Adjuvants and Glucan Particle Vaccines

 描述（由申请方提供）：为了增加目前非常有限的获批佐剂库，疫苗和佐剂新制剂的检测非常重要。β-葡聚糖颗粒（GP）是一种新型的实验性疫苗载体，其高度靶向吞噬性抗原呈递细胞。可生物降解的颗粒可以含有抗原和佐剂，并且可以在不同的注射部位进行免疫。许多佐剂，包括Toll样受体（TLR）和炎性体信号传导的先天免疫激活剂，携带可有助于疫苗反应原性的显著的炎性潜能。这些途径的佐剂活化剂包括单磷酰脂质A（MPLA，活化TLR 4）和含有皂苷的QS-21（活化NLRP 3炎性体）。佐剂的反应原性可以通过包含在特定的疫苗制剂中来降低。我们假设，一种以上的佐剂与抗原组合成β-葡聚糖颗粒疫苗是安全有效的，诱导对实验性鼠疫疫苗的强烈抗原特异性应答，并且疫苗应答受到先天免疫应答的影响。这些反应可能是对特定佐剂和颗粒本身中的β-葡聚糖的反应。鼠疫耶尔森氏菌是一种引起鼠疫的高致病性病原体，目前缺乏许可的疫苗。我们建议使用MPLA和QS-21单独或组合在含有临床相关候选疫苗-鼠疫V/F1抗原的GP疫苗中进行小鼠实验，以研究有助于疫苗应答的特异性先天免疫受体，并在腺鼠疫和肺鼠疫小鼠模型中测试所选疫苗制剂的保护作用。

 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.