While passive immunotherapies have demonstrated safety and some improvement on biomarkers and cognition in Alzheimer’s disease clinical trials, they come at a price. Antibodies are expensive to produce and administer. Active vaccines are a cheaper alternative, but can elicit self-directed cellular immune responses and cause neuroinflammation. Now, in the August 2 Alzheimer’s & Dementia, researchers led by Michael Agadjanyan and Anahit Ghochikyan at the Institute for Molecular Medicine, Huntington Beach, California, report that an active DNA-based Aβ vaccine appears safe and produces a strong immune response in monkeys, suggesting it could work in people. To improve safety, the authors vaccinated with DNA coding for only a small fragment of Aβ, together with DNA for numerous viral epitopes that pumped up the immune system without causing harmful self-immunity. DNA costs much less to make than peptides or antibodies, and is also easier to transport and store, Agadjanyan said. The authors hope soon to test this vaccine in preventative AD clinical trials. Currently there are several approved DNA vaccines for animals that prevent diseases such as West Nile Virus and rhabdovirus, but none for people, although a number are in clinical trials.
Other scientists found the results promising. “This is a very clever and sophisticated vaccine,” said Dave Morgan at the University of South Florida, Tampa. Andreas Muhs, from the company AC Immune in Lausanne, Switzerland, told Alzforum, “The safety data presented in the manuscript are quite convincing.”
In 2002 Elan Corporation halted trials of their active vaccine AN-1792 because six percent of patients developed meningoencephalitis, a form of brain inflammation (see ARF related news story). Many scientists believe this was due to auto-reactive T cell responses. To avoid this, most current active immunization strategies deliver a short N-terminal fragment of Aβ that does not trigger T cells (ARF related news story; and ARF related news story. This method may not generate a strong enough immune response, however, as B cells cannot produce antibodies without the involvement of T helper cells.
Agadjanyan and colleagues previously showed they could activate T cells by coupling a synthetic epitope recognized by T cells with the N-terminal fragment of Aβ, in either a peptide or DNA vaccine (see ARF related news story; ARF related news story). The DNA vaccine reduced soluble Aβ and amyloid plaques and restored memory in triple transgenic mice. To further boost the T cell response, particularly in elderly people who tend to have weaker immune systems, the researchers later added eight epitopes from common viruses such as tetanus and hepatitus B. This enhanced vaccine looked safe and effective in Tg2576 mice (see ARF related news story).
In the current paper, the authors extend the work to rhesus macaques. Monkeys and people share virtually the same major histocompatibility complex (MHC) class II proteins. These molecules present antigens to immune cells and are key mediators of the immune response. Co-first authors Claire Evans at Ichor Medical Systems, San Diego, California, and Hayk Davtyan at the Institute for Molecular Medicine, injected the DNA vaccine into the leg muscles of 10 monkeys three times over six weeks, using electroporation to induce cells to take up the DNA. Three additional monkeys received control vectors. Vaccinated monkeys developed strong anti-Aβ antibody titers, but no autoreactive cellular immune responses, the researchers report. Titers gradually waned over six months, but jumped back up when the researchers gave the animals booster injections. Isolating the anti-Aβ antibodies made by the macaques, the authors found they bound to plaques in AD brain, as well as to synthetic Aβ oligomers, fibrils, and monomers in vitro. They also protected cells from the cytotoxic effects of Aβ in culture.
Agadjanyan would like to test the vaccine in people. He is working with neurologists to design prevention trials. Agadjanyan pointed out that other epitopes, for example from tau or α-synuclein, could be added to the vaccine platform. In this way, the vaccine could simultaneously immunize against several pathogenic proteins.
Muhs suggested that future studies should characterize how the antibodies raised by this vaccine affect different forms of Aβ. Do they prevent oligomer-mediated toxicity, for example? He suggested further studies are needed to demonstrate in-vivo efficacy against amyloid pathology. Meanwhile, Morgan recommended that researchers avoid active vaccination until passive antibody immunization has been shown to help AD patients. Active immunization inherently carries more risk than passive, since it cannot be undone, Morgan said. He added, “I think it’s still an open question as to whether this approach would avoid the problems seen in the Elan trial. Even monoclonal antibodies, which elicit no T cell response, cause some adverse events.”—Madolyn Bowman Rogers
- Human Aβ Vaccine Snagged by CNS Inflammation
- Slow and Steady—Active Immunization Crawls Toward Promise
- Aβ Vaccine Leads to Safer Immune Response in Mice
- New Memory Cells from the Hippocampus?
- AD Immunotherapy: Toward Prevention, DNA-based Vaccines?
- Experimental AD Vaccine Hitches a Ride on Tetanus Toxin
- Evans CF, Davtyan H, Petrushina I, Hovakimyan A, Davtyan A, Hannaman D, Cribbs DH, Agadjanyan MG, Ghochikyan A. Epitope-based DNA vaccine for Alzheimer's disease: Translational study in macaques. Alzheimers Dement. 2013 Jul 31; PubMed.