By Deborah Borfitz 

February 6, 2024 | Investigators with The University of New Mexico (UNM) and the National Institutes of Health (NIH) have succeeded in developing a cholesterol-lowering vaccine that works independently of statins. It could become the next vaccine-based approach targeting PCSK9 (proprotein convertase subtilisin/kexin type 9 serine protease) to enter clinical trials, according to Bryce Chackerian, Ph.D., professor in the department of molecular genetics and microbiology at the UNM Health Sciences Center.  

In a study with non-human primates, the vaccine lowered low-density lipoprotein (LDL) cholesterol levels by targeting two different parts of the PCSK9 protein, inducing antibodies interfering with its ability to regulate the amount of cholesterol in the bloodstream. The efficacy of the novel bivalent vaccine was recently reported in NPJ Vaccines (DOI: 10.1038/s41541-023-00743-6) and, Chackerian reports, the technology has been optioned to a pharmaceutical company. 

One of the chief advancements demonstrated in the study is the vaccine’s ability to break “immunological tolerance,” the mechanisms that impair the immune system to mount responses against self-antigens. It is not yet widely appreciated that vaccines can be designed to inhibit a protein made by the body, which the immune system is naturally reluctant to do. Autoimmunity is generally thought to be bad, says Chackerian, as is the case with rheumatoid arthritis and type 1 diabetes.  

As it turns out, the vaccine technology used here is “one of the most efficient ways of getting around those mechanisms... in terms of inducing antibody responses,” Chackerian says. To do this, researchers arrayed portions of PCSK9 at super-high density on the surface of virus-like particles (VLPs). 

The same technique can be used to prompt immune responses against almost anything, including pathogens and opioids, Chackerian adds. He has been working on the alternative vaccine-based approach for nearly 25 years, starting when he was a postdoctoral fellow at the NIH.  

In terms of safety of the immune responses, Chackerian continues, “we sort of stumbled on a target with PCSK9 that is perfect.” Antibodies against the protein don’t cause adverse effects, based on seven years of experience with real-world use of PCSK9 monoclonal antibodies. 

Market Need 

Even a small reduction in LDL cholesterol can have clinically significant effects, points out Chackerian. The PCSK9 monoclonal shot can reduce bad cholesterol levels by as much as 60% and, while the original price has dropped by more than half to roughly $6,000 annually, that is still more than some insurance companies will pay and most out-of-pocket payers can afford. “Given that somewhere around one-third of the population has elevated LDL cholesterol, it would bankrupt the healthcare system if everyone were on these PCSK9 inhibitors, so there is really strict [eligibility] criteria.” 

For Chackerian, the primary motivation for work on a PCSK9 vaccine is that “cardiovascular disease is not just a first-world issue... There is no way that people in the developing world are going to have the ability to access these drugs because of their expense.” 

Statin drugs, in contrast, are low cost or free for insured individuals and work for a large percentage of the population, he continues. But compliance can be problematic since people need to remember to take the pills daily. 

Other issues are that not everyone responds to statins, the effects are modest, and some people experience side effects such as muscle pain and damage. In low- and middle-income countries, statin use also tends to fall far below targets set by the World Health Organization (The Lancet Global Health, DOI: 10.1016/S2214-109X(21)00551-9). 

Several groups have been working on vaccines that modulate PCSK9 activity, says Chackerian. Among them are an Austrian tech company called AFFiRis AG whose vaccine technology demonstrated a modest reduction in LDL cholesterol in early-stage clinical trials (European Journal of Clinical Pharmacology, DOI: 10.1007/s00228-021-03149-2).  

Vaxxinity (Cape Canaveral, Florida) announced last March that it has initiated a phase 1 dose-escalation trial of its VXX-401 vaccine. Data in non-human primates showed that the vaccine was well tolerated and provided durable and significant LDL reduction of 30% to 50% change from baseline. 

Chackerian says that’s on par with the efficacy of the bivalent vaccine (which reduced cholesterol levels by 30%) but the responses were not quite as long-lived. “The big advantage of the vaccine-based approach is you don’t have to take that daily [statin] pill or get that [PCSK9 monoclonal] shot every four weeks.” 

Long-Lasting Effect 

In an earlier study (Vaccine, DOI: 10.1016/j.vaccine.2015.09.044), Chackerian and his team showed how their VLP-based vaccine targeting one region of the PCSK9 protein lowered cholesterol in a small group of nonhuman primates, “but it only seemed to work in combination with statins,” he says. By doubling that to two regions, the vaccine was optimized to induce a strong, long-lasting effect all on its own. 

The preclinical studies involved healthy monkeys with low LDL cholesterol levels, he notes. “It remains to be seen what sort of effects we’d see in humans who have high levels of LDL cholesterol.” 

Clinical trials will also be needed to pinpoint the threshold level of antibodies required to elicit a therapeutic effect. From the study with monkeys, whose immune response to vaccines is akin to humans, antibody levels dropped in half after about 20 weeks. 

The same sort of vaccine technology has been used in clinical trials by the now-defunct Swiss company Cytos, which was developing a hypertension vaccine that targeted angiotensin, as well as other groups directing their efforts at amyloid beta to fight Alzheimer’s disease, Chackerian says. When participants were vaccinated, the durability of their antibody response was comparable to what was seen in monkeys, providing “more evidence” that the longevity seen in the latest bivalent PCSK9 vaccine is going to be like what will be seen in humans.   

“The downside of vaccines is that one person might respond very strongly.... [while] another person might not, and so you have to take that into account when developing the boosting schedule,” says Chackerian. His guess is that people given the bivalent PCSK9 vaccine will need a booster shot somewhere between six and 12 months. The vaccine itself could likely be made for “tens of dollars a dose,” since the basis is a simple bacteriophage that can be produced using a relatively inexpensive bacterial expression system. 

Targeted Approach

To build the novel PCSK9 vaccine, researchers first looked at the protein’s structure to identify regions that actively interacted with the LDL receptor, says Chackerian. They then made an educated guess at which would be the best two to display on the surface of the vaccine platform.  

Targeting additional epitopes of PCSK9 would perhaps enhance the vaccine’s effectiveness even further, but two seems to be the sweet spot based on a preliminary cost/benefit analysis, Chackerian says. More isn’t necessarily better, he adds. As shown in prior studies, attaching antibodies to the entire surface of PCSK9 isn’t enough to block its function since an antibody can still bind to the wrong side of the protein. 

“We think... [an] approach targeting the part of the protein that is most critically involved in its function is probably the best approach,” says Chackerian. “The sort of reductions we’re seeing with the two sites are pretty good, so that’s what we’re going for.”  

Development efforts to date have had few impediments other than the COVID-19 pandemic, which temporarily limited access to macaques from primate research centers, he says. The major barrier currently is being a public university without the wherewithal to run the clinical trials required to bring the vaccine to market.  

But if the licensing option is exercised, and all goes well, the bivalent PCSK9 vaccine could start going into people as soon as the next three to five years. Not only are Good Manufacturing Practices for producing the vaccine well established, says Chackerian, approval by the Food and Drug Administration would also be based solely on LDL cholesterol lowering and not prevention of cardiovascular disease, which marketed PCSK9 inhibitors have proven ability to do.