刚地弓形虫病多表位疫苗的研究进展

doi:10.12140/j.issn.1000-7423.2022.05.015

摘要/Abstract

摘要：

刚地弓形虫可感染几乎所有温血动物,引起人兽共患弓形虫病。尽管弓形虫病疫苗的研发已取得很大进展,但目前仍无预防人类弓形虫病的疫苗。研究发现,只用一种或几种候选抗原仅能诱导对弓形虫的部分保护性免疫,这限制了它们的应用。因此,利用速殖子、缓殖子和子孢子的多种抗原表位,开发由寄生虫生活史各个阶段组成的多价疫苗可能是完全保护性免疫所必需的。选用寄生虫生活史不同阶段的多表位组合已成为获得安全和有效疫苗的最佳策略。基于多表位的疫苗因其诱导保护性免疫应答能力强而作为新的疫苗候选物受到关注。本文概述了多表位疫苗的免疫学基础、设计与构建策略,总结了弓形虫多表位疫苗的最新研究进展,并展望了多表位疫苗作为一种新的疫苗开发和评估策略的应用前景。

关键词: 弓形虫病, B细胞和T细胞表位, 多表位疫苗, 抗原表位

Abstract:

Toxoplasma gondii infects almost all warm-blooded animals causing toxoplasmosis in humans and animals. Despite the significant progress in the recent efforts toward developing an effective vaccine against toxoplasmosis, no human vaccines are available to prevent this disease. However, vaccines based on a single or a few antigen candidates was only able to elicit partial protective immunity against T. gondii infection. Therefore, developing a polyvalent vaccine consisting of antigens from all stages of the parasite life cycle, including tachyzoites, bradyzoites, and sporozoites, is likely to be essential for sterile immunity. The combination of multi-epitopes from antigens of different stages of the parasite life cycle has become an promising strategy for building a potent, safe, and effective vaccine. Epitope-based vaccines have gained attention as novel vaccine candidates due to their ability of inducing protective immune responses. In this review, we have summarized the immunological basis, design, and construction strategy of epitope vaccines. We have reviewed the latest research advances of T. gondii epitope vaccines, and the application prospect of epitope vaccines as a new vaccine development and evaluation strategy.

Key words: Toxoplasmosis, B- and T-cell epitopes, Multi-epitope vaccine, Antigenic epitope

中图分类号:

R531.8

李润花, 殷国荣. 刚地弓形虫病多表位疫苗的研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(5): 661-667.

LI Run-hua, YIN Guo-rong. Research advances of multi-epitope vaccine candidates against toxoplasmosis[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2022, 40(5): 661-667.

