Live attenuated non-transmissible (LANT) Klebsiella pneumoniae vaccines

项目摘要 最近的一项研究表明，约有495万例死亡与细菌抗菌素耐药性有关。 (AMR)其中包括约127万例可归因于细菌AMR的死亡。肺炎克雷伯菌， 在住院、免疫抑制和慢性病患者中通常引起肺炎和败血症， 占AMR相关死亡的17.5%，占AMR所致死亡的19.9%。由于 随着抗生素管道的减少，需要其他针对这些感染的方法。我们建议发展 K.肺炎疫苗，以防止这些感染的发生，从而减少对抗菌药物的需求。 治疗和阻断病原体传播。在这里，我们描述了一个活的减毒克雷伯氏菌的发展。 肺炎疫苗具有优异的安全性和耐受性，同时保持免疫原性。的主要目标 目前的应用是为了证明我们可以开发活的口服K。安全性好的肺炎疫苗 由于降低了传播的可能性，在此称为减毒活病毒非传播性（LANT） 疫苗。为了实现这一目标，我们将基因工程活减毒K。肺炎候选疫苗 其中阿拉伯糖控制的必需单链DNA结合蛋白（SSB）的合成严格限制了 疫苗接种后的复制。我们还将确定我们是否可以通过以下方式实现广泛的保护： 被膜下抗原我们将完成评估体内持久性的临床前安全性和有效性研究， 免疫原性和候选K的保护效力。肺炎LANT疫苗。结束时 的这个项目，我们预计表明，一个优化的K。肺炎LANT疫苗停止复制， 在体外和体内不存在阿拉伯糖，但仍具有免疫原性， 用野生型K.肺炎。如果我们取得成功，这些成果将为发展铺平道路 具有广泛保护性、安全性和免疫原性的K.肺炎疫苗。

PROJECT SUMMARY A recent study showed that there were ~4.95 million deaths associated with bacterial antimicrobial resistance (AMR) in 2019 which included ~1.27 million deaths attributable to bacterial AMR. Klebsiella pneumoniae, which commonly causes pneumonia and sepsis in hospitalized, immunosuppressed, and chronically ill patients, was responsible for 17.5% of the deaths associated with AMR and 19.9% of the deaths attributable to AMR. Due to the dwindling antibiotic pipeline, other approaches to target these infections are needed. We propose to develop K. pneumoniae vaccines to prevent these infections from occurring, thereby reducing the need for antimicrobial therapy and interrupting pathogen transmission. Here, we describe development of a live attenuated K. pneumoniae vaccine with excellent safety and tolerability while maintaining immunogenicity. The main goal of the current application is to show that we can develop live oral K. pneumoniae vaccines with excellent safety due to reduced potential for transmission, designated here as Live Attenuated Non-Transmissible (LANT) vaccines. To achieve this goal, we will genetically engineer a live attenuated K. pneumoniae candidate vaccine in which arabinose-controlled synthesis of the essential single stranded DNA-binding protein (SSB) strictly limits post-vaccination replication. We will also determine whether we can achieve broad protection mediated by subcapsular antigens. We will complete pre-clinical safety and efficacy studies assessing the in vivo persistence, immunogenicity, and protective efficacy of candidate K. pneumoniae LANT vaccines in mice. At the conclusion of this project, we anticipate demonstrating that an optimized K. pneumoniae LANT vaccine stops replicating in the absence of arabinose in vitro as well as in vivo but is still immunogenic and can protect animals against challenge with wild-type K. pneumoniae. If we are successful, these results will pave the way for development of a broadly protective, safe and immunogenic K. pneumoniae vaccine.