Genomic Analysis of Salmonella Typhi from a Typhoid Conjugate Vaccine Trial

Background Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, continues to pose a major public health challenge in many low- and middle-income countries (LMICs). The World Health Organization recommended typhoid conjugate vaccine (TCV) use in countries with a high burden of disease, and/or high rates of antimicrobial resistance (AMR). Recent introductions of TCVs into national immunisation programmes are expected to substantially reduce this burden. In Malawi, a Phase 3, double-blind, randomized, controlled trial enrolled 28,130 healthy children aged 9 months through 12 years of age to receive either TCV (Typbar-TCV, Bharat Biotech) or meningococcal A conjugate vaccine (MCV). Methods To investigate the short-term evolutionary dynamics of S. Typhi after TCV vaccination, we conducted Illumina whole genome sequencing of bacterial isolates collected during a phase 3 randomized, controlled vaccine trial in Malawian children. We compared isolates from the TCV intervention arm to the MCV control arm with regard to: (i) S. Typhi lineage distribution, (ii) AMR profile, (iii) mutations in genes associated with Vi capsule biosynthesis and expression, and (iv) phylogenetic population structure.

背景 肠炎沙门氏菌伤寒血清型（Salmonella enterica serovar Typhi, S. Typhi）是伤寒热的病原体，目前仍是诸多低中收入国家（low- and middle-income countries, LMICs）面临的重大公共卫生挑战。世界卫生组织（World Health Organization）推荐在疾病负担较高或抗菌药物耐药性（antimicrobial resistance, AMR）高发国家使用伤寒结合疫苗（typhoid conjugate vaccine, TCV）。近期将TCV纳入国家免疫规划的举措预计将大幅降低这一疾病负担。在马拉维开展的一项三期双盲随机对照试验中，研究人员招募了28130名年龄介于9月龄至12岁的健康儿童，将其随机分为两组，分别接种Typbar-TCV（巴拉特生物技术公司Bharat Biotech生产的TCV）与A群脑膜炎球菌结合疫苗（meningococcal A conjugate vaccine, MCV）。
方法 为探究TCV接种后伤寒沙门氏菌的短期进化动态，我们对马拉维儿童三期随机对照疫苗试验中采集的细菌分离株开展了Illumina全基因组测序。我们从以下四个方面对比了TCV干预组与MCV对照组的分离株：(i) 伤寒沙门氏菌谱系分布；(ii) 抗菌药物耐药性谱；(iii) Vi荚膜生物合成与表达相关基因的突变；(iv) 系统发育群体结构。