Advances in the study of HLA-restricted epitope vaccines

Figures & data

Table 1. HLA-restricted epitope vaccines against cancer

Protein	Epitope	Adjuvant	Patients/Animals	Methods	Results	Ref.
MUC1	CT3–27(CQCRRKNYGQ LDIFPARDTY HPMSEYPTYH)(#1) CT18–49(HPMSEYPTYH THGRYVPPSS TDRSPYEKVS AG)(#2) CT37–69(STDRSPYEKV SAGNGGSSLS YTNPAVAAAS ANL)(#3) MUC1 TR (PDTRPAPGST APPAHGVTSA)	GM-CSF	transgenic mice for human MUC1 (MUC1.Tg)	The mice was injected with a combination of 50μg of peptide#1, 50μg of peptide #2, and 50μg of peptide #3 in a total volume of 100μl.	survival can be significantly prolonged in vaccinated MUC1.Tg mice challenged with MUC1-expressing tumor cells, without induction of autoimmune responses	37
CEA	CEA625–667	aluminum hydroxide gel	Female BALB/c mice	Mice were immunized intramuscularly with 100μg of pcDNA3.0, pcDNA-CEA625–667, or pcDNA-triCEA625–667 in 1:1 (v/v) of 3% aluminum hydroxide gel, respectively.	Induced strong antigen-specific T cell proliferation. Triple-repeated CEA peptides vaccine significantly elevated levels of IFN-γsecreted by T cells	39
MAGE	MAGE-A3112–120 (KVAELVHFL) MAGE-A3271–279 (FLWGPRALV)		HLA-A*0201 transgenic mice	Mice were immunized at the base of the tail with 100 mg of MAGE-A3112–120 (KVAELVHFL) or MAGE-A3 271–279 (FLWGPRALV) plus 120 mg of hepatitis B virus core	generate high-avidity TCRs against MAGE-A3.	43
	MAGE-1 peptide (EADPTGHSY)		HLA-A1 positive and melanoma cells expressed the MAGE-1 peptide, (EADPTGHSY) patients.	Four monthly intradermal injections of increasing numbers of peptide-pulsed APCs (l0^5^, 5 × l0,^5 10^6, and 10^7cells) for the four consecutive injections.	Induced autologous melanoma-reactive and peptide-specific cellular CTL response.	54
	MAGE-A4278–299 (ALAETSYVKV LEHVVRVNAR VR) MAGE-A4143–154 (NYKRCFPVIF GK)	OK432 Montanide ISA-51	pulmonary metastatic colon cancer patients.	The patient was vaccinated with 1 or 10 mg MAGE-A4-H/K-HELP mixed with OK432 (0.02KE) and Montanide ISA-51 four times at 2-week intervals	Induced MAGE-A4-specific Th1 and T-cell 1 immune responses and the production of MAGE-A4-specific complement-fixing IgG antibodies. Significantly decreased Tumor growth and carcinoembryonic antigen tumor marker.	55
gp100	gp100 (IMDQVPFSV, 209–217(210 M))	Interleukin-2 Montanide ISA-51	Stage III, IV cutaneous melanoma, expression of HLA-A0201, an absence of brain metastases	Patients were treated with gp100 peptide plus Montanide ISA-51 once every 3 weeks, followed by interleukin-2 intravenous bolus every 8 h.	Compared with interleukin-2 alone, vaccine plus interleukin-2 significantly improved clinical response rate (16% vs. 6%) and progression-free survival (2.2 mo; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 mo; 95% CI, 1.5 to 1.8).	53
HER-2/neu	AE37 (Ac-LRMKGVGSPY VSRLLGICL-NH2, Ii-Key hybrid of HER-2/neu peptide 776–790)	GM-CSF	Disease-free, node-negative breast cancer patients.	Each person received 100 μg, 500 μg or 1000 μg of AE37 peptide mixed with 250 μg, 125 μg, 30 μg or 0 μg GM-CSF inoculations for 6 mo.	The optimal biologic dose (OBD) of the novel AE37 hybrid vaccine: 500 μg of peptide with GM-CSF (30–125 μg) which significantly increased in proliferative responses at long-term follow-up.	57
HER-2/neu	E75 (KIFGSLAFL, HER-2/neu; 369–377)	GM-CSF	Disease-free lymph node-positive (NP), lymph node-negative (NN) and HLA-A2/A3 breast cancer patients,	Patients were vaccinated over 6 mo (3, 4, or 6 times) with different doses of E75 (100 μg, 500 μg, or 1000 μg) plus GM-CSF (250 μg or 125 μg).	Phase I The optimal biologic dose (OBD): 1000 μg E75 plus 250 μg GM-CSF monthly × 6. Phase II 24 mo landmark analysis disease free survival (DFS): Vaccinated group, 94.3%; control group, 86.8%.	59
HER-2/neu	GP2 (IISAVVGIL HER-2/neu, 654–662)	GM-CSF	Disease-free, lymph node-negative and HLA-A2 breast cancer patients	Patients received 100 μg, 500 μg, or 1000 μg of GP2 peptide mixed with 250 μg of GM-CSF.	Elicit an significant immune response .	61

Table 2. Examples of HLA-restricted epitope vaccines in preventing infectious disease

