Vaccine protection against multidrug-resistant Klebsiella pneumoniae in a non-human primate model of severe lower respiratory tract infection

Klebsiella pneumoniae is a human gut communal organism and notorious opportunistic pathogen. The relative high burden of asymptomatic colonization by K. pneumoniae is often compounded by multidrug resistance-a potential problem for individuals with significant comorbidities or other risk factors for infection. A carbapenem-resistant K. pneumoniae strain classified as multilocus sequence type 258 (ST258) is widespread in the United States and can be resistant to many classes of clinically useful antibiotics. Thus, treatment of ST258 infections is often difficult. Inasmuch as new preventive and/or therapeutic measures are needed for treatment of such infections, we developed an ST258 pneumonia model in cynomolgus macaques and tested the ability of an ST258 capsule polysaccharide type 2 (CPS2) vaccine to moderate disease severity. Compared with sham-vaccinated animals, those vaccinated with ST258 CPS2 had significantly less disease as assessed by radiograph 24 h after intrabronchial installation of 108 CFUs of ST258. All macaques vaccinated with CPS2 ultimately developed ST258-specific antibodies that significantly enhanced serum bactericidal activity and killing of ST258 by macaque neutrophils ex vivo. Consistent with a protective immune response to CPS2, transcripts encoding inflammatory mediators were increased in infected lung tissues obtained from CPS-vaccinated animals compared with control, sham-vaccinated macaques. Taken together, our data provide support to the idea that vaccination with ST258 CPS can be used to prevent or moderate infections caused by ST258. As with studies performed decades earlier, we propose that this approach can be extended to include multiple capsule types Overall design: time series

肺炎克雷伯菌（Klebsiella pneumoniae）是人类肠道共生菌群的常见成员，同时也是臭名昭著的条件致病菌。该菌无症状定植的相对高发率往往伴随多重耐药性，这对于伴有显著合并症或其他感染高危因素的个体而言，是一项潜在的临床难题。被归类为多位点序列分型258（multilocus sequence type 258, ST258）的碳青霉烯类耐药肺炎克雷伯菌菌株在美国广泛流行，且可对多种临床常用抗生素类别产生耐药性，因此ST258感染的治疗往往极具挑战性。
鉴于此类感染亟需新型预防及/或治疗手段，我们构建了食蟹猴（cynomolgus macaques）ST258肺炎感染模型，并测试了ST258荚膜多糖2型（capsule polysaccharide type 2, CPS2）疫苗对疾病严重程度的缓解效果。相较于假接种（sham-vaccinated）的对照动物，经ST258 CPS2免疫的食蟹猴在支气管内接种10^8菌落形成单位（colony-forming unit, CFU）的ST258后24小时，经影像学检查评估的病症显著减轻。所有经CPS2免疫的食蟹猴最终均产生了ST258特异性抗体，该抗体可显著增强血清杀菌活性，并在体外提升食蟹猴中性粒细胞对ST258的杀伤能力。与针对CPS2的保护性免疫应答相符，相较于假接种的对照食蟹猴，经CPS免疫的动物的感染肺组织中，编码炎症介质的转录本水平显著升高。综上，本研究数据支持"使用ST258 CPS疫苗可预防或缓解ST258引发的感染"这一结论。与数十年前开展的相关研究类似，我们提出该策略可扩展至覆盖多种荚膜血清型。
整体实验设计：时间序列实验