<p>Isolates and sequence data included in the study.</p>

Background Klebsiella pneumoniae causes ~20% of sepsis in neonates, with ~40% crude mortality. A vaccine administered to pregnant women, protecting against ≥70% of K. pneumoniae infections, could avert ~400,000 cases and ~80,000 deaths annually, mostly in Africa and South Asia. Vaccine formulations targeting the capsular polysaccharide (K) or lipopolysaccharide (O) antigens are in development. Global K. pneumoniae populations display extensive K and O diversity, necessitating a polyvalent vaccine targeted to the serotypes associated with neonatal disease in relevant geographical regions. We investigated the prevalence of K and O types associated with neonatal sepsis in Africa and South Asia to inform maternal vaccine design. Methods and findings We analysed 1,930 K. pneumoniae neonate blood isolates from 13 surveillance studies across 35 sites in 13 countries. We used pathogen whole-genome sequencing to predict K and O serotypes and adjust for local transmission clusters, and Bayesian hierarchical meta-analysis to estimate K and O prevalence overall and per region, treating site as a random effect. Eighty-seven K loci were identified. KL2, KL102, KL25, KL15, and KL62 accounted for 49% of isolates. We estimate that 20 K loci, combining the eight most prevalent per region, could cover 72.9% of all infections (95% credible interval: [69.4%, 76.5%]) and ≥70% in each of Eastern, Western, and Southern Africa and South Asia. Preliminary findings from three sites suggested sufficient temporal stability of K loci to maintain 20-valent K vaccine coverage over 5–10 years, but more longitudinal data are needed to support this prediction. O types were far less diverse (n = 14 types). We estimate the top-5 (O1⍺β,2⍺, O1⍺β,2β, O2⍺, O2β, and O4) would cover 86.2% [82.6, 89.9%] of total infections (76%–92% per region), while the top-10 would cover ~99% of infections in all four regions. The main limitations of our study are the reliance on genome sequences to predict K and O serotypes (as serological typing is not available) and a lack of longitudinal data to explore stability of antigen prevalence over time. Conclusions Neonatal sepsis is associated with diverse K and O types, with substantial geographic and temporal variation even after adjusting for localised transmission clusters. Despite this, a single 20-valent K vaccine could theoretically cover ≥70% of infections in all target regions. Locally-targeted vaccines could achieve higher coverage with lower valency, but are less feasible. In principle, very high coverage could be achieved with lower valency O-based vaccines, however, the protective efficacy against disease of antibodies targeting the O antigen remains uncertain. Further research is needed on cross-reactivity, antigen exposure, and stability of antigens over time, to better inform vaccine development.研究背景 肺炎克雷伯菌（Klebsiella pneumoniae）引发约20%的新生儿败血症，粗死亡率达40%。若为孕妇接种可预防≥70%肺炎克雷伯菌感染的疫苗，每年可避免约40万例感染、8万例死亡，其中绝大多数病例与死亡发生在非洲与南亚。当前针对荚膜多糖（capsular polysaccharide，简称K）或脂多糖（lipopolysaccharide，简称O）抗原的疫苗配方正处于研发阶段。全球肺炎克雷伯菌种群展现出广泛的K与O抗原多样性，因此需要开发针对相关地理区域内引发新生儿疾病的血清型的多价疫苗。本研究旨在明确非洲与南亚地区与新生儿败血症相关的K与O血清型的流行情况，为母体疫苗研发提供依据。 研究方法与结果 本研究分析了来自13个国家35个研究点的13项监测研究中的1930株肺炎克雷伯菌新生儿血液分离株。采用病原菌全基因组测序预测K与O血清型，并对局部传播集群进行校正；同时采用贝叶斯分层荟萃分析（Bayesian hierarchical meta-analysis）估算总体及各区域的K与O血清型流行率，将研究点作为随机效应。本研究共鉴定出87个K基因座。KL2、KL102、KL25、KL15与KL62占分离株总数的49%。研究估算，结合各区域前8种最流行的K基因座的20价疫苗，可覆盖72.9%的所有感染病例（95%置信区间：[69.4%, 76.5%]），在东非、西非、南非以及南亚各区域的覆盖度均≥70%。来自3个研究点的初步结果显示，K基因座具有足够的时间稳定性，可在5至10年内维持20价K疫苗的覆盖度，但需更多纵向数据以验证这一推测。O抗原型的多样性则低得多（共14种）。研究估算，排名前5的O型（O1⍺β,2⍺、O1⍺β,2β、O2⍺、O2β与O4）可覆盖86.2% [82.6, 89.9%]的总感染病例（各区域覆盖度为76%~92%），而排名前10的O型可覆盖所有四个区域中约99%的感染病例。本研究的主要局限性在于：仅能通过基因组序列预测K与O血清型（无法开展血清学分型），且缺乏纵向数据以探究抗原流行率随时间的稳定性。 研究结论 新生儿败血症与多样的K与O抗原型相关，即使在校正局部传播集群后，仍存在显著的地理与时间变异。尽管存在上述多样性，单一组分20价K疫苗理论上可在所有目标区域覆盖≥70%的感染病例。针对性本地的疫苗可在更低价数下实现更高的覆盖度，但可行性较差。原则上，基于O抗原的低价比疫苗可实现极高的覆盖度，但靶向O抗原的抗体对疾病的保护效力仍不明确。未来需开展更多关于交叉反应性、抗原暴露以及抗原随时间稳定性的研究，以更好地指导疫苗研发。