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 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。该菌无症状定植的负担普遍较高，且常伴随多重耐药性，这对合并多种基础疾病或存在其他感染高危因素的人群而言是潜在的健康威胁。在美国广泛流行的碳青霉烯类耐药肺炎克雷伯菌多位点序列分型258（multilocus sequence type 258，ST258）菌株，可对多种临床常用抗生素类别产生耐药性，因此该菌株引发的感染往往难以治疗。鉴于此类感染亟需新型预防与/或治疗手段，我们构建了食蟹猕猴（cynomolgus macaques）的ST258肺炎模型，并评估了ST258 2型荚膜多糖（CPS2）疫苗缓解疾病严重程度的能力。与假接种组动物相比，经ST258 CPS2免疫的猕猴在支气管内接种10⁸菌落形成单位（CFUs）ST258菌株后24小时，通过X光影像评估的疾病严重程度显著更低。所有经CPS2免疫的猕猴最终均产生了ST258特异性抗体，这些抗体可显著增强血清杀菌活性，并在体外提升猕猴中性粒细胞对ST258的杀伤能力。与假接种的对照组猕猴相比，经CPS免疫的感染猕猴的感染肺组织中，编码炎症介质的转录本水平显著升高，这与针对CPS2的保护性免疫应答特征相符。综上，本研究数据支持ST258 CPS2疫苗可用于预防或缓解ST258引发的感染这一观点。与数十年前开展的相关研究一致，我们提出该策略可拓展至涵盖多时间序列下的多种荚膜类型。