Table 4.

Classification of HSV-1-related vaccines.

Class	Name	Building Strategies	Result	Stage	Refs
Live attenuated vaccines	HSV-1 0$\mathrm{\Delta }$NLS	Removal of codons 19 ~ 104 and 489 ~ 694 from the ICP0 gene, lack of the NLS region, and a portion of the C-terminal oligomerization domain of ICP0	Protection against ocular HSV-1 attacks	Mouse model	[161]
			Elicits a strong B-lymphocyte response; maintains vision in the absence of HSV-1 glycoprotein M or thymidine kinase recognition	Mouse model	[162]
	HSV-l 0$\mathrm{\Delta }$RlNG	Removal of codons 19 ~ 162 of the ICP0 gene removes several cysteine residues required for ICP0 E3 ligase activity	Significant short-term efficacy in ocular HSV-1 infection, but poor long-term prophylaxis	Mouse model	[163]
	RVx-201	HSV-2 0ΔNLS Mutation	Fatal HSV-2 genital excitation is extremely protective against HSV-2 reactivation	Guinea pig model	https://rationalvaccines.com/
	R2	Encodes a pUL37 periplasmic protein with a mutation in region 2	Reduces the severity of acute and recurrent HSV-2 disease. Does not cause neurological complications and provides better prophylaxis	Guinea pig model	[164]
	HSV-1-GS6264	Five missense mutations in the gene encoding UL37	HSV cannot invade nerves and prevent HSV infection	Guinea pig model	[165,166]
	VC2	gK aa31-68 and UL20 aa4-22 deletions in recombinant VC2	Protective effect of live attenuated HSV-1 VC2 vaccine against HSV-2 genital infection in a guinea pig model of genital herpes.	Guinea pig model	[167]
			Protective immune responses can be generated at the site of attack to protect against HSV-1-induced ocular pathogenesis	Mouse model	[168]
Subunit vaccine	gB1 vaccine	Delivery of HSV-1 glycoprotein B (gB1) using feline immunodeficiency virus (FIV) vector LAW34	Cross-neutralizing antibodies and cell-mediated responses were elicited, protecting against HSV-1 infection in mice.	Mouse model	[169–172]
	gD-2	HSV-2 glycoprotein D (gD2-AS04) and the adjuvants aluminium hydroxide and 3-o-deacylated monophosphoryl lipid a (MPL)	Effective in preventing HSV-1 genital disease and infection, but not effective in preventing HSV-2 disease or infection	Clinical Phase III	[173]
	GEN-003	gD2/ICP4 + matrix M2 adjuvant	Demonstrates good safety and efficacy in clinical trials and stimulates humoral and cellular immune responses	Clinical Phase III	[174]
	Trivalent subunit vaccine	HSV-2 subunits containing (gC2, gD2 and gE2) + CpG	Neutralizing antibodies and significant CD4+ T-cell responses were produced in rhesus monkeys. Protection against vaginal infections was up to 95 percent in guinea pigs after vaccination.	Rhesus monkey model; Guinea pig model; Clinical Phase I	[175, 16]
Nucleic acid vaccine	Polyvalent DNA vaccine SL-V20	pGX27 with tpa, Flt3L, HSV-2 gB, and UL39; pGX27 with gD2, ICP0, and ICP4; pGX27 with IL-12, IL-21 and MIP-1α	Enhanced antiviral T-cell response; Significant increase in 15-day survival and a significant reduction in vaginal viral load.	Mouse model; Clinical Phase I	[176]
	mRNA vaccine BNT163	Encodes three HSV-2 glycoproteins	Prevention of HSV cell entry and transmission, as well as counteracting the immunosuppressive properties of HSV.	Clinical Phase I	http://www.biontech.de/
	Nucleotide-modified mRNA lipid nanoparticle vaccines	mRNA lipid nanoparticles expressing glycoproteins gC, gD, gE (mRNA-LNP)	Prevents HSV-1 and HSV-2 genital herpes; ability to prevent nHSV in offspring is similar to subunit vaccines; BioNTech to begin Phase I clinicals in 2022.	Mouse model; Guinea pig model; Clinical Phase I	[177, 178]
Replication-deficient vaccine	gH-deficient vaccine	HSV-1 gH coding deletion (SC16∆gH)	Significant reduction in oedema and erythema; Clinical trials were inconclusive	Guinea Pig Model; Clinical trials	[179, 166]
	ΔgD-2	gD2-deficient HSV	Activation of a long-lasting ADCC effect providing active and passive protection against HSV-1 and HSV-2	Mouse Model; Preclinical	[180, 181]