What are Cholesterol Vaccines?

Published

2 years ago

July 25, 2023

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By Syed S. A. Reviewed by Sophia Coveney

Low-density lipoproteins (LDLs)
PCSK9 gene
Therapeutic strategies
Inclisiran
References
Further reading

High levels of low-density lipoprotein (LDL) cholesterol can cause artery blockages and diseases like heart attacks and strokes. Further, it raises the risk of cardiovascular disease (CVD). Thickened arteries and veins with cholesterol. Image Credit: NPW-STUDIO/Shutterstock.com

Although medicine and lifestyle modifications can considerably lower LDL, a considerable portion of at-risk individuals who are receiving therapy nevertheless experience a cardiovascular event.

Vaccines targeting proprotein convertase subtilisin/kexin 9 (PCSK9), an important regulator of LDL receptors, can be highly beneficial. Low-density lipoproteins (LDLs)

There are five main forms of lipoprotein that transport cholesterol in the body's aqueous extracellular environment. The primary organ for the metabolism of cholesterol and control of plasma cholesterol levels is the liver.

When the liver repackages intrahepatic cholesterol into very low-density lipoprotein (VLDL), either through de novo synthesis or gut absorption, the process of LDL production starts.

Once in the bloodstream, VLDL is changed into more cholesterol-rich species, intermediate-density lipoprotein (IDL), and ultimately LDL, by the enzymes lipoprotein lipase and cholesteryl ester transfer protein (CETP). By clearing them through LDL receptors on the hepatic surface, the liver predominantly controls the quantity of these circulating lipoprotein types.

LDL receptors (LDL-R), highly expressed in hepatocytes, interact with LDL in plasma to remove it from circulation. LDL is endocytosed and undergoes lysosomal degradation as a result of LDL-R binding. LDL-R is then recycled back to the cell surface after this procedure.

Circulating LDL particles can pass through the endothelium of artery walls, where they can oxidize, cause inflammation, and damage the adjacent smooth muscle cells and overlaying endothelium. PCSK9 gene

PCSK gene forms a protein that helps control the quantity of cholesterol in the bloodstream. The body produces cholesterol, a waxy, fatty molecule, and it can also be consumed through foods that contain animals.

The quantity of low-density lipoprotein receptors, which are proteins on the surface of cells, is regulated by the PCSK9 protein. These receptors are essential for controlling the amount of cholesterol in the circulation.

Low-density lipoproteins (LDLs), the main transporters of cholesterol in the blood, attach to the receptors. The liver, which removes the majority of extra cholesterol from the body, contains a lot of low-density lipoprotein receptors.

The rate at which cholesterol is eliminated from the bloodstream depends on the quantity of low-density lipoprotein receptors on the surface of liver cells. More cholesterol can stay in the bloodstream because the PCSK9 protein destroys low-density lipoprotein receptors before they reach the cell surface. Cholesterol testing. Image Credit: megaflopp/Shutterstock.com Therapeutic strategies

The finding that the LDL receptor is encouraged to degrade by the PCSK9 opened up a new method for regulating plasma LDL cholesterol levels. Monoclonal antibodies were the mainstay of the initial therapeutic strategies to lower PCSK9 levels in circulation. Related StoriesSelection bias in women's health studies may mask earlier onset menopause for Black and Hispanic womenHow does your Skin Change during Menopause?Endocrine Society's new Scientific Statement focuses on endocrine-related changes and aging

Alirocumab, evolocumab, and inclisiran are three pharmaceuticals that can lower PCSK9 activity and are offered in the US. Fully humanized monoclonal antibodies that are injected subcutaneously every 2 to 4 weeks, alirocumab and evolocumab, are very effective at reducing both total and LDL cholesterol.

They typically lower LDL cholesterol levels by 50% to 60%, whether used as monotherapy or in conjunction with a statin. As long as the treatment is given, the effect lasts.

FDA-approved bempedoic acid, a non-statin medication, lowers LDLc by blocking ATP citrate lyase, a crucial enzyme in the process that produces cholesterol. It is administered to patients in the US who have established atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia.

