Alzheimer’s disease: Toward the rational design of an effective vaccine.

Abstract

The promising clinical results with the human monoclonal antibodies aducanumab and solanezumab targeting β-amyloidin Alzheimer’s disease treatment, confirm both the amyloid cascade hypothesis and protective natural immunity, while strengthening the immunotherapeutic approach. That aducanumab recognizes a conformational epitope formed by oligomers emphasizes the need for whole β-amyloid, not just its B-cell epitopes as have been the norm to avoid pro-inflammatory Th1-reactions. That truncated β-amyloid having N-terminal pyroglutamate is present only in diseased brain simplies a new useful vaccine antigen. Another relevant antigen is the tau protein, which shows a close association and cooperativity with β-amyloid in exacerbating this disease. Hence, effective vaccines may be polyvalent, presenting to the immune system a number of antigens relevant to induce an immune response to prevent or slowdown the onset of this disease. The presence of both B and T cell epitopes in the antigens, require a sole Th2 immunity to avert brain inflammation; a task that cannot be attain with adjuvants that under any conditions induce Th1and/or Th17immunities.Hence, new vaccine adjuvants are need to safely induce Th2 while inhibiting Th1 immunity, an objective that can be achieved with certain fucosylated glycans or triterpene glycosides, which apparently bind to the DC-SIGN lectin on dendritic cells polarizing the immune response toward Th2 immunity. Because the triterpene glycosides have the pharmacophore needed to co-stimulate T cells, they may ameliorate the T-cell anergy associated with immunosenescence and responsible for poor vaccine efficacy in theelderly population, a critical issue for an Alzheimer’s vaccine.

A retrospective analysis of the Alzheimer's disease vaccine progress – The critical need for new development strategies

“…Of relevance is that a derivative from the inflammatory glycoside QS‐21 has been found to be an effective Th2‐only adjuvant (Marciani ). In effect, the available information indicates that the single Fuc p residue of this new glycoside, QT‐0101, is the group responsible for its anti‐inflammatory properties, presumably acting at the DC‐SIGN level (Marciani ).…”

Promising Results from Alzheimer’s Disease Passive Immunotherapy Support the Development of a Preventive Vaccine

“…A consequence of the disappointing clinical results observed with A β -immunogens has been the development of alternative constructs that aim to mimic the epitopes responsible for A β neurotoxicity. Hence, besides the clinically unsuccessful A β 1-15 derived immunogens [30, 31], certain constructs based on this sequence have been developed, which show beneficial effects in transgenic mouse models [32, 33]. Nonetheless, the fact that all of the clinically failed human vaccines and mAbs were found initially to be effective in AD transgenic mouse models raises serious concerns.…”

“…Clinical studies have shown that vaccines having A β -derived immunogens without T-cell epitopes, but formulated with Th1 adjuvants, despite exhibiting beneficial effects in AD transgenic mouse models; they did not benefit humans [30, 31]. Another factor contributing to these vaccines' poor performance and side effects s has been the absence of effective sole anti-inflammatory Th2 adjuvants [34, 69].…”

“…The fact that vaccines like Affitope AD02, and presumably CAD106, have peptides mimicking A β 1-15 , conjugated to a KLH or virus-like-particle carrier by maleimide crosslinkers, indicates that the potential maleimide's interference with the immunoresponse was not considered [48, 74]. Thus, there is little information to explain these vaccines' failures, a deficiency that may have contributed to the disappointments, since all the vaccines had related immunogens based on the A β 1-15 region (Table 1) [31, 72, 75]. The results for the vaccines ACC-001 and CAD106 [76, 77], having immunogens derived from A β 1-15 , show that they induced antibodies against that sequence which removed plaque, causing brain volume's loss.…”

“…This requirement resembles that for vaccines against T-cell mediated autoimmune diseases, which also need a sole anti-inflammatory immunity [93]. Therefore, an obstacle in AD vaccine development has been that the available adjuvants, e.g., QS-21, CpG DNA, monophosphoryl lipid A and dsRNA, are mainly TLR ligands that stimulate a proinflammatory Th1/Th17 immune response, irrespective of the presence of T-cell epitopes in the immunogen [30, 31, 34]. A fact that is seldom recognized in AD vaccine development is that the adjuvants used in the current AD vaccines are largely proinflammatory ones (Table 1).…”