Poster Presentation & Lightning Talk Asia-Pacific Vaccine and Immunotherapy Congress 2024

Mix & Match: Impact of delayed intervals and repeated COVID-19 mRNA boosters on systemic and mucosal antibody responses. (#107)

Kevin J Selva 1 , Wen Shi Lee 1 , Jennifer Audsley 2 , Mai C Trieu 3 , Arnold Reynaldi 4 , Jo Peterson 5 , Helen E Kent 1 , Julie Nyugen 1 , Thakshila Haripriya Amarasena 1 , Robyn Esterbauer 1 , Ebene R Haycroft 1 , Pradhipa Ramanathan 1 , Miles P Davenport 4 , Timothy E Schlub 6 , Joseph Sasadeusz 5 , Adam K Wheatley 1 , Jennifer A Juno 1 , Amy W Chung 1 , Stephen J Kent 1 7
  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. Kirby Institute, Uni of New South Wales, Kensington, NEW SOUTH WALES, Australia
  5. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VICTORIA, Australia
  6. Sydney School of Public Health, Faculty of Medicine and Health, Uni of Sydney, Sydney, NEW SOUTH WALES, Australia
  7. Melbourne Sexual Health Centre, Department of Infectious Diseases,, Alfred Hospital and Central Clinical School, Monash Uni, Melbourne, VICTORIA, Australia

Updated COVID-19 mRNA boosters have been effective at boosting humoral responses against circulating and emerging variants. However, it remains unclear if delaying dosing intervals for COVID-19 boosters could further improve antibody responses (magnitude, neutralisation), such as that previously observed with the primary COVID-19 vaccine regimes. Furthermore, little is known about how repeated mRNA boosters would impact IgG subclass switching (from IgG1 to IgG4), particularly in individuals who have received non-mRNA primary COVID-19 vaccines (Vaxzevria; AstraZeneca).

Here, we conducted a randomized controlled trial (Nov 2022 – Aug 2023) and recruited participants to either receive the Moderna BA.1 bivalent mRNA booster upon recruitment (immediate arm) or 3 months following recruitment (delayed arm). Follow-up visits were completed for 48 participants (24 per arm), with paired saliva and plasma samples collected following each visit (Immediate: Day 0, 7, 14, 28, 84, 168; Delayed: 3 months prior, Day 0, 7, 14, 28, 84). Furthermore, 40% of the cohort had received 2 x Vaxzevria as their primary vaccine and were receiving the BA.1 bivalent booster as their second mRNA booster.

Neutralisation profiles between the immediate and delayed arms were similar in both plasma (against ancestral SARS-CoV-2; Omicron BA.1, XBB.1.5) and saliva (against ancestral). The magnitude and half-life of plasma and salivary antibody responses (total IgG and IgA) against ancestral and Omicron variants (BA.1, XBB.1.5) were also comparable across both immediate and delayed arms.

Prior to their second mRNA booster, ancestral IgG4 responses were significantly elevated (110-fold increase; p<0.001) in individuals with primary mRNA vaccines (2 x mRNA + 1 x mRNA booster) as compared to individuals with primary Vaxzevria vaccines (2 x Vaxzevria + 1 x mRNA booster). This difference in IgG4 responses between primary mRNA and Vaxzevria cohorts shrunk 2 weeks after the BA.1 bivalent mRNA booster (6-fold increase; p<0.01), as individuals with primary Vaxzevria vaccines developed strong IgG4 responses against ancestral SARS-CoV2 (38-fold increase, pre- vs post-booster; p<0.001) and Omicron variants (BA.1, 28-fold increase; p<0.001) (XBB.1.5, 5-fold increase; p<0.001).

Our findings suggest that while COVID-19 mRNA boosters do enhance protective antibodies, delayed boosting does not provide much benefit to antibody responses. Furthermore, we note that the second mRNA booster significantly increased IgG4 responses in individuals who received the primary Vaxzevria vaccines. Future work should be done to better understand the impact of elevated IgG4 following repeated mRNA boosters.