A new AD vaccine co-opts memory T helper cells to cajole B cells into producing anti-Aβ antibodies, report researchers in the March 13 Journal of Neuroscience. Done primarily in mice, the study raises hope that the vaccine could walk the thin line between rousing a strong attack on Aβ and inciting a dangerous inflammatory response.
To achieve this balance, Michael Agadjanyan from the University of California, Irvine, and colleagues engineered a protein that repeats the first 12 amino acids of Aβ three times, interspersing each with a stretch of the tetanus toxin. Most adults have memory T cells that recognize that toxin because they were inoculated against the bacterium earlier in life. "The tetanus toxin epitopes should stimulate a T helper cell response that induces B cells to make antibodies to Aβ," said Agadjanyan.
The method builds on previous work from Agadjanyan and UCI colleague David Cribbs, in which they had created a mixed peptide vaccine containing Aβ1-11 and a synthetic T cell-activating peptide (see ARF related news story). The newer version takes advantage of existing memory T cells.
The approach could be a way to overcome a significant challenge for Alzheimer's vaccines, according to Lars Lannfelt of Uppsala University, Sweden. "The main problem with active vaccines is that old people have a weak immune system," said Lannfelt. As people age, the pool of naïve T cells ready to take on a new antigen thins, but because of public health vaccination efforts, most people carry pre-existing memory T helper cells that recognize tetanus epitopes. In theory, those cells will present the recombinant epitope vaccine for Alzheimer's, called Lu AF20513, to B cells, and some of those will generate anti-Aβ antibodies. Whether Lu AF20513 can solve the age problem will remain unknown until it is tested in people, said Lannfelt. So far, Agadjanyan's group has only studied lab animals.
The method may also help avoid problems seen with an earlier active AD vaccine developed by Elan Pharmaceuticals (AN1792), which in some 6 percent of clinical trial participants caused an autoreactive inflammatory immune response that led to meningoencephalitis (see ARF related news story). Despite this setback, immunotherapy remains a popular research track, in part because many studies have shown that it reduces amyloid pathology in mice (see ARF related news story and ARF news story).
In the current study, the researchers first detail immune responses to the vaccine in tetanus-naïve Tg2576 mice, which overexpress a mutant form of amyloid precursor protein. Agadjanyan and colleagues used four- to six-month-old animals, which typically have early-stage Alzheimer's-like pathology. Any immunization against Alzheimer's in patients will have to take place early on, said Agadjanyan.
Eleven monthly subcutaneous injections of the protein vaccine induced B cell production of anti-Aβ antibodies without eliciting an autoreactive anti-Aβ T cell response. Lu AF20513 suppressed amyloid plaque formation and accumulation of soluble forms of Aβ. The number of amyloid-containing blood vessels did not increase in the treated mice as compared to controls, and the authors found no microhemorrhages in the brains of the mice. However, the authors did observe an increase in the ratio of amyloid-containing blood vessels to brain tissue plaques in the vaccinated mice, suggesting that, as amyloid clears from the brain, it moves to the vasculature.
First author Hayk Davtyan and colleagues purified anti-Aβ1-12 antibodies from the sera of Lu AF20513-immunized mice and found they reduced the toxic effects of Aβ42 oligomers and fibrils in cultured neurons. The antibodies also bound amyloid plaques in brain tissue from a patient with Alzheimer's disease.
Unlike people, mice never receive routine tetanus vaccinations. To simulate the human situation, the researchers injected another set of mice with one of the tetanus epitopes three times over six weeks. The researchers then waited for six months, during which memory T cells developed, said Agadjanyan. Then they gave the mice a single immunization with Lu AF20513. The vaccine induced a fast and strong T helper cell response to the tetanus epitopes, which led to production of anti-Aβ antibodies. The researchers did not report on whether the vaccine could prevent or rescue the cognitive defects that develop in the Tg2576 mice, but Agadjanyan said he expects to publish those data soon.
The UC Irvine researchers reported that vaccinating cynomolgus monkeys and guinea pigs led to therapeutically relevant levels of anti-Aβ antibodies. "It was interesting that they have tested the vaccine in 14 monkeys and they got quite good titers from two immunizations," said Lannfelt. "However, they don’t tell us how long these titers lasted." Human testing will be the key for the future of Lu AF20513, said Niels Andreasen of the Karolinska Institute in Stockholm, Sweden, "I have seen so many times that treatments have different effects when you test them in humans.” Agadjanyan hopes to test this vaccine in people.—Susan Young
- Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Poghosyan A, Marleau AM, Movsesyan N, Kiyatkin A, Rasool S, Larsen AK, Madsen PJ, Wegener KM, Ditlevsen DK, Cribbs DH, Pedersen LO, Agadjanyan MG. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial. J Neurosci. 2013 Mar 13;33(11):4923-34. PubMed.