Association of plasma ferritin and plasma iron at time of vaccination with the immune response to SARS-CoV-2 vaccination: a longitudinal cohort study

Giulia Pestoni¹Dominik Menges²Craig Fenwick³Pornpimol Scheuchzer¹Julia Braun²Sarah R Haile²Tala Ballouz²Christophe Zeder^4,5Nicole U. Stoffel^4,6Michael B. Zimmermann⁷Milo Alan Puhan²Anja Frei²Diego Moretti^1*

• ¹Swiss Distance University of Applied Sciences, Brig, Switzerland
• ²Universitat Zurich, Zürich, Switzerland
• ³Centre Hospitalier Universitaire Vaudois Service d'immunologie et allergie, Lausanne, Switzerland
• ⁴Eidgenossische Technische Hochschule Zurich Departement Chemie und Angewandte Biowissenschaften, Zürich, Switzerland
• ⁵Eidgenossische Technische Hochschule Zurich Departement Gesundheitswissenschaften und Technologie, Zürich, Switzerland
• ⁶University of Oxford, Oxford, United Kingdom
• ⁷John Radcliffe Hospital, Oxford, United Kingdom

Introduction: Recent studies have shown a link between iron status and immune response following infection or vaccination. We aimed to investigate whether plasma ferritin and plasma iron concentrations at time of vaccination were associated with the development and temporal decay of immune response to SARS-CoV-2 vaccination over 6 months. Materials and methods: We used data from the Zurich SARS-CoV-2 Vaccine Cohort (n=572). Participants were recruited from a random sample stratified by age groups (18-64 years, >65 years) and vaccine types (Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Johnson & Johnson JNJ-78436735). Iron parameters were measured at baseline (prior to vaccination), whereas different immunity markers were measured at baseline, 4 weeks, 6 weeks, 3 months, and 6 months. We investigated the association between plasma ferritin and plasma iron levels and immunity markers using linear mixed-effect models, and estimated half-life based on linear decay models. Results: Plasma ferritin and plasma iron concentrations were within the normal physiological range, and the prevalence of iron deficiency (4.5%) and inflammation (2.3%) was low. For every 50 ug/L increase in plasma ferritin concentration, we observed a 5.2% increase in Anti-S IgG antibodies, and a 13.6-19.9% increase in neutralizing antibodies against the Ancestral, Delta, and Omicron BA1 viral variants. Similarly, the highest plasma ferritin quartile showed a 14.9% increase in Anti-S IgG antibodies, and a 47.1-82.2% increase in Anti-Ancestral, Anti-Delta, and Anti-Omicron neutralizing antibodies compared to the lowest quartile. Despite high concentrations at 6 months, shorter mean half-lives of Anti-S IgG antibodies were observed in the highest quartiles of plasma ferritin concentrations (Q3: 121.4 days; Q4: 109.8 days vs. Q1: 152.1 days). Plasma iron results were less consistent and generally no evidence for associations was found. Conclusion: In this predominantly iron-replete cohort, higher plasma ferritin at the time of vaccination was associated with stronger vaccination-induced humoral immune responses to SARS-CoV-2 over 6 months.