A paper in npj vaccines in September 2023 presents the results of a study assessing the efficacy of VLP-based vaccines displaying linear peptides from PCSK9 in reducing cholesterol levels in non-human primates. The authors state that elevated low-density lipoprotein cholesterol (LDL-C) is an “important risk factor” in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown promise in reducing elevated LDL-C levels. Thus, the team evaluated the cholesterol-lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes identified within the LDL receptor binding domain of PCSK9.  

Why is cholesterol important? 

The paper suggests that cardiovascular disease (CVD) is the “leading cause of global mortality”, responsible for about 19 million deaths in 2020. For atherosclerotic cardiovascular disease (ASCVD), elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) are a “major risk factor”.  

“Reducing levels of circulating LDL-C can lower the risk of ASCVD.” 

LDL is sometimes known as “bad cholesterol”, but it comprises “most” of the body’s cholesterol. 

Treatment targets 

Although statins are usually used to decrease LDL-C levels and the risk of cardiovascular events, their effectiveness “varies amongst individuals”. They are “generally well-tolerated” but can be associated with “serious adverse effects”; these “limitations” have prompted the development of non-statin lipid-lowering therapies.  

LDL-C is taken out of circulation by the low-density lipoprotein receptor (LDL-R), most abundantly expressed in the liver. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serum-associated secretory protein that “directly inhibits the recycling of LDL-R”. In doing so it “mediates higher levels of circulating LDL-C”. It has therefore become a “major therapeutic target” for preventing ASCVD by “lowering circulating LDL-C”.  

The research team identifies three FDA-approved PCSK9 therapies that effectively reduce LDL-C levels in combination with statins. However, “both mAb- and siRNA-based PCSK9 inhibitors are expensive”.  

Enter: vaccines 
“Vaccines are another promising approach for modulating PCSK9 activity. Vaccines have several potential advantages over other therapeutic approaches; they are relatively inexpensive to produce, which could reduce patient costs, and they will likely require fewer doses, potentially increasing patient compliance.”  

The authors recognise that the immunological mechanisms of self-tolerance “normally restrict the ability to induce antibody responses against self-antigens” like PCSK9. However, these can be overcome by displaying self-antigens at “high density” on the surface of nanoparticle-based vaccine platforms, like virus-like particles (VLPs). These have been validated as an approach in trials.  

The study 

Previously, the team engineered VLP-based vaccines that displayed different linear peptides from human PCSK9 that were “predicted to interact with LDL-R”. Several vaccine candidates were identified. This study expands on this by testing the efficacy of two VLP-based vaccines that display two species-specific linear peptides from PCSK9 in “multiple animal models”. There were several ways that the study extended preliminary studies: 

  • Evaluated the immunogenicity of VLP-based PCSK9 vaccines that targeted species-specific PCSK9 sequences and confirmed they could “break immunological tolerance” 
  • Showed that PCSK9 VLP vaccines could lower cholesterol levels in the LDLR+/- mice, which had “elevated cholesterol levels” 
  • Compared the efficacy of vaccines targeting individual PCSK9 epitopes and bivalent vaccines targeting multiple epitopes, demonstrating that there are “important differences in how these vaccines affect circulating PCSK9 levels” 
  • Measured the longevity of anti-PCSK9 antibodies in mice and macaques 
  • Evaluated the efficacy of lead PCSK9 vaccines in lowering LDL-C in larger groups of non-human primates, both with and without statin co-administration 
“These studies identified a PCSK9 vaccine regimen that induces long-lived anti-PCSK9 antibody responses and effectively lowers circulating LDL-C in primates without requiring co-administration of statins.”  

The paper concludes that a bivalent vaccine comprising VLPs displaying two different PCSK9-derived peptides can induce robust anti-PCSK9 antibody responses, decrease serum PCSK9 levels, increase liver-expressed LDL-R, and efficiently lower cholesterol levels in mice and macaques.  

“These findings strongly support the development of an alternative vaccine-based approach for inhibiting PCSK9 activity and lowering LDL-C.”  

Do you think vaccine-based approaches can be developed to meet the medical need presented by LDL-C levels?  

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