Table1_Comparison of Shigella GMMA and glycoconjugate four-component formulations in animals.DOCX

Shigellosis is leading bacterial cause of diarrhea with high prevalence in children younger than 5 years in low- and middle-income countries, and increasing number of reports of Shigella cases associated to anti-microbial resistance. No vaccines against Shigella are still licensed, but different candidates based on the O-antigen portion of lipopolysaccharides are in clinic. Generalized Modules for Membrane Antigens (GMMA) have been proposed as an alternative delivery system for the O-antigen, and a 4-component vaccine candidate (altSonflex1-2-3), containing GMMA from S. sonnei and S. flexneri 1b, 2a and 3a is being tested in a phase 1/2 clinical trial, with the aim to elicit broad protection against the most prevalent Shigella serotypes. Here, the 4-component GMMA vaccine candidate has been compared to a more traditional glycoconjugate formulation for the ability to induce functional antibodies in mice and rabbits. In mice, in the absence of Alhydrogel, GMMA induce higher IgG antibodies than glycoconjugates and stronger bactericidal titers against all Shigella serotypes. In the presence of Alhydrogel, GMMA induce O-antigen specific IgG levels similar to traditional glycoconjugates, but with a broader range of IgG subclasses, resulting in stronger bactericidal activity. In rabbits, GMMA elicit higher functional antibodies than glycoconjugates against S. sonnei, and similar responses to S. flexneri 1b, 2a and 3a, independently from the presence of Alhydrogel. Different O-antigen based vaccines against Shigella are now in clinical stage and it will be of particular interest to understand how the preclinical findings in the different animal models translate in humans.

志贺菌病（Shigellosis）是引发腹泻的首要细菌性病因，在低收入及中等收入国家的5岁以下儿童中患病率居高不下，且与抗菌药物耐药相关的志贺菌感染病例报告数量持续增加。
目前尚无获批上市的志贺菌病疫苗，但多款基于脂多糖（lipopolysaccharides, LPS）O抗原的候选疫苗正处于临床研发阶段。
膜抗原通用模块（Generalized Modules for Membrane Antigens, GMMA）被提议作为O抗原的新型递送系统，一款包含宋内志贺菌（S. sonnei）以及福氏志贺菌（S. flexneri）1b、2a、3a来源GMMA的四组分候选疫苗（altSonflex1-2-3）目前正开展1/2期临床试验，旨在诱导针对当前主流流行志贺菌血清型的广谱保护效力。
本研究将该四组分GMMA候选疫苗与传统糖结合疫苗配方进行对比，评估二者在小鼠和兔体内诱导功能性抗体的能力。
在未添加Alhydrogel佐剂的条件下，GMMA诱导产生的IgG抗体水平高于糖结合疫苗，且针对所有志贺菌血清型的杀菌滴度更强。
当添加Alhydrogel佐剂时，GMMA诱导产生的O抗原特异性IgG水平与传统糖结合疫苗相当，但可触发更广泛的IgG亚类应答，进而展现出更强的杀菌活性。
在兔体内实验中，无论是否添加Alhydrogel佐剂，GMMA诱导产生的针对宋内志贺菌的功能性抗体水平均高于糖结合疫苗；而针对福氏志贺菌1b、2a、3a的抗体应答水平则与糖结合疫苗相似。
当前已有多款基于O抗原的志贺菌疫苗进入临床试验阶段，明确不同动物模型中的临床前研究结果如何转化至人体临床应用，将具有重要的科研价值。