GSK-933776

The development of amyloid β (Aβ) vaccines for Alzheimer's disease (AD) has consistently failed clinically, an outcome that is assumed to result from flaws in the proposed role of Aβ as the crucial causative agent of this disease. This opinion resulted in this research approach being disregarded, yet, review of the development of these vaccines indicates that they are more suited to transgenic mice, which is unsurprising given that these animal models were used to determine the efficacy of these vaccines, and that the approach overlooked research findings relevant to AD vaccines. Hence, new strategies using new immunogens and anti-inflammatory adjuvants mimicking the natural protective immunity against AD should be implemented to develop effective preventive vaccines.

The promising results obtained with aducanumab and solanezumab against Alzheimer's disease (AD) strengthen the vaccine approach to prevent AD, despite of the many clinical setbacks. It has been problematic to use conjugated peptides with Th1/Th2 adjuvants to induce immune responses against conformational epitopes formed by Aβ oligomers, which is critical to induce protective antibodies. Hence, vaccination should mimic natural immunity by using whole or if possible conjugated antigens, but biasing the response to Th2 with anti‐inflammatory adjuvants. Also, selection of the carrier and cross‐linking agents is important to prevent suppression of the immune response against the antigen. That certain compounds having phosphorylcholine or fucose induce a sole Th2 immunity would allow antigens with T‐cell epitopes without inflammatory autoimmune reactions to be used. Another immunization method is DNA vaccines combined with antigenic ones, which favors the clonal selection and expansion of high affinity antibodies needed for immune protection, but this also requires Th2 immunity. Since AD transgenic mouse models have limited value for immunogen selection as shown by the clinical studies, screening may require the use of validated antibodies and biophysical methods to identify the antigens that would be most likely recognized by the human immune system and thus capable to stimulate a protective antibody response.imageTo induce an anti‐Alzheimer's disease protective immunity and prevent possible damage triggered by antigens having B‐cell epitopes‐only, whole antigens might be used; while inducing Th2 immunity with sole anti‐inflammatory fucose‐based adjuvants. This approach would avert a damaging systemic inflammatory immunity and the suppression of immunoresponse against the antigen because of carrier and cross‐linkers; immune requirements that extend to DNA vaccines.