Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
Research Technologies Branch, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2024 Jun 25;43(6):114285. doi: 10.1016/j.celrep.2024.114285. Epub 2024 May 30.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination.
前蛋白转化酶枯草溶菌素 9（PCSK9）是一种控制胆固醇动态平衡的血浆蛋白。在这里，我们设计了一种名为 HIT01 的人 PCSK9 模拟物，它与任何人类蛋白质都没有连续的 9 个残基，作为一种潜在的心脏病发作疫苗。用 HIT01 对小鼠进行免疫接种可分别降低 LDL 和胆固醇水平 40%和 30%。用 HIT01-K21Q-R218E（一种不易裂解的变体）对食蟹猴进行免疫接种可引发高滴度的 PCSK9 定向抗体反应，并在每次免疫接种后 2 周显著降低胆固醇血清水平。然而，HIT01-K21Q-R218E 免疫接种也会使血清 PCSK9 水平增加高达 5 倍，这可能是由于 PCSK9 结合抗体改变了 PCSK9 的半衰期。虽然用 PCSK9 模拟物进行疫苗接种可以诱导阻断 PCSK9 与 LDL 受体相互作用的抗体，但 PCSK9 结合抗体似乎改变了 PCSK9 的内稳态水平，从而影响了其疫苗的效果。然而，我们的结果表明了通过接种疫苗增加可溶性调节因子半衰期的一种机制。