Pathogen	Epitopes	Adjuvant	Patients/Animals	Immunization	Results	Ref.
HIV	Gag433 (FLGKIWPS), Gag150 (T2L, RLLNAWVKV), Vif23 (I9V, SLVKHHMYV), Env67 (V2I, NIWATHACV), Vif101 (M9L, GLADQLIHL), Vpu66 (A9V, ALVEMGHHV) and Pol606 (T9V, KLGKAGYVV)		18–50 y males, HLA-A*0201^+, HIV-1 seropositivity for 1 y or more, no clinical AIDS, never received antiretroviral therapy, and not received any other vaccine or immune-modulating medicine within 3 mo .	Patients received 1 × 10^7 monocyte-derived dendritic cells MDDCs subcutaneously (weeks 0, 2, 4 and 8), pulsed with seven CD8^+ T-cell epitopes and three CD4^+ T-cell epitopes	T-cell responses specific for one or more epitopes were induced in all 12 individuals	63
	EP1043 EP1090		Healthy adults	Patients received EP-1043 only (50 μg or 200 μg), DNA vaccine EP1090 only (4 mg), EP1043 plus EP1090 (200 μg + 4 mg in 4 single injections at 0, 1, 3 and 6 mo.	Sixty-eight percent (32/47) of subjects had a positive CD4+ T response after two vaccinations.	64
Influenza virus	196 influenza H1N1 peptides that contained residues of highly conserved proteome sequences of the human H1N1, H3N2, H1N2, H5N1, and avian influenza A strainss	TiterMax® Gold	HLA-A2(A*0201), A24(A*2402), B7 (B*0702), DR2 (DRB1*1501), DR3 (DRB1*0301), and DR4 (DRB1*0401) transgenic mice	Mice were injected subcutaneously at the base of tail with 100 µl of the immunization peptide pool in TiterMax® Gold adjuvant (1:1).	The most favorable sequences for a T cell epitope-based vaccine are the 17 H1N1 T cell epitopes of the PB1, PB2, and M1 proteins and can induce protective effect against live influenza challenge.	65
	PA130–138, PB1430–438 PB2549–557	CpG-ODN	HLA-A24 transgenic (A24Tg) mice	Mice were immunized with a mixture of peptide-liposome conjugates and CpG-ODN or poly(I:C) (10 µg/mouse) and re-immunized one and two weeks later	More than half of the mice survived lethal influenza virus challenge during both effector and memory CTL phases.	66
HBV	HBx(52–60), HBx(92–100), HBx(115–123), HBx(140–148)		HLA-A*0201 transgenic (HLA-A2.1/^Kb Tg) mice C57BL/6^nu/nu mice	HLA-A2.1/^Kb Tg mice received VLP- or epitope-pulsed DCs. C57BL/6^nu/nu mice which were inoculated subcutaneously with 5 × 10^6 SNU-398 tumor cells received 1 × 10^8 stimulated splenocytes derived from immunized HLA-A2.1/Kb Tg mice.	Induce high immunogenicity and significant antitumor effects.	69
HPV	HPV-16 E712–20 (MLDLQPETT) HPV-16 E786–93 (TLGIVZPI)		HLA-A2 positive women with high-grade cervical or vulvar intraepithelial neoplasia who were positive for HPV 16	Patients received 50 mg of the HPV-16 E7 peptide in aqueous solution injected intradermally in a volume of 100 ml	12 of 18 patients cleared the virus from cervical scrapings by the fourth vaccine injection.	70
Listeriolysin monocytogenes	listeriolysin O (LLO) 91–99 peptide, GYKDGNEYI. H2-K^d-restricted	DCs	BALB/c mice	2 × 10^5 LLO 91–99 peptide-pulsed DCs, intravenously. Two injections with a 1 week interval between them.	Strongly enhanced LLO 91–99-specific CD8^+ T cells exhibiting epitope-specific cytotoxic activity and IFN-γ production. Significantly improved protective immunity against L. monocytogenes.	74
Trypanosoma cruzi	Ibosomal P2 protein (TcP2β). HLA-A*0201-restricted		HLA-A2.1 transgenic mice (HHD mice	pcDNA3-TcP2β or pcDNA3 alone (100 μg) injected into the tibialis anterior muscles Immunized 3 times at 15 d intervals.	Reduced parasitemia after challenge with a lethal T. cruzi dose.	77
Plasmodium falciparum	HLA-A2-restricted MAP-1,MAP-2 and MAP-3 multiple peptide.	Montanide ISA 51	C57BL/6 mice expressing the human HLA-A2 transgene BALB/c, A/J and outbred CD1 mice	20 μg of tetraepitope MAP in 100 μl PBS emulsified in 100 μl Montanide ISA 51 or PBS plus Montanide ISA 51 alone immunized groups of six mice each by three subcutaneous injections delivered at 4-week intervals.	All three MAPs could induce both antibody and cellular responses. MAP-2 vaccines could reduce the growth of blood stage parasites in erythrocyte cultures to various degrees.	78
Toxoplasma gondii	HLA-A02-restricted peptides HLA-A03-restricted peptides HLA-B07-restricted peptides	PARDE GLA-SE Pam2Cys	HLA-A*0201 Kb transgenic mice HLA-A*1101 transgenic mice HLA-B*0702 transgenic mice	50 μg of each peptide was administered per mouse with PARDE,GLA-SE, orPam2Cys. Mice were boosted once or twice in 2 week interval.	Induced splenocytes to produce IFN-γ. Protected mice against challenge with high numbers of Type II parasites	75,76,82

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