Despite the serious public health impact of Crimean-Congo hemorrhagic fever (CCHF), the efficacy of antivirals targeting the causative agent, CCHF virus (CCHFV), remains debatable. Neutralizing monoclonal antibodies (MAbs) targeting the CCHFV glycoprotein Gc have been reported to protect mice against challenge with the prototype CCHFV strain, IbAr10200. However, due to extensive sequence diversity of CCHFV glycoproteins, it is unknown whether these MAbs neutralize other CCHFV strains. We initially used a CCHF virus-like particle (VLP) system to generate 11 VLP moieties, each possessing a glycoprotein from a genetically diverse CCHFV strain isolated in either Africa, Asia, the Middle East, or southeastern Europe. We used these VLPs in biosafety level 2 conditions to efficiently screen MAb cross-neutralization potency. Of the 16 MAbs tested, 3 (8A1, 11E7, and 30F7) demonstrated cross-neutralization activity with most CCHF VLPs, with 8A1 neutralizing all VLPs tested. Although binding studies suggest that none of the MAbs compete for the same epitope, combining 11E7, 30F7, or both 11E7 and 30F7 with 8A1 had no additive effect on increasing neutralization in this system. To confirm our findings from the VLP system, the 3 MAbs capable of strain cross-neutralization were confirmed to effectively neutralize 5 diverse CCHFV strains in vitro. Passaging CCHFV strains in the presence of sub-neutralizing concentrations of MAbs did not generate escape mutants resistant to subsequent neutralization. This study demonstrates the utility of the VLP system for screening neutralizing MAbs against multiple CCHFV strains, and provides the first evidence that a single MAb can effectively neutralize a number of diverse CCHFV strains in vitro, which may lead to development of future CCHF therapeutics.

中文翻译：

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鉴定针对克里米亚-刚果出血热病毒的广泛中和的单克隆抗体。

尽管克里米亚-刚果出血热（CCHF）对公共健康造成了严重影响，但针对病原体CCHF病毒（CCHFV）的抗病毒药的疗效仍然值得商de。据报道，针对CCHFV糖蛋白Gc的中和性单克隆抗体（MAbs）可保护小鼠免受CCHFV原型IbAr10200攻击。但是，由于CCHFV糖蛋白具有广泛的序列多样性，因此尚不知道这些单克隆抗体是否会中和其他CCHFV菌株。我们最初使用CCHF病毒样颗粒（VLP）系统生成11个VLP部分，每个部分都具有从非洲，亚洲，中东或东南欧分离出的遗传多样性CCHFV株中获得的糖蛋白。我们在生物安全性2级条件下使用了这些VLP，以有效筛选MAb的交叉中和效价。在测试的16个单克隆抗体中，有3个（8A1，11E7和30F7）展示了大多数CCHF VLP的交叉中和活性，而8A1中和了所有测试的VLP。尽管结合研究表明，没有一个单克隆抗体竞争相同的表位，但将11E7、30F7或11E7和30F7与8A1组合使用不会增加该系统中的中和作用。为了证实我们从VLP系统中获得的发现，已证实能够交叉中和菌株的3种单克隆抗体可在体外有效中和5种不同的CCHFV菌株。在亚中和浓度的单抗存在下传代CCHFV菌株不会产生对随后的中和具有抗性的逃逸突变体。这项研究证明了VLP系统可用于针对多种CCHFV菌株筛选中和的单克隆抗体，