Immune imprinting is a phenomenon in which prior antigenic experiences influence responses to subsequent infection or vaccination^1,2. The effects of immune imprinting on serum antibody responses after boosting with variant-matched SARS-CoV-2 vaccines remain uncertain. Here, we characterized the serum antibody responses after mRNA vaccine boosting of mice and human clinical trial participants. In mice, a single dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike minimally imprinted serum responses elicited by Omicron boosters, enabling generation of type-specific antibodies. However, imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron vaccine. In both SARS-CoV-2 infected or uninfected humans who received two Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with Omicron variants as well as more distantly related sarbecoviruses. Because serum neutralizing responses against Omicron strains and other sarbecoviruses were abrogated after pre-clearing with Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes targeted by the antecedent mRNA-1273 primary series. Thus, the antibody response to Omicron-based boosters in humans is imprinted by immunizations with historical mRNA-1273 vaccines, but this outcome may be beneficial as it drives expansion of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and distantly related sarbecoviruses.

免疫印记是一种现象，其中先前的抗原经历影响对后续感染或疫苗接种的反应^1,2。使用变异匹配的 SARS-CoV-2 疫苗加强免疫后，免疫印记对血清抗体反应的影响仍不确定。在这里，我们对小鼠和人类临床试验参与者的 mRNA 疫苗加强后的血清抗体反应进行了表征。在小鼠中，单剂临床前版本的编码 Wuuhan-1 的 mRNA-1273 疫苗可以最小程度地印记 Omicron 加强剂引起的血清反应，从而能够产生类型特异性抗体。然而，在接受两次 mRNA-1273 初免剂量后接受 Omicron 加强疫苗的小鼠中观察到了印记，第二次加强剂量的 Omicron 疫苗减轻了这种效应。在 SARS-CoV-2 感染或未感染的人中，在注射两剂或更多剂量的原型 mRNA-1273 疫苗后接受两剂 Omicron 匹配加强剂后，尖峰结合和中和血清抗体与 Omicron 变体以及更远亲的抗体发生交叉反应沙贝克病毒。由于用 Wuuhan-1 刺突蛋白预清除后，针对 Omicron 病毒株和其他 sarbecovirus 的血清中和反应被消除，因此 XBB.1.5 在人类中加强诱导的抗体集中在先前 mRNA-1273 初级系列靶向的保守表位上。因此，人类对基于 Omicron 的加强剂的抗体反应受到历史 mRNA-1273 疫苗免疫的影响，但这一结果可能是有益的，因为它推动了交叉中和抗体的扩展，从而抑制了新出现的 SARS-CoV-2 变种的感染，并且远缘相关的sarbecoviruses。