Pan-lyssavirus therapeutics and mechanisms of protection against lyssaviruses

摘要 狂犬病在没有治疗的情况下几乎是100%致命的，估计每年有5.9万人死亡。 如果疫苗管理得当，它们是非常有效的，使它们成为最经济的疫苗之一。 传染病中的高影响力干预措施。约有30,000人接受暴露后治疗 美国每年都表示需要针对RABV的治疗选择。值得注意的是，15种与狂犬病有关的病毒 (溶沙病毒)具有类似的致命性，但差异足以逃避当前疫苗和生物制品的保护， 它们是基于经典狂犬病病毒(RABV)的。 我们之前设计了一种结构信息嵌合糖蛋白(G)来整合大的胞外结构域 两种不同的溶血病毒，RABV和莫科拉病毒(MOKV)的区域。在体内，这种疫苗引起了中和 针对RABV和MOKV的抗体并用含有MOK G或MOKV的病毒保护 基于对RABV G的了解，这些初步数据表明：i)嵌合体G包括 RABV和MOKV的重要抗原区以及II)诱导的抗体应具有保护作用 挑战。此外，一些数据还提出了令人信服的建议，即抗体机制除了 中和可能有助于保护。 提出了三个独立但相互补充的目标，以将R21的发现推向新的水平。 第一个目标是研究嵌合G溶酶病毒疫苗的免疫原性和保护性。 一组不同的重要溶血病毒。目的2检测非RABV溶酶病毒的抗原区 糖蛋白(G)，并通过分离和鉴定确定其抗原区 中和单抗(MAbs)。防御RABV的教条是中和 抗体是必要的，也是充分的。这还没有对非RABV溶血病毒进行研究，也没有 完全得到了我们之前研究的初步数据的支持。因此，目标3将重新审视这一机制 在暴露前和暴露后应用程序中对LyssaVirus的保护，并重新定义 用于预防狂犬病的中和和非中和抗体。

Abstract Rabies disease is nearly 100% lethal in the absence of treatment, killing an estimated 59,000 people annually. When vaccines are properly administered, they are highly efficacious, making them one of the most economically high-impact interventions among infectious diseases. About 30,000 people receive post-exposure treatment in the USA annually indicating the need for treatment options against RABV. Of note, fifteen rabies-related viruses (lyssaviruses) are similarly lethal, but divergent enough to evade protection from current vaccines and biologics, which are based on the classical rabies virus (RABV). We previously designed a structurally-informed chimeric glycoprotein (G) to incorporate large ectodomain regions of two divergent lyssaviruses, RABV and Mokola virus (MOKV). In vivo, this vaccine elicited neutralizing antibodies against both RABV and MOKV and protected against challenge with viruses containing MOK G or RABV G. Based on knowledge of the RABV G, these preliminary data suggest that i) the chimeric G includes important antigenic regions from both RABV and MOKV and that ii) the elicited antibodies should protect against challenge. Moreover, some data also raised the compelling suggestion that antibody mechanisms in addition to neutralization may contribute to protection. Three independent but complementary aims are proposed to take the discoveries of the R21 to the next level. The first Aim will investigate the immunogenicity and protective quality of a chimeric G lyssavirus vaccine against a panel of different lyssaviruses of importance. Aim 2 examines antigenic regions of non-RABV lyssavirus glycoproteins (G) and delineate the antigenic regions on the lyssavirus Gs by isolating and characterizing neutralizing monoclonal antibodies (mAbs). The dogma for protection against RABV is that neutralizing antibodies are necessary and sufficient. This has not been studies for non-RABV lyssaviruses and is not completely supported by preliminary data from our previous study. Therefore, Aim 3 will revisit the mechanism of protection against Lyssaviruses in pre- and post-exposure applications and redefine the function of neutralizing and non-neutralizing antibodies for protection from rabies.