Precision Vaccination Against LDL Cholesterol Reduces Atherosclerotic Plaque in Mice

Vaccination technology has advanced to the point at which tiny fragments of a protein can be used to direct the adaptive immune system to attack very specific targets. In this case, the target is LDL cholesterol. Reducing the amount of LDL cholesterol in the bloodstream is a proven strategy to slow the onset and progression of atherosclerosis. In this condition, damaged lipids carried in the bloodstream irritate cells in the blood vessel wall, leading to a runaway process of inflammation and cell death that generates fatty plaques. These eventually lead to rupture or blockage of blood vessels that is severe enough to result in death. A global reduction in blood lipids - in cholesterol in the bloodstream - reduces the input of damaged lipids to this process.

In recent years the research community has broadened its efforts in this direction, moving beyond pharmaceuticals such as statins in order to find more efficient means of long-term reduction in blood lipids. Examples other than the vaccination approach noted here include PCSK9 gene therapies, or similar efforts that target other genes noted to significantly reduce cholesterol levels without side-effect in mammals. Diversity in research for any particular therapeutic goal is usually a good sign for future progress.

Researchers report successful vaccination of atherosclerotic mice with a small chunk of protein snipped out of "bad cholesterol." Vaccination reduced plaque levels in test mice, and other experiments with human blood samples identified the class of T cells likely responsible for positive outcomes. The results suggest that a comparable strategy could form the basis of a human vaccine. "We knew atherosclerosis had an inflammatory component but until recently didn't have a way to counteract that. We now find that our vaccination actually decreases plaque burden by expanding a class of protective T cells that curb inflammation."

So-called "bad cholesterol" is actually an amalgam of the lipid cholesterol carried on Low Density Lipoprotein, or "LDL". To create the new vaccine, the team engineered a short stretch (or peptide) of the core LDL protein. They then undertook a type of molecular fishing expedition, using a version of the peptide mounted on a scaffold called a tetramer as bait, to identify what immune cells became active in its presence. To do that, the researchers obtained human blood from two groups - women with plaque accumulation in their carotid arteries versus women without plaque formation - and screened those samples for immune cells that latched onto the peptide. In both groups, the peptide bound to subset of CD4+ T cells known as T regulatory cells (or "Tregs"). But the percentage of Tregs from atherosclerotic subjects was much smaller, and other types of T cells were much more common than in healthy donors, suggesting that the Tregs may undergo some kind of molecular switch that hampers their effectiveness once cardiovascular disease progresses.

Beyond addressing a major health concern, this paper exemplifies next-generation vaccinology. "We are now engineering vaccines to be more specific. Once we can manipulate the immune response with a single peptide or epitope, we will be able to create more highly targeted vaccines with fewer non-specific responses." These results is evidence that this goal is feasible against atherosclerosis, but more work is needed to create a vaccine appropriate for human use. A preventative, not just a treatment like statins, is needed to block plaque deposition, because atherosclerosis can go undiagnosed. "Men in their 50's with apparently normal cholesterol may be at risk, and seemingly healthy people occasionally suffer fatal heart attacks. Only then their docs realize they had atherosclerotic disease." A widely available vaccine that prevented plaque formation would make that scenario a thing of the past.



Rather than using CRISPR to disable the PCSK9 gene in the liver, it may just be cheaper and easier to use a Supramolecular Peptide Nanofiber vaccine that selectively raises an antibody response to the PCSK9 protein, but not a T cell response to the protein.

"Active immunotherapies raising antibody responses against autologous targets are receiving increasing interest as alternatives to the administration of manufactured antibodies. The challenge in such an approach is generating protective and adjustable levels of therapeutic antibodies while at the same time avoiding strong T cell responses that could lead to autoimmune reactions. Here we demonstrate the design of an active immunotherapy against TNF-mediated inflammation using short synthetic peptides that assemble into supramolecular peptide nanofibers. Immunization with these materials, without additional adjuvants, was able to break B cell tolerance and raise protective antibody responses against autologous TNF in mice. The strength of the anti-TNF antibody response could be tuned by adjusting the epitope content in the nanofibers, and the T-cell response was focused on exogenous and non-autoreactive T-cell epitopes. "

Posted by: Jim at April 13th, 2018 11:51 AM

Many ways being found to turn the immune system 'on', but now we need more ways to turn the damned thing off.

Posted by: Neal Asher at April 14th, 2018 2:04 AM

Does vaccine only prevent forming of new plaques or really cleares out the existing ones?

Posted by: Ariel at April 14th, 2018 8:07 AM

@Ariel: I think it probably takes some of the pressure off by reducing the pace of formation, allowing natural processes to catch up somewhat on clearing out existing plaque.

Posted by: Reason at April 14th, 2018 8:20 AM

It reduces plaque most likely by reducing the frequency of misfolded proteins (loss of proteostasis) and by the reduction of inflammation caused by protein debris etc... As reason suggests, this takes the pressure of the cleanup systems and allows plaque regression.

We will be covering this paper in our next Journal Club with Dr. Medvedik if you would care to join us.

Posted by: Steve Hill at April 15th, 2018 4:50 AM

Vaccination is a very expensive and ineffective approach to the treatment of atherosclerosis. There are cheaper and more effective ones, but they are for some reason ignored.
See Regression of atherosclerosis: lessons learned from genetically modified mouse models
Sebastian Zimmer, Alena Grebe, Siril S. Bakke et al., and Eicke Latz (2016). Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Science Translational Medicine: 8(333), 333ra50 DOI:10.1126/scitranslmed.aad6100

Posted by: Dmitry Dzhagarov at April 16th, 2018 1:07 AM
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