Toxicity of beta-amyloid vaccination in patients with Alzheimer's disease.

Abstract

On January 18, 2002, Elan Corporation and American Home Products reported their decision to temporarily suspend dosing in a phase 2a study of their experimental antiAlzheimer’s disease vaccine (AN-1792) after 4 patients showed clinical signs of central nervous system (CNS) inflammation. AN-1792, also known as AIP-001, is a 42amino acid peptide ( -amyloid) vaccine coupled with an immune adjuvant (QS-21), a purified saponin derivative. This double-blind, placebo-controlled study is being conducted in the United States and four European countries and was designed to measure the immune response to AN-1792 in patients with mild to moderate Alzheimer’s disease. To date, approximately 360 patients have received multiple doses of AN-1792. The presence of a virus within the cerebrospinal fluid was reported in 1 of the 4 patients with CNS inflammation under investigation. However, the cause of inflammation remains to be determined. The 4 reported cases occurred in France, where 97 patients have received the study drug. Dramatic results obtained with AN-1792 in transgenic animal models of Alzheimer’s disease raised unprecedented hope for an effective treatment of this devastating disorder. The vaccine increases -amyloid clearance through mechanisms not fully understood. Centrally, the vaccine appears to activate -amyloid phagocytosis by microglial monocytes. Peripherally, serum antibodies appear to bind and sequester -amyloid, thereby altering its equilibrium between the CNS and plasma. There are many agents and mechanisms that can result in CNS inflammation. One explanation for the encephalitis could be external contamination during lumbar punctures, which are required as part of the protocol. It is unlikely that the QS-21 adjuvant used in this trial is the source of the viruses, as it is not of animal origin but is a highly purified saponin derived from the bark of the Quillaja saponaria Molina tree. Viral, bacterial, fungal, and parasitic pathogens may breach the blood–brain barrier and enter the CNS through paracellular or transcellular mechanisms. Recent studies appear to indicate that -amyloid vaccination may alter the permeability of the blood–brain barrier. In the mouse, the complex formed by -amyloid and immunoglobulins appears to have a 3.9to 4.6-fold greater permeability coefficient than nonspecific monoclonal antibodies. It has been also reported that in transgenic mice the passively administered antibodies can cross the blood–brain barrier to act directly in the CNS. This suggests that -amyloid immunization may cause abnormal leakage of the blood–brain barrier and increase the chance that pathogenic microorganisms will reach the CNS. It is also possible and perhaps more likely that the adverse events of AN-1792 observed in patients with Alzheimer’s disease could reflect an autoimmune inflammatory response triggered by T-lymphocyte activation after immune-system stimulation with -amyloid. T-cell lines specific to -amyloid contain a high percentage of CD8-positive cytotoxic T cells, which are capable of lysing cells that overproduce -amyloid. It is of paramount importance to clarify the nature and mechanism of the observed adverse effects on the CNS associated with AN-1792. As other therapeutic anti-amyloid vaccination strategies are being pursued, we urgently need to understand if the observed toxic effects are specific to AN1792 or also occur with other immunization approaches.