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

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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.

IMPORTANCE

Knowledge 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.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Zunyou Wu, Jennifer M. McGoogan (2020)

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SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

Lirong Zou, Feng Ruan, Mingxing Huang … (2020)

To the Editor: The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, and has been declared a public health emergency of international concern by the World Health Organization, may progress to a pandemic associated with substantial morbidity and mortality. SARS-CoV-2 is genetically related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries in 2002–2003. 1 The epidemic of SARS-CoV was successfully contained through public health interventions, including case detection and isolation. Transmission of SARS-CoV occurred mainly after days of illness 2 and was associated with modest viral loads in the respiratory tract early in the illness, with viral loads peaking approximately 10 days after symptom onset. 3 We monitored SARS-CoV-2 viral loads in upper respiratory specimens obtained from 18 patients (9 men and 9 women; median age, 59 years; range, 26 to 76) in Zhuhai, Guangdong, China, including 4 patients with secondary infections (1 of whom never had symptoms) within two family clusters (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The patient who never had symptoms was a close contact of a patient with a known case and was therefore monitored. A total of 72 nasal swabs (sampled from the mid-turbinate and nasopharynx) (Figure 1A) and 72 throat swabs (Figure 1B) were analyzed, with 1 to 9 sequential samples obtained from each patient. Polyester flock swabs were used for all the patients. From January 7 through January 26, 2020, a total of 14 patients who had recently returned from Wuhan and had fever (≥37.3°C) received a diagnosis of Covid-19 (the illness caused by SARS-CoV-2) by means of reverse-transcriptase–polymerase-chain-reaction assay with primers and probes targeting the N and Orf1b genes of SARS-CoV-2; the assay was developed by the Chinese Center for Disease Control and Prevention. Samples were tested at the Guangdong Provincial Center for Disease Control and Prevention. Thirteen of 14 patients with imported cases had evidence of pneumonia on computed tomography (CT). None of them had visited the Huanan Seafood Wholesale Market in Wuhan within 14 days before symptom onset. Patients E, I, and P required admission to intensive care units, whereas the others had mild-to-moderate illness. Secondary infections were detected in close contacts of Patients E, I, and P. Patient E worked in Wuhan and visited his wife (Patient L), mother (Patient D), and a friend (Patient Z) in Zhuhai on January 17. Symptoms developed in Patients L and D on January 20 and January 22, respectively, with viral RNA detected in their nasal and throat swabs soon after symptom onset. Patient Z reported no clinical symptoms, but his nasal swabs (cycle threshold [Ct] values, 22 to 28) and throat swabs (Ct values, 30 to 32) tested positive on days 7, 10, and 11 after contact. A CT scan of Patient Z that was obtained on February 6 was unremarkable. Patients I and P lived in Wuhan and visited their daughter (Patient H) in Zhuhai on January 11 when their symptoms first developed. Fever developed in Patient H on January 17, with viral RNA detected in nasal and throat swabs on day 1 after symptom onset. We analyzed the viral load in nasal and throat swabs obtained from the 17 symptomatic patients in relation to day of onset of any symptoms (Figure 1C). Higher viral loads (inversely related to Ct value) were detected soon after symptom onset, with higher viral loads detected in the nose than in the throat. Our analysis suggests that the viral nucleic acid shedding pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 4 and appears different from that seen in patients infected with SARS-CoV. 3 The viral load that was detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients. These findings are in concordance with reports that transmission may occur early in the course of infection 5 and suggest that case detection and isolation may require strategies different from those required for the control of SARS-CoV. How SARS-CoV-2 viral load correlates with culturable virus needs to be determined. Identification of patients with few or no symptoms and with modest levels of detectable viral RNA in the oropharynx for at least 5 days suggests that we need better data to determine transmission dynamics and inform our screening practices.