Another oral chemical, gemcabene calcium, has been tested in rat experiments for its lipid-lowering actions that are not dependent on PPARs (peroxisome proliferator-activated receptor alpha). In male rats, this chemical reduced LDLc, TG, and apolipoprotein C-III levels. It is currently being researched. Inclisiran

A small interfering RNA (siRNA) called inclisiran prevents PCSK9 from being synthesized inside cells. When given to people taking the highest dosage of a statin, inclisiran cuts LDL cholesterol by 50%.

In one study, two doses of 284 mg of inclisiran, or 300 mg of inclisiran sodium, given on days 1 and 90, resulted in a 52.6% reduction in LDL cholesterol at 180 days.

Data from the same trial followed the same patients for 360 days. It was revealed that inclisiran might offer long-lasting reductions in LDL cholesterol levels, with the possibility of a once-every-six-month treatment regimen.

In another study, patients with atherosclerotic cardiovascular disease (ORION-10 trial) and those with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent were enrolled in a trial. Patients were also enrolled in the ORION-10 trial. Even though they were taking statin medication at the maximum tolerable dose, their LDL cholesterol levels were increased. A subcutaneous injection of inclisiran (284 mg) or a placebo was given to patients randomly in a 1:1 ratio on day 1, day 90, and then every six months for a total of 540 days.

There were two coprimary endpoints in each trial. First was the placebo-corrected percentage change in LDL cholesterol level from baseline to 510th day. Second was the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.

Although injection-site adverse events were more frequent with inclisiran than with placebo, the reactions were typically mild, and none were severe or persistent. Overall, adverse events were comparable between the inclisiran and placebo groups in each trial.

With inclisiran, given subcutaneously every six months, LDL cholesterol levels were reduced by about 50%. According to the investigation, inclisiran can be dosed sparingly to achieve long-lasting drops in LDL cholesterol levels.

Further understanding of the LDL mechanism and the trial of different therapeutic agents in patients can add to the existing therapy. References Pokhrel B, Yuet WC, Levine SN (2023). PCSK9 Inhibitors. [Updated 2022 May 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448100/ Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP. (2020). ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Crismaru I, Pantea Stoian A, Bratu OG, Gaman MA, Stanescu AMA, Bacalbasa N, Diaconu CC (2020). Low-density lipoprotein cholesterol lowering treatment: the current approach. Lipids Health Dis. May 6;19(1):85. doi: 10.1186/s12944-020-01275-x. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ (2017). Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Pan Y, Zhou Y, Wu H, Chen X, Hu X, Zhang H, Zhou Z, Qiu Z, Liao Y. (2017). A Therapeutic Peptide Vaccine Against PCSK9. Sci Rep. Oct 2;7(1):12534. doi: 10.1038/s41598-017-13069-w. Wadhera RK, Steen DL, Khan I, Giugliano RP, Foody JM (2016). A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. May-Jun;10(3):472-89. doi: 10.1016/j.jacl.2015.11.010. Crossey E, Amar MJA, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT (2015). A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. Oct 26;33(43):5747-5755. doi: 10.1016/j.vaccine.2015.09.044. PCSK9 gene. [Online]. Medline Plus. Available at: https://medlineplus.gov/genetics/gene/pcsk9/

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Last Updated: Jul 24, 2023

Sports

Sources: Rangers, Mets to swap Semien, Nimmo

Published

2 hours ago

November 23, 2025

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Sources: Rangers, Mets to swap Semien, Nimmo

The New York Mets and Texas Rangers have agreed to a trade that would send second baseman Marcus Semien to the Mets and outfielder Brandon Nimmo to the Rangers, sources told ESPN on Sunday.

Nimmo agreed to waive his no-trade clause, sources said, allowing the deal to be consummated, pending MLB approval. His tenure with the Mets started when they chose him with the 13th overall pick in the 2011 draft.

Semien, a three-time All-Star, joined the Rangers in 2022 and won a World Series with them the next season.

Texas entered the offseason looking for areas to save money, with its payroll being cut and four players — Semien, shortstop Corey Seager, and right-handers Jacob deGrom and Nathan Eovaldi — set to make in excess of $25 million next year. While the Rangers will actually take on more long-term money in Nimmo, who is owed $101.25 million over the next five seasons, the per-year sum is lower, with Semien set to make $72 million for the next three seasons.

