Adjuvants and Glucan Particle Vaccines

 说明(由申请人提供)：对疫苗和佐剂的新配方进行测试对于增加目前非常有限的已批准佐剂池非常重要。β-葡聚糖颗粒(GP)是一种新型的实验疫苗载体，能在很大程度上靶向吞噬抗原提呈细胞。该可生物降解颗粒可同时含有抗原和佐剂，并可在不同的注射部位免疫。许多佐剂，包括Toll样受体(TLR)的天然免疫激活剂和炎症体信号转导，具有显著的炎症潜能，可促进疫苗的反应性。这些途径的佐剂激活剂包括单磷酰脂A(Mpla，激活TLR4)和含有皂苷的QS-21(激活NLRP3炎症体)。通过将佐剂纳入特定的疫苗配方，可以降低佐剂的反应性。我们假设在β-葡聚糖颗粒疫苗中结合多种佐剂和抗原是安全有效的，可以诱导对实验性鼠疫疫苗产生强烈的抗原特异性反应，并且疫苗反应受到先天免疫反应的影响。这些反应可能既是对特定佐剂的反应，也是对颗粒本身的β-葡聚糖的反应。鼠疫耶尔森氏菌是一种引起鼠疫的高毒力病原体，目前还缺乏获得许可的疫苗。我们建议在含有临床相关候选疫苗-鼠疫V/F1抗原的GP疫苗中单独或联合使用Mpla和QS-21进行小鼠实验，以研究有助于疫苗反应的特定先天免疫受体，并测试选定的疫苗配方在小鼠腺鼠疫和肺鼠疫模型中的保护作用。

 DESCRIPTION (provided by applicant): The testing of new formulations for vaccines and adjuvants is important in order to increase the current very limited pools of approved adjuvants. Beta-glucan particles (GP) are a new type of experimental vaccine carriers that to a high degree target phagocytic antigen-presenting cells. The biodegradable particles can contain both antigen and adjuvants, and can be immunized at different injection sites. A number of adjuvants, including innate immunity activators of Toll-like receptor (TLR) and inflammasome signaling, carry significant inflammatory potential that can contribute to vaccine reactogenicity. Adjuvant activators of these pathways include monophosphoryl lipid A (MPLA, activating TLR4) and QS-21 containing saponins (activating the NLRP3 inflammasome). Reactogenicity by adjuvant can be reduced by the inclusion into particular vaccine formulations. We hypothesize that combinations of more than one adjuvant together with antigens into beta- glucan particle vaccines are safe and effective, induce strong antigen-specific responses to experimental plague vaccines, and that the vaccine responses are impacted by innate immune responses. These responses may be both to the specific adjuvant and to the beta-glucan in the particle itself. Yersinia pestis is a highly virulent pathogen causing plague, and licensed vaccines are lacking. We propose to perform mouse experiments using MPLA and QS-21 individually or in combinations in GP vaccines containing clinically relevant vaccine candidates - plague V/F1 antigens for antigen-specific responses, to investigate the specific innate immunity receptors that contribute to vaccine responses, and to test selected vaccine formulations in protection in mouse models of bubonic and pneumonic plague.