Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified. These findings suggest that memory T-cell immunity to seasonal coronaviruses does not strongly influence the outcome of SARS-CoV-2 infection in unvaccinated individuals.

E.T.C., K.M.S.B., and A.B. are employees of Helix.

Funding was provided to the Desert Research Institute (DRI) by the Nevada Governors Office of Economic Development. Funding was provided by Renown Health and the Renown Health Foundation. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI63029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimers Research Foundation, the JPB Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union Horizon 2020 research and innovation program under grant agreement No. 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the Square Foundation, Grandir - Fonds de solidarite pour lenfance, Fondation du Souffle, the SCOR Corporate Foundation for Science, William E. Ford, General Atlantic Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic Co-President, Managing Director and Head of business in EMEA, and the General Atlantic Foundation, the Battersea & Bowery Advisory Group, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM and the University of Paris Cite. A.N.S. is supported by European Union Horizon Health research and innovation program under grant agreement No 101057100, project UNDINE. The study was supported by the ORCHESTRA project, which has received funding from the European Union Horizon 2020 research and innovation program under grant agreement No 10101616. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). The COVIDeF study group was supported by the French Ministry of Health, Fondation AP-HP et Programme Hospitalier de Recherche Clinique (PHRC COVID-19-20-0048). Y.Z. and H.C.S. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. G.N. and A.N. are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. This project has received funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program (grant agreement no. 948959). This work is supported by the Swiss National Science Foundation (grant # 310030L_197721 to JF). This work is supported by ERN-RITA. The Canarian Sequencing Hub is funded by Instituto de Salud Carlos III (COV20_01333, and COV20_01334, and PI20/00876) and Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), co-financed by the European Regional Development Funds, A way of making Europe, from the European Union, and Cabildo Insular de Tenerife (CGIEU0000219140 and Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19). This work was funded, at least in part, by grants AJF202019 and AJF20259 from Al Jalila Foundation, Dubai, United Arab Emirates. Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All the enrolled participants provided written informed consent for participation and were recruited through protocols conforming to local ethics requirements. For patients enrolled in the Helix DNA Discovery Project, ethics approval was reviewed and obtained from the Western Institutional Review Board. For patients enrolled in the Healthy Nevada Project (HNP), the University of Nevada, Reno Institutional Review Board approved the study (project 956068-12). For patients enrolled in the French COVID cohort (ClinicalTrials.gov NCT04262921), ethics approval was obtained from the Comite de Protection des Personnes Ile De France VI (ID RCB, 2020-A00256-33) or the Ethics Committee of Erasme Hospital (P2020/203). For participants enrolled in the COV-Contact study (ClinicalTrials.gov NCT04259892), ethics approval was obtained from the CPP IDF VI (ID RCB, 2020-A00280-39). For patients enrolled in the Italian cohort, ethics approval was obtained from the University of Milano-Bicocca School of Medicine, San Gerardo Hospital, Monza-Ethics Committee of the National Institute of Infectious Diseases Lazzaro Spallanzani (84/2020) (Italy), and the Comitato Etico Provinciale (NP 4000-Studio CORONAlab). STORM-Health care workers were enrolled in the STudio OsseRvazionale sullo screening dei lavoratori ospedalieri per COVID-19 (STORM-HCW) study, with approval from the local institutional review board (IRB) obtained on June 18, 2020. Patients and relatives from San Raffaele Hospital (Milan) were enrolled in COVID-BioB/Gene-COVID protocols and, for additional studies, TIGET-06, with the approval of the local ethics committee. Patients and relatives from Rome were enrolled in Protocol no. 50/20 (Tor Vergata University Hospital). Informed consent was obtained from each patient. For the patients enrolled in the COVIDeF Study Group (ClinicalTrials.gov NCT04352348), ethics approval was obtained from the Comite de Protection des Personnes Ile de France XI (ID RCB, 2020-A00754-35). For patients enrolled in Spain, the study was approved by the Committee for Ethical Research of the Infanta Leonor University Hospital, code 008-20; the Committee for Ethical Research of the 12 de Octubre University Hospital, code 16/368; the Bellvitge University Hospital, code PR127/20; the University Hospital of Gran Canaria Dr. Negrin, code 2020-200-1 COVID-19; and the Vall d Hebron University Hospital, code PR(AMI)388/2016. Anonymized samples were sequenced at the National Institute of Allergy and Infectious Diseases (NIAID) through the Uniformed Services University of the Health Sciences(USUHS)/the American Genome Center (TAGC) under nonhuman subject research conditions; no additional IRB consent was required at the National Institutes of Health (NIH). For patients enrolled in the Swedish COVID cohort, ethics approval was obtained from the Swedish Ethical Review Agency (2020-01911 05). For patients enrolled in the SARS-CoV-2 Human Challenge Characterisation Study, ethics approval was obtained from the UK Health Research Authority Ad Hoc Specialist Ethics Committee (reference: 20/UK/0002). Written informed consent was obtained from participants before screening and enrollment.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data supporting the findings of this study are available within the manuscript and supplemental files. The whole-genome sequencing data of anonymized patients recruited through the National Institutes of Health (NIH) and sequenced at the National Institute of Allergy and Infectious Diseases (NIAID) through the Uniformed Services University of the Health Sciences (USUHS)/the American Genome Center (TAGC) are available under dbGaP submission phs002245.v1. Other patients were not consented to share the raw WES/WGS data files beyond the research and clinical teams.