The impact of a delayed SARS-CoV-2 vaccine dose interval on the immune system: B cell maturation and antibody neutralization

Abstract

Early in the COVID-19 vaccine rollout, Canada implemented a dose-sparing strategy by delaying second doses to increase first-dose coverage. A longer interval between doses was associated with improved antibody titres and inhibition of variants. These improvements may reflect enhanced B cell affinity maturation during the extended interval. This study examines the effects of an extended dose interval on B cell maturation after the primary dose series and following a booster dose in mRNA vaccine recipients from Manitoba. Blood samples were collected at multiple timepoints from participants who received either a short or extended dose interval. Peripheral blood mononuclear cells were isolated and stained with fluorescent probes to detect and phenotype antigen-specific B cells over time using flow cytometry. A delayed dose interval led to a greater increase in Spike-specific and RBD-specific B cells and antigen-specific memory B cells 1-2 weeks after the second dose compared to a standard dose interval. Spike-specific and RBD-specific B cells in the standard dose interval participants increased to match the levels in the delayed dose interval participants 6 months after the second dose. The impact of a third dose in both groups did not result in differences in the proportions of SARS-CoV-2-specific B cells between participants with standard or extended dose intervals. To investigate the impact of dose interval on antibody maturation over time, PBMCs from various post-vaccination timepoints were stimulated in vitro to differentiate memory B cells into antibody-secreting plasma cells. Antibodies derived from antibody-secreting plasma cells in participants with a delayed dose interval saw increased affinity and a wider breadth of inhibition for SARS-CoV-2 RBD 10-14 days following the second dose of the vaccine compared to standard dose interval participants. The third dose did not result in differences in the breadth of inhibition between participants with standard or extended dose intervals. Dosing intervals affect B cell phenotypic proportions and antibody responses following vaccination. Extended intervals transiently increase SARS-CoV-2-specific B cell frequencies and antibody breadth, suggesting greater maturation, but shorter intervals eventually yield comparable responses. The study will shed light on whether the establishment of long-term memory B cells is also affected, with implications for future vaccine strategies.