Peptide vaccine

The traditional vaccines are the whole live or fixed pathogens. The second generation of vaccines is mainly the protein purified from the pathogen. The third generation of vaccines is the DNA or plasmid that can express the proteins of the pathogen. Peptide vaccines are the latest step in the evolution of vaccines.{{cite book | vauthors = Schneble E, Clifton GT, Hale DF, Peoples GE | title = Vaccine Design | chapter = Peptide-Based Cancer Vaccine Strategies and Clinical Results | series = Methods in Molecular Biology | volume = 1403 | pages = 797–817 | date = 2016 | pmid = 27076168 | doi = 10.1007/978-1-4939-3387-7_46 | publisher = Springer | isbn = 978-1-4939-3387-7 | place = New York, NY | veditors = Thomas S }}

Compared with the traditional vaccines such as the whole fixed pathogens or protein molecules, the peptide vaccines have several advantages and disadvantages.{{cite journal | vauthors = Skwarczynski M, Toth I | title = Peptide-based synthetic vaccines | journal = Chemical Science | volume = 7 | issue = 2 | pages = 842–854 | date = February 2016 | pmid = 28791117 | pmc = 5529997 | doi = 10.1039/C5SC03892H }}

Advantages:

• The vaccines are fully synthesized by chemical synthesis and can be treated as chemical entity.
• With more advanced solid-phase peptide synthesis (SPPS) using automation and microwave techniques, the production of peptides becomes more efficient.
• The vaccines do not have any biological contamination since they are chemically synthesized.
• The vaccines are water-soluble and can be kept stable under simple conditions.
• The peptides can be specially designed for specificity. A single peptide vaccine can be designed to have multiple epitopes to generate immune responses for several diseases.
• The vaccines only contain a short peptide chain, so they are less like to lead to allergic or auto-immune responses.

Disadvantages:

• Poor immunogenicity.
• Unstable in cells.
• Lack of native conformation.
• Only effective for a limited population.

The whole peptide vaccine is to mimic the epitope of an antigen, so epitope design is the most important stage of vaccine development and requires an accurate understanding of the amino acid sequence of the immunogenic protein interested. The designed epitope is expected to generate strong and long-period immuno-response against the pathogen. The followings are the points to consider when designing the epitope:

• The non-dominant epitope could generate a stronger immune response than the dominant epitope. Ex. The antibodies from people infected by hookworm can recognize the dominant epitope of the antigen called Necator americanus APR-1 protein, but the antibodies can't induce protection against hookworm. However, other non-dominant epitopes on APR-1 protein show the ability to induce the production of neutralizing antibodies against hookworm. Therefore, the non-dominant epitopes are the better candidate for peptide vaccines against hookworm infection.{{cite journal | vauthors = Pearson MS, Pickering DA, Tribolet L, Cooper L, Mulvenna J, Oliveira LM, Bethony JM, Hotez PJ, Loukas A | display-authors = 6 | title = Neutralizing antibodies to the hookworm hemoglobinase Na-APR-1: implications for a multivalent vaccine against hookworm infection and schistosomiasis | journal = The Journal of Infectious Diseases | volume = 201 | issue = 10 | pages = 1561–1569 | date = May 2010 | pmid = 20367477 | doi = 10.1086/651953 | doi-access = free }}
• Take hypersensitivity into consideration. Ex. Some IgE-inducing epitopes cause hypersensitivity reactions after vaccination in humans due to the overlap with IgG epitopes in the Na-ASP-2 protein which is an antigen from hookworm.{{cite journal | vauthors = Diemert DJ, Pinto AG, Freire J, Jariwala A, Santiago H, Hamilton RG, Periago MV, Loukas A, Tribolet L, Mulvenna J, Correa-Oliveira R, Hotez PJ, Bethony JM | display-authors = 6 | title = Generalized urticaria induced by the Na-ASP-2 hookworm vaccine: implications for the development of vaccines against helminths | journal = The Journal of Allergy and Clinical Immunology | volume = 130 | issue = 1 | pages = 169–76.e6 | date = July 2012 | pmid = 22633322 | doi = 10.1016/j.jaci.2012.04.027 | doi-access = free }}
• Some short peptide epitopes need elongating to maintain the native conformation. The elongated sequences can include proper secondary structure. Also, some short peptides can be stabled or cyclized together to maintain the proper conformation. Ex. B-cell epitopes could only have 5 amino acids. To induce an immune response, a sequence from yeast GCN4 protein is used to improve the conformation of the peptide vaccines by forming alpha-helix..{{cite journal | vauthors = Cooper JA, Hayman W, Reed C, Kagawa H, Good MF, Saul A | title = Mapping of conformational B cell epitopes within alpha-helical coiled coil proteins | journal = Molecular Immunology | volume = 34 | issue = 6 | pages = 433–440 | date = April 1997 | pmid = 9307059 | doi = 10.1016/S0161-5890(97)00056-4 }}
• Use adjuvants associated with the epitope to induce the immune response.{{cite journal | vauthors = Azmi F, Ahmad Fuaad AA, Skwarczynski M, Toth I | title = Recent progress in adjuvant discovery for peptide-based subunit vaccines | journal = Human Vaccines & Immunotherapeutics | volume = 10 | issue = 3 | pages = 778–796 | date = March 2014 | pmid = 24300669 | pmc = 4130256 | doi = 10.4161/hv.27332 }}

