Hwang Wontae, Wantuch Paeton L, Bernshtein Biana, Zhiteneva Julia A, Slater Damien M, Vater Kian Hutt, Sridhar Sushmita, Oliver Elizabeth, Roach David J, Rao Sowmya R, Turbett Sarah E, Knoot Cory J, Harding Christian M, Amin Mohammed Nurul, Cross Alan S, LaRocque Regina C, Rosen David A, Harris Jason B
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
Department of Pediatrics, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO, USA.
Lancet Microbe. 2025 Apr;6(4):100988. doi: 10.1016/j.lanmic.2024.100988. Epub 2025 Feb 11.
Klebsiella pneumoniae is a leading cause of infection-related deaths globally, yet little is known about human antibody responses to invasive K pneumoniae. We sought to determine whether the O-specific polysaccharide antigen is immunogenic in humans with K pneumoniae bloodstream infection. We also sought to define the cross-reactivity of human antibody responses among structurally related K pneumoniae O-specific polysaccharide subtypes and to assess the effect of capsule production on O-specific polysaccharide-targeted antibody binding and function.
In this prospective cohort study, we compared plasma antibody responses to O-specific polysaccharide in a cohort of consecutively enrolled patients with K pneumoniae bloodstream infection with controls, specifically a cohort of healthy individuals and a cohort of individuals with Enterococcus spp bloodstream infection. Patients were enrolled at the Massachusetts General Hospital, a tertiary hospital with affiliated clinics in the USA. We excluded patients whose isolates were not confirmed to be K pneumoniae by whole-genome sequencing. The primary outcome was the measurement of plasma IgG, IgM, and IgA antibody responses. We performed flow cytometry to measure the effects of K pneumoniae capsule production on O-specific polysaccharide antibody binding and O-specific polysaccharide antibody-mediated complement deposition, using patient isolates with variable levels of capsule production and isogenic capsule-deficient strains derived from these isolates.
We enrolled 129 consecutive patients with suspected K pneumoniae bloodstream infection between July 24, 2021, and August 4, 2022, of whom 69 patients (44 [64%] male and 25 [36%] female) with confirmed K pneumoniae bloodstream infection were eligible for immunological evaluation. Common O-specific polysaccharide serotypes (O1, O2, O3, and O5) accounted for 57 (83%) of 69 infections. O-specific polysaccharide was immunogenic in patients with K pneumoniae bloodstream infection, and peak O-specific polysaccharide-IgG antibody responses in patients were ten-fold to 30-fold higher than antibody responses detected in healthy controls, depending on the serotype. There was cross-reactivity among similar O-specific polysaccharide subtypes, including the O1v1 and O1v2, O2v1 and O2v2, and O3 and O3b subtypes, as well as between the O1 and O2 types. Capsule produced by both hyperencapsulated and non-hyperencapsulated K pneumoniae inhibited O-specific polysaccharide-targeted antibody binding and function.
O-specific polysaccharide was immunogenic in patients with K pneumoniae bloodstream infection, supporting its potential as a candidate vaccine antigen. The cross-reactivity observed between similar O-specific polysaccharide subtypes in patients with K pneumoniae bloodstream infection suggests that it might not be necessary to include all subtypes in an O-specific polysaccharide-based vaccine. However, these observations are tempered by the fact that capsule production, even in non-highly encapsulated strains, has the potential to interfere with O-specific polysaccharide antibody binding. This finding could limit the effectiveness of vaccines that exclusively target O-specific polysaccharide.
National Institute of Allergy and Infectious Diseases at the National Institutes of Health.
肺炎克雷伯菌是全球感染相关死亡的主要原因之一，但对于人类针对侵袭性肺炎克雷伯菌的抗体反应知之甚少。我们试图确定O特异性多糖抗原在肺炎克雷伯菌血流感染患者中是否具有免疫原性。我们还试图明确人类抗体反应在结构相关的肺炎克雷伯菌O特异性多糖亚型之间的交叉反应性，并评估荚膜产生对O特异性多糖靶向抗体结合及功能的影响。
在这项前瞻性队列研究中，我们比较了连续入组的肺炎克雷伯菌血流感染患者队列中针对O特异性多糖的血浆抗体反应与对照组，具体为健康个体队列和肠球菌属血流感染个体队列。患者在美国一家设有附属诊所的三级医院——马萨诸塞州总医院入组。我们排除了经全基因组测序未确认分离株为肺炎克雷伯菌的患者。主要结局是测量血浆IgG、IgM和IgA抗体反应。我们使用具有不同荚膜产生水平的患者分离株及其衍生的同基因荚膜缺陷菌株，通过流式细胞术测量肺炎克雷伯菌荚膜产生对O特异性多糖抗体结合及O特异性多糖抗体介导的补体沉积的影响。
在2021年7月24日至2022年8月4日期间，我们连续入组了129例疑似肺炎克雷伯菌血流感染患者，其中69例确诊为肺炎克雷伯菌血流感染的患者（44例[64%]男性和25例[36%]女性）符合免疫评估条件。常见的O特异性多糖血清型（O1、O2、O3和O5）占69例感染中的57例（83%）。O特异性多糖在肺炎克雷伯菌血流感染患者中具有免疫原性，患者中O特异性多糖-IgG抗体反应峰值比健康对照中检测到的抗体反应高10倍至30倍，具体取决于血清型。相似的O特异性多糖亚型之间存在交叉反应，包括O1v1和O1v2、O2v1和O2v2、O3和O3b亚型，以及O1和O2型之间。高荚膜产生型和非高荚膜产生型肺炎克雷伯菌产生的荚膜均抑制O特异性多糖靶向抗体的结合及功能。
O特异性多糖在肺炎克雷伯菌血流感染患者中具有免疫原性，支持其作为候选疫苗抗原的潜力。在肺炎克雷伯菌血流感染患者中观察到的相似O特异性多糖亚型之间的交叉反应性表明，基于O特异性多糖的疫苗可能无需包含所有亚型。然而，这些观察结果因以下事实而受到影响：即使在非高荚膜产生菌株中，荚膜产生也有可能干扰O特异性多糖抗体结合。这一发现可能会限制仅靶向O特异性多糖的疫苗的有效性。
美国国立卫生研究院国家过敏和传染病研究所。
