Rossi Omar, Citiulo Francesco, Giannelli Carlo, Cappelletti Emilia, Gasperini Gianmarco, Mancini Francesca, Acquaviva Alessandra, Raso Maria Michelina, Sollai Luigi, Alfini Renzo, Aruta Maria Grazia, Vitali Claudia Giorgina, Pizza Mariagrazia, Necchi Francesca, Rappuoli Rino, Martin Laura B, Berlanda Scorza Francesco, Colucci Anna Maria, Micoli Francesca
GSK Global Health Vaccines R&D (GVGH), Siena, Italy.
GSK Vaccines Srl, Siena, Italy.
NPJ Vaccines. 2023 Sep 5;8(1):130. doi: 10.1038/s41541-023-00725-8.
Shigellosis is a leading cause of diarrheal disease in low-middle-income countries (LMICs). Effective vaccines will help to reduce the disease burden, exacerbated by increasing antibiotic resistance, in the most susceptible population represented by young children. A challenge for a broadly protective vaccine against shigellosis is to cover the most epidemiologically relevant serotypes among >50 Shigella serotypes circulating worldwide. The GMMA platform has been proposed as an innovative delivery system for Shigella O-antigens, and we have developed a 4-component vaccine against S. sonnei, S. flexneri 1b, 2a and 3a identified among the most prevalent Shigella serotypes in LMICs. Driven by the immunogenicity results obtained in clinic with a first-generation mono-component vaccine, a new S. sonnei GMMA construct was generated and combined with three S. flexneri GMMA in a 4-component Alhydrogel formulation (altSonflex1-2-3). This formulation was highly immunogenic, with no evidence of negative antigenic interference in mice and rabbits. The vaccine induced bactericidal antibodies also against heterologous Shigella strains carrying O-antigens different from those included in the vaccine. The Monocyte Activation Test used to evaluate the potential reactogenicity of the vaccine formulation revealed no differences compared to the S. sonnei mono-component vaccine, shown to be safe in several clinical trials in adults. A GLP toxicology study in rabbits confirmed that the vaccine was well tolerated. The preclinical study results support the clinical evaluation of altSonflex1-2-3 in healthy populations, and a phase 1-2 clinical trial is currently ongoing.
志贺氏菌病是低收入和中等收入国家（LMICs）腹泻病的主要病因。有效的疫苗将有助于减轻疾病负担，而抗生素耐药性增加使这一负担在以幼儿为代表的最易感人群中更加严重。研发一种针对志贺氏菌病的广泛保护性疫苗面临的一个挑战是，要覆盖全球流行的50多种志贺氏菌血清型中与流行病学最相关的血清型。通用多价苗（GMMA）平台已被提议作为一种用于志贺氏菌O抗原的创新递送系统，我们已研发出一种针对宋内志贺氏菌、1b型、2a型和3a型福氏志贺氏菌的四组分疫苗，这些血清型在低收入和中等收入国家最常见的志贺氏菌血清型中被鉴定出来。在第一代单组分疫苗临床免疫原性结果的推动下，我们构建了一种新的宋内志贺氏菌GMMA，并将其与三种福氏志贺氏菌GMMA组合成四组分氢氧化铝配方（altSonflex1-2-3）。该配方具有高度免疫原性，在小鼠和兔子中没有负性抗原干扰的证据。该疫苗还诱导产生了针对携带与疫苗中不同O抗原的异源志贺氏菌菌株的杀菌抗体。用于评估疫苗配方潜在反应原性的单核细胞激活试验显示，与在多项成人临床试验中已证明安全的宋内志贺氏菌单组分疫苗相比没有差异。一项在兔子身上进行的GLP毒理学研究证实该疫苗耐受性良好。临床前研究结果支持在健康人群中对altSonflex1-2-3进行临床评估，目前一项1/2期临床试验正在进行。
