Lessons from the AN 1792 Alzheimer vaccine: lest we forget
Introduction
The presence of high densities of neuritic plaques in the cerebral cortices is a criterion for the post-mortem diagnosis of Alzheimer’s disease (AD). It is widely believed, but still unproven, that the fibrillar amyloid-β (Aβ) peptide found in neuritic plaques is neurotoxic and causes the neurodegeneration which accompanies the disease. The view that Aβ deposition drives the pathogenesis of AD (amyloid hypothesis) has received support from a wide range of molecular, genetic and animal studies (see [40]; cf. [16], [36]).
Recently a therapeutic approach was developed that uses a vaccine to generate antibodies which target Aβ in order to facilitate its removal from the brain. Such vaccines were successfully tested in mouse models of AD [15], [26], [39] and they showed no adverse side effects in Phase I clinical trials. However, Phase IIa clinical trials had to be abandoned after some patients who had received the AN 1792 vaccine developed meningoencephalitis [5], [46]. The present authors and others [34], [36] had cautioned that vaccines against Aβ could have deleterious side-effects. One of our concerns relates to the fact that vaccination against a ubiquitous and naturally-occurring peptide might cause a widespread inflammatory response, potentially resembling what would be seen in an autoimmune disease. Since vaccines of this type have never been tested in humans before, it was difficult to be certain in advance whether such vaccines would have adverse outcomes. As data trickle out from the AN 1792 trials, it is becoming increasingly evident that the immunotherapy approach faces some serious problems.
Section snippets
Lessons from the AN 1792 vaccination trials
Elan Pharmaceuticals and Wyeth Corporation jointly conducted human trials that involved vaccination with synthetic pre-aggregated Aβ1–42 (AN 1792). The immunisation schedule for the Phase IIa trial involved injections into the deltoid muscle of 225 μg AN 1792 with 50 μg QS-21 (an immunogenic adjuvant) at baseline and after 1, 3, 6, 9 and 12 months [33]. The Phase IIa trials were suspended in January 2002, only a few months into the study. While scant details have been released in the subsequent
Vaccinated transgenic mice are not valid models of human trials
Nicoll et al. [32] commented that several of their neuropathological observations on the brain from a patient in the Phase I trials “were not predicted by the mouse models of Aβ immunotherapy”. One difference was the presence of high densities of neurofibrillary tangles and neuropil threads, even in areas of cortex where few plaques were evident. Another difference was the extensive infiltration of the meninges and neuropil by CD4+ lymphocytes, and of the cerebral white matter by macrophages.
Conclusions
On balance, the available evidence indicates that the AN 1792 vaccine enhanced the production of Aβ antibodies in the sera of AD patients. However, this therapy did not slow the rate of cognitive decline. Furthermore, the antibody titres produced by patients showed substantial individual variability. The genetic heterogeneity of these patients, combined with an acquired resistance of their T-cells to generate antibodies against Aβ, probably contributed to the variable antibody titre. We do not
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