Skip to main content
Log in

New progress in active immunotherapy targeting to amyloid beta

  • Mini Reviews
  • Special Topic Chemistry from Chinese Female Chemists
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is one of the most common types of dementia whose hallmarks include neurofibrillary tangles and senile plaques. The latter are mainly composed of amyloid-β proteins (Aβ), and it’s suggested that Aβ may be the causative factor in AD pathogenesis. Immunotherapy targeting Aβ for preventing aggregation of Aβ and mildly clearing amyloid plaques has been a hot topic since 1999. Although the first clinical trial of Aβ vaccine, AN-1792, failed in phase II, its results suggested some key points in the design of Aβ vaccines. Avoiding the possible toxic Aβ specific T cell response and inducing a Th2 type cellular immune response may be beneficial for Aβ immunotherapy. Many associations and research groups are working on Aβ vaccine and some progress has been made in recent years. In this review, we have provided a detailed summary of past Aβ vaccines, which have been sorted by the immunogen, and we also discuss some recent progress and future perspectives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Wimo A, Prince M. Alzheimer’s Disease International. World Alzheimer Report 2010, 2010

    Google Scholar 

  2. Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, Greco A, Seripa D, Pilotto A. Immunotherapy for Alzheimer’s disease: from anti-beta-amyloid to tau-based immunization strategies. Immunotherapy, 2012, 4: 213–238

    Article  CAS  Google Scholar 

  3. Hamley IW. The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem Rev, 2012, 112: 5147–5192

    Article  CAS  Google Scholar 

  4. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science, 1992, 256: 184–185

    Article  CAS  Google Scholar 

  5. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med, 2008, 14: 837–842

    Article  CAS  Google Scholar 

  6. Schenk D, Basi GS, Pangalos MN. Treatment strategies targeting amyloid beta-protein. CSH Perspect Med, 2012, 2: a006387

    Google Scholar 

  7. Wu WH, Lei P, Liu Q, Hu J, Gunn AP, Chen MS, Rui YF, Su XY, Xie ZP, Zhao YF, Bush AI, Li YM. Sequestration of copper from beta-amyloid promotes selective lysis by cyclen-hybrid cleavage agents. J Biol Chem, 2008, 283: 31657–31664

    Article  CAS  Google Scholar 

  8. Panza F, Logroscino G, Imbimbo BP, Solfrizzi V. Is there still any hope for amyloid-based immunotherapy for Alzheimer’s disease? Curr Opin Psychiatr, 2014, 27: 128–137

    Article  Google Scholar 

  9. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 1999, 400: 173–177

    Article  CAS  Google Scholar 

  10. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 2003, 61: 46–54

    Article  CAS  Google Scholar 

  11. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med, 2003, 9: 448–452

    Article  CAS  Google Scholar 

  12. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol, 2004, 14: 11–20

    Article  CAS  Google Scholar 

  13. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M. Bapineuzumab 201 clinical trial I. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology, 2009, 73: 2061–2070

    Article  CAS  Google Scholar 

  14. Monsonego A, Weiner HL. Immunotherapeutic approaches to Alzheimer’s disease. Science, 2003, 302: 834–838

    Article  CAS  Google Scholar 

  15. Monsonego A, Maron R, Zota V, Selkoe DJ, Weiner HL. Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer’s disease. Proc Natl Acad Sci USA, 2001, 98: 10273–10278

    Article  CAS  Google Scholar 

  16. Cribbs DH, Ghochikyan A, Vasilevko V, Tran M, Petrushina I, Sadzikava N, Babikyan D, Kesslak P, Kieber-Emmons T, Cotman CW, Agadjanyan MG. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol, 2003, 15: 505–514

    Article  CAS  Google Scholar 

  17. Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest, 2003, 112: 415–422

    Article  CAS  Google Scholar 

  18. Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, Fisher Y, Owens T, Weiner HL. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA, 2006, 103: 5048–5053

    Article  CAS  Google Scholar 

  19. Tabira T. Immunization therapy for Alzheimer disease: a comprehensive review of active immunization strategies. Tohoku J Exp Med, 2010, 220: 95–106

    Article  CAS  Google Scholar 

  20. Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M, Saing T, Cribbs DH. 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: 1580–1586

    Article  CAS  Google Scholar 

  21. Liu B, Frost JL, Sun J, Fu H, Grimes S, Blackburn P, Lemere CA. MER5101, a novel Abeta1-15:DT conjugate vaccine, generates a robust anti-Abeta antibody response and attenuates Abeta pathology and cognitive deficits in APPswe/PS1DeltaE9 transgenic mice. J Neurosci, 2013, 33: 7027–7037

