Refinement of a DNA Based Alzheimer's Disease Epitope Vaccine in Rabbits

Overview

Journal Hum Vaccin Immunother

Specialty Allergy & Immunology

Date 2013 Feb 13

PMID 23399748

Citations 23

Authors

Anahit Ghochikyan

Hayk Davtyan

Irina Petrushina

Armine Hovakimyan

Nina Movsesyan

Arpine Davtyan

Anatoly Kiyatkin

David H Cribbs

Michael G Agadjanyan

Affiliations

Soon will be listed here.

Abstract

We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ 11-PADRE by modifying this vaccine to express protein 3Aβ 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aβ 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aβ 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compared with p3Aβ 11-PADRE vaccine. Anti-Aβ 11 antibodies recognized all forms of human β-amyloid peptide (monomers, oligomers and fibrils), bound to amyloid plaques in brain sections from an AD case and reduced oligomer- and fibril-mediated cytotoxicity ex vivo. These findings suggest that AV-1955 could represent an effective DNA epitope vaccine for AD therapy, pending safety and efficacy studies that are currently being conducted in Rhesus monkeys.

Citing Articles

mRNA Vaccine for Alzheimer's Disease: Pilot Study.

Hovakimyan A, Chilingaryan G, King O, Capocchi J, Chadarevian J, Davtyan H Vaccines (Basel). 2024; 12(6).

PMID: 38932388 PMC: 11209092. DOI: 10.3390/vaccines12060659.

Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates.

Hovakimyan A, Zagorski K, Chailyan G, Antonyan T, Melikyan L, Petrushina I NPJ Vaccines. 2022; 7(1):117.

PMID: 36224191 PMC: 9556597. DOI: 10.1038/s41541-022-00544-3.

Immunogenicity of MultiTEP-Platform-Based Recombinant Protein Vaccine, PV-1950R, Targeting Three B-Cell Antigenic Determinants of Pathological α-Synuclein.

Zagorski K, Chailyan G, Hovakimyan A, Antonyan T, Kiani Shabestari S, Petrushina I Int J Mol Sci. 2022; 23(11).

PMID: 35682759 PMC: 9181659. DOI: 10.3390/ijms23116080.

Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies.

Kim C, Hovakimyan A, Zagorski K, Antonyan T, Petrushina I, Davtyan H NPJ Vaccines. 2022; 7(1):1.

PMID: 35013319 PMC: 8748802. DOI: 10.1038/s41541-021-00424-2.

Effects of Aβ-derived peptide fragments on fibrillogenesis of Aβ.

Abedin F, Kandel N, Tatulian S Sci Rep. 2021; 11(1):19262.

PMID: 34584131 PMC: 8479085. DOI: 10.1038/s41598-021-98644-y.

References

Alexander J, Fikes J, Hoffman S, Franke E, Sacci J, Appella E . The optimization of helper T lymphocyte (HTL) function in vaccine development. Immunol Res. 1998; 18(2):79-92. DOI: 10.1007/BF02788751. View

Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud P . Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008; 3(5):e2124. PMC: 2358976. DOI: 10.1371/journal.pone.0002124. View

Lesne S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A . A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006; 440(7082):352-7. DOI: 10.1038/nature04533. View

Luxembourg A, Hannaman D, Ellefsen B, Nakamura G, Bernard R . Enhancement of immune responses to an HBV DNA vaccine by electroporation. Vaccine. 2005; 24(21):4490-3. DOI: 10.1016/j.vaccine.2005.08.014. View

Bureau M, Gehl J, Deleuze V, Mir L, Scherman D . Importance of association between permeabilization and electrophoretic forces for intramuscular DNA electrotransfer. Biochim Biophys Acta. 2000; 1474(3):353-9. DOI: 10.1016/s0304-4165(00)00028-3. View

Demotz S, Barbey C, Corradin G, Amoroso A, Lanzavecchia A . The set of naturally processed peptides displayed by DR molecules is tuned by polymorphism of residue 86. Eur J Immunol. 1993; 23(2):425-32. DOI: 10.1002/eji.1830230219. View

Town T, Tan J, Flavell R, Mullan M . T-cells in Alzheimer's disease. Neuromolecular Med. 2005; 7(3):255-64. DOI: 10.1385/NMM:7:3:255. View

Agadjanyan M, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M . Prototype Alzheimer's disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol. 2005; 174(3):1580-6. DOI: 10.4049/jimmunol.174.3.1580. View

Candore G, Balistreri C, Colonna-Romano G, Grimaldi M, Lio D, Listi F . Immunosenescence and anti-immunosenescence therapies: the case of probiotics. Rejuvenation Res. 2008; 11(2):425-32. DOI: 10.1089/rej.2008.0662. View

10.

Baraldo K, Mori E, Bartoloni A, Petracca R, Giannozzi A, Norelli F . N19 polyepitope as a carrier for enhanced immunogenicity and protective efficacy of meningococcal conjugate vaccines. Infect Immun. 2004; 72(8):4884-7. PMC: 470654. DOI: 10.1128/IAI.72.8.4884-4887.2004. View

11.

Gilman S, Koller M, Black R, Jenkins L, Griffith S, Fox N . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005; 64(9):1553-62. DOI: 10.1212/01.WNL.0000159740.16984.3C. View

12.

Huang C, Monie A, Weng W, Wu T . DNA vaccines for cervical cancer. Am J Transl Res. 2010; 2(1):75-87. PMC: 2826824. View

13.

Tang D, DeVit M, Johnston S . Genetic immunization is a simple method for eliciting an immune response. Nature. 1992; 356(6365):152-4. DOI: 10.1038/356152a0. View

14.

Kayed R, Canto I, Breydo L, Rasool S, Lukacsovich T, Wu J . Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers. Mol Neurodegener. 2010; 5:57. PMC: 3019145. DOI: 10.1186/1750-1326-5-57. View

15.

Alexander J, del Guercio M, Maewal A, Qiao L, Fikes J, Chesnut R . Linear PADRE T helper epitope and carbohydrate B cell epitope conjugates induce specific high titer IgG antibody responses. J Immunol. 2000; 164(3):1625-33. DOI: 10.4049/jimmunol.164.3.1625. View

16.

Davtyan H, Ghochikyan A, Movsesyan N, Ellefsen B, Petrushina I, Cribbs D . Delivery of a DNA vaccine for Alzheimer's disease by electroporation versus gene gun generates potent and similar immune responses. Neurodegener Dis. 2012; 10(1-4):261-4. PMC: 3363347. DOI: 10.1159/000333359. View

17.

Wang B, Ugen K, Srikantan V, Agadjanyan M, Dang K, Refaeli Y . Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993; 90(9):4156-60. PMC: 46465. DOI: 10.1073/pnas.90.9.4156. View

18.

Movsesyan N, Mkrtichyan M, Petrushina I, Ross T, Cribbs D, Agadjanyan M . DNA epitope vaccine containing complement component C3d enhances anti-amyloid-beta antibody production and polarizes the immune response towards a Th2 phenotype. J Neuroimmunol. 2008; 205(1-2):57-63. PMC: 2637203. DOI: 10.1016/j.jneuroim.2008.08.016. View

19.

van Drunen Littel-van den Hurk S, Hannaman D . Electroporation for DNA immunization: clinical application. Expert Rev Vaccines. 2010; 9(5):503-17. DOI: 10.1586/erv.10.42. View

20.

Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, Petrushina I, Movsesyan N . Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. J Biol Chem. 2007; 282(31):22376-86. PMC: 2435219. DOI: 10.1074/jbc.M700088200. View