Immunogenicity of DNA- and recombinant protein-based Alzheimer disease epitope vaccines

Abstract

Alzheimer disease (AD) process involves the accumulation of amyloid plaques and tau tangles in the brain, nevertheless the attempts at targeting the main culprits, neurotoxic β-amyloid (Aβ) peptides, have thus far proven unsuccessful for improving cognitive function. Important lessons about anti-Aβ immunotherapeutic strategies were learned from the first active vaccination clinical trials. AD progression could be safely prevented or delayed if the vaccine (1) induces high titers of antibodies specific to toxic forms of Aβ; (2) does not activate the harmful autoreactive T cells that may induce inflammation; (3) is initiated before or at least at the early stages of the accumulation of toxic forms of Aβ. Data from the recent passive vaccination trials with bapineuzumab and solanezumab also indicated that anti-Aβ immunotherapy might be effective in reduction of the AD pathology and even improvement of cognitive and/or functional performance in patients when administered early in the course of the disease. For the prevention of AD the active immunization strategy may be more desirable than passive immunotherapy protocol and it can offer the potential for sustainable clinical and commercial advantages. Here we discuss the active vaccine approaches, which are still in preclinical development and vaccines that are already in clinical trials.

Keywords: Alzheimer disease; DNA vaccine; adjuvants; electroporation; immune responses; liposome-based vaccination; protein vaccine.

Figure 1. Humoral and cellular immune responses generated in mice by DNA-based epitope vaccine using TDS-IM EP system and protein-based AD epitope vaccine formulated with Quil-A adjuvant. (A and B) Cellular responses are specific to Thep protein, but not Aβ₄₀ peptide. Splenocytes were re-stimulated with 10 µg/mL protein or Aβ₄₀ peptide. (C) Concentrations of anti-Aβ antibodies were detected after 3rd immunizations in sera from individual mice. Bars indicate average ± SD (n = 5 per group, **P ≤ 0.01, ****P ≤ 0.0001).

Figure 2. Humoral and cellular immune responses generated by different formulations of protein- and DNA-based AD epitope vaccines, AV-1982R and AV-1959D, respectively. (A) Concentrations of anti-Aβ antibodies were detected after 3rd immunizations in sera from individual mice. (B) Cellular responses are specific to Thep protein, but not Aβ₄₀ peptide. Splenocytes were re-stimulated with 10 µg/mL Thep protein or Aβ₄₀ peptide. Bars indicate average ± SD. Statistical differences in all groups were calculated relative to Liposomes/AV-1982R/AV-1959D immunized group using two-tailed t test (n = 6 per group, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001).