Dually Active Anthrax Vaccine Against Bacilli and Toxins

描述（由申请人提供）：我们研究的总体目标是开发一种有效的，双活性的炭疽疫苗（DAAV），同时提供对杆菌和毒素的保护。由炭疽芽孢杆菌引起的全身炭疽感染导致广泛的败血症、毒血症和几乎无一例外的死亡。炭疽的发病涉及两个关键过程，即杆菌的复制和毒素的释放。杆菌用多γ - d -谷氨酸（PGA）胶囊保护自己，以逃避免疫监视，同时分泌大量毒素。因此，我们假设一种有效的策略需要既杀死杆菌又破坏毒素。我们进一步假设可以基于荚膜芽孢杆菌PGA和毒素核心保护抗原（PA）这两种主要毒力因子构建DAAV。我们的初步研究表明，PGA-PA偶联物诱导了有效的抗pa和抗pga抗体，并保护免疫小鼠免受炭疽毒素和类似杆菌的致命攻击。这种疫苗优于现有的仅针对炭疽毒素的疫苗。

DESCRIPTION (provided by applicant): The overall goal of our study is to develop an effective, dually active anthrax vaccine (DAAV) that confers simultaneous protection against both the bacilli and the toxins. Systemic anthrax infection by Bacillus anthracis results in extensive septicemia, toxemia, and almost invariably death. The pathogenesis of anthrax involves two crucial processes, i.e., replication of bacilli and release of toxins. The bacilli protect themselves with a poly-gamma-D-glutamic acid (PGA) capsule to evade immune surveillance while secreting large amounts of toxins. Hence, we hypothesize that an effective strategy needs to both kill the bacilli and destroy the toxins. We further hypothesize that a DAAV can be constructed based on the two major virulence factors, specifically, the bacillus capsular PGA and the toxin core protective antigen (PA). Our preliminary study demonstrates that PGA-PA conjugates induce potent anti-PA and anti-PGA antibodies and protect immunized mice against lethal challenges with both anthrax toxin and analogous bacilli. Such vaccines are superior to existing vaccines that solely target anthrax toxins. The focus of our proposed study is to further develop and optimize PA/PGA-based DAAVs. We will prepare libraries of three classes of DAAV constructs (DAAV-X, E, and C) by systematically varying their structures. We will derive optimal constructs by comparing their ability to elicit anti-PGA and anti-PA antibodies and their ability to protect mice against challenges with lethal toxins and virulent bacilli. Optimized DAAVs will be tested for their efficacy in protecting mice and rabbits against anthrax spore challenges. Aim 1. To optimize "cross-linked" PGA-PA conjugates (DAAV-X). Aim 2. To create and optimize "end-linked" PGA-PA conjugates (DAAV-E). Aim 3. To develop combination anthrax vaccines consisting of mixtures of PA and PGA-based conjugates (DAAV-C). Aim 4. To evaluate the effectiveness of optimized DAAV candidates in various animal models of anthrax infection.