The trade is the first move in what’s expected to be a busy winter for both teams — particularly the Mets. As a result of the team’s slow collapse over the season’s final 3½ months, New York missed the postseason and eventually underwent significant turnover in its coaching staff. The acquisition of Semien — who won a Gold Glove this year — aligns with president of baseball operations David Stearns’ primary goal this winter of improving run prevention.

World

US hails ‘tremendous progress’ on Ukraine peace plan – but says negotiators ‘need more time’

Published

4 hours ago

November 23, 2025

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US hails 'tremendous progress' on Ukraine peace plan - but says negotiators 'need more time'

The US secretary of state has hailed a “tremendous amount of progress” on peace talks after the US and Ukraine delegations met in Geneva – but said that negotiators would “need more time”.

Marco Rubio said the meetings in Switzerland on Sunday have been “the most productive and meaningful” of the peace process so far.

He said the US was making “some changes” to the peace plan, seemingly based on Ukrainian suggestions, “in the hopes of further narrowing the differences and getting closer to something that both Ukraine and obviously the United States are very comfortable with”.

Mr Rubio struck an optimistic tone talking to the media after discussions but was light on the details, saying there was still work to be done.

“I don’t want to declare victory or finality here. There’s still some work to be done, but we are much further ahead today at this time than we were when we began this morning and where we were a week ago for certain,” Mr Rubio said.

He also stressed: “We just need more time than what we have today. I honestly believe we’ll get there.”

Sky News’ defence analyst Michael Clarke said on the initial US-Russian 28-point peace plan that it was Donald Trump against the world, with maybe only Moscow on his side.

Mr Rubio praised the Ukrainian attitude towards the talks and said Mr Trump was “quite pleased” after he previously said in a social media post that Ukraine’s leaders had expressed “ZERO GRATITUDE” for US efforts.

Ukrainian President Volodymyr Zelenskyy said in his nightly address on Sunday that there are signs that “President Trump’s team hears us”.

In a news release on Sunday evening, the White House said the day “marked a significant step forward”.

“Ukrainian representatives stated that, based on the revisions and clarifications presented today, they believe the current draft reflects their national interests and provides credible and enforceable mechanisms to safeguard Ukraine’s security in both the near and long term,” it claimed.

Despite diplomatic progress in Geneva the finish line remains a long way off

John Sparks

International correspondent

@sparkomat

We’ve witnessed a day of determined and decidedly frantic diplomacy in this well-heeled city.

Camera crews were perched on street corners and long convoys of black vehicles swept down Geneva’s throughfares as the Ukrainians worked hard to keep the Americans on side.

Secretary of state Marco Rubio did not want to go into details at a press “gaggle” held at the US Mission this evening, but he seemed to think they had made more progress in the last 96 hours than the previous 10 months combined.

The Ukrainian leader Volodymyr Zelenskyy also seemed satisfied enough, posting on Telegram that there were “signals President Trump’s team is hearing us” after a day of “numerous meetings and negotiations”.

That said, we are a long way from the finish line here – something Rubio acknowledged when he said that any proposal agreed here would have to be handed over to the Russians.

At that point, negotiations to stop the war would surely get tougher.

President Putin has shown little or no inclination to stop the conflict thus far.

This, then, is the most important reason the Ukrainians seem determined to keep the Americans on side.

European leaders have presented a counter proposal to the widely criticised US-Russian peace plan, with suggestions including a cap on Ukraine’s peacetime army and readmitting Moscow into the G8.

This will only take place if the plan is agreed to by the US, Russia and Ukraine, and the G7 signs off on the move. Russia was expelled after annexing Crimea in 2014.

The counter proposal also includes US guarantees to Ukraine that mirror NATO’s Article 5 – the idea that “an armed attack against one NATO member shall be considered an attack against them all”.

The initial peace plan was worked up by the White House and Kremlin without Ukraine’s involvement, and it acquiesces to many of Russia’s previous demands.

It covers a range of issues – from territorial concessions to reconstruction programmes, the future Ukrainian relationship with NATO and the EU, and educational reforms in both Ukraine and Russia.