Multi-Epitope Vaccines: a Promising Strategy Against Tumors and Viral Infections

LETTER TO THE EDITOR

Multi-epitope vaccines: a promising strategy against tumors and viral infections

Lifang Zhang

Cellular & Molecular Immunology (2018) 15, 182–184; doi:10.1038/cmi.2017.92; published online 11 September 2017

mmune responses play a critical role that can induce strong cellular and initially carried out using software from Iin fighting tumors and viral infections. humoral immune responses simulta- the European Bioinformatics Institute An antigenic epitope is a basic unit that neously; (III) they consist of multiple website (http://www.ebi.ac.uk/Tools/ elicits either a cellular or a humoral epitopes from different tumor or virus clustalw2). Then, the structure, hydro- immune response. A multi-epitope vac- antigens that can expand the spectra of philicity and flexibility, and transmem- cine composed of a series of or over- targeted tumors or viruses; (IV) they brane domains of the target antigen are lapping peptides is therefore an ideal introduce some components with adjuvant predicted and analyzed by methods approach for the prevention and treat- capacity that can enhance the immuno- including GOR,16 Hoop and Woods17 ment of tumors or viral infections.1–5 genicity and long-lasting immune and artificial neural network (http:// Although some multi-epitope vaccines responses; and (V) they reduce unwanted strucbio.biologie.uni-konstanz.de). Anti- have entered phase I clinical trials, for components that can trigger either patho- genic propensity value is further evalu- example, EMD640744 in patients with logical immune responses or adverse ated using the Kolaskar and Tongaonkar advanced solid tumors,6 designing effica- effects. Well-designed multi-epitope vac- approach (http://bio.dfci.harvard.edu/ cious multi-epitope vaccines remains a cines with such advantages should become Tools/antigenic.pl). Finally, the B-cell- great challenge. An ideal multi-epitope powerful prophylactic and therapeutic dominant epitope is determined by com- vaccine should be designed to include agents against tumors and viral infections. prehensive analysis and comparison, and fi epitopes that can elicit CTL, Th and B Current problems in the eld of T-cell epitopes including MHC-I restric- cells and induce effective responses multi-epitope vaccine design and devel- tion CTL and MHC-restriction Th epi- against a targeted tumor or virus opment include the selection of appro- topes are predicted using the SYFPEITHI (Figure 1). priate candidate antigens and their network database (http://www.syfpeithi. Compared to classical vaccines and immunodominant epitopes and the de/Scripts/MHCServer.dll/EpitopePredic- single-epitope vaccines, multi-epitope vac- development of an effective delivery tion.htm). All the above-mentioned pro- cines have unique design concepts4–11 with system. Development of a successful grams are provided on the EXPASY fi the following properties: (I) they consist of multi-epitope vaccine rst depends on server (http://www.expasy.org/tools). multiple MHC-restricted epitopes that can the selection of appropriate candidate Recently, we have developed a multi- be recognized by TCRs of multiple clones antigens and their immunodominant epitope vaccine, named EBV LMP2m, from various T-cell subsets; (II) they epitopes. The prediction of appropriate which encodes multiple CTL, Th and B EBV LMP2 11 consist of CTL, Th and B-cell epitopes antigenic epitopes of a target protein by epitopes from the gene. immunoinformatic methods is extremely Expression of the recombinant multi- Department of Microbiology and Immunology, important for designing a multi-epitope epitope protein from the constructed Institute of Molecular Virology and Immunology, vaccine.12,13 In our laboratory, we always multi-epitope vaccine gene was opti- Wenzhou Medical University, Wenzhou 325035, use immunoinformatic tools to predict mized to maximize its production in E. China coli fi Correspondence: Professor L Zhang, Department and screen the immunogenic T- and . The speci c CTL and Th cell reac- of Microbiology and Immunology, Institute of B-cell epitopes of the target antigens, tions and B-cell activation (serum-speci- Molecular Virology and Immunology, Wenzhou then design peptides rich in epitopes or fic IgG and mucosal IgA antibodies) Medical University, Wenzhou 325035, China. 7,8,11,14,15 E-mail: [email protected] overlapping epitopes. For the were analyzed in BALB/c mice Received: 22 July 2017; Accepted: 1 August prediction of B-cell epitopes, multiple immunized with the multi-epitope 2017 alignments of the target antigen are vaccine. The multi-epitope-specificserum Multi-epitope vaccines LZhang

