Genetic variation in HLA, IGKV, and HHEX loci influences mRNA vaccine-induced humoral protection against COVID-19
Humoral immune responses to COVID-19 vaccination vary widely across individuals, yet the genetic determinants of functional antibody protection beyond binding antibodies after two immunizations remain poorly understood. We performed genome-wide association studies on antigen-specific antibody concentrations and live-virus neutralization activities after two and three vaccine doses in two German cohorts of SARS-CoV-2 infection-naïve individuals (RisCoin study n = 2,877; KoCo19 study n = 1,654). We found the HLA locus to be associated with differential live-virus neutralizing and anti-SARS-CoV-2 spike antibodies after both the second and third vaccinations. Consistent with its effect on third-dose neutralization, the HLA was additionally associated with a reduced incidence of breakthrough infection. We further replicated an association with antibody concentrations at the IGKV locus and discovered an association at the HHEX locus, implicating pathways linked to memory B-cell biology. Together, these findings reveal host genetic factors shaping neutralizing immunity and vaccine-induced protection against infection, with implications for personalized vaccination strategies.
Authors
- Raquel Rubio‐Acero
- Veit Hornung (ORCID: https://orcid.org/0000-0002-4150-194X)
- Helga‐Paula Török (ORCID: https://orcid.org/0000-0002-6883-5034)
- Marcel Stern (ORCID: https://orcid.org/0000-0002-7692-6905)
- Barbara Puzek (ORCID: https://orcid.org/0009-0008-3480-0416)
- Christof Geldmacher (ORCID: https://orcid.org/0000-0001-6777-7621)
- Eleftheria Zeggini (ORCID: https://orcid.org/0000-0003-4238-659X)
- Andreas Wieser (ORCID: https://orcid.org/0000-0002-8703-9228)
- Michael Höelscher (ORCID: https://orcid.org/0000-0002-7642-1835)
- Sarah Kim-Hellmuth (ORCID: https://orcid.org/0000-0001-8791-5729)
- Gaia Lupoli (ORCID: https://orcid.org/0000-0002-2786-6627)
- Sibylle Koletzko (ORCID: https://orcid.org/0000-0003-2374-8778)
- Ana Zhelyazkova (ORCID: https://orcid.org/0000-0002-8085-5003)
- Noemi Castelletti (ORCID: https://orcid.org/0000-0002-6598-5352)
- Paul R. Wratil (ORCID: https://orcid.org/0000-0003-0942-0637)
- Oliver Till Keppler (ORCID: https://orcid.org/0000-0002-1384-8946)
- Jochen Rech
- Alexander Choukèr (ORCID: https://orcid.org/0000-0002-0133-4104)
- Kristina Adorjan (ORCID: https://orcid.org/0000-0001-7501-9556)
- Thu Giang Le Thi (ORCID: https://orcid.org/0000-0002-2504-9551)
- Berthold Koletzko (ORCID: https://orcid.org/0000-0002-5345-7165)
- Irene Charlotte Schoof
- Christian Janke
Institutions
- University of Bern (CH)
- TUM Klinikum (DE)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- German Center for Infection Research (DE)
- Institut für Psychiatrische Phänomik und Genomik (DE)
- University of Warmia and Mazury in Olsztyn (PL)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1016/j.celrep.2026.117981
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Bundesministerium für Bildung und Forschung
- Bundesministerium für Gesundheit
- Bayerisches Staatsministerium für Wissenschaft und Kunst