sci Rep. 2016; 6:30357. PMC: 4960544. DOI: 10.1038/srep30357. View

19.

Cui X, Cao Z, Sen G, Chattopadhyay G, Fuller D, Fuller J . A novel tetrameric gp350 1-470 as a potential Epstein-Barr virus vaccine. Vaccine. 2013; 31(30):3039-45. PMC: 3700395. DOI: 10.1016/j.vaccine.2013.04.071. View

20.

Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti J, Lanzavecchia A . Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004; 304(5667):104-7. DOI: 10.1126/science.1093933. View