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Author and article information

Contributors

Irene A. Abela:

ORCID: https://orcid.org/0000-0002-5566-8628

Role: ConceptualizationRole: Data curationRole: InvestigationRole: SupervisionRole: Writing – original draftRole: Writing – review and editingRole: MethodologyRole: Visualization

Magdalena Schwarzmüller: Role: Data curationRole: MethodologyRole: Writing – review and editingRole: InvestigationRole: Visualization

Agne Ulyte:

ORCID: https://orcid.org/0000-0001-7419-9778

Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Thomas Radtke:

ORCID: https://orcid.org/0000-0002-1723-1070

Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Sarah R. Haile:

ORCID: https://orcid.org/0000-0002-4704-6570

Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Priska Ammann: Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Alessia Raineri:

ORCID: https://orcid.org/0009-0007-7128-9656

Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Sonja Rueegg: Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Selina Epp: Role: Formal analysisRole: InvestigationRole: Data curationRole: MethodologyRole: Writing – review and editing

Christoph Berger:

ORCID: https://orcid.org/0000-0002-2373-8804

Role: Data curationRole: Writing – review and editing

Jürg Böni: Role: Data curationRole: Writing – review and editing

Amapola Manrique:

ORCID: https://orcid.org/0000-0003-3982-398X

Role: Project administrationRole: Writing – review and editing

Annette Audigé: Role: Data curationRole: Writing – review and editing

Michael Huber:

ORCID: https://orcid.org/0000-0002-0384-0000

Role: Data curationRole: Writing – review and editing

Peter W. Schreiber:

ORCID: https://orcid.org/0000-0001-8123-2601

Role: Data curationRole: Writing – review and editing

Thomas Scheier:

ORCID: https://orcid.org/0000-0001-7805-1025

Role: Data curationRole: Writing – review and editing

Jan Fehr:

ORCID: https://orcid.org/0000-0003-1113-9895

Role: Data curationRole: MethodologyRole: Writing – review and editingRole: Investigation

Jacqueline Weber: Role: Data curationRole: Writing – review and editingRole: Investigation

Peter Rusert: Role: Data curationRole: InvestigationRole: Writing – review and editing

Huldrych F. Günthard:

ORCID: https://orcid.org/0000-0002-1142-6723

Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review and editing

Roger D. Kouyos:

ORCID: https://orcid.org/0000-0002-9220-8348

Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review and editing

Milo A. Puhan:

ORCID: https://orcid.org/0000-0003-4721-1879

Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – review and editing

Susi Kriemler:

ORCID: https://orcid.org/0000-0002-3384-7940

Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – review and editing

Alexandra Trkola:

ORCID: https://orcid.org/0000-0003-1013-876X

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review and editingRole: Visualization

Chloé Pasin:

ORCID: https://orcid.org/0000-0001-8730-790X

Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review and editingRole: ConceptualizationRole: Data curationRole: Formal analysisRole: Visualization

Satya Dandekar: Role: Editor

Journal

Journal ID (nlm-ta): mBio

Journal ID (iso-abbrev): mBio

Journal ID (publisher-id): mbio

Title: mBio

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2150-7511

Publication date (Electronic, collection): February 2024

Publication date (Electronic, pub): 25 January 2024

Publication date PMC-release: 25 January 2024

Volume: 15

Issue: 2

Electronic Location Identifier: e02722-23

Affiliations

[1 ]Institute of Medical Virology, University of Zurich; , Zurich, Switzerland

[2 ]Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich; , Zurich, Switzerland

[3 ]Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich; , Zurich, Switzerland

[4 ]University Children Hospital Zurich; , Zurich, Switzerland

[5 ]Collegium Helveticum; , Zurich, Switzerland

University of California, Davis; , Davis, California, USA

Author notes

Address correspondence to Irene A. Abela, irene.abela@ 123456usz.ch

H.F.G. reports having received honoraria from Gilead Sciences, Merck, ViiV, GSK, Janssen, Johnson and Johnson, and Novartis for serving on DSMB and/or advisory boards and has received a travel grant from Gilead Sciences. In addition, he has received grants from the Swiss National Science Foundation (SNSF), the Swiss HIV Cohort Study, the Yvonne Jacob Foundation, and the NIH and unrestricted research grants from Gilead Sciences, all paid to the institution. A.T. has received honoraria from Roche Diagnostics for consultant activity, grants from the SNSF, the Swiss HIV Cohort Study, and the Pandemiefonds of the UZH foundation, and unrestricted research grants from Gilead Sciences. I.A.A. has received honoraria from MSD and Sanofi, a travel grant from Gilead Sciences, and a grant from Promedica foundation. R.D.K. has received grants from SNSF, the National Institutes of Health, and Gilead Sciences. C.P. has received a grant from the Collegium Helveticum.