Virus and virus-like particle-based immunogens for Alzheimer's disease induce antibody responses against amyloid-beta without concomitant T cell responses.
A vaccine targeting the amyloid-beta (Abeta) peptide is a promising potential immunotherapy for Alzheimer's disease patients. However, experience from a recent clinical trial of a candidate Abeta vaccine has suggested that it is important to develop techniques to induce high titer antibodies against Abeta associated with vaccine efficacy while reducing the T cell responses against Abeta that were potentially responsible for serious side effects. We have previously demonstrated that immunization with self- and foreign antigens arrayed in a repetitive fashion on the surface of virus-like particles (VLPs) induces high titer antibody responses at low doses and in the absence of potentially inflammatory adjuvants. In this study, we examined the antibody and T cell responses upon immunization with human papillomavirus VLP- and Qbeta bacteriophage-based Abeta vaccines. Immunization with Abeta conjugated to VLPs or Qbeta elicited anti-Abeta antibody responses at low doses and without the use of adjuvants. The flexibility of these virus-based display systems allowed us to link and induce antibodies against short Abeta-derived peptides from the amino- and carboxyl-termini of the peptide. Immunization of mice with Abeta peptide in combination with Freund's adjuvant elicited predominantly IgG2c antibodies and strong T cell proliferative responses against Abeta. In contrast, VLP-conjugated Abeta peptides elicited more balanced isotype responses, dominated by IgG1. Both VLP and Qbeta-based Abeta vaccines induced weak or negligible T cell responses against Abeta. T cell responses were largely directed against linked viral epitopes. Taken together, virus-based vaccines that allow the presentation of Abeta in a repetitive dense array are new and potentially more effective vaccine candidates for Alzheimer's disease.
Chackerian
Bryce
B
Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA. bchackerian@salud.unm.edu <bchackerian@salud.unm.edu>
Rangel
Marisa
M
Hunter
Zoe
Z
Peabody
David S
DS
D017908:Allolevivirus / Q000276:immunology*; D000544:Alzheimer Disease / Q000276:immunology* / Q000821:virology; D023582:Alzheimer Vaccines / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes