Cross-protective HCoV immunity reduces symptom development during SARS-CoV-2 infection

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 (SARSCoV2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a crosssectional cohort including children and adults (n = 882), all first exposed to SARSCoV2 (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 SARSCoV2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARSCoV2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARSCoV2 infection was associated with a strong correlation between mucosal and systemic SARSCoV2 antispike responses. Individuals with preexisting HCoVS1 reactivity exhibited significantly higher antibody responses to SARSCoV2 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 crossreactive HCoV immunity, asymptomatic individuals presented with higher preexisting HCoVS1 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 SARSCoV2 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 SARSCoV2 and HCoVs in a population without prior exposure to SARSCoV2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development. IMPORTANCE Knowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARSCoV2) 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 SARSCoV2 in Switzerland in 2020–2021, revealed several key findings. Preexisting HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARSCoV2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARSCoV2, although low in magnitude, retained activity against SARSCoV2 variants underlining the importance of maintaining local mucosal immunity to SARSCoV2. While the crossprotective effect of HCoV immunity was not sufficient to block infection by SARSCoV2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating panprotective coronavirus vaccines by inducing potent mucosal immune responses.