Poster Presentation 12th Australasian Virology Society Meeting 2024

Boosting four-mula:  Impact of elevated IgG4 following repeated COVID-19 mRNA boosters. (#244)

Kevin J Selva 1 , Wen Shi Lee 1 , Jennifer Audsley 2 , Mai C Trieu 3 , Carissa Aurelia 1 , Joanne Patterson 4 , Helen E Kent 1 , Julie Nyugen 1 , Thakshila Haripriya Amarasena 1 , Robyn Esterbauer 1 , Ebene Haycroft 1 , Pradhipa Ramanathan 1 , Timothy E Schlub 5 , Joseph Sasadeusz 4 , Adam Wheatley 1 , Jennifer Juno 1 , Amy W Chung 1 , Stephen J Kent 1 6
  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. Department of Clinical Science, Influenza Centre, Uni of Bergen, Bergen, Norway
  4. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VICTORIA, Australia
  5. Sydney School of Public Health, Faculty of Medicine and Health, Uni of Sydney, Sydney, NEW SOUTH WALES, Australia
  6. Melbourne Sexual Health Centre, Department of Infectious Diseases,, Alfred Hospital and Central Clinical School, Monash Uni, Melbourne, VICTORIA, Australia

COVID-19 mRNA boosters generate IgG antibodies which protect against SARS-CoV-2 infection through both viral neutralisation and non-neutralising activity (involving complement and innate immune cells). Importantly, repeated mRNA boosters cause IgG subclass switching from IgG1 to IgG4. While it is assumed that IgG4 can still neutralize virus similarly to IgG1, it is much poorer at activating complement and innate immune cells to induce non-neutralising protection.

At present, it remains unclear if IgG4 class switching following repeated mRNA boosters is affected by ancestral imprinting or if it would affect individuals who initially received non-mRNA primary COVID-19 vaccines (Vaxzevria; AstraZeneca) in a similar way. Moreover, its effect at the mucosa remains understudied. Here, we characterized IgG4 responses in cohorts with either 2x mRNA or 2x non-mRNA (Vaxzevria) primary COVID-19 vaccines, after they received repeated mRNA boosters (up to 4). 

While pre-booster ancestral spike IgG4 responses were initially elevated (110-fold increase; p<0.001) in individuals with primary mRNA vaccines (2x mRNA + 1x mRNA booster) as compared to individuals with primary Vaxzevria vaccines (2x Vaxzevria + 1x mRNA booster). these differences shrunk 2 weeks after the 2nd mRNA boosters, as individuals with primary Vaxzevria vaccines developed strong IgG4 responses against ancestral (38-fold increase, pre- vs post-booster; p<0.001) and Omicron variant spikes (BA.1, 28-fold increase; p<0.001) (XBB.1.5, 5-fold increase; p<0.001), which remained elevated for 3 months.

Furthermore, while receptor binding domain (RBD) specific IgG4 antibodies also remained largely ancestral-centric, IgG4 antibodies against Omicron RBD (BA.1, XBB.1.5, JN.1) rose significantly with increasing mRNA boosters (p<0.05). Through epitope binning, we also narrowed down that >40% of RBD-specific IgG4 antibodies targeted the ACE2 binding site on the RBD, potentially impacting neutralizing activity.

Our findings highlight how yearly COVID-19 mRNA boosters continue to shape IgG4 class switching and may have wider implications on COVID-19 humoral responses against emerging viral variants.