Department of Dermatology, Johns Hopkins University, Baltimore, MD, United States.
Integrated Biotherapeutics Inc., Rockville, MD, United States.
Front Immunol. 2024 Apr 3;15:1373367. doi: 10.3389/fimmu.2024.1373367. eCollection 2024.
is the leading cause of skin and soft tissue infections (SSTIs) in the U.S. as well as more serious invasive diseases, including bacteremia, sepsis, endocarditis, surgical site infections, osteomyelitis, and pneumonia. These infections are exacerbated by the emergence of antibiotic-resistant clinical isolates such as methicillin-resistant (MRSA), highlighting the need for alternatives to antibiotics to treat bacterial infections. We have previously developed a multi-component toxoid vaccine (IBT-V02) in a liquid formulation with efficacy against multiple strains of prevalent in the industrialized world. However, liquid vaccine formulations are not compatible with the paucity of cold chain storage infrastructure in many low-to-middle income countries (LMICs). Furthermore, whether our IBT-V02 vaccine formulations are protective against isolates from LMICs is unknown. To overcome these limitations, we developed lyophilized and spray freeze-dried formulations of IBT-V02 vaccine and demonstrated that both formulations had comparable biophysical attributes as the liquid formulation, including similar levels of toxin neutralizing antibodies and protective efficacy against MRSA infections in murine and rabbit models. To enhance the relevancy of our findings, we then performed a multi-dimensional screen of 83 clinical isolates from LMICs (e.g., Democratic Republic of Congo, Palestine, and Cambodia) to rationally down-select strains to test in our models based on broad expression of IBT-V02 targets (i.e., pore-forming toxins and superantigens). IBT-V02 polyclonal antisera effectively neutralized toxins produced by the clinical isolates from LMICs. Notably, the lyophilized IBT-V02 formulation exhibited significant efficacy in various preclinical infection models against the clinical isolates from LMICs, which was comparable to our liquid formulation. Collectively, our findings suggested that lyophilization is an effective alternative to liquid vaccine formulations of our IBT-V02 vaccine against infections, which has important implications for protection from isolates from LMICs.
是美国皮肤和软组织感染（SSTIs）以及更严重的侵袭性疾病的主要原因，包括菌血症、败血症、心内膜炎、手术部位感染、骨髓炎和肺炎。这些感染因耐抗生素的临床分离株的出现而加剧，如耐甲氧西林金黄色葡萄球菌（MRSA），这凸显了需要抗生素替代品来治疗细菌感染。我们之前开发了一种多组分类毒素疫苗（IBT-V02），以液体配方形式对流行于工业化世界的多种菌株有效。然而，液体疫苗配方与许多中低收入国家（LMICs）缺乏冷链储存基础设施不兼容。此外，我们的 IBT-V02 疫苗配方是否对来自 LMICs 的 分离株具有保护作用尚不清楚。为了克服这些限制，我们开发了 IBT-V02 疫苗的冻干和喷雾冷冻干燥配方，并证明这两种配方在物理特性方面与液体配方相当，包括类似水平的毒素中和抗体和对 MRSA 感染的保护效力在小鼠和兔模型中。为了提高我们研究结果的相关性，我们对来自 LMICs（例如，刚果民主共和国、巴勒斯坦和柬埔寨）的 83 株 临床分离株进行了多维筛选，根据 IBT-V02 靶标的广泛表达（即，形成孔的毒素和超抗原），对要在我们的模型中测试的菌株进行了合理的选择。IBT-V02 多克隆抗血清可有效中和来自 LMICs 的 临床分离株产生的毒素。值得注意的是，冻干 IBT-V02 配方在针对来自 LMICs 的 临床分离株的各种临床前感染模型中表现出显著的 功效，与我们的液体配方相当。总的来说，我们的研究结果表明，冻干是我们的 IBT-V02 疫苗针对 感染的液体疫苗配方的有效替代方案，这对保护来自 LMICs 的 分离株具有重要意义。
