Rudi E, Gaillard E, Bottero D, Ebensen T, Guzman C A, Hozbor Daniela
Laboratorio VacSal, Instituto de Biotecnología y Biología Molecular (IBBM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, CCT-CONICET La Plata, La Plata, Argentina.
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Front Immunol. 2024 Nov 28;15:1506638. doi: 10.3389/fimmu.2024.1506638. eCollection 2024.
We previously identified -derived outer membrane vesicles (OMVs) as a promising immunogen for improving pertussis vaccines. In this study, we evaluated the efficacy of our vaccine prototype in immunization strategies aimed at reducing disease transmission by targeting colonization in the upper airways while maintaining protection against severe disease by reducing colonization in the lower respiratory tract.
We assessed different mucosal administration strategies in a murine model, including homologous mucosal 2-dose prime-boost schedules and heterologous prime-boost strategies combining intramuscular (IM) systemic immunization with mucosal routes (intranasal, IN; or sublingual, SL). We utilized alum and c-di-AMP as adjuvants for the systemic and mucosal formulations of the OMV vaccine prototype, respectively. A homologous prime/boost IM immunization schedule and commercial vaccines were used for comparisons.
All tested heterologous schemes induced higher levels of specific IgG with significant avidity, as well as higher levels of IgG1 and IgG2c, compared to the corresponding homologous prime-boost 2-dose schemes via mucosal routes (OMV or OMV). High IgA levels were observed post- challenge following OMV treatments and heterologous treatments where the second dose was administered via a mucosal route (prime-pull scheme). Furthermore, schemes involving the intranasal route, whether in a homologous or heterologous scheme, induced the highest levels of IL-17 and IFN-γ. Accordingly, these schemes showed superior efficacy against nasal colonization than the commercial vaccines. Homologous intranasal immunization exhibited the highest protective capacity against nasal colonization while maintaining an excellent level of protection in the lower respiratory tract. To further enhance protection against nasal colonization, we performed a comparative analysis of formulations containing either single or combined adjuvants, administered via homologous intranasal route. These assays revealed that the use of alum combined with c-di-AMP, did not enhance the immune protective capacity in comparison with that observed for the formulation containing c-di-AMP alone.
All the experiments presented here demonstrate that the use of OMVs, regardless of the scheme applied (except for OMV), significantly outperformed acellular pertussis (aP) vaccines, achieving a higher reduction in bacterial colonization in the upper respiratory tract (p<0.01).
我们之前已确定源自[具体内容]的外膜囊泡（OMV）是一种有望改进百日咳疫苗的免疫原。在本研究中，我们评估了疫苗原型在免疫策略中的功效，该策略旨在通过靶向在上呼吸道的定植来减少疾病传播，同时通过减少在下呼吸道的定植来维持对严重疾病的保护。
我们在小鼠模型中评估了不同的黏膜给药策略，包括同源黏膜2剂初免-加强方案以及将肌肉内（IM）全身免疫与黏膜途径（鼻内，IN；或舌下，SL）相结合的异源初免-加强策略。我们分别将明矾和环状二腺苷单磷酸（c-di-AMP）用作OMV疫苗原型全身和黏膜制剂的佐剂。使用同源初免/加强IM免疫方案和商业疫苗进行比较。
与通过黏膜途径（OMV或OMV）的相应同源初免-加强2剂方案相比，所有测试的异源方案均诱导产生了具有显著亲和力的更高水平的特异性IgG，以及更高水平的IgG1和IgG2c。在接受OMV处理和第二剂通过黏膜途径给药的异源处理（初免-拉动方案）后的攻毒后观察到高IgA水平。此外，涉及鼻内途径的方案，无论是同源还是异源方案，均诱导产生了最高水平的白细胞介素-17（IL-17）和干扰素-γ（IFN-γ）。因此，这些方案在预防鼻定植方面显示出比商业疫苗更高的功效。同源鼻内免疫在预防鼻定植方面表现出最高的保护能力，同时在下呼吸道维持了出色的保护水平。为了进一步增强对鼻定植的保护，我们对通过同源鼻内途径给药的含单一佐剂或联合佐剂的制剂进行了比较分析。这些试验表明，与单独含c-di-AMP的制剂相比，使用明矾与c-di-AMP联合并未增强免疫保护能力。
此处展示的所有实验均表明，无论应用何种方案（OMV除外），使用OMV均显著优于无细胞百日咳（aP）疫苗，在上呼吸道实现了更高程度的细菌定植减少（p<0.01）。