图/表 2

参考文献 61

[1]	Dubey JP. History of the discovery of the life cycle of Toxoplasma gondii[J]. Int J Parasitol, 2009, 39(8): 877-882. pmid: 19630138
[2]	Barros M,, Teixeira D,, Vilanova M, et al. Vaccines in congenital toxoplasmosis: advances and perspectives[J]. Front Immunol, 2021, 11: 621997. doi: 10.3389/fimmu.2020.621997
[3]	Csep A,, Vaida LL,, Negruţiu BM, et al. Research on demographic, clinical and paraclinical aspects in pregnant women infected with Toxoplasma gondii[J]. Exp Ther Med, 2022, 23(2): 123. doi: 10.3892/etm.2021.11046
[4]	Hajissa K,, Zakaria R,, Suppian R, et al. An evaluation of a recombinant multiepitope based antigen for detection of Toxoplasma gondii specific antibodies[J]. BMC Infect Dis, 2017, 17(1): 807. doi: 10.1186/s12879-017-2920-9 pmid: 29284420
[5]	Lakhrif Z,, Moreau A,, Hérault B, et al. Targeted delivery of Toxoplasma gondii antigens to dendritic cells promote immunogenicity and protective efficiency against toxoplasmosis[J]. Front Immunol, 2018, 9: 317. doi: 10.3389/fimmu.2018.00317 pmid: 29515595
[6]	Zhang ZC,, Li YH,, Wang MY, et al. Immune protection of rhoptry protein 21 (ROP21) of Toxoplasma gondii as a DNA vaccine against toxoplasmosis[J]. Front Microbiol, 2018, 9: 909. doi: 10.3389/fmicb.2018.00909
[7]	Liu Y,, Cao AP,, Li YW, et al. Immunization with a DNA vaccine encoding Toxoplasma gondii Superoxide dismutase (TgSOD) induces partial immune protection against acute toxoplasmosis in BALB/c mice[J]. BMC Infect Dis, 2017, 17(1): 403. doi: 10.1186/s12879-017-2507-5
[8]	Li YW,, Zhou HY. Moving towards improved vaccines for Toxoplasma gondii[J]. Expert Opin Biol Ther, 2018, 18(3): 273-280. doi: 10.1080/14712598.2018.1413086
[9]	Chu KB,, Quan FS. Advances in Toxoplasma gondii vaccines: current strategies and challenges for vaccine development[J]. Vaccines (Basel), 2021, 9(5): 413.
[10]	Hiszczyńska-Sawicka E,, Gatkowska JM,, Grzybowski MM, et al. Veterinary vaccines against toxoplasmosis[J]. Parasitology, 2014, 141(11): 1365-1378. doi: 10.1017/S0031182014000481 pmid: 24805159
[11]	Zhou CX,, Zhou DH,, Liu GX, et al. Transcriptomic analysis of porcine PBMCs infected with Toxoplasma gondii RH strain[J]. Acta Trop, 2016, 154: 82-88. doi: 10.1016/j.actatropica.2015.11.009
[12]	Cong H,, Yuan Q,, Zhao QL, et al. Comparative efficacy of a multi-epitope DNA vaccine via intranasal, peroral, and intramuscular delivery against lethal Toxoplasma gondii infection in mice[J]. Parasit Vectors, 2014, 7: 145. doi: 10.1186/1756-3305-7-145 pmid: 24685150
[13]	Foroutan M,, Ghaffarifar F. Calcium-dependent protein kinases are potential targets for Toxoplasma gondii vaccine[J]. Clin Exp Vaccine Res, 2018, 7(1): 24-36. doi: 10.7774/cevr.2018.7.1.24
[14]	Cong H,, Gu QM,, Yin HE, et al. Multi-epitope DNA vaccine linked to the A2/B subunit of cholera toxin protect mice against Toxoplasma gondii[J]. Vaccine, 2008, 26(31): 3913-3921. doi: 10.1016/j.vaccine.2008.04.046 pmid: 18555564
[15]	Cheong FW,, Fong MY,, Lau YL. Identification and characterization of epitopes on Plasmodium knowlesi merozoite surface protein-142 (MSP-142) using synthetic peptide library and phage display library[J]. Acta Trop, 2016, 154: 89-94. doi: 10.1016/j.actatropica.2015.11.005 pmid: 26624919
[16]	Stoloff GA,, Caparros-Wanderley W. Synthetic multi-epitope peptides identified in silico induce protective immunity against multiple influenza serotypes[J]. Eur J Immunol, 2007, 37(9): 2441-2449. pmid: 17668898
[17]	Alonso-Padilla J,, Lafuente EM,, Reche PA. Computer-aided design of an epitope-based vaccine against Epstein-Barr virus[J]. J Immunol Res, 2017, 2017: 9363750.
[18]	Thompson CP,, Lourenço J,, Walters AA, et al. A naturally protective epitope of limited variability as an influenza vaccine target[J]. Nat Commun, 2018, 9(1): 3859. doi: 10.1038/s41467-018-06228-8 pmid: 30242149
[19]	Huang SY,, Jensen MR,, Rosenberg CA, et al. In silico and in vivo analysis of Toxoplasma gondii epitopes by correlating survival data with peptide-MHC-I binding affinities[J]. Int J Infect Dis, 2016, 48: 14-19. doi: 10.1016/j.ijid.2016.04.014
[20]	Palatnik-de-Sousa CB,, Soares IS,, Rosa DS. Editorial: epitope discovery and synthetic vaccine design[J]. Front Immunol, 2018, 9: 826. doi: 10.3389/fimmu.2018.00826 pmid: 29720983
[21]	Ma FS,, Zhang L,, Wang Y, et al. Advance on prediction methods of B-cell antigen epitope[J]. China Animal Husb Vet Med, 2016, 43(1): 63-67. (in Chinese)
