Oral Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2026

Does increasing SARS-CoV-2 IgG4 following repeated mRNA boosters impact antibody functions towards Omicron variants and sarbecoviruses? (#35)

Kevin J Selva 1 , Wen Shi Lee 1 , Alther L Enriquez 1 , L. Carissa Aurelia 1 , Jennifer Audsley 2 , Helen E Kent 1 , Emily M Eriksson 3 4 , Nicholas Kiernan-Walker 3 4 , Judy Chang 5 , Janine Trevillyan 5 6 , Phillip Pymm 3 4 , Wai-Hong Tham 3 4 7 , Laura E Downie 8 , Adam K Wheatley 1 , Jennifer A Juno 1 , Stephen J Kent 1 9 , Amy W Chung 1
  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, Uni of Melbourne, Melbourne, VICTORIA, Australia
  2. Department of Infectious Diseases, Peter Doherty Institute for Infection and Immunity, Uni of Melbourne and Royal Melbourne Hospital, Melbourne, VICTORIA, Australia
  3. The Water and Eliza Hall Institute of Medical Research, Parkville, VICTORIA, Australia
  4. Department of Medical Biology, The University of Melbourne, Melbourne, VICTORIA, Australia
  5. Victorian Critical Vaccinees Collection (VC2), Peter Doherty Institute for Infection and Immunity, Uni of Melbourne, Melbourne, VICTORIA, Australia
  6. Department of Infectious Diseases, Austin Health, Heidelberg, VICTORIA, Australia
  7. Research School of Biology, Australian National University, Canberra, AUSTRALIAN CAPITAL TERRITORY, Australia
  8. Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, VICTORIA, Australia
  9. Melbourne Sexual Health Centre, Department of Infectious Diseases,, Alfred Hospital and Central Clinical School, Monash Uni, Melbourne, VICTORIA, Australia

Updated COVID-19 mRNA boosters protect against severe disease and death by SARS-CoV-2, especially among vulnerable populations. However, repeated mRNA vaccines/boosters have been linked to uni-directional IgG subclass switching of spike-specific antibodies towards IgG4 (IgG3→IgG1→IgG2→IgG4).

In contrast to IgG3 and IgG1, IgG4 binds poorly to Fc gamma receptors (FcγR) present on NK cells (FcγRIIIa) or phagocytes (FcγRIIa) limiting Fc-mediated non-neutralising anti-viral responses. However, its impacts across Omicron variants and sarbecoviruses remain underexplored. Furthermore, IgG4 undergoes Fab-arm exchange in vivo—forming non-symmetrical bispecific antibodies—which could weaken their binding to escape viral variants. Sequential subclass switching could also favor pre-existing biases from ancestral imprinting.

Here, we show that plasma and salivary IgG4 increased substantially following 4 exposures to mRNA vaccines/boosters, in either primary mRNA vaccinees (mRNA cohort; 2x mRNA vaccine + 2x mRNA boosters) or adenovirus-vector vaccinees (Vaxzevria cohort; 2x adenoviral-vector vaccine + 4x mRNA boosters).

Elevated class-switched IgG4 negatively correlated with plasma concentrations of IgG1 targeting Omicron spikes (BA.1, XBB.1.5, JN.1), peaking 4 weeks after their 4th mRNA dose in both cohorts (mRNA: r=-0.53 to -0.66, p<0.01; Vaxzevria: r=-0.65 to -0.71, p<0.01). While ancestral imprinting greatly influenced IgG4 spike responses—particularly towards the RBD—IgG4 responses trended similarly to total IgG, resulting in comparable proportions of IgG4 (%IgG4 / total IgG) across Omicron variants.

Omicron spike-specific plasma antibody engagement with FcγRIIa and FcγRIIIa improved overall following boosters, however these responses also negatively associated with rising IgG4 (mRNA: r=-0.74 to -0.86, p<0.0001; Vaxzevria: r=-0.73 to -0.88, p<0.001). Similar trends were observed in saliva, though IgG4 had a weaker impact. Depletion of IgG4 increased IgG1 binding against viral variants (+13-16%), highlighting how sequential subclass switching results in epitope competition. Similarly, IgG4 depletion also rescued Fc-receptor engagement across Omicron variants, particularly FcγRIIIa (+11-14% binding; p<0.0001).

Spike-specific IgG4 was also cross-reactive to sarbecoviruses found in bats (RaTG13, RsSHC014, HKU3) and pangolins (GX-P5L, GD-1). Increased proportions of cross-reactive IgG4 negatively associated with FcγRIIa and FcγRIIIa engagement across sarbecoviruses (mRNA: r=-0.54 to -0.93, p<0.01; Vaxzevria: r=-0.63 to -0.94, p<0.01), highlighting the wider implications of class-switched IgG4.

Through epitope blocking, we determined that a majority of ancestrally-imprinted RBD IgG4 (mRNA: 61-71%, p<0.0001; Vaxzevria: 43-52%, p<0.0001) targeted the receptor binding motif—the mutational hotspot binding ACE2 receptor. IgG4 depletion revealed that while IgG4 greatly neutralised ancestral SARS-CoV-2, its direct contribution towards BA.1 or XBB.1.5 neutralisation were more modest.

Our findings underscore the growing urgency to better understand and mitigate IgG4 class-switching following mRNA vaccines/boosters.

  1. Elevated SARS-CoV-2 IgG4 in plasma and mucosa following repeated mRNA boosters impact antibody functions to Omicron and sarbecoviruses Selva, Kevin J. et al. eBioMedicine, Volume 123, 106087