Prolonged evolution of the human B cell response to SARS-CoV-2 infection

Abstract

A comprehensive understanding of the kinetics and evolution of the human B cell response to SARS-CoV-2 infection will facilitate the development of next-generation vaccines and therapies. Here, we longitudinally profiled this response in mild and severe COVID-19 patients over a period of five months. Serum neutralizing antibody (nAb) responses waned rapidly but spike (S)-specific IgG+ memory B cells (MBCs) remained stable or increased over time. Analysis of 1,213 monoclonal antibodies (mAbs) isolated from S-specific MBCs revealed a primarily de novo response that displayed increased somatic hypermutation, binding affinity, and neutralization potency over time, providing evidence for prolonged antibody affinity maturation. B cell immunodominance hierarchies were similar across donor repertoires and remained relatively stable as the immune response progressed. Cross-reactive B cell populations, likely re-called from prior endemic beta-coronavirus exposures, comprised a small but stable fraction of the repertoires and did not contribute to the neutralizing response. The neutralizing antibody response was dominated by public clonotypes that displayed significantly reduced activity against SARS-CoV-2 variants emerging in Brazil and South Africa that harbor mutations at positions 501, 484 and 417 in the S protein. Overall, the results provide insight into the dynamics, durability, and functional properties of the human B cell response to SARS-CoV-2 infection and have implications for the design of immunogens that preferentially stimulate protective B cell responses.

A combination of RBD and NTD neutralizing antibodies limits the generation of SARS-CoV-2 spike neutralization-escape mutants

“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted June 11, 2021. ; https://doi.org/10.1101/2021.06.10.447999 doi: bioRxiv preprint early memory B-cell response to SARS-CoV-2 infection in each donor and are consistent with previous studies (34)(35)(36). From the cloned pairs of VH and VL genes of the four donors, we expressed and purified mAbs in a human IgG1 background using our yeast expression platform.…”

“…Competitive binding of mAbs to recombinant SARS-CoV-2 RBD with hACE2 was evaluated using the ForteBio Octet HTX instrument (Molecular Devices) as described previously (34). Briefly, IgGs were captured onto AHC biosensors (Molecular Devices) to achieve a sensor response between 1-1.4 nm followed by an inert IgG to occupy any remaining binding sites on the biosensor.…”

Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection

“…The memory B cell compartment accumulates mutations and undergoes clonal evolution over the initial 6 months after infection 4,9,21,22 . To determine whether the memory compartment continues to evolve between 6 and 12 months, we obtained 1105 paired antibody heavy and light chain sequences from 10 individuals that were also assayed at the earlier time points, 6 of which were vaccinated (Fig.…”

Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets

“…Our group and others have identified MBCs against the spike, nucleoprotein (NP), and open reading frame 8 (ORF8) proteins in convalescence, and some studies show that these populations persist several months after infection (Dan et al, 2021;Guthmiller et al, 2021;Hartley et al, 2020;Rodda et al, 2021). Beyond their longevity, spike-specific MBCs continue to adapt to SARS-CoV-2 up to 6 months post-infection, in a manner consistent with antigen persistence and ongoing germinal centers (GCs) (Gaebler et al, 2021;Sakharkar et al, 2021;Sokal et al, 2021).…”