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• Gp100 peptide vaccine is studied to treat melanoma. To generate a greater in vitro CTL response, the peptide, gp100:209-217(210M), is modified and binds to HLA-A2*0201. After vaccination, more circulating T cells can recognize and kill melanoma cancer cells in vitro.{{cite journal | vauthors = Marincola FM, Rivoltini L, Salgaller ML, Player M, Rosenberg SA | title = Differential anti-MART-1/MelanA CTL activity in peripheral blood of HLA-A2 melanoma patients in comparison to healthy donors: evidence of in vivo priming by tumor cells | journal = Journal of Immunotherapy with Emphasis on Tumor Immunology | volume = 19 | issue = 4 | pages = 266–277 | date = July 1996 | pmid = 8877721 | doi = 10.1097/00002371-199607000-00003 }}
• Rindopepimut is the epidermal growth factor receptor (EGFR)-derived peptide vaccine to treat glioblastoma multiforme (GBM). The 14-mer peptide is coupled with keyhole limpet hemocyanin (KLH), which can reduce the risk of cancer.{{cite journal | vauthors = Neal DE, Sharples L, Smith K, Fennelly J, Hall RR, Harris AL | title = The epidermal growth factor receptor and the prognosis of bladder cancer | journal = Cancer | volume = 65 | issue = 7 | pages = 1619–1625 | date = April 1990 | pmid = 2311071 | doi = 10.1002/1097-0142(19900401)65:7<1619::aid-cncr2820650728>3.0.co;2-q | s2cid = 12449093 | doi-access = free }}
• E75, GP2, and AE37 are three different HER2/neu-derived single-peptide vaccines to treat breast cancer. HER2/neu usually has low expression in healthy tissues. E75 consisting of 9 amino acids is the immunodominant epitope of the HER2 protein. GP2 consisting of 9 amino acids is the subdominant epitope. Both E75 and GP2 stimulate the CD8+ lymphocytes but GP2 has a lower affinity than E75. AE37 stimulates CD4+ lymphocytes.{{cite journal | vauthors = Palatnik-de-Sousa CB, Soares IS, Rosa DS | title = Editorial: Epitope Discovery and Synthetic Vaccine Design | journal = Frontiers in Immunology | volume = 9 | pages = 826 | date = 2018-04-18 | pmid = 29720983 | pmc = 5915546 | doi = 10.3389/fimmu.2018.00826 | doi-access = free }}

