Dadonaite Bernadeta, Burrell Allison R, Logue Jenni, Chu Helen Y, Payne Daniel C, Haslam David B, Staat Mary A, Bloom Jesse D
Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
J Virol. 2025 Apr 15;99(4):e0010925. doi: 10.1128/jvi.00109-25. Epub 2025 Mar 25.
The immune response to viral infection is shaped by past exposures to related virus strains, a phenomenon known as imprinting. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), much of the population has been imprinted by a viral spike from an early strain, either through vaccination or infection during the early stages of the COVID-19 pandemic. As a consequence of this imprinting, infection with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited by the imprinting strain. Here we compare the neutralizing antibody specificities of imprinted individuals versus infants infected with a recent strain. Specifically, we use pseudovirus-based deep mutational scanning to measure how spike mutations affect neutralization by the serum antibodies of adults and children imprinted by the original vaccine versus infants with a primary infection by an XBB* variant. While the serum neutralizing activity of the imprinted individuals primarily targets the spike receptor-binding domain (RBD), the serum neutralizing activity of infants infected with only XBB* mostly targets the spike N-terminal domain. In these infants, secondary exposure to the XBB* spike via vaccination shifts more of the neutralizing activity toward the RBD, although the specific RBD sites targeted are different from imprinted adults. The dramatic differences in neutralization specificities among individuals with different exposure histories likely impact SARS-CoV-2 evolution.IMPORTANCEWe show that a person's exposure history to different SARS-CoV-2 strains strongly affects which regions on the viral spike that their neutralizing antibodies target. In particular, infants who have just been infected once with a recent viral strain make neutralizing antibodies that target different regions of the viral spike than adults or children who have been exposed to both older and more recent strains. This person-to-person heterogeneity means that the same viral mutation can have different impacts on the antibody immunity of different people.
对病毒感染的免疫反应受过去接触相关病毒株的影响，这一现象被称为印记。对于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）而言，大部分人群已被早期毒株的病毒刺突所印记，这或是通过接种疫苗，或是在新冠疫情早期阶段感染所致。由于这种印记，感染较新的SARS-CoV-2毒株主要会增强由印记毒株引发的交叉反应抗体。在此，我们比较了有印记个体与感染了近期毒株的婴儿的中和抗体特异性。具体而言，我们使用基于假病毒的深度突变扫描来测量刺突突变如何影响由原始疫苗印记的成人和儿童以及初次感染XBB变体的婴儿的血清抗体的中和作用。虽然有印记个体的血清中和活性主要针对刺突受体结合域（RBD），但仅感染XBB的婴儿的血清中和活性大多针对刺突N端结构域。在这些婴儿中，通过接种疫苗再次接触XBB*刺突会使更多的中和活性转向RBD，尽管所针对的特定RBD位点与有印记的成年人不同。不同暴露史个体之间中和特异性的显著差异可能会影响SARS-CoV-2的进化。重要性我们表明，一个人对不同SARS-CoV-2毒株的暴露史会强烈影响其中和抗体所靶向的病毒刺突上的区域。特别是，刚感染过一次近期毒株的婴儿产生的中和抗体所靶向的病毒刺突区域与接触过较旧和较新毒株的成年人或儿童不同。这种个体间的异质性意味着相同的病毒突变对不同人的抗体免疫可能有不同影响。