	( 马凡舒,, 张蕾,, 王洋, 等. B细胞抗原表位预测方法的研究进展[J]. 中国畜牧兽医, 2016, 43(1): 63-67.)
[22]	Hajissa K,, Zakaria R,, Suppian R, et al. Epitope-based vaccine as a universal vaccination strategy against Toxoplasma gondii infection: a mini-review[J]. J Adv Vet Anim Res, 2019, 6(2): 174-182. doi: 10.5455/javar.2019.f329
[23]	Pulendran B,, Ahmed R. Immunological mechanisms of vaccination[J]. Nat Immunol, 2011, 12(6): 509-517. doi: 10.1038/ni.2039 pmid: 21739679
[24]	Bastos LM,, Macêdo AG Jr,, Silva MV, et al. Toxoplasma gondii-derived synthetic peptides containing B-and T-cell epitopes from GRA2 protein are able to enhance mice survival in a model of experimental toxoplasmosis[J]. Front Cell Infect Microbiol, 2016, 6: 59.
[25]	Hajissa K,, Zakaria R,, Suppian R, et al. Immunogenicity of multiepitope vaccine candidate against Toxoplasma gondii infection in BALB/c mice[J]. Iran J Parasitol, 2018, 13(2): 215-224. pmid: 30069205
[26]	Zhang TE,, Yin LT,, Li RH, et al. Protective immunity induced by peptides of AMA1, RON2 and RON4 containing T-and B-cell epitopes via an intranasal route against toxoplasmosis in mice[J]. Parasit Vectors, 2015, 8: 15. doi: 10.1186/s13071-015-0636-5
[27]	Dodangeh S,, Fasihi-Ramandi M,, Daryani A, et al. Protective efficacy by a novel multi-epitope vaccine, including MIC3, ROP8, and SAG1, against acute Toxoplasma gondii infection in BALB/c mice[J]. Microb Pathog, 2021, 153: 104764. doi: 10.1016/j.micpath.2021.104764
[28]	Shi JD,, Zhang J,, Li SJ, et al. Epitope-based vaccine target screening against highly pathogenic MERS-CoV: an in silico approach applied to emerging infectious diseases[J]. PLoS One, 2015, 10(12): e0144475. doi: 10.1371/journal.pone.0144475
[29]	Patronov A,, Doytchinova I. T-cell epitope vaccine design by immunoinformatics[J]. Open Biol, 2013, 3(1): 120139. doi: 10.1098/rsob.120139
[30]	Correia BE,, Bates JT,, Loomis RJ, et al. Proof of principle for epitope-focused vaccine design[J]. Nature, 2014, 507(7491): 201-206. doi: 10.1038/nature12966
[31]	Zhou J,, Wang L,, Lu G, et al. Epitope analysis and protection by a ROP19 DNA vaccine against Toxoplasma gondii[J]. Parasite, 2016, 23: 17. doi: 10.1051/parasite/2016017
[32]	Lu G,, Wang L,, Zhou AH, et al. Epitope analysis, expression and protection of SAG5A vaccine against Toxoplasma gondii[J]. Acta Trop, 2015, 146: 66-72. doi: 10.1016/j.actatropica.2015.03.013
[33]	Mahajan B,, Berzofsky JA,, Boykins RA, et al. Multiple antigen peptide vaccines against Plasmodium falciparum malaria[J]. Infect Immun, 2010, 78(11): 4613-4624. doi: 10.1128/IAI.00533-10 pmid: 20823210
[34]	Khan AM,, Miotto O,, Heiny AT, et al. A systematic bioinformatics approach for selection of epitope-based vaccine targets[J]. Cell Immunol, 2006, 244(2): 141-147. pmid: 17434154
[35]	Moise L,, Gutierrez A,, Kibria F, et al. iVAX: an integrated toolkit for the selection and optimization of antigens and the design of epitope-driven vaccines[J]. Hum Vaccin Immunother, 2015, 11(9): 2312-2321. doi: 10.1080/21645515.2015.1061159
[36]	de Groot AS,, Moise L,, Terry F, et al. Better epitope discovery, precision immune engineering, and accelerated vaccine design using immunoinformatics tools[J]. Front Immunol, 2020, 11: 442. doi: 10.3389/fimmu.2020.00442 pmid: 32318055
[37]	Zhang NZ,, Chen J,, Wang M, et al. Vaccines against Toxoplasma gondii: new developments and perspectives[J]. Expert Rev Vaccines, 2013, 12(11): 1287-1299. doi: 10.1586/14760584.2013.844652
[38]	Muñoz-Medina JE,, Sánchez-Vallejo CJ,, Méndez-Tenorio A, et al. In silico identification of highly conserved epitopes of influenza A H1N1, H2N2, H3N2, and H5N1 with diagnostic and vaccination potential[J]. Biomed Res Int, 2015, 2015: 813047.
[39]	Sahay B,, Nguyen CQ,, Yamamoto JK. Conserved HIV epitopes for an effective HIV vaccine[J]. J Clin Cell Immunol, 2017, 8(4): 518.
[40]	Comber JD,, Karabudak A,, Shetty V, et al. MHC class Ⅰ presented T cell epitopes as potential antigens for therapeutic vaccine against HBV chronic infection[J]. Hepat Res Treat, 2014, 2014: 860562.
[41]	Ramana J,, Mehla K. Immunoinformatics and epitope prediction[J]. Methods Mol Biol, 2020, 2131: 155-171. doi: 10.1007/978-1-0716-0389-5_6 pmid: 32162252
[42]	Forouharmehr A. Engineering an efficient poly-epitope vaccine against Toxoplasma gondii infection: a computational vaccinology study[J]. Microb Pathog, 2021, 152: 104646. doi: 10.1016/j.micpath.2020.104646
