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Abstract：
Numerous clinical parameters link to severe coronavirus disease 2019, but factors that prevent symptomatic disease remain unknown. We investigated the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a cross-sectional cohort including children and adults (n = 882), all first exposed to SARS-CoV-2 (March 2020 to March 2021) in Switzerland. Saliva (n = 4,993) and plasma (n = 7,486) antibody reactivity to the four HCoVs (subunit S1 [S1]) and SARS-CoV-2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARS-CoV-2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARS-CoV-2 infection was associated with a strong correlation between mucosal and systemic SARS-CoV-2 anti-spike responses. Individuals with pre-existing HCoV-S1 reactivity exhibited significantly higher antibody responses to SARS-CoV-2 in both plasma (IgG regression coefficients = 0.20, 95% CI = [0.09, 0.32], P < 0.001) and saliva (IgG regression coefficient = 0.60, 95% CI = [0.088, 1.11], P = 0.025). Saliva neutralization activity was modest but surprisingly broad, retaining activity against Wuhan (median NT50 = 32.0, 1Q-3Q = [16.4, 50.2]), Alpha (median NT50 = 34.9, 1Q-3Q = [26.0, 46.6]), and Delta (median NT50 = 28.0, 1Q-3Q = [19.9, 41.7]). In line with a rapid mucosal defense triggered by cross-reactive HCoV immunity, asymptomatic individuals presented with higher pre-existing HCoV-S1 activity in plasma (IgG HKU1, odds ratio [OR] = 0.53, 95% CI = [0.29,0.97], P = 0.038) and saliva (total HCoV, OR = 0.55, 95% CI = [0.33, 0.91], P = 0.019) and higher SARS-CoV-2 reactivity in saliva (IgG S2 fold change = 1.26, 95% CI = [1.03, 1.54], P = 0.030). By investigating the systemic and mucosal immune responses to SARS-CoV-2 and HCoVs in a population without prior exposure to SARS-CoV-2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development.IMPORTANCEKnowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is critical to understanding the coexistence of current endemic coronaviruses and to building knowledge potential future zoonotic coronavirus transmissions. This study, which retrospectively analyzed a large cohort of individuals first exposed to SARS-CoV-2 in Switzerland in 2020-2021, revealed several key findings. Pre-existing HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARS-CoV-2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARS-CoV-2, although low in magnitude, retained activity against SARS-CoV-2 variants underlining the importance of maintaining local mucosal immunity to SARS-CoV-2. While the cross-protective effect of HCoV immunity was not sufficient to block infection by SARS-CoV-2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating pan-protective coronavirus vaccines by inducing potent mucosal immune responses.
摘要：
许多临床参数与2019年严重冠状病毒疾病有关，但预防有症状疾病的因素仍然未知。我们调查了严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）和地方性人类冠状病毒（HCoV）抗体反应对纵向儿童队列（n=2,917）和包括儿童和成人的横断面队列（n=882）症状的影响。所有人都是在瑞士首次接触SARS-CoV-2（2020年3月至2021年3月）。唾液（n=4,993）和血浆（n=7,486）抗体对四个HCoV（亚基S1[S1]）和SARS-CoV-2（S1，受体结合域，S2亚基[S2]，核衣壳蛋白）的测定以及对SARS-CoV-2武汉的中和活性，阿尔法,Delta,和Omicron（BA.2）在一个子集的个体中。最近推断的SARS-CoV-2感染与粘膜和全身性SARS-CoV-2抗尖峰反应之间的强相关性相关。具有预先存在的HCoV-S1反应性的个体在两种血浆中均表现出对SARS-CoV-2的抗体应答显着升高（IgG回归系数=0.20，95％CI=[0.09，0.32]，P<0.001）和唾液（IgG回归系数=0.60，95％CI=[0.088，1.11]，P=0.025)。唾液中和活性适中，但令人惊讶的是广泛，对武汉的保留活性(NT50中位数=32.0，1Q-3Q=[16.4，50.2])，Alpha（NT50中位数=34.9，1Q-3Q=[26.0，46.6]），和Delta（NT50中位数=28.0，1Q-3Q=[19.9，41.7]）。与交叉反应性HCoV免疫引发的快速粘膜防御一致，无症状个体血浆中预先存在的HCoV-S1活性较高(IgGHKU1,比值比[OR]=0.53,95%CI=[0.29,0.97],P=0.038）和唾液（总HCoV，OR=0.55，95%CI=[0.33，0.91]，P=0.019）和唾液中更高的SARS-CoV-2反应性（IgGS2倍数变化=1.26，95％CI=[1.03，1.54]，P=0.030)。通过调查未事先接触SARS-CoV-2或接种疫苗的人群对SARS-CoV-2和HCoV的全身和粘膜免疫反应，我们确定了与症状缺乏相关的特异性抗体反应性.重要信息了解人类冠状病毒（HCoV）免疫与严重急性呼吸道综合症冠状病毒2型（SARS-CoV-2）感染之间的相互作用对于了解当前地方性冠状病毒的共存以及建立潜在的未来人畜共患冠状病毒传播的知识至关重要。这项研究,该研究回顾性分析了2020-2021年在瑞士首次接触SARS-CoV-2的一大群人，揭示了几个关键发现。预先存在的HCoV免疫力，特别是粘膜抗体反应，在改善SARS-CoV-2感染后的免疫反应和减少症状发展方面发挥了重要作用。对SARS-CoV-2的粘膜中和活性，尽管幅度较低，针对SARS-CoV-2变体的保留活性强调了维持对SARS-CoV-2的局部粘膜免疫的重要性。尽管HCoV免疫的交叉保护作用不足以阻止SARS-CoV-2感染，但本研究表明对限制症状性疾病具有显着影响。这些发现支持通过诱导有效的粘膜免疫反应来产生泛保护性冠状病毒疫苗的可行性。
