State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, P. R. China.
Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, P. R. China.
PLoS Pathog. 2024 Oct 15;20(10):e1012623. doi: 10.1371/journal.ppat.1012623. eCollection 2024 Oct.
It is a great challenge to isolate the broadly neutralizing antibodies (bnAbs) against foot-and-mouth disease virus (FMDV) due to its existence as seven distinct serotypes without cross-protection. Here, by vaccination of pig with FMDV serotypes O and A whole virus antigens, we obtained 10 bnAbs against serotypes O, A and/or Asia1 by dissecting 216 common clonotypes of two serotypes O and A specific porcine B-cell receptor (BCR) gene repertoires containing total 12720 B cell clones, indicating the induction of cross-serotype bnAbs after sequential vaccination with serotypes O and A antigens. The majority of porcine bnAbs (9/10) were derived from terminally differentiated B cells of different clonal lineages, which convergently targeted the conserved "RGDL" motif on structural protein VP1 of FMDV by mimicking receptor recognition to inhibit viral attachment to cells. Cryo-EM complex structures revealed that the other bnAb pOA-2 specifically targets a novel inter-pentamer antigen structure surrounding the viral three-fold axis, with a highly conserved determinant at residue 68 on VP2. This unique binding pattern enabled cross-serotype neutralization by destabilizing the viral particle. The evolutionary analysis of pOA-2 demonstrated its origin from an intermediate B-cell, emphasizing the crucial role of somatic hypermutations (SHMs) in balancing the breadth and potency of neutralization. However, excessive SHMs may deviate from the trajectory of broad neutralization. This study provides a strategy to uncover bnAbs against highly mutable pathogens and the cross-serotype antigenic structures to explore broadly protective FMDV vaccine.
由于口蹄疫病毒 (FMDV) 存在七个不同的血清型，没有交叉保护，因此分离针对该病毒的广谱中和抗体 (bnAbs) 是一项巨大的挑战。在这里，通过用 FMDV 血清型 O 和 A 的全病毒抗原对猪进行免疫接种，我们通过分析包含总共 12720 个 B 细胞克隆的两个血清型 O 和 A 特异性猪 B 细胞受体 (BCR) 基因库中的 216 个共同克隆型，获得了针对血清型 O、A 和/或 Asia1 的 10 种 bnAbs，这表明在先后用血清型 O 和 A 抗原进行免疫接种后，诱导了交叉血清型 bnAbs。大多数猪 bnAbs（9/10）来自不同克隆谱系的终末分化 B 细胞，它们通过模拟受体识别来针对 FMDV 结构蛋白 VP1 上的保守“RGDL”基序，从而趋同地靶向该基序，抑制病毒附着到细胞上。冷冻电镜复合物结构揭示了另一种 bnAb pOA-2 特异性地针对围绕病毒三倍轴的新型五聚体间抗原结构，在 VP2 上的 68 位残基上存在高度保守的决定簇。这种独特的结合模式通过破坏病毒颗粒的稳定性来实现交叉血清型中和。pOA-2 的进化分析表明其起源于中间 B 细胞，强调了体细胞高频突变 (SHMs) 在平衡中和的广度和效力方面的关键作用。然而，过多的 SHMs 可能会偏离广谱中和的轨迹。本研究提供了一种揭示针对高度可变异病原体的 bnAbs 的策略，并揭示了交叉血清型抗原结构，以探索具有广泛保护作用的口蹄疫疫苗。