[43]	Parvizpour S,, Pourseif MM,, Razmara J, et al. Epitope-based vaccine design: a comprehensive overview of bioinformatics approaches[J]. Drug Discov Today, 2020, 25(6): 1034-1042. doi: S1359-6446(20)30113-6 pmid: 32205198
[44]	Ip PP,, Nijman HW,, Daemen T. Epitope prediction assays combined with validation assays strongly narrows down putative cytotoxic T lymphocyte epitopes[J]. Vaccines (Basel), 2015, 3(2): 203-220.
[45]	Agallou M,, Athanasiou E,, Koutsoni O, et al. Experimental validation of multi-epitope peptides including promising MHC class Ⅰ- and Ⅱ-restricted epitopes of four known Leishmania infantum proteins[J]. Front Immunol, 2014, 5: 268. doi: 10.3389/fimmu.2014.00268 pmid: 24959167
[46]	Saha S,, Raghava GPS. Prediction of continuous B-cell epitopes in an antigen using recurrent neural network[J]. Proteins, 2006, 65(1): 40-48. doi: 10.1002/prot.21078
[47]	Javadi Mamaghani A,, Fathollahi A,, Spotin A, et al. Candidate antigenic epitopes for vaccination and diagnosis strategies of Toxoplasma gondii infection: a review[J]. Microb Pathog, 2019, 137: 103788. doi: 10.1016/j.micpath.2019.103788
[48]	Sette A,, Fikes J. Epitope-based vaccines: an update on epitope identification, vaccine design and delivery[J]. Curr Opin Immunol, 2003, 15(4): 461-470. pmid: 12900280
[49]	Xu QQ,, Ma XJ,, Wang FK, et al. Design and construction of a chimeric multi-epitope gene as an epitope-vaccine strategy against ALV-J[J]. Protein Expr Purif, 2015, 106: 18-24. doi: 10.1016/j.pep.2014.10.007
[50]	Parmiani G,, Russo V,, Maccalli C, et al. Peptide-based vaccines for cancer therapy[J]. Hum Vaccin Immunother, 2014, 10(11): 3175-3178. doi: 10.4161/hv.29418
[51]	Li MD,, Kaminskas LM,, Marasini N. Recent advances in nano/microparticle-based oral vaccines[J]. J Pharm Investig, 2021, 51(4): 425-438. doi: 10.1007/s40005-021-00537-9
[52]	El Bissati K,, Zhou Y,, Dasgupta D, et al. Effectiveness of a novel immunogenic nanoparticle platform for Toxoplasma peptide vaccine in HLA transgenic mice[J]. Vaccine, 2014, 32(26): 3243-3248. doi: 10.1016/j.vaccine.2014.03.092 pmid: 24736000
[53]	Bissati KE,, Chentoufi AA,, Krishack PA, et al. Adjuvanted multi-epitope vaccines protect HLA-A11: 01 transgenic mice against Toxoplasma gondii*[J]. JCI Insight, 2016, 1(15): e85955.
[54]	Wang YH,, Wang M,, Wang GX, et al. Increased survival time in mice vaccinated with a branched lysine multiple antigenic peptide containing B- and T-cell epitopes from T. gondii antigens[J]. Vaccine, 2011, 29(47): 8619-8623. doi: 10.1016/j.vaccine.2011.09.016
[55]	Cao AP,, Liu Y,, Wang JJ, et al. Toxoplasma gondii: vaccination with a DNA vaccine encoding T- and B-cell epitopes of SAG1, GRA2, GRA7 and ROP16 elicits protection against acute toxoplasmosis in mice[J]. Vaccine, 2015, 33(48): 6757-6762. doi: 10.1016/j.vaccine.2015.10.077 pmid: 26518401
[56]	Blanchard N,, Gonzalez F,, Schaeffer M, et al. Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum[J]. Nat Immunol, 2008, 9(8): 937-944. doi: 10.1038/ni.1629 pmid: 18587399
[57]	Sun XM,, Zou J,, Elashram Saeed AA, et al. DNA vaccination with a gene encoding Toxoplasma gondii GRA6 induces partially protection in BALB/c mice with an H-2Ld allele[J]. Parasit Vectors, 2011, 4: 213. doi: 10.1186/1756-3305-4-213
[58]	Foroutan M,, Ghaffarifar F,, Sharifi Z, et al. Vaccination with a novel multi-epitope ROP8 DNA vaccine against acute Toxoplasma gondii infection induces strong B and T cell responses in mice[J]. Comp Immunol Microbiol Infect Dis, 2020, 69: 101413. doi: 10.1016/j.cimid.2020.101413
[59]	Foroutan M,, Barati M,, Ghaffarifar F. Enhancing immune responses by a novel multi-epitope ROP8 DNA vaccine plus interleukin-12 plasmid as a genetic adjuvant against acute Toxoplasma gondii infection in BALB/c mice[J]. Microb Pathog, 2020, 147: 104435. doi: 10.1016/j.micpath.2020.104435
[60]	Khodadadi M,, Ghaffarifar F,, Dalimi A, et al. Immunogenicity of in-silico designed multi-epitope DNA vaccine encoding SAG1, SAG3 and SAG5 of Toxoplasma gondii adjuvanted with CpG-ODN against acute toxoplasmosis in BALB/c mice[J]. Acta Trop, 2021, 216: 105836. doi: 10.1016/j.actatropica.2021.105836
[61]	Guo JJ,, Zhou AH Sun XH, et al. Immunogenicity of a virus-like-particle vaccine containing multiple antigenic epitopes of Toxoplasma gondii against acute and chronic toxoplasmosis in mice[J]. Front Immunol, 2019, 10: 592. doi: 10.3389/fimmu.2019.00592

