Pfizer Vaccine Research and Development, Pearl River, New York, USA.
Microbiol Spectr. 2024 Jun 4;12(6):e0421323. doi: 10.1128/spectrum.04213-23. Epub 2024 May 3.
A US collection of invasive serotype O1 bloodstream infection (BSI) isolates were assessed for genotypic and phenotypic diversity as the basis for designing a broadly protective O-antigen vaccine. Eighty percent of the BSI isolate serotype O1 strains were genotypically ST95 O1:K1:H7. The carbohydrate repeat unit structure of the O1a subtype was conserved in the three strains tested representing core genome multi-locus sequence types (MLST) sequence types ST95, ST38, and ST59. A long-chain O1a CRM lattice glycoconjugate antigen was generated using oxidized polysaccharide and reductive amination chemistry. Two ST95 strains were investigated for use in opsonophagocytic assays (OPA) with immune sera from vaccinated animals and in murine lethal challenge models. Both strains were susceptible to OPA killing with O1a glycoconjugate post-immune sera. One of these, a neonatal sepsis strain, was found to be highly lethal in the murine challenge model for which virulence was shown to be dependent on the presence of the K1 capsule. Mice immunized with the O1a glycoconjugate were protected from challenges with this strain or a second, genotypically related, and similarly virulent neonatal isolate. This long-chain O1a CRM lattice glycoconjugate shows promise as a component of a multi-valent vaccine to prevent invasive infections.
The serotype O1 O-antigen serogroup is a common cause of invasive bloodstream infections (BSI) in populations at risk such as newborns and the elderly. Sequencing of US BSI isolates and structural analysis of O polysaccharide antigens purified from strains that are representative of genotypic sub-groups confirmed the relevance of the O1a subtype as a vaccine antigen. O polysaccharide was purified from a strain engineered to produce long-chain O1a O-antigen and was chemically conjugated to CRM carrier protein. The resulting glycoconjugate elicited functional antibodies and was protective in mice against lethal challenges with virulent K1-encapsulated O1a isolates.
对美国一组侵袭性 O1 血清型血流感染（BSI）分离株进行了基因和表型多样性评估，为设计广泛保护性 O 抗原疫苗奠定了基础。80%的 BSI 分离株 O1 血清型菌株在基因上为 ST95 O1:K1:H7 型。在所测试的三种代表核心基因组多位点序列类型（MLST）序列类型 ST95、ST38 和 ST59 的菌株中，O1a 亚型的碳水化合物重复单元结构是保守的。使用氧化多糖和还原胺化化学方法生成长链 O1a CRM 晶格糖缀合物抗原。使用来自接种动物的免疫血清对两种 ST95 菌株进行了调理吞噬测定（OPA）和小鼠致死性挑战模型研究。两种菌株均对 O1a 糖缀合物免疫后血清的 OPA 杀伤敏感。其中一株为新生儿败血症株，在小鼠挑战模型中具有高度致死性，其毒力依赖于 K1 荚膜的存在。用 O1a 糖缀合物免疫的小鼠可免受该菌株或另一种遗传上相关且同样具有毒力的新生分离株的挑战。这种长链 O1a CRM 晶格糖缀合物有望成为预防侵袭性感染的多价疫苗的组成部分。
O 血清型 O1 抗原血清群是新生儿和老年人等高危人群侵袭性血流感染（BSI）的常见原因。对美国 BSI 分离株进行测序和对代表遗传亚群的菌株 O 多糖抗原进行结构分析，证实了 O1a 亚型作为疫苗抗原的相关性。从一株经工程改造以产生长链 O1a O 抗原的菌株中纯化 O 多糖，并与 CRM 载体蛋白化学偶联。由此产生的糖缀合物引起了功能性抗体，并在小鼠中对具有毒力的 K1 包裹的 O1a 分离株的致死性挑战具有保护作用。
