A systematic investigation into the genetic and non-genetic factors underlying the human antiviral antibody repertoire

Immunoglobulins are among the most important anti-viral effectors of the human immune system. The biological mechanisms underlying antibody production and maintenance are relatively well understood. However, a broader model of how host intrinsic factors and external processes influence humoral responses to viral infections is lacking. Here, we investigate how age, sex, genetics, health-related habits, and immune factors relate to the anti-viral antibody repertoire of healthy humans. We used VirScan, a high-throughput technology based on phage-display immunoprecipitation sequencing (PhIP-seq), to characterize antibody reactivity against more than 90,000 viral epitopes in 1,212 healthy adults of European and African descent. By comparing VirScan with various serological assays, we first show that PhIP-seq-based antibody repertoires recapitulate expected serostatuses and uncover considerable variation in epitope-specific reactivity. In addition to age and sex effects, we find that the antibody repertoire is strongly associated with active smoking, which results in increased antibody levels against rhinoviruses. We provide evidence that individuals born in Central Africa and Europe differ in antigenic reactivity to common herpesviruses by targeting different viral proteins. By comparing antibody repertoires to 169 immune cell parameters, we find that HLA-DR expression in circulating dendritic cells is associated with increased reactivity against EBV. Finally, we conducted a GWAS of antibody binding against more than 2,600 viral peptides. We confirmed a strong effect of HLA and IGH loci and the FUT2 gene and identified new associations with antibodies against adenoviruses and saliviruses. These findings highlight the determinants of human variation in the humoral response to viruses and broaden perspectives on how the antibody repertoire is generated and maintained. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement The study received funding from the Wenner-Gren Foundation and benefited from the support of the French government program Investissement d'Avenir, managed by the Agence Nationale de la Recherche (reference 10-LABX-69-01). ### Author Declarations 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: The Institut Pasteur (Pasteur ID-RCB Number:2012-A00238-35), the Comités de Protection des Personnes, Ouest 6 and Sud Méditerranée (CPP), the Agence Nationale de Sécurité du Médicament (ANSM) and the Commission nationale de l'informatique et des libertés (CNIL) gave ethical approval for the Milieu Intérieur clinical study and this work. The ethics committee of Ghent University (B670201214647), the Ethics Board of Institut Pasteur (EVOIMMUNOPOP-281297), the Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé (CCITRS), the CPP and the CNIL gave ethical approval for the EvoImmunoPop study and this work. 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 The PhIP-seq VirScan v.3 raw and processed data generated in this study have been deposited in the Institut Pasteur data repository, OWEY, which can be accessed via the following link: https://doi.org/10.XXXXX/owey.f83a-XXXX. The MI SNP array data can be accessed in the European Genome-Phenome Archive (EGA) with the accession code EGAS00001002460. The EIP SNP array data can be accessed in OWEY via the following link: https://doi.org/10.48802/owey.pyk2-5w22. All MI and EIP datasets can be accessed by submitting a data access request to respective data access committees (DAC). The DAC informs all the research participants of the data access request and grants data access if the request is consistent with the informed consent signed by the participants. In particular, research on MI and EIP datasets is restricted to research on the genetic and environmental determinants of human variation in immune responses. Data access is typically granted two months after request submission.