A new analysis of B cells and more than 1,000 different monoclonal antibodies from 8 patients with COVID-19 shows that, contrary to previous hypotheses, protective B cell responses to the SARS-CoV-2 spike protein remain stable and continue to evolve over a 5-month period, many months after the initial period of active viral replication. However, a large proportion of the neutralizing antibodies generated from these long-lasting B cells did not efficiently recognize various emerging SARS-CoV-2 variants from Brazil and South Africa. These results - from an academia-industry collaboration - will help inform the design of future COVID-19 vaccines that work to constrain viral evolution and stimulate better neutralizing antibody and B cell responses against emerging SARS-CoV-2 variants. Mrunal Sakharkar and colleagues profiled spike protein-specific B cell and antibody responses in 8 patients with mild and severe COVID-19 over five months. Consistent with previous findings, they observed a significant decline in neutralizing antibody levels in the blood over time; however, levels of spike protein-specific memory B cells remained stable or even increased during the same time frame. As well, over the course of 120 days, monoclonal antibodies isolated from these B cells underwent increased somatic hypermutation, binding affinity, and neutralization potency - all signs of persistent B cell activity. The researchers also observed cross-neutralizing B cell populations, but these comprised just a small fraction of the B cell repertoire and were not prominent in the neutralizing response to SARS-CoV-2. Rather, a large proportion of the neutralizing antibody response only targeted conserved epitopes shared between SARS-CoV-2 and SARS-CoV and did not efficiently recognize emerging SARS-CoV-2 variants from Brazil and South Africa that harbor mutations at amino acid positions 417 and 484 of the spike protein. Thus, the authors suggest careful monitoring of circulating SARS-CoV-2 variants for variability in these protein sites to determine how these mutations impact vaccine-induced immunity.