Department of Enteric Infections, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.
EBioMedicine. 2021 Apr;66:103308. doi: 10.1016/j.ebiom.2021.103308. Epub 2021 Apr 1.
Diarrheal diseases are a leading cause of global morbidity and mortality affecting all ages, but especially children under the age of five in resource-limited settings. Shigella is a leading contributor to diarrheal diseases caused by bacterial pathogens and is considered a significant antimicrobial resistance threat. While improvements in hygiene, and access to clean water help as control measures, vaccination remains one of the most viable options for significantly reducing morbidity and mortality.
Flexyn2a is a bioconjugate vaccine manufactured using novel conjugation methodologies enzymatically linking the O-polysaccharide of S. flexneri 2a to exotoxin A of Pseudomonas aeruginosa. The protective capacity of Flexyn2a was assessed in a controlled human infection model after two intramuscular immunizations. Immune responses pre- and post-immunization and/or infection were investigated and are described here.
Flexyn2a induced lipopolysaccharide (LPS)-specific serum IgG responses post-immunization which were associated with protection against shigellosis. Additionally, several other immune parameters, including memory B cell responses, bactericidal antibodies and serum IgA, were also elevated in vaccinees protected against shigellosis. Immunization with Flexyn2a also induced gut-homing, LPS-specific IgG and IgA secreting B cells, indicating the vaccine induced immune effectors functioning at the site of intestinal infection.
Collectively, the results of these immunological investigations provide insights into protective immune mechanisms post-immunization with Flexyn2a which can be used to further guide vaccine development and may have applicability to the larger Shigella vaccine field.
Funding for this study was provided through a Wellcome Trust grant.
腹泻病是导致全球发病率和死亡率的主要原因，影响所有年龄段的人群，但在资源有限的环境中，尤其影响 5 岁以下儿童。志贺氏菌是细菌性病原体引起的腹泻病的主要病原体之一，被认为是严重的抗生素耐药威胁。虽然改善卫生条件和获得清洁水有助于作为控制措施，但疫苗接种仍然是显著降低发病率和死亡率的最可行选择之一。
Flexyn2a 是一种使用新型偶联方法制造的生物缀合物疫苗，通过酶将福氏志贺氏菌 2a 的 O-多糖与铜绿假单胞菌的外毒素 A 连接。在两次肌肉内免疫接种后，在受控的人体感染模型中评估了 Flexyn2a 的保护能力。本文描述了免疫接种前后和/或感染后的免疫反应。
Flexyn2a 诱导了免疫接种后的脂多糖（LPS）特异性血清 IgG 反应，与预防志贺氏菌病有关。此外，在预防志贺氏菌病的疫苗接种者中，还升高了其他几种免疫参数，包括记忆 B 细胞反应、杀菌抗体和血清 IgA。Flexyn2a 免疫接种还诱导了肠道归巢、LPS 特异性 IgG 和 IgA 分泌 B 细胞，表明疫苗诱导了在肠道感染部位发挥作用的免疫效应物。
这些免疫学研究的结果提供了 Flexyn2a 免疫接种后保护性免疫机制的见解，可用于进一步指导疫苗开发，并可能适用于更大的志贺氏菌疫苗领域。
本研究的资金由惠康信托基金提供。
