Research and Development, Emergent BioSolutions Canada Inc., Winnipeg, MB, Canada.
Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
Front Immunol. 2022 May 17;13:893921. doi: 10.3389/fimmu.2022.893921. eCollection 2022.
has been acquiring multiple drug resistance and has evolved into superbugs such as Methicillin/Vancomycin-resistant (MRSA/VRSA) and, consequently, is a major cause of nosocomial and community infections associated with high morbidity and mortality for which no FDA-approved vaccines or biotherapeutics are available. Previous efforts targeting the surface-associated antigens have failed in clinical testing. Here, we generated hyperimmune products from sera in rabbits against six major toxins targeted by an experimental vaccine (IBT-V02) and demonstrated significant efficacy for an anti-virulence passive immunization strategy. Extensive binding and neutralizing titers were analyzed against six extracellular toxins from individual animal sera. All IBT-V02 immunized animals elicited the maximum immune response upon the first boost dose against all pore-forming vaccine components, while for superantigen (SAgs) components of the vaccine, second and third doses of a boost were needed to reach a plateau in binding and toxin neutralizing titers. Importantly, both anti-staphylococcus hyperimmune products consisting of full-length IgG (IBT-V02-IgG) purified from the pooled sera and de-speciated F(ab') (IBT-V02-F(ab')2) retained the binding and neutralizing titers against IBT-V02 target toxins. F(ab') also exhibited cross-neutralization titers against three leukotoxins (HlgAB, HlgCB, and LukED) and four SAgs (SEC1, SED, SEK, and SEQ) which were not part of IBT-V02. F(ab') also neutralized toxins in bacterial culture supernatant from major clinical strains of . efficacy data generated in bacteremia and pneumonia models using USA300 strain demonstrated dose-dependent protection by F(ab'). These efficacy data confirmed the staphylococcal toxins as viable targets and support the further development effort of hyperimmune products as a potential adjunctive therapy for emergency uses against life-threatening infections.
已经出现了多重耐药性，并进化成了耐甲氧西林/万古霉素的超级细菌（MRSA/VRSA）等，因此成为了医院和社区感染的主要原因，这些感染与高发病率和死亡率有关，而目前还没有获得 FDA 批准的疫苗或生物疗法。以前针对表面相关抗原的努力在临床测试中都失败了。在这里，我们从针对实验疫苗（IBT-V02）靶向的六种主要毒素的兔子血清中产生了超免疫产品，并证明了针对抗毒力被动免疫策略的显著疗效。对来自个体动物血清的六种细胞外毒素进行了广泛的结合和中和效价分析。所有接受 IBT-V02 免疫的动物在第一次加强剂量时都对所有孔形成疫苗成分产生了最大的免疫反应，而对于疫苗的超抗原（SAg）成分，需要第二次和第三次加强剂量才能达到结合和毒素中和效价的平台。重要的是，由来自混合血清的全长 IgG（IBT-V02-IgG）纯化而成的抗金黄色葡萄球菌超免疫产品和去特异性 F(ab')（IBT-V02-F(ab')2）保留了针对 IBT-V02 靶毒素的结合和中和效价。F(ab')还对三种白细胞毒素（HlgAB、HlgCB 和 LukED）和四种 SAg（SEC1、SED、SEK 和 SEQ）具有交叉中和效价，这些毒素不在 IBT-V02 范围内。F(ab')还中和了来自主要临床金黄色葡萄球菌株的细菌培养上清液中的毒素。使用 USA300 株在菌血症和肺炎模型中生成的疗效数据表明，F(ab')的剂量依赖性保护。这些疗效数据证实了葡萄球菌毒素是可行的靶标，并支持进一步开发超免疫产品作为针对危及生命的金黄色葡萄球菌感染的紧急用途的潜在辅助疗法。
