Waning immunity and IgG4 responses following bivalent mRNA boosting

Waning immunity and IgG4 responses following bivalent mRNA boosting

23 February 2024 | Ninaad Lasrado, Ai-ri Y. Collier, Jessica Miller, Nicole P. Hachmann, Jinyan Liu, Trisha Anand, Esther A. Bondzie, Jana L. Fisher, Camille R. Mazurek, Robert C. Patio, Stefanie L. Rodrigues, Marjorie Rowe, Nehalee Surve, Darren A. Ty, Cindy Wu, Taras M. Chicz, Xin Tong, Bette Korber, Ryan P. McNamara, Dan H. Barouch
This study investigates the immune responses following bivalent mRNA boosting against SARS-CoV-2 variants, focusing on neutralizing antibody (NAb) responses, IgG subclass switching, and Fc functional activity. The research shows that bivalent mRNA boosters induce modest NAb responses against XBB variants, which wane rapidly within three months, while they induce more robust and sustained NAb responses against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses are primarily IgG2 and IgG4 with poor Fc functional activity, whereas a third monovalent mRNA boost induces robust IgG1 and IgG3 responses with enhanced Fc activity. The study highlights significant immune imprinting to the ancestral spike and isotype switching to IgG4 responses after bivalent mRNA boosting, with important implications for future booster designs. The findings suggest that bivalent mRNA boosting may be limited by immune imprinting and that multiple mRNA immunizations may lead to IgG4 responses with poor functional activity. The study also shows that bivalent mRNA boosting results in minimal cellular immune responses, with only minor increases in CD4 and CD8 T cell responses. Overall, the study underscores the importance of considering immune imprinting and IgG subclass switching in the development of future SARS-CoV-2 boosters.This study investigates the immune responses following bivalent mRNA boosting against SARS-CoV-2 variants, focusing on neutralizing antibody (NAb) responses, IgG subclass switching, and Fc functional activity. The research shows that bivalent mRNA boosters induce modest NAb responses against XBB variants, which wane rapidly within three months, while they induce more robust and sustained NAb responses against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses are primarily IgG2 and IgG4 with poor Fc functional activity, whereas a third monovalent mRNA boost induces robust IgG1 and IgG3 responses with enhanced Fc activity. The study highlights significant immune imprinting to the ancestral spike and isotype switching to IgG4 responses after bivalent mRNA boosting, with important implications for future booster designs. The findings suggest that bivalent mRNA boosting may be limited by immune imprinting and that multiple mRNA immunizations may lead to IgG4 responses with poor functional activity. The study also shows that bivalent mRNA boosting results in minimal cellular immune responses, with only minor increases in CD4 and CD8 T cell responses. Overall, the study underscores the importance of considering immune imprinting and IgG subclass switching in the development of future SARS-CoV-2 boosters.
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[slides and audio] Waning immunity and IgG4 responses following bivalent mRNA boosting