Oral Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2026

Persistence of IgG4 skewing over 12 months following a fourth dose of a bivalent mRNA or protein-based COVID-19 vaccine (#36)

Nadia Mazarakis 1 , Franny Muteba 2 , Carissa Aurelia 2 , Zheng Quan (Ryan) Toh 1 , Eleanor Frances Georgina Neal 1 , Kathryn Bright 1 , Skyy Luu 1 , Leanne Quah 1 , Yan Yung Ng 1 , Cattram Nguyen 1 , John Hart 1 , Lien Anh Ha Do 1 , Anna Rudel 1 , Shashini Dassanayake 1 , Rachel A Higgins 1 , Darren Ong 1 , Fran Justice 1 , Emma Watts 1 , Siddhartha Mahanty 2 , Kanta Subbarao 2 , Kim Mulholland 1 , Claire von Mollendorf 1 , Amy Chung 2 , Paul Licciardi 1
  1. Murdoch Children's Research Institute, Parkville, VIC, Australia
  2. The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia

Introduction: Repeated mRNA vaccination (i.e. ≥3 doses) skews IgG4 responses, raising concerns associated with impaired antibody functions (e.g. FcR functions, neutralisation) and reduced protection.

Objective: We conducted a randomised controlled trial (RCT) to compare immunogenicity of a bivalent mRNA (mRNA-1273.214/mRNA-1273.222) or protein (NVX-CoV-2373) COVID-19 vaccine given as a fourth dose in healthy adults. The overall objective was to determine Spike-specific IgG4 skewing over a 12-month period post-vaccination and the impact on antibody function.

Methods: We conducted a RCT (N=456) in Melbourne, Australia (ClinicalTrials.gov Identifier: NCT05543356). We measured Spike-specific IgG (total) and subclasses IgG1, IgG2, IgG3, IgG4 to Ancestral, BA.5, XBB.1.5 and JN.1 Spike trimer at baseline (day 0), and at 1 month, 6 months and 12 months post-vaccination using an established multiplex assay. Fc receptor dimer and C1q hexamer binding were measured via multiplex assays as high throughput surrogate assessments for ADCC (FcγRIIIa dimer binding), ADCP (FcγRIIa binding) and ADCD (C1q hexamer binding). Cell based functional assays including ADCP and ADCC was also measured in a subset (n=20/group) using a validated assay.

Results: Participants were randomised into either the bivalent mRNA (n=90) or protein (n=88) vaccine groups. IgG4 levels against Ancestral strain were found to be higher in participants that had 3 prior mRNA doses compared to those who had 1 prior mRNA dose at baseline and at all other post-vaccination timepoints (protein; ~12-fold, mRNA; ~19-fold). However, these results were also accompanied by a modest increase in IgG1 levels (protein; ~1.8-fold, mRNA; 1.5-fold). Although overall IgG1 levels remained the highest proportion of IgG subclasses. Both IgG1 and IgG4 responses remained stable over time in both groups for Ancestral, BA.5, and XBB.1.5. However, for JN.1, this response was less pronounced for IgG1 JN.1 response, with strong waning observed by 12 months post-vaccination, with increased IgG4 skewing. FcR receptor function (FCgRIIaH, FCgRaR, and FCgR3af) was significantly higher in the mRNA vaccine group compared with the protein vaccine group, which was sustained to 12 months. Breakthrough analysis observed no differences in IgG1 and IgG4 levels and function between documented breakthrough infections and no breakthrough infections cohorts.

Conclusion: While IgG4 levels were elevated following repeated mRNA vaccination, this was also associated with increased IgG1 levels. These results suggest that the higher IgG1 levels combated against reduced FcR function associated with high IgG4, which was not associated with increased risk of breakthrough infections. These results have important implications for ongoing booster strategies using mRNA vaccines.