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Figure 1 The molecular and cellular mechanism of immune responses induced by a multi-epitope vaccine. Multi-epitope vaccines can be composed of CTL, Th and B-cell epitopes in a series or overlapping epitope peptides. Through TCR, CD8+ precursor CTL (CD8+ pCTL) recognizes the complex of CTL antigen peptides bound to MHC class I molecules that are displayed by target cells (tumor cells or virus- infected cells). Antigen presenting cells (APC) take up the multi-epitope vaccine and present the Th antigen peptides bound to MHC class II molecules to Th0 cells. Th0 cells are differentiated into Th1, Th2 and CD4+ CTL cells. Th1 cells secrete cytokines that stimulate CD8+ pCTL to generate effector CTL cells, the latter of which will kill the target cells by both the perforin/granzyme and the Fas/FasL pathways. Th2 cells recognize the Th epitope bound to MHC class II molecules that are presented by B cells. After being activated, Th2 cells express CD40L molecules and secrete cytokines to stimulate B-cell activation; CD4+ CTL cells secrete cytotoxins, directly killing the target cells by releasing granules containing perforin and granzyme B. B cells recognize and take up the B epitopes of the multi-epitope vaccine by BCR, presenting the Th epitopes bound to MHC class II molecules to activate Th2 cells. The B cells then proliferate and differentiate into plasma cells after binding to the CD40L molecules and cytokines provided by activated Th2 cells. The plasma cells secrete multi-epitope vaccine-speciﬁc antibodies to perform anti-tumor or anti-virus tasks in target cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). antibodies in patients with EBV-related and western blotting. All the analyses immunogenicity. Therefore, EBV LMP2m tumors (nasopharyngeal carcinoma) or demonstrated that the multi-epitope vac- could be considered as a potential vaccine EBV infection were analyzed using ELISA cine EBV LMP2m had a very high candidate and diagnostic agent.

