Structure Guided Design of Bacteriophage Qβ Mutants as Next Generation Carriers for Conjugate Vaccines.
Structure Guided Design of Bacteriophage Qβ Mutants as Next Generation Carriers for Conjugate Vaccines.
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DOI：
10.1021/acschembio.1c00906
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发表时间：
2022-11-18
影响因子：
4
通讯作者：
Huang, Xuefei
中科院分区：
文献类型：
--
作者：
Sungsuwan, Suttipun;Wu, Xuanjun;Shaw, Vincent;Kavunja, Herbert;McFall-Boegeman, Hunter;Rashidijahanabad, Zahra;Tan, Zibin;Lang, Shuyao;Nick, Setare Tahmasebi;Lin, Po-han;Yin, Zhaojun;Ramadan, Sherif;Jin, Xiangshu;Huang, Xuefei
疫苗是治疗和预防疾病的重要工具。对于有效的结合疫苗来说，载体至关重要，但可用于临床应用的载体却很少。此外，目前蛋白质载体的一个缺点是结合疫苗会诱导高水平的针对载体的抗体，已知这会干扰针对靶抗原的免疫应答。为了克服这些挑战，我们获得了一种新兴蛋白质载体的近原子分辨率晶体结构，即噬菌体 Qβ 病毒样颗粒。根据详细的结构信息，设计了噬菌体Qβ（mQβ）的新型突变体，其与一类重要的肿瘤抗原肿瘤相关糖抗原（TACA）缀合后，引发了强大的抗TACA IgG反应，但与野生型Qβ-TACA缀合物相比，产生了较低水平的抗载体抗体。在针对小鼠侵袭性乳腺癌的治疗模型中，即使进行化疗，100% 未免疫的小鼠也会在短短 12 天内死于肿瘤。相比之下，用 mQβ-TACA 缀合物免疫的小鼠中有 80% 完全没有肿瘤。除了 TACA 之外，为了帮助开发预防 COVID-19 的疫苗，基于 mQβ 的结合疫苗已被证明可以诱导高水平的针对 SARS-CoV-2 病毒肽抗原的 IgG 抗体，证明了其通用性。因此，mQβ是一种有前途的下一代结合疫苗载体平台，基于结构的合理设计是开发新型疫苗载体的有力策略。
Vaccines are critical tools to treat and prevent diseases. For an effective conjugate vaccine, the carrier is crucial, but few carriers are available for clinical applications. In addition, a drawback of current protein carriers is that high levels of antibodies against the carrier are induced by the conjugate vaccine, which are known to interfere with the immune responses against the target antigen. To overcome these challenges, we obtained the near atomic resolution crystal structure of an emerging protein carrier, i.e., the bacteriophage Qβ virus like particle. On the basis of the detailed structural information, novel mutants of bacteriophage Qβ (mQβ) have been designed, which upon conjugation with tumor associated carbohydrate antigens (TACAs), a class of important tumor antigens, elicited powerful anti-TACA IgG responses and yet produced lower levels of anticarrier antibodies as compared to those from the wild type Qβ-TACA conjugates. In a therapeutic model against an aggressive breast cancer in mice, 100% unimmunized mice succumbed to tumors in just 12 days even with chemotherapy. In contrast, 80% of mice immunized with the mQβ-TACA conjugate were completely free from tumors. Besides TACAs, to aid in the development of vaccines to protect against COVID-19, the mQβ based conjugate vaccine has been shown to induce high levels of IgG antibodies against peptide antigens from the SARS-CoV-2 virus, demonstrating its generality. Thus, mQβ is a promising next-generation carrier platform for conjugate vaccines, and structure-based rational design is a powerful strategy to develop new vaccine carriers.
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