    Article  CAS  Google Scholar 

  22. Kou J, Song M, Pattanayak A, Lim J E, Yang J, Cao D, Li L, Fukuchi K. Combined treatment of Abeta immunization with statin in a mouse model of Alzheimer’s disease. J Neuroimmunol, 2012, 244: 70–83

    Article  CAS  Google Scholar 

  23. Arai H, Suzuki H, Yoshiyama T, Lobello K, Peng Y, Liu E, Ketter N, Margolin R, Jackson N, Fujimoto Y. Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC-001]) and the QS-21 adjuvant in Japanese individuals with mild-to-moderate Alzheimer’s disease: a phase IIa, multicenter, randomized, adjuvant and placebo clinical trial. Alzheimers Dement, 2013, 9: P282

    Article  Google Scholar 

  24. Donnelly JJ, Ulmer JB, Shiver JW, Liu MA. DNA vaccines. Annu Rev Immunol, 1997, 15: 617–648

    Article  CAS  Google Scholar 

  25. Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine: a novel immunotherapeutic strategy. PLoS One, 2008, 3: e2124

    Article  Google Scholar 

  26. Kim HD, Tahara K, Maxwell JA, Lalonde R, Fukuiwa T, Fujihashi K, Van Kampen KR, Kong FK, Tang DC, Fukuchi K. Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Abeta1-6 upregulates IL-10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer’s disease. J Gene Med, 2007, 9: 88–98

    Article  CAS  Google Scholar 

  27. Lewis PJ, Van Drunen Littel-Van Den H, Babiuk LA. Altering the cellular location of an antigen expressed by a DNA-based vaccine modulates the immune response. J Virol, 1999, 73: 10214–10223

    CAS  Google Scholar 

  28. Boutajangout A, Goni F, Knudsen E, Schreiber F, Asuni A, Quartermain D, Frangione B, Chabalgoity A, Wisniewski T, Sigurdsson EM. Diminished amyloid-beta burden in Tg2576 mice following a prophylactic oral immunization with a salmonella-based amyloid-beta derivative vaccine. J Alzheimers Dis, 2009, 18: 961–972

    CAS  Google Scholar 

  29. Wiessner C, Wiederhold KH, Tissot AC, Frey P, Danner S, Jacobson LH, Jennings GT, Luond R, Ortmann R, Reichwald J, Zurini M, Mir A, Bachmann MF, Staufenbiel M. The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci, 2011, 31: 9323–9331

    Article  CAS  Google Scholar 

  30. Ishii Y, Nakae T, Sakamoto F, Matsuo K, Matsuo K, Quan YS, Kamiyama F, Fujita T, Yamamoto A, Nakagawa S, Okada N. A transcutaneous vaccination system using a hydrogel patch for viral and bacterial infection. J Control Release, 2008, 131: 113–120

    Article  CAS  Google Scholar 

  31. Matsuo K, Okamoto H, Kawai Y, Quan YS, Kamiyama F, Hirobe S, Okada N, Nakagawa S. Vaccine efficacy of transcutaneous immunization with amyloid beta using a dissolving microneedle array in a mouse model of Alzheimer’s disease. J Neuroimmunol, 2014, 266: 1–11

    Article  CAS  Google Scholar 

  32. Wang S, Yu Y, Geng S, Wang D, Zhang L, Xie X, Wu B, Li C, Xu H, Li X, Hu Y, Zhang L, Kaether C, Wang B. A coimmunization vaccine of Abeta42 ameliorates cognitive deficits without brain inflammation in an Alzheimer’s disease model. Alzheimers Res Ther, 2014, 6: 26

    Article  Google Scholar 

  33. Wang CM, Devries S, Camboni M, Glass M, Martin PT. Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer’s disease. Neurobiol Dis, 2010, 39: 409–422

    Article  Google Scholar 

  34. Camboni M, Wang CM, Miranda C, Yoon JH, Xu R, Zygmunt D, Kaspar BK, Martin PT. Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer’s disease. Neurobiol Dis, 2014, 62: 31–43

    Article  CAS  Google Scholar 

  35. Kang C. Identification of peptides that specifically bind Aβ1-40 amyloid in vitro and amyloid plaques in Alzheimer’s disease brain using phage display. Neurobiol Dis, 2003, 14: 146–156

    Article  CAS  Google Scholar 

  36. Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W. Development of AFFITOPE vaccines for Alzheimer’s disease (AD): from concept to clinical testing. J Nutr Health Aging, 2009, 13: 264–267

