Bayarri-Olmos Rafael, Sutta Adrian, Rosbjerg Anne, Mortensen Mie Mandal, Helgstrand Charlotte, Nielsen Per Franklin, Pérez-Alós Laura, González-García Beatriz, Johnsen Laust Bruun, Matthiesen Finn, Egebjerg Thomas, Hansen Cecilie Bo, Sette Alessandro, Grifoni Alba, da Silva Antunes Ricardo, Garred Peter
Laboratory of Molecular Medicine, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Recombinant Protein and Antibody Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Front Immunol. 2024 Dec 10;15:1412873. doi: 10.3389/fimmu.2024.1412873. eCollection 2024.
Throughout the COVID-19 pandemic, the emergence of new viral variants has challenged public health efforts, often evading antibody responses generated by infections and vaccinations. This immune escape has led to waves of breakthrough infections, raising questions about the efficacy and durability of immune protection. Here we focus on the impact of SARS-CoV-2 Delta and Omicron spike mutations on ACE-2 receptor binding, protein stability, and immune response evasion. Delta and Omicron variants had 3-5 times higher binding affinities to ACE-2 than the ancestral strain (KD = 23.4 nM, KD = 8.08 nM, KD = 4.77 nM, KD = 4.47 nM). The pattern recognition molecule mannose-binding lectin (MBL) has been shown to recognize the spike protein. Here we found that MBL binding remained largely unchanged across the variants, even after introducing mutations at single glycan sites. Although MBL binding decreased post-vaccination, it increased by 2.6-fold upon IgG depletion, suggesting a compensatory or redundant role in immune recognition. Notably, we identified two glycan sites (N717 and N801) as potentially essential for the structural integrity of the spike protein. We also evaluated the antibody and T cell responses. Neutralization by serum immunoglobulins was predominantly mediated by IgG rather than IgA and was markedly impaired against the Delta (5.8-fold decrease) and Omicron variants BA.1 (17.4-fold) and BA.2 (14.2-fold). T cell responses, initially conserved, waned rapidly within 3 months post-Omicron infection. Our data suggests that immune imprinting may have hindered antibody and T cell responses toward the variants. Overall, despite decreased antibody neutralization, MBL recognition and T cell responses were generally unaffected by the variants. These findings extend our understanding of the complex interplay between viral adaptation and immune response, underscoring the importance of considering MBL interactions, immune imprinting, and viral evolution dynamics in developing new vaccine and treatment strategies.
在整个新冠疫情期间，新病毒变种的出现给公共卫生工作带来了挑战，这些变种常常能逃避由感染和疫苗接种产生的抗体反应。这种免疫逃逸导致了一波又一波的突破性感染，引发了人们对免疫保护的有效性和持久性的质疑。在此，我们聚焦于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）德尔塔和奥密克戎毒株刺突蛋白突变对血管紧张素转化酶2（ACE-2）受体结合、蛋白质稳定性及免疫逃逸的影响。德尔塔和奥密克戎变种与ACE-2的结合亲和力比原始毒株高3至5倍（解离常数KD分别为23.4纳摩尔、8.08纳摩尔、4.77纳摩尔、4.47纳摩尔）。模式识别分子甘露糖结合凝集素（MBL）已被证明可识别刺突蛋白。我们发现，即使在单个聚糖位点引入突变后，各变种间MBL的结合情况基本保持不变。尽管接种疫苗后MBL结合减少，但在去除免疫球蛋白G（IgG）后其增加了2.6倍，这表明MBL在免疫识别中具有补偿或冗余作用。值得注意的是，我们确定了两个聚糖位点（N717和N801）对刺突蛋白的结构完整性可能至关重要。我们还评估了抗体和T细胞反应。血清免疫球蛋白的中和作用主要由IgG介导而非IgA，并且针对德尔塔变种（降低了5.8倍）以及奥密克戎变种BA.1（降低了17.4倍）和BA.2（降低了14.2倍）时明显受损。T细胞反应最初较为保守，但在感染奥密克戎毒株后的3个月内迅速减弱。我们的数据表明，免疫印记可能阻碍了针对这些变种的抗体和T细胞反应。总体而言，尽管抗体中和作用降低，但MBL识别和T细胞反应通常不受这些变种的影响。这些发现扩展了我们对病毒适应性与免疫反应之间复杂相互作用的理解，强调了在制定新的疫苗和治疗策略时考虑MBL相互作用、免疫印记及病毒进化动态的重要性。
