National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing 400038, China.
Department of Clinical Hematology, College of Pharmacy, Army Medical University, Chongqing 400038, China.
Biomed Pharmacother. 2024 May;174:116611. doi: 10.1016/j.biopha.2024.116611. Epub 2024 Apr 20.
The emergence of drug-resistant strains of Klebsiella pneumoniae (K. pneumoniae) has become a significant challenge in the field of infectious diseases, posing an urgent need for the development of highly protective vaccines against this pathogen.
In this study, we identified three immunogenic extracellular loops based on the structure of five candidate antigens using sera from K. pneumoniae infected mice. The sequences of these loops were linked to the C-terminal of an alpha-hemolysin mutant (mHla) from Staphylococcus aureus to generate a heptamer, termed mHla-EpiVac. In vivo studies confirmed that fusion with mHla significantly augmented the immunogenicity of EpiVac, and it elicited both humoral and cellular immune responses in mice, which could be further enhanced by formulation with aluminum adjuvant. Furthermore, immunization with mHla-EpiVac demonstrated enhanced protective efficacy against K. pneumoniae channeling compared to EpiVac alone, resulting in reduced bacterial burden, secretion of inflammatory factors, histopathology and lung injury. Moreover, mHla fusion facilitated antigen uptake by mouse bone marrow-derived cells (BMDCs) and provided sustained activation of these cells.
These findings suggest that mHla-EpiVac is a promising vaccine candidate against K. pneumoniae, and further validate the potential of mHla as a versatile carrier protein and adjuvant for antigen design.
耐多药肺炎克雷伯菌（K. pneumoniae）的出现给传染病领域带来了巨大挑战，迫切需要开发针对这种病原体的高度保护性疫苗。
在这项研究中，我们基于感染肺炎克雷伯菌的小鼠血清，利用五种候选抗原的结构，鉴定了三个免疫原性的细胞外环。这些环的序列被连接到来自金黄色葡萄球菌的α-溶血素突变体（mHla）的 C 末端，以产生一种七聚体，称为 mHla-EpiVac。体内研究证实，与 mHla 融合显著增强了 EpiVac 的免疫原性，在小鼠中诱导了体液和细胞免疫反应，用铝佐剂配方可进一步增强这种反应。此外，与单独使用 EpiVac 相比，mHla-EpiVac 免疫可提高针对肺炎克雷伯菌通道的保护效力，从而降低细菌负荷、炎症因子的分泌、组织病理学和肺损伤。此外，mHla 融合促进了小鼠骨髓来源细胞（BMDCs）对抗原的摄取，并为这些细胞提供了持续的激活。
这些发现表明，mHla-EpiVac 是一种有前途的针对肺炎克雷伯菌的疫苗候选物，进一步验证了 mHla 作为一种多功能载体蛋白和佐剂用于抗原设计的潜力。