• EpiVacCorona, a peptide-based vaccine against COVID-19.
• IC41 is a peptide vaccine candidate against the Hepatitis C virus. It consists of five synthetic peptides along with the synthetic adjuvant called poly-l-arginine.{{cite journal | vauthors = Firbas C, Jilma B, Tauber E, Buerger V, Jelovcan S, Lingnau K, Buschle M, Frisch J, Klade CS | display-authors = 6 | title = Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects | journal = Vaccine | volume = 24 | issue = 20 | pages = 4343–4353 | date = May 2006 | pmid = 16581161 | doi = 10.1016/j.vaccine.2006.03.009 }}
• Multimeric-001 is the most efficient peptide vaccine candidate against influenza. It contains B- and T-cell epitopes from Hemagglutinin. Matrix I and nucleoprotein are combined into a single recombinantly-expressed polypeptide.{{cite journal | vauthors = Atsmon J, Caraco Y, Ziv-Sefer S, Shaikevich D, Abramov E, Volokhov I, Bruzil S, Haima KY, Gottlieb T, Ben-Yedidia T | display-authors = 6 | title = Priming by a novel universal influenza vaccine (Multimeric-001)-a gateway for improving immune response in the elderly population | journal = Vaccine | volume = 32 | issue = 44 | pages = 5816–5823 | date = October 2014 | pmid = 25173483 | doi = 10.1016/j.vaccine.2014.08.031 }}{{cite journal | vauthors = van Doorn E, Liu H, Ben-Yedidia T, Hassin S, Visontai I, Norley S, Frijlink HW, Hak E | display-authors = 6 | title = Evaluating the immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Multimeric-001) either as a standalone vaccine or as a primer to H5N1 influenza vaccine: Phase IIb study protocol | journal = Medicine | volume = 96 | issue = 11 | pages = e6339 | date = March 2017 | pmid = 28296763 | doi = 10.1097/md.0000000000006339 | pmc = 5369918 }}
• Alzheimer peptide vaccines: CAD106,{{cite journal | vauthors = Wiessner C, Wiederhold KH, Tissot AC, Frey P, Danner S, Jacobson LH, Jennings GT, Lüönd R, Ortmann R, Reichwald J, Zurini M, Mir A, Bachmann MF, Staufenbiel M | display-authors = 6 | title = The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects | journal = The Journal of Neuroscience | volume = 31 | issue = 25 | pages = 9323–9331 | date = June 2011 | pmid = 21697382 | doi = 10.1523/jneurosci.0293-11.2011|pmc=6623465 }} UB311,{{cite journal | vauthors = Wang CY, Finstad CL, Walfield AM, Sia C, Sokoll KK, Chang TY, Fang XD, Hung CH, Hutter-Paier B, Windisch M | display-authors = 6 | title = Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer's disease | journal = Vaccine | volume = 25 | issue = 16 | pages = 3041–3052 | date = April 2007 | pmid = 17287052 | doi = 10.1016/j.vaccine.2007.01.031 }} Lu, AF20513,{{cite journal | vauthors = Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Poghosyan A, Marleau AM, Movsesyan N, Kiyatkin A, Rasool S, Larsen AK, Madsen PJ, Wegener KM, Ditlevsen DK, Cribbs DH, Pedersen LO, Agadjanyan MG | display-authors = 6 | title = Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial | journal = The Journal of Neuroscience | volume = 33 | issue = 11 | pages = 4923–4934 | date = March 2013 | pmid = 23486963 | doi = 10.1523/jneurosci.4672-12.2013|pmc=3634356 }} ABvac40,{{cite journal | vauthors = Lacosta AM, Pascual-Lucas M, Pesini P, Casabona D, Pérez-Grijalba V, Marcos-Campos I, Sarasa L, Canudas J, Badi H, Monleón I, San-José I, Munuera J, Rodríguez-Gómez O, Abdelnour C, Lafuente A, Buendía M, Boada M, Tárraga L, Ruiz A, Sarasa M | display-authors = 6 | title = Safety, tolerability and immunogenicity of an active anti-Aβ₄₀ vaccine (ABvac40) in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase I trial | journal = Alzheimer's Research & Therapy | volume = 10 | issue = 1 | pages = 12 | date = January 2018 | pmid = 29378651 | doi = 10.1186/s13195-018-0340-8| doi-access = free | pmc = 5789644 }} ACI-35,{{cite journal | vauthors = Hickman DT, López-Deber MP, Ndao DM, Silva AB, Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A, Karastaneva H, Nagel-Steger L, Willbold D, Riesner D, Nicolau C, Baldus M, Pfeifer A, Muhs A | display-authors = 6 | title = Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases | journal = The Journal of Biological Chemistry | volume = 286 | issue = 16 | pages = 13966–13976 | date = April 2011 | pmid = 21343310 | doi = 10.1074/jbc.m110.186338 | pmc=3077597 | doi-access = free }} AADvac-1.{{cite journal | vauthors = Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M | title = First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model | journal = Alzheimer's Research & Therapy | volume = 6 | issue = 4 | pages = 44 | date = 2014 | pmid = 25478017 | doi = 10.1186/alzrt278|pmc=4255368 | doi-access = free }}

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