Background There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. Methods Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. Results Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. Conclusions and Relevance Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

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混合免疫和 SARS-CoV-2 抗体：HEROES-RECOVER 前瞻性队列研究的结果

背景 关于混合免疫是否因免疫赋予事件（SARS-CoV-2 感染或 COVID-19 疫苗接种）的计数和顺序而异的数据有限。我们从美国六个州的一组医护人员、急救人员和其他一线工作人员中研究了混合免疫对 SARS-CoV-2 抗体水平影响的异质性。方法 暴露包括事件计数（感染和疫苗剂量的总和）和事件顺序，分为疫苗接种和/或感染的七种排列。结果是通过酶联免疫吸附测定测量针对祖先 SARS-CoV-2 刺突蛋白受体结合域 (RBD) 的血清结合抗体水平（总 RBD 结合 Ig）。在第 1 次至第 7 次事件发生后 365 天内检查平均抗体水平。结果分析包括 2020 年 8 月 7 日至 2023 年 4 月 15 日期间测量的 5,793 名参与者。在接种一剂或两剂疫苗之前对感染的混合免疫在第二次和第三次事件后引发了适度优越的抗体反应（与单独感染或疫苗剂量相比）。在第 4 次和第 5 次事件（额外剂量）后，这种优势并不明显。在疫苗接种前感染的成年人中，抗 RBD 早期反应（与仅接种疫苗相比）调整后的几何平均比 (95% CI) 分别为 1.23 (1.14-1.33)、1.09 (1.03-1.14)、0.87 (0.81-0.94) 和第 2-5 次事件后分别为 0.99 (0.85-1.15)。疫苗接种后感染引起了优异的反应：抗 RBD 早期反应（与仅接种疫苗相比）的调整几何平均比（95% CI）为：0.93（0.75-1.17）、1.11（1.06-1.16）、1.17（1.11-1.24） ) 和第 2-5 个事件后分别为 1.20 (1.07-1.34)。结论和相关性 通过感染和疫苗接种史的排列反映抗体水平异质性的研究结果可以为 COVID-19 疫苗接种政策提供信息。