Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA
mSphere. 2021 Feb 3;6(1):e00977-20. doi: 10.1128/mSphere.00977-20.
A protective vaccine is the only viable way to stop the spread of gonorrhea in the face of rising antibiotic resistance. However, the notorious phase and antigenic variation of surface proteins remains one of the challenges in vaccine development. To facilitate vaccine advancement efforts, we carried out comprehensive bioinformatic analyses of sequence variation by comparing 34 gonorrhea antigen candidates among >5,000 clinical isolates deposited in the PubMLST database. Eight protein antigens showed exceptional conservation by having a single allele variant distributed in >80% of isolates. An additional 18 vaccine candidates were represented by ≤3 alleles in >50% of isolates globally. Phylogenetic analyses highlighted closely related antigen variants and additionally showed that AniA and FetB were the closest between and Up to 44% of alleles for both antigens have premature stop codons, suggesting differential expression. Mapping polymorphisms to the available three-dimensional structures of 12 antigens revealed low-frequency surface polymorphisms. PorB and TbpB possessed numerous high-prevalence polymorphic sites. While TbpA was also highly variable, conserved loops were nonetheless identified. A high degree of sequence conservation, the distribution of a single antigen variant among strains globally, or low-frequency sequence polymorphisms in surface loops make ACP, AniA, BamA, BamE, MtrE, NspA, NGO0778, NGO1251, NGO1985, OpcA, PldA, Slam2, and ZnuD promising candidates for a gonorrhea vaccine. Finally, the commonly used FA1090 strain emerges as a vaccine prototype, as it carries antigen sequence types identical to the most broadly distributed antigen variants., the Gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. 's "superbug" status, its high morbidity, and the serious health impact associated with gonorrhea highlight the importance of vaccine development. One of the longstanding barriers to developing an effective vaccine against is the remarkable variability of surface-exposed antigens. In this report, we addressed this roadblock by applying extensive bioinformatic analyses to 34 gonorrhea antigen candidates among >5,000 clinical isolates. Our studies are important, as they reveal promising, conserved gonorrhea vaccine candidates and aid structural vaccinology. Moreover, these approaches are broadly applicable to other infectious diseases where surface antigen variability impedes successful vaccine design.
一种保护性疫苗是阻止淋病在抗生素耐药性日益严重的情况下传播的唯一可行方法。然而，表面蛋白的著名阶段和抗原变异仍然是疫苗开发的挑战之一。为了促进疫苗研发工作，我们通过比较 PubMLST 数据库中 >5000 个临床分离株中 34 种淋病抗原候选物，进行了全面的序列变异生物信息学分析。有 8 种蛋白质抗原的单一等位基因变异在 >80%的分离株中分布，表现出异常的保守性。另外 18 种疫苗候选物在全球 >50%的分离株中仅由 ≤3 个等位基因代表。系统发育分析突出了密切相关的抗原变异，此外还表明 AniA 和 FetB 之间的亲缘关系最接近。多达 44%的这两种抗原的等位基因都有过早的终止密码子，提示差异表达。将多态性映射到可用的 12 种抗原的三维结构上，揭示了低频率的表面多态性。PorB 和 TbpB 具有许多高流行的多态性位点。虽然 TbpA 也高度可变，但仍识别出保守环。高度的序列保守性、全球 菌株中单一抗原变异的分布或表面环中低频率的序列多态性使 ACP、AniA、BamA、BamE、MtrE、NspA、NGO0778、NGO1251、NGO1985、OpcA、PldA、Slam2 和 ZnuD 成为淋病疫苗的有前途的候选物。最后，常用的 FA1090 菌株作为疫苗原型出现，因为它携带与最广泛分布的抗原变异体相同的抗原序列类型。革兰氏阴性菌 是一种导致性传播感染淋病的细菌，被归类为研究和开发工作的高优先级病原体。由于其“超级细菌”的地位、高发病率以及与淋病相关的严重健康影响，疫苗的开发显得尤为重要。开发针对 有效疫苗的长期障碍之一是表面暴露抗原的显著变异性。在本报告中，我们通过对 >5000 个临床 分离株中的 34 种淋病抗原候选物进行广泛的生物信息学分析来解决这一障碍。我们的研究很重要，因为它们揭示了有前途的、保守的淋病疫苗候选物，并有助于结构疫苗学。此外，这些方法广泛适用于其他表面抗原变异性阻碍成功疫苗设计的传染病。