抗原基因	表位氨基酸序列	氨基酸数	文献
表面抗原1 SAG1	TCPDKKSTA	9	[7]
	KSFKDILPK	9	[14]
	LGPVKLSAEGPT	12	[54]
	TCPDKKSTA	9	[12]
	ILPKLTENPW	10
表面抗原2 SAG2	STFWPCLLR	9	[14]
顶端膜抗原1 AMA1	CAELCDPSNKPGHLL	15	[26]
致密颗粒1 GRA1	DTMKSMQRDED	11	[12]
致密颗粒2 GRA2	TAAKTHTVRGFKV	13	[54]
致密颗粒4 GRA4	SGLTGVKDS	9	[12]
致密颗粒5 GRA5	AVVSLLRLLK	10	[14]
致密颗粒6 GRA6	AMLTAFFLR	9	[14]
	HPGSVNEFDF	10	[56-57]
致密颗粒7 GRA7	SYFAADRLVP	10	[54]
棒状体蛋白2 ROP2	GDVVIEELFNRIPETS	16	[12]
棒状体颈部蛋白2 RON2	LTAGGPLPHGSWSWSGTPPEVQTTGGSQIS	30	[26]
棒状体颈部蛋白4 RON4	KEQFFQFLQHLSADYPKQVQTVYEFLGWVADK	32