Voss William N, Mallory Michael A, Byrne Patrick O, Marchioni Jeffrey M, Knudson Sean A, Powers John M, Leist Sarah R, Dadonaite Bernadeta, Townsend Douglas R, Kain Jessica, Huang Yimin, Satterwhite Ed, Castillo Izabella N, Mattocks Melissa, Paresi Chelsea, Munt Jennifer E, Scobey Trevor, Seeger Allison, Premkumar Lakshmanane, Bloom Jesse D, Georgiou George, McLellan Jason S, Baric Ralph S, Lavinder Jason J, Ippolito Gregory C
bioRxiv. 2024 Jan 23:2024.01.22.576742. doi: 10.1101/2024.01.22.576742.
We used plasma IgG proteomics to study the molecular composition and temporal durability of polyclonal IgG antibodies triggered by ancestral SARS-CoV-2 infection, vaccination, or their combination ("hybrid immunity"). Infection, whether primary or post-vaccination, mainly triggered an anti-spike antibody response to the S2 domain, while vaccination predominantly induced anti-RBD antibodies. Immunological imprinting persisted after a secondary (hybrid) exposure, with >60% of the ensuing serological response originating from the initial antibodies generated during the first exposure. We highlight one instance where hybrid immunity arising from breakthrough infection resulted in a marked increase in the breadth and affinity of a highly abundant vaccination-elicited plasma IgG antibody, SC27. With an intrinsic binding affinity surpassing a theoretical maximum (K < 5 pM), SC27 demonstrated potent neutralization of various SARS-CoV-2 variants and SARS-like zoonotic viruses (IC ∼0.1-1.75 nM) and provided robust protection . Cryo-EM structural analysis unveiled that SC27 binds to the RBD class 1/4 epitope, with both VH and VL significantly contributing to the binding interface. These findings suggest that exceptionally broad and potent antibodies can be prevalent in plasma and can largely dictate the nature of serological neutralization.
▪ Infection and vaccination elicit unique IgG antibody profiles at the molecular level▪ Immunological imprinting varies between infection (S2/NTD) and vaccination (RBD)▪ Hybrid immunity maintains the imprint of first infection or first vaccination▪ Hybrid immune IgG plasma mAbs have superior neutralization potency and breadth.
我们采用血浆IgG蛋白质组学研究了由原始SARS-CoV-2感染、疫苗接种或二者联合（“混合免疫”）引发的多克隆IgG抗体的分子组成和时间耐久性。感染，无论是初次感染还是疫苗接种后感染，主要引发针对S2结构域的抗刺突抗体反应，而疫苗接种主要诱导抗RBD抗体。二次（混合）暴露后免疫印记持续存在，随后超过60%的血清学反应源自首次暴露时产生的初始抗体。我们重点介绍了一个实例，即突破性感染产生的混合免疫导致一种高度丰富的疫苗接种诱导的血浆IgG抗体SC27的广度和亲和力显著增加。SC27的内在结合亲和力超过理论最大值（K<5 pM），对多种SARS-CoV-2变体和类SARS人畜共患病毒表现出强大的中和作用（IC∼0.1 - 1.75 nM）并提供强大的保护。冷冻电镜结构分析表明，SC27与RBD 1/4类表位结合，VH和VL对结合界面均有显著贡献。这些发现表明，异常广泛且有效的抗体可能在血浆中普遍存在，并能在很大程度上决定血清中和的性质。
▪ 感染和疫苗接种在分子水平上引发独特的IgG抗体谱
▪ 免疫印记在感染（S2/NTD）和疫苗接种（RBD）之间存在差异
▪ 混合免疫维持首次感染或首次疫苗接种的印记
▪ 混合免疫IgG血浆单克隆抗体具有卓越的中和效力和广度
