The spillover of animal coronaviruses (aCoVs) to humans has caused SARS, MERS, and COVID-19. While antibody responses displaying cross-reactivity between SARS-CoV-2 and seasonal/common cold human coronaviruses (hCoVs) have been reported, potential cross-reactivity with aCoVs and the diagnostic implications are incompletely understood. Here, we probed for antibody binding against all seven hCoVs and 49 aCoVs represented as 12,924 peptides within a phage-displayed antigen library. Antibody repertoires of 269 recovered COVID-19 patients showed distinct changes compared to 260 unexposed pre-pandemic controls, not limited to binding of SARS-CoV-2 antigens but including binding to antigens from hCoVs and aCoVs with shared motifs to SARS-CoV-2. We isolated broadly reactive monoclonal antibodies from recovered COVID-19 patients that bind a shared motif of SARS-CoV-2, hCoV-OC43, hCoV-HKU1, and several aCoVs, demonstrating that interspecies cross-reactivity can be mediated by a single immunoglobulin. Employing antibody binding data against the entire CoV antigen library allowed accurate discrimination of recovered COVID-19 patients from unexposed individuals by machine learning. Leaving out SARS-CoV-2 antigens and relying solely on antibody binding to other hCoVs and aCoVs achieved equally accurate detection of SARS-CoV-2 infection. The ability to detect SARS-CoV-2 infection without knowledge of its unique antigens solely from cross-reactive antibody responses against other hCoVs and aCoVs suggests a potential diagnostic strategy for the early stage of future pandemics. Creating regularly updated antigen libraries representing the animal coronavirome can provide the basis for a serological assay already poised to identify infected individuals following a future zoonotic transmission event.

动物冠状病毒 (aCoV) 向人类的溢出导致了 SARS、MERS 和 COVID-19。虽然已报告显示 SARS-CoV-2 与季节性/普通感冒人类冠状病毒 (hCoV) 之间存在交叉反应的抗体反应，但与 aCoV 的潜在交叉反应及其诊断意义尚不完全清楚。在这里，我们在噬菌体展示的抗原库中探测了抗体与所有 7 种 hCoV 和 49 种 aCoV 的结合，这些抗体表示为 12,924 种肽。与 260 名未暴露的大流行前对照相比，269 名康复的 COVID-19 患者的抗体库显示出明显的变化，不仅限于 SARS-CoV-2 抗原的结合，还包括与 hCoV 和 aCoV 的抗原的结合，这些抗原具有与 SARS-CoV-2 相同的基序. 我们从康复的 COVID-19 患者中分离出具有广泛反应性的单克隆抗体，这些抗体结合 SARS-CoV-2、hCoV-OC43、hCoV-HKU1 和几种 aCoV 的共同基序，证明种间交叉反应可以由单一免疫球蛋白介导。利用针对整个 CoV 抗原库的抗体结合数据，可以通过机器学习准确地区分康复的 COVID-19 患者和未暴露的个体。排除 SARS-CoV-2 抗原，仅依靠抗体与其他 hCoV 和 aCoV 的结合，同样可以准确地检测 SARS-CoV-2 感染。仅通过针对其他 hCoV 和 aCoV 的交叉反应抗体反应，在不知道其独特抗原的情况下检测 SARS-CoV-2 感染的能力表明了未来大流行早期的潜在诊断策略。