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The successful immunotherapy of a challenges and opportunities. Immunother- 11 Lin X, Chen S, Xue X, Lu L, Zhu S, Li W et al. – multi-epitope vaccine is also associated apy 2017; 9:361 371. Chimerically fused antigen rich of 3 Kuo T, Wang C, Badakhshan T, Chilukuri S, overlapped epitopes from latent membrane with an effective vaccine delivery system. BenMohamed L. The challenges and oppor- protein 2 (LMP2) of Epstein-Barr At present, both virus-like particles tunities for the development of a T-cell virus as a potential vaccine and (VLPs)7,8,14 and nanoparticles18,19 have epitope-based herpes simplex vaccine. Vac- diagnostic agent. Cell Mol Immunol 2016; cine 2014; 32:6733–6745. – been used as vehicles for delivering 13:492 501. 4 He R, Yang X, Liu C, Chen X, Wang L, 12 Yin D, Li L, Song X, Li H, Wang J, Ju W et al. multi-epitope vaccines. We have used Xiao M et al. Efficient control of A novel multi-epitope recombined protein for two types of VLPs: hepatitis B core antigen chronic LCMV infection by a CD4 T cell diagnosis of human brucellosis. BMC Infect (HBcAg)-VLPs and hepatitis B surface epitope-based heterologous prime-boost Dis 2016; 16:219. vaccination in a murine model. Cell Mol 13 Cherryholmes GA, Stanton SE, Disis ML. antigen (HBsAg)-VLPs. Our data have Immunol 2017; e-pub ahead of print 13 Current methods of epitope identification shownthateitherHBcAgorHBsAg- March 2017; doi:10.1038/cmi. for cancer vaccine design. Vaccine 2015; 5 Lu IN, Farinelle S, Sausy A, Muller CP. 33:7408–7414. VLPs multi-epitope vaccines strongly elicit Identification of a CD4 T-cell epitope in the specifically humoral and cellular immune 14 Jiang P, Du W, Xiong Y, Lv Y, Feng J, Zhu S hemagglutinin stalk domain of pandemic et al. Hepatitis B virus core antigen as a fl responses and generate vigorous immune H1N1 in uenza virus and its antigen-driven carrier for Chlamydia trachomatis MOMP responses of the individual epitopes car- TCR usage signature in BALB/c mice. Cell multi-epitope peptide enhances protection 14 – 7,8,14 Mol Immunol 2017; :511 520. against genital chlamydial infection. Onco- ried by the multi-epitope vaccine. 6 Lennerz V, Gross S, Gallerani E, Sessa C, target 2015; 6:43281–43292. Mach N, Boehm S et al. Immunologic In summary, multi-epitope vaccines 15 Shen X, Jin J, Ding Y, Wang P, Wang A, response to the survivin-derived multi-epi- can be considered as a promising strategy Xiao D et al. Novel immunodominant epitope vaccine EMD640744 in patients with topes derived from MAGE-A3 and its signifi- against tumors and viral infections. advanced solid tumors. Cancer Immunol cance in serological diagnosis of Immunoinformatics methods can help Immunother 2014; 63:381–394. 7 Jiang P, Cai Y, Chen J, Ye X, Mao S, Zhu S gastric cancer. J Cancer Res Clin Oncol to predict and screen appropriate epitopes 2013; 139:1529–1538. fi et al. Evaluation of tamdem Chlamydia tra- for designing an ef cacious multi-epitope chomatis MOMP multi-epitopes vaccine in 16 Garnier J, Gibrat JF, Robson B. GOR method vaccine. Both VLPs and nanoparticles BALB/c mice model. Vaccine 2017; 35: for predicting protein secondary structure used for delivering a multi-epitope vac- 3096–3103. from amino acid sequence. Methods Enzy- mol 1996; 266:540–553. cine could increase its immunogenicity. 8 Zhu S, Feng Y, Rao P, Xue X, Chen S, Li W et al. Hepatitis B virus surface antigen as 17 Hoop TP, Woods KR. Prediction of antigenic delivery vector can enhance Chlamydia tra- determinants from amino acid sequences. CONFLICT OF INTEREST chomatis MOMP multi-epitope immune Proc Natl Acad Sci USA 1981; 78: – Theauthordeclaresnoconflict of interest. response in mice. Appl Microbiol Biotechnol 3824 3828. 2014; 98:4107–4117. 18 Kuai R, Ochyl LJ, Bahjat KS, Schwendeman 9 Saadi M, Karkhah A, Nouri HR. Development A, Moon JJ. Designer vaccine nanodiscs for of a multi-epitope peptide vaccine inducing personalized cancer immunotherapy. Nat robust T cell responses against brucellosis Mater 2017; 16:489–496. 1 Buonaguro L. HEPAVAC consortium. Devel- using immunoinformatics based approaches. 19 Alipour Talesh G, Ebrahimi Z, Badiee A, opments in cancer vaccines for hepatocellu- Infect Genet Evol 2017; 51:227–234. Mansourian M, Attar H, Arabi L et al. Poly lar carcinoma. Cancer Immunol Immunother 10 Lu C, Meng S, Jin Y, Zhang W, Li Z, Wang F (I:C)-DOTAP cationic nanoliposome contain- 2016; 65:93–99. et al. A novel multi-epitope vaccine from ing multi-epitope HER2-derived peptide pro- 2 Brennick CA, George MM, Corwin WL, MMSA-1 and DKK1 for multiple myeloma motes vaccine-elicited anti-tumor immunity Srivastava PK, Ebrahimi-Nik H. Neoepitopes immunotherapy. Br J Haematol 2017; 178: in a murine model. Immunol Lett 2016; as cancer immunotherapy targets: key 413–426. 176:57–64.

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