    Article  CAS  Google Scholar 

  37. Acero G, Manoutcharian K, Vasilevko V, Munguia ME, Govezensky T, Coronas G, Luz-Madrigal A, Cribbs DH, Gevorkian G. Immunodominant epitope and properties of pyroglutamate-modified Abeta-specific antibodies produced in rabbits. J Neuroimmunol, 2009, 213: 39–46

    Article  CAS  Google Scholar 

  38. Perez-Garmendia R, Ibarra-Bracamontes V, Vasilevko V, Luna-Munoz J, Mena R, Govezensky T, Acero G, Manoutcharian K, Cribbs DH, Gevorkian G. Anti-11[E]-pyroglutamate-modified amyloid beta antibodies cross-react with other pathological Abeta species: relevance for immunotherapy. J Neuroimmunol, 2010, 229: 248–255

    Article  CAS  Google Scholar 

  39. Dalgediene I, Lasickiene R, Budvytyte R, Valincius G, Morkuniene R, Borutaite V, Zvirbliene A. Immunogenic properties of amyloid beta oligomers. J Biomed Sci, 2013, 20: 10

    Article  CAS  Google Scholar 

  40. Rasool S, Albay R 3rd, Martinez-Coria H, Breydo L, Wu J, Milton S, Misra S, Tran A, Pensalfini A, Laferla F, Kayed R, Glabe CG. Vaccination with a non-human random sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition and micro hemorrhage in Tg2576 mice. Mol Neurodegener, 2012, 7: 37

    Article  CAS  Google Scholar 

  41. Webster SJ, Mruthinti S, Hill WD, Buccafusco JJ, Terry AV Jr. An aqueous orally active vaccine targeted against a RAGE/AB complex as a novel therapeutic for Alzheimer’s disease. Neuromol Med, 2012, 14: 119–130

    Article  CAS  Google Scholar 

  42. Kofler J, Lopresti B, Janssen C, Trichel AM, Masliah E, Finn OJ, Salter RD, Murdoch GH, Mathis CA, Wiley CA. Preventive immunization of aged and juvenile non-human primates to beta-amyloid. J Neuroinflamm, 2012, 9: 84

    Article  CAS  Google Scholar 

  43. Guan X, Zou J, Gu H, Yao Z. Short amyloid-beta immunogens with spacer-enhanced immunogenicity without junctional epitopes for Alzheimer’s disease immunotherapy. Neuroreport, 2012, 23: 879–884

    Article  CAS  Google Scholar 

  44. Xing X, Sha S, Li Y, Zong L, Jiang T, Cao Y. Immunization with a new DNA vaccine for Alzheimer’s disease elicited Th2 immune response in BALB/c mice by in vivo electroporation. J Neurol Sci, 2012, 313: 17–21

    Article  CAS  Google Scholar 

  45. Sha S, Xing XN, Guo WS, Li Y, Zong LX, Guo R, Cao YP. In vivo electroporation of a new gene vaccine encoding ten repeats of Abeta3–10 prevents brain Abeta deposition and delays cognitive impairment in young Tg-APPswe/PSEN1dE9 mice. Neurochem Res, 2012, 37: 1534–1544

    Article  CAS  Google Scholar 

  46. Li Y, Ma Y, Zong LX, Xing XN, Guo R, Jiang TZ, Sha S, Liu L, Cao YP. Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Abeta3-10 reduces AD-like pathology and cognitive impairment in Tg-APPswe/PSEN1dE9 mice. J Neuroimmunol, 2012, 249: 16–26

    Article  CAS  Google Scholar 

  47. Olkhanud PB, Mughal M, Ayukawa K, Malchinkhuu E, Bodogai M, Feldman N, Rothman S, Lee JH, Chigurupati S, Okun E, Nagashima K, Mattson MP, Biragyn A. DNA immunization with HBsAg-based particles expressing a B cell epitope of amyloid beta-peptide attenuates disease progression and prolongs survival in a mouse model of Alzheimer’s disease. Vaccine, 2012, 30: 1650–1658

    Article  CAS  Google Scholar 

  48. Tan L, Wang H, Tan X, Zou J, Yao Z. Yeast expressed foldable quadrivalent Abeta15 elicited strong immune response against Abeta without Abeta-specific T cell response in wild C57BL/6 mice. Hum Vacc Immunother, 2012, 8: 1090–1098

    Article  CAS  Google Scholar 

  49. 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. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J Neurosci, 2013, 33: 4923–4934

