Louisiana State University Health Sciences Center, Department of Microbiology, Immunology, and Parasitology, 1901 Perdido St., New Orleans, LA 70112, USA.
Louisiana State University Health Sciences Center, Department of Microbiology, Immunology, and Parasitology, 1901 Perdido St., New Orleans, LA 70112, USA.
Vaccine. 2021 Jul 5;39(30):4099-4107. doi: 10.1016/j.vaccine.2021.06.001. Epub 2021 Jun 12.
The fungal genus Candida includes common commensals of the human mucosal membranes, and the most prevalently isolated species, C. albicans, poses a threat of candidemia and disseminated infection associated with an unacceptably high mortality rate and an immense $4 billion burden (US) yearly. Nevertheless, the demand for a vaccine remains wholly unfulfilled and increasingly pressing. We developed a double-peptide construct that is feasible for use in humans with the intention of preventing morbid infection by targeting epitopes derived from fructose bisphosphate aldolase (Fba) and methionine synthase (Met6) which are expressed on the C. albicans cell surface. To test the applicability of the design, we vaccinated mice via the intramuscular (IM) route with the conjugate denoted Fba-Met6 MP12 and showed that the vaccine enhanced survival against a lethal challenge. Because overall endpoint IgG1 and IgG2a antibody titers were robust and these mouse subclasses are associated with protective functionality, we investigated the potential of Fba and Met6 specific antibodies to facilitate the well-defined anti-Candida response by complement, which opsonizes fungi for degradation by primary effectors. Notably, reductions in the fungal burdens and enhanced survival were both abrogated in MP12-vaccinated mice that were pre-challenge dosed with cobra venom factor (CVF), a complement depleting factor. Altogether, we demonstrated that complement is relevant to MP12-based protection against disseminated C. albicans, delineating that a novel, multivalent targeted vaccine against proteins on the surface of C. albicans can enhance the natural response to infection.
假丝酵母属真菌包括人类黏膜的常见共生菌，其中最普遍分离到的物种白假丝酵母，对念珠菌血症和播散性感染构成威胁，相关死亡率高得不可接受，每年造成 40 亿美元（美国）的巨大负担。尽管如此，对疫苗的需求仍然完全未得到满足，而且越来越迫切。我们开发了一种双肽构建体，旨在针对来源于果糖二磷酸醛缩酶（Fba）和甲硫氨酸合酶（Met6）的表位，预防由其表达于白假丝酵母细胞表面引起的严重感染，该构建体对人类使用是可行的。为了测试设计的适用性，我们通过肌肉内（IM）途径用 Fba-Met6 MP12 缀合物对小鼠进行了疫苗接种，并表明该疫苗增强了对致死性挑战的存活能力。由于总体终点 IgG1 和 IgG2a 抗体滴度很高，而这些小鼠亚类与保护功能相关，因此我们研究了 Fba 和 Met6 特异性抗体的潜力，以通过补体促进明确的抗假丝酵母反应，补体使真菌被调理，以便主要效应物降解。值得注意的是，在预先用 cobra venom factor（CVF，一种补体耗竭因子）进行挑战前给药的 MP12 疫苗接种小鼠中，真菌负荷减少和存活能力增强都被消除。总之，我们证明了补体与基于 MP12 的播散性白假丝酵母菌保护有关，阐明了针对白假丝酵母表面蛋白的新型、多价靶向疫苗可以增强对感染的天然反应。
