Table 1.

Summary of prophylactic EBV vaccines.

Platform/Antigen/Adjuvant	Animal/ Clinical trial	Published year	Results
1. EBV envelope protein vaccines
Subunit vaccine, purified full length gp340 from virus, with liposome, Freund’s adjuvant, lipid A	Mice,	1984	Antibody responses were induced (70).
	Cottontop
	tamarins
Subunit vaccine, Purified full length gp340 from virus	Cottontop	1985	Protection against malignant lymphoma (151).
	tamarins
Subunit vaccine, purified gp350/gp220 from yeast and mammalian cells	Rabbits	1988	EBV-specific neutralizing antibodies were induced (152).
Subunit vaccine, purified gp340, incorporated into immune-stimulating complexes	Cottontop	1988	Protection against malignant lymphoma (153).
	tamarins
Subunit vaccine, recombinant gp340 adjuvanted with Alum	Cottontop	1994	Protection of 3/5 cottontop tamarins against malignant lymphoma (154).
	tamarins
Subunit vaccine, recombinant single chain gp350 with Freund’s adjuvant versus Alum	Rabbits	1999	High titers of neutralizing antibody elicited (155).
Subunit vaccine, recombinant single chain gp350 with AS04 versus alum	Phase II	2007	Induced neutralizing antibodies in 70% of human subjects, and decreased IM by 78% (156).
Subunit vaccine, recombinant tetrameric versus monomeric gp3501-470 adjuvanted with alum/CpG-ODN	Mice	2013	Tetrameric gp350 induced ∼20- fold higher titers of IgG and >19-fold higher neutralizing titers at the highest dose (157).
Subunit vaccine, self- assembling nanoparticles expressing gp3501-123	Mice	2015	gp350-nanoparticle elicited 10- to 100-fold higher neutralizing titers compared to soluble gp350 (158).
Subunit vaccine, recombinant monomeric gH/gL, trimeric gH/gL and trimeric gB, adjuvanted with alum/CpG-ODN	Rabbits	2016	Trimeric and monomeric gH/gL, trimeric gB, and tetrameric gp350 induced EBV-neutralizing titers >100-, 20-, 18-, and 4-fold higher, respectively, than monomeric gp350 (159).
Subunit vaccine, Fc-fused gp350 dimer with Alum	Mice	2018	Elicited significantly higher neutralizing titers than gp350 monomer (160).
Subunit vaccine, self-assembling nanoparticles expressing gH/gL or gH/gL/gp42 with SAS adjuvant	Mice, cynomolgus macaques	2019	gH/gL and gH/gL/gp42-ferritin nanoparticles elicited >40- and ~4-fold higher neutralization titers for B cells in monkeys compared with soluble proteins; for epithelial cells, >25- and ~4-fold higher neutralizing titers were elicited. (161).
Subunit vaccine, recombinant trimeric gB, monomeric gH/gL and their combination, adjuvanted with alum/CpG-ODN	Rabbits, humanized mice	2021	Sera from rabbits immunized trimeric gB or monomeric gH/gL protected humanized mice from lethal dose EBV challenge and markedly decreased EBV loads. Immunization with the combination of gB and gH/gL elicited strong synergistic neutralizing activity (162).
2. EBV Virus-Like particle (VLP) vaccines
EBV-derived VLP, produced via the deletion of the EBV terminal repeats, EBNA2, EBNA 3A, 3B and 3C, LMP1 and BZLF1	Mice	2011	EBV-specific humoral and cellular immune responses were induced (163).
EBV-derived VLP, produced by fusing EBNA1 and EBNA3C to the major tegument protein BNRF1	Humanized mice	2018	Potent CD4+ T cell responses elicited, and EBV loads were reduced (164).
Newcastle disease virus (NDV) VLP, expressing gp350/220 Ectodomain	Mice	2015	Elicited neutralizing antibody responses, but not higher than that of soluble gp350/220 (165).
NDV VLP, expressing gH/gL-EBNA1 or gB-LMP2	Mice	2017	Elicited EBV-specific T-cell responses and higher EBV neutralizing titers (166).
3. Synthesized mRNA EBV vaccines
Synthesized mRNA encoding gp350, gB, gH/gL and gp42	Mice	2021	Elicited ~20- and ~100-fold higher neutralizing activities for B cells and epithelial cells respectively compared to human sera.