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 Neisseria gonorrhoeae 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 N. gonorrhoeae isolates deposited in the Neisseria 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 N. gonorrhoeae isolates globally. Phylogenetic analyses highlighted closely related antigen variants and additionally showed that AniA and FetB were the closest between N. gonorrhoeae and N. meningitidis. Up to 44% of N. meningitidis 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 N. gonorrhoeae 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 N. gonorrhoeae FA1090 strain emerges as a vaccine prototype, as it carries antigen sequence types identical to the most broadly distributed antigen variants.

中文翻译：

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淋球菌候选疫苗变异性的综合生物信息学评估

面对不断上升的抗生素耐药性，保护性疫苗是阻止淋病传播的唯一可行方法。然而，淋病奈瑟菌表面蛋白的臭名昭著的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，我们通过比较存放在Neisseria PubMLST 数据库中的 > 5,000 个临床淋病奈瑟菌分离株中的34 种淋病抗原候选物，对序列变异进行了全面的生物信息学分析。八种蛋白质抗原通过在大于 80% 的分离物中分布单个等位基因变体而表现出特殊的保守性。在>50% 的淋病奈瑟菌中，另外 18 种候选疫苗由 ≤3 个等位基因表示全球隔离。系统发育分析突出了密切相关的抗原变体，此外还显示 AniA 和 FetB 是淋病奈瑟菌和脑膜炎奈瑟菌之间最接近的。两种抗原的高达 44% 的脑膜炎奈瑟氏球菌等位基因具有提前终止密码子，表明存在差异表达。将多态性映射到 12 种抗原的可用三维结构揭示了低频表面多态性。PorB 和 TbpB 拥有许多高流行的多态性位点。虽然 TbpA 也是高度可变的，但仍然确定了保守的循环。高度的序列保守性，单一抗原变异体在淋病奈瑟菌中的分布全球菌株或表面环中的低频序列多态性使 ACP、AniA、BamA、BamE、MtrE、NspA、NGO0778、NGO1251、NGO1985、OpcA、PldA、Slam2 和 ZnuD 有望成为淋病疫苗的候选者。最后，常用的淋病奈瑟菌 FA1090 菌株作为疫苗原型出现，因为它携带的抗原序列类型与分布最广泛的抗原变体相同。