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，每年估计有59，000人死亡。 当疫苗得到适当管理时，它们是非常有效的，使它们成为最经济的疫苗之一。 传染病的高效干预措施。约有3万人在接触后接受治疗， 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 （狂犬病病毒）具有类似的致命性，但差异足以逃避当前疫苗和生物制剂的保护， 其基于经典狂犬病病毒（RABV）。 我们以前设计了一种结构上知情的嵌合糖蛋白（G）， 两种不同的狂犬病毒属病毒，RABV和Mokola病毒（MOKV）的区域。在体内，该疫苗引起中和 抗RABV和MOKV的抗体，并保护其免受含有MOK G或MOK G的病毒的攻击。 拉布湾基于对RABV G的了解，这些初步数据表明i）嵌合G包括 和ii）所引发的抗体应保护免受RABV和MOKV两者的重要抗原区域， 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 中和可有助于保护。 提出了三个独立但互补的目标，以将R21的发现提升到一个新的水平。 第一个目标是研究嵌合G狂犬病病毒疫苗的免疫原性和保护性质量， 一组重要的不同狂犬病毒属。目的2检查非RABV狂犬病病毒的抗原区域 糖蛋白（G），并通过分离和表征描绘狂犬病病毒G上的抗原区域 中和单克隆抗体（mAb）。防御RABV的教条是， 抗体是必要的和足够的。这还没有针对非RABV狂犬病毒属的研究， 这完全得到了我们之前研究的初步数据的支持。因此，目标3将重新审视该机制 在暴露前和暴露后应用中保护免受Lyssaviruses，并重新定义 中和和非中和抗体，用于预防狂犬病。

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.