Elsevier

Neurobiology of Aging

Volume 25, Issue 5, May–June 2004, Pages 609-615
Neurobiology of Aging

Lessons from the AN 1792 Alzheimer vaccine: lest we forget

https://doi.org/10.1016/j.neurobiolaging.2003.12.020Get rights and content

Abstract

Recent clinical and neuropathological data show that the AN 1792 vaccine enhanced the production of antibodies in the sera of Alzheimer’s disease (AD) patients, but it appears to have been ineffective at stimulating the removal of deposits from the brain or at slowing the rate of cognitive decline. The 19 cases of meningoencephalitis were not linked in an obvious way to serum antibody titre, but they may have been linked to infiltration of the brain by antibodies and/or T-cells. Brain imaging indicated that oedema associated with the neuroinflammation did not reflect the typical distribution of neuritic plaques in AD. These outcomes were not anticipated by experiments on transgenic mice because compared to humans, these mice have less genetic variability, and their plaques have a different chemical composition, making them far more soluble and easier to remove. Furthermore, the consequences of vaccination are different. Vaccination of transgenic mice removes superfluous human while leaving endogenous mouse Aβ intact, whereas in humans the immune response is directed against an endogenous target that occurs naturally and is present in healthy brain tissue. The most important lesson to be learned from the AN 1792 trials is that new strategies for treating AD should not be tested on humans until they have been extensively tested on non-murine species.

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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