Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
mBio. 2021 Jun 29;12(3):e0122721. doi: 10.1128/mBio.01227-21.
Burkholderia pseudomallei is the causative agent of melioidosis, a fatal disease with a high mortality rate. The intrinsic resistance to commonly used antibiotics combined with the complex bacterial life cycle has hampered the development of preventive and therapeutic interventions and vaccines. Furthermore, the need of humoral and cell-mediated immunity in protection against B. pseudomallei has complicated the development of effective vaccines. Antigen delivery vaccine platforms that promote humoral and cellular responses while maintaining a safe profile are a roadblock to developing subunit vaccines against intracellular pathogens. Gold nanoparticles (AuNPs) were used for the delivery of multicomponent antigens with the goal of inducing vaccine-mediated immunity, promoting protection against melioidosis disease. Different nanoglycoconjugates using predicted immunogenic protein candidates, Hcp1, FlgL, OpcP, OpcP1, OmpW, and hemagglutinin, were covalently coupled to AuNPs, together with the lipopolysaccharide (LPS) from Burkholderia thailandensis, which acted as an additional antigen. Animals immunized with individually coupled (AuNP-protein-LPS) formulations containing OpcP or OpcP1, together with CpG as an adjuvant, showed a significant increase in protection, whereas a nanovaccine combination (AuNP-Combo2-LPS) showed significant and complete protection against a lethal intranasal B. pseudomallei challenge. Animals immunized with AuNP-Combo2-LPS showed robust humoral antigen-specific (IgG and IgA) responses with higher IgG2c titer, indicating a T1-skewed response and promotion of macrophage uptake. In addition, immunization with the nanovaccine combination resulted in a mixed antigen-specific T1-T17 cytokine profile after immunization. This study provides the basis for an elegant and refined multicomponent glycoconjugate vaccine formulation capable of eliciting both humoral and cell-mediated responses against lethal B. pseudomallei challenge. Melioidosis is a complex human disease associated with a wide range of complications caused by the Gram-negative bacillus Burkholderia pseudomallei. The global burden of melioidosis is estimated to have 165,000 cases per year and 89,000 fatal outcomes. The endemicity of B. pseudomallei includes a wide range of tropical regions in Asia, Africa, Latin America, and Australia. Therefore, a viable alternative to prevent human infections is the development of an effective vaccine; however, no approved vaccine for human use is available. This study provides a vaccine strategy against B. pseudomallei and an immune-stimulatory platform to induce strong humoral and T-cell-mediated immunity.
类鼻疽伯克霍尔德菌是类鼻疽病的病原体，这是一种致命疾病，死亡率很高。其对常用抗生素的固有耐药性，加上复杂的细菌生命周期，阻碍了预防和治疗干预措施以及疫苗的发展。此外，体液和细胞介导免疫在预防类鼻疽伯克霍尔德菌感染中的作用，使得有效疫苗的开发变得复杂。抗原传递疫苗平台在保持安全特性的同时促进体液和细胞反应，是开发针对细胞内病原体的亚单位疫苗的一个障碍。金纳米颗粒 (AuNPs) 被用于传递多种成分的抗原，以诱导疫苗介导的免疫，促进对类鼻疽病的保护。使用预测的免疫原性蛋白候选物 Hcp1、FlgL、OpcP、OpcP1、OmpW 和血凝素，将不同的纳米糖缀合物共价偶联到 AuNPs 上，同时加入来自伯克霍尔德菌泰国亚种的脂多糖 (LPS)，作为额外的抗原。用单独偶联（AuNP-蛋白-LPS）制剂免疫的动物，含有 OpcP 或 OpcP1，并加入 CpG 作为佐剂，显示出显著增加的保护作用，而纳米疫苗组合（AuNP-Combo2-LPS）显示出对致命的鼻内类鼻疽伯克霍尔德菌挑战的显著和完全保护。用 AuNP-Combo2-LPS 免疫的动物表现出针对抗原特异性（IgG 和 IgA）的强大体液反应，IgG2c 滴度更高，表明 T1 偏向反应和促进巨噬细胞摄取。此外，免疫接种纳米疫苗组合后，免疫后会产生混合的抗原特异性 T1-T17 细胞因子谱。这项研究为一种精致的多组分糖缀合物疫苗配方提供了基础，该配方能够针对致命的类鼻疽伯克霍尔德菌挑战，引发体液和细胞介导的反应。类鼻疽病是一种复杂的人类疾病，与革兰氏阴性杆菌类鼻疽伯克霍尔德菌引起的多种并发症有关。类鼻疽病的全球负担估计每年有 16.5 万例病例和 8.9 万例死亡。类鼻疽伯克霍尔德菌的流行范围包括亚洲、非洲、拉丁美洲和澳大利亚的广泛热带地区。因此，预防人类感染的可行替代方法是开发有效的疫苗；然而，目前尚无供人类使用的批准疫苗。本研究提供了一种针对类鼻疽伯克霍尔德菌的疫苗策略和一种免疫刺激平台，可诱导强烈的体液和 T 细胞介导的免疫。
