Virus and virus-like particle-based immunogens for Alzheimer's disease induce antibody responses against amyloid-β without concomitant T cell responses

Abstract

A vaccine targeting the amyloid-beta (Aβ) peptide is a promising potential immunotherapy for Alzheimer's disease patients. However, experience from a recent clinical trial of a candidate Aβ vaccine has suggested that it is important to develop techniques to induce high titer antibodies against Aβ associated with vaccine efficacy while reducing the T cell responses against Aβ 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 Qβ bacteriophage-based Aβ vaccines. Immunization with Aβ conjugated to VLPs or Qβ elicited anti-Aβ 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 Aβ-derived peptides from the amino- and carboxyl-termini of the peptide. Immunization of mice with Aβ peptide in combination with Freund's adjuvant elicited predominantly IgG2c antibodies and strong T cell proliferative responses against Aβ. In contrast, VLP-conjugated Aβ peptides elicited more balanced isotype responses, dominated by IgG1. Both VLP and Qβ-based Aβ vaccines induced weak or negligible T cell responses against Aβ. T cell responses were largely directed against linked viral epitopes. Taken together, virus-based vaccines that allow the presentation of Aβ in a repetitive dense array are new and potentially more effective vaccine candidates for Alzheimer's disease.