mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and uncertainty about the durability of immune memory following vaccination have raised questions about the need for a third "booster" vaccine dose. In this study, we longitudinally profile both antibody and cellular memory responses in a cohort of 61 individuals out to 6 months post-mRNA vaccination. Despite an expected decay from peak antibody levels and neutralizing titers, we observe that memory B cell responses, including memory cells specific for the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, are generated by mRNA vaccination and continue to increase between 3- and 6-months post-vaccination. Notably, the majority of memory B cells induced by mRNA vaccines are capable of cross-binding variants of concern, and memory cells continue to improve their variant-binding capabilities over time, resulting in greater variant cross-binding than a longitudinal comparison cohort of SARS-CoV-2 convalescent individuals. B cell receptor sequencing of mRNA vaccine-induced memory cells revealed that variant-binding clones are significantly more hypermutated than wild-type only binding clones found in the same lineages. These data indicate mRNA vaccines promote ongoing germinal center activity for months after vaccination that result in both quantitative and qualitative improvement of B cell memory to variants over time. Moreover, activation of memory B cells in vitro confirmed that these cells can rapidly respond to produce functional antibody, supporting a role for memory cells upon potential re-exposure to antigen. In addition to serology and B cell memory, we also quantified memory CD4+ and CD8+ T cell responses induced by mRNA vaccination. Together, these integrated findings demonstrate robust immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination and provide insights into the generation of variant-specific memory responses, which may inform future policy and vaccine design efforts.