    Article  CAS  Google Scholar 

  50. Feng G, Wang W, Qian Y, Jin H. Anti-Abeta antibodies induced by Abeta-HBc virus-like particles prevent Abeta aggregation and protect PC12 cells against toxicity of Abeta1-40. J Neurosci Meth, 2013, 218: 48–54

    Article  CAS  Google Scholar 

  51. Guan X, Yang J, Gu H, Zou J, Yao Z. Immunotherapeutic efficiency of a tetravalent Abeta1-15 vaccine in APP/PS1 transgenic mice as mouse model for Alzheimer’s disease. Hum Vacc Immunother, 2013, 9: 1643–1653

    Article  CAS  Google Scholar 

  52. Guo W, Sha S, Xing X, Jiang T, Cao Y. Reduction of cerebral Abeta burden and improvement in cognitive function in Tg-APPswe/PSEN1 dE9 mice following vaccination with a multivalent Abeta3-10 DNA vaccine. Neurosci Lett, 2013, 549: 109–115

    Article  CAS  Google Scholar 

  53. Matsumoto Y, Niimi N, Kohyama K. Development of a new DNA vaccine for Alzheimer disease targeting a wide range of abeta species and amyloidogenic peptides. PLoS One, 2013, 8: e75203

    Article  CAS  Google Scholar 

  54. Richter M, Hoffmann R, Singer D. T-cell epitope-dependent immune response in inbred (C57BL/6J, SJL/J, and C3H/HeN) and transgenic P301S and Tg2576 mice. J Pept Sci, 2013, 19: 441–451

    Article  CAS  Google Scholar 

  55. Yano A, Miwa Y, Kanazawa Y, Ito K, Makino M, Imai S, Hanada N, Nisizawa T. A novel method for enhancement of peptide vaccination utilizing T-cell epitopes from conventional vaccines. Vaccine, 2013, 31: 1510–1515

    Article  CAS  Google Scholar 

  56. Yu YZ, Wang S, Bai JY, Zhao M, Chen A, Wang WB, Chang Q, Liu S, Qiu WY, Pang XB, Xu Q, Sun ZW. Effective DNA epitope chimeric vaccines for Alzheimer’s disease using a toxin-derived carrier protein as a molecular adjuvant. Clin Immunol, 2013, 149: 11–24

    Article  CAS  Google Scholar 

  57. Yu YZ, Wang WB, Chen A, Chang Q, Liu S, Zhao M, Wang S, Qiu WY, Pang XB, Xu Q, Sun ZW. Strikingly reduced amyloid burden and improved behavioral performance in Alzheimer’s disease mice immunized with recombinant chimeric vaccines by hexavalent foldable Abeta1-15 fused to toxin-derived carrier proteins. J Alzheimers Dis, 2014, 41: 243–260

    CAS  Google Scholar 

  58. Mantile F, Trovato M, Santoni A, Barba P, Ottonello S, De Berardinis P, Prisco A. Alum and squalene-oil-in-water emulsion enhance the titer and avidity of anti-A beta antibodies induced by multimeric protein antigen (1–11)E2, preserving the Igg1-skewed isotype distribution. Plos One, 2014, 9

    Google Scholar 

  59. Davtyan H, Ghochikyan A, Hovakimyan A, Davtyan A, Cadagan R, Marleau AM, Albrecht RA, Garcia-Sastre A, Agadjanyan MG. A dual vaccine against influenza & Alzheimer’s disease failed to enhance anti-beta-amyloid antibody responses in mice with pre-existing virus specific memory. J Neuroimmunol, 2014, 277: 77–84

    Article  CAS  Google Scholar 

  60. Li S, Wei Z, Chen J, Chen Y, Lv Z, Yu W, Meng Q, Jin Y. Oral administration of a fusion protein between the cholera toxin b subunit and the 42-amino acid isoform of amyloid-beta peptide produced in silkworm pupae protects against Alzheimer’s disease in mice. PLoS One, 2014, 9: e113585

    Article  Google Scholar 

  61. Mastelic B, Ahmed S, Egan WM, Del Giudice G, Golding H, Gust I, Neels P, Reed SG, Sheets RL, Siegrist CA, Lambert PH. Mode of action of adjuvants: implications for vaccine safety and design. Biologicals, 2010, 38: 594–601

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yan-Mei Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, G., Chen, YX. & Li, YM. New progress in active immunotherapy targeting to amyloid beta. Sci. China Chem. 58, 383–389 (2015). https://doi.org/10.1007/s11426-014-5310-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-014-5310-9

Keywords

Navigation