Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD

Abstract

AN1792 + QS-21 elicited a positive antibody response to Abeta42 in more than half of this elderly study population.

Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

“…5). As mentioned above, recent analysis of data from the AN-1792 clinical trial has produced encouraging results including demonstration of a reduction in plaque load and attenuation of cognitive decline in vaccinated AD patients who produced high titers of anti-Aβ antibodies [28,29,33]. On the other hand, Th1, but not Th2 type of immune response in vaccinated AD patients has been implicated in cell-mediated autoimmune response resulted in meningoencephalitis.…”

“…Despite the adverse events (meningoencephalitis) in the AN-1792 clinical trial, follow up studies demonstrated that strong anti-Aβ antibody responses, rather than autoimmune T cell responses generated in AD patients, were capable of reducing AD pathology and diminishing the progressive cognitive decline associated with the disease [24,[28][29][30][31][32][33]. More specifically, published data from AN-1792 clinical trials suggest that the aseptic meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of high titers of anti-Aβ antibodies may have been therapeutic to the AD patients.…”

“…These data along with preclinical studies demonstrated that anti-Aβ antibodies directed to N-terminal region of Aβ 42 are effective in clearance of amyloid plaques [16,34,35]. On the contrary, the strong autoreactive Th1-type response specific to Aβ is thought to underlie the development of meningoencephalitis observed in the AN-1792 trial [30,31,33]. It is known that Th1-type pro-inflammatory immune responses that are important for the generation of protection against viral infections and cancer are also implicated in autoimmune disorders, whereas Th2-type anti-inflammatory responses have generally been shown to inhibit autoimmune disease.…”

“…The first human AD vaccine consisted of fibrillar Aβ 42 formulated in QS21 adjuvant (AN-1792 trial) that induced strong Th1-type anti-Aβ immune responses [19], even in Th2-prone BALB/c mice [20]. This AN-1792 clinical trial was halted due to the development of meningoencephalitis in a small proportion of the subjects [21][22][23][24][25][26], but follow up studies have demonstrated that strong anti-Aβ antibody responses specific to the linear Aβ [1][2][3][4][5][6][7][8] peptide [27] in some patients reduced AD pathology and diminished the cognitive decline associated with the disease [24,[27][28][29][30][31][32][33]. These data along with preclinical studies demonstrated that anti-Aβ antibodies directed to N-terminal region of Aβ 42 are effective in clearance of amyloid plaques [16,34,35].…”

“…It is known that Th1-type pro-inflammatory immune responses that are important for the generation of protection against viral infections and cancer are also implicated in autoimmune disorders, whereas Th2-type anti-inflammatory responses have generally been shown to inhibit autoimmune disease. It is important, therefore, that future AD immunotherapy results in the clearing of Aβ peptides by specific anti-Aβ antibodies while limiting the Th1-type immune response [28][29][30][31][32][33]. To reduce the risk of an adverse T cell-mediated immune response to Aβ-immunotherapy, we developed an epitope vaccine, PADRE-Aβ 1-15 -MAP, and demonstrated that immunizations with this vaccine induced high titers of anti-Aβ antibodies, but not anti-PADRE antibodies.…”