Abstract
BackgroundA recent human clinical trial of an Alzheimer's disease (AD) vaccine using amyloid beta (Aβ) 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants. The development of a vaccine with mutant Aβ peptides that avoids the use of an adjuvant may result in an effective and safer human vaccine.ResultsAll peptides tested showed high antibody responses, were long-lasting, and demonstrated good memory response. Epitope mapping indicated that peptide mutation did not lead to epitope switching. Mutant peptides induced different inflammation responses as evidenced by cytokine profiles. Ig isotyping indicated that adjuvant-free vaccination with peptides drove an adequate Th2 response. All anti-sera from vaccinated mice cross-reacted with human Aβ in APP/PS1 transgenic mouse brain tissue.ConclusionOur study demonstrated that an adjuvant-free vaccine with different Aβ peptides can be an effective and safe vaccination approach against AD. This study represents the first report of adjuvant-free vaccines utilizing Aβ peptides carrying diverse mutations in the T-cell epitope. These largely positive results provide encouragement for the future of the development of human vaccinations for AD.
Highlights
A recent human clinical trial of an Alzheimer's disease (AD) vaccine using amyloid beta (Aβ) 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants
Antibody response Mutated and wild type (Wt) Aβ1–42 peptide vaccinations induced clear antibody responses after 2 inoculations and high antibody level after 3 inoculations, while no antibody could be detected in the control group (Figure 1)
In our study of non-adjuvant peptide vaccines, inflammation levels varied minimally among the groups of mice vaccinated with mutated amyloid β (Aβ) peptides, and those levels differed from controls as well as levels in mice vaccinated with Wt peptide
Summary
A recent human clinical trial of an Alzheimer's disease (AD) vaccine using amyloid beta (Aβ) 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants. The first attempt at developing such a vaccine was documented in 1999, when Schenk et al reported that Aβ1–42, when used as an active vaccine, can effectively remove Aβ plaques in AD transgenic mouse brains [3]. Another milestone vaccine study published in 2000 showed that the use of Aβ1–42 plus adjuvant as an active vaccine in the AD transgenic mouse model induced an effective remission of Aβ plaques in the brain [4], and led to cognitive and behavioral improvements [5]. Weiner et al reported plaque-lowering in PDAPP transgenic mice after an intranasal inoculation of Aβ without adjuvant [9]
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