Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma

Abstract

Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.

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“…Recent evidence from the COVID-19 pandemic suggests that this population may derive a unique benefit from a vaccine strategy that drives a robust germinal center response. Studies of COVID-19 vaccine response in participants with hematologic neoplasia (lymphoma, myeloma) demonstrated that total IgG titers were substantially lower in this population following vaccination [37 ▪ ]. Surprisingly, both avidity and neutralization titers were higher in this population following vaccination as compared to healthy controls, especially at earlier time points, suggesting a more robust germinal center response.…”

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“…There are several caveats to the study by Keppler-Hafkemeyer et al 1 . The authors evaluated antibody avidity using a modified ELISA assay by adding a chaotropic agent to disrupt the hydrogen bonding between antigen and antibody, in order to elute antibodies that bind weakly to antigen.…”

“…Despite the tremendous amount of knowledge gained in COVID-19 research, there remains a lack of clarity about how to identify those who are most immunosuppressed and how best to prevent and treat severe COVID-19 infections. Keppler-Hafkemeyer et al 1 and Denkinger et al 10 highlight the importance of in-depth analysis when profiling immune responses to vaccination and the need for continued exploration of protective measures for immunosuppressed populations.…”

“…Antibody quantification is frequently used as a surrogate for antibody efficacy, but this ignores the strength of antibody binding to the target antigen (avidity). In this issue of Nature Cancer, Keppler-Hafkemeyer et al 1 report that patients with hematological malignancies (lymphoma and myeloma) produce antibodies with higher avidity than matched healthy controls after the second vaccine dose. Thus, even though these patients develop lower antibody levels than healthy controls after vaccination, the reduction in virus neutralization is better than predicted.…”

“…Consistent with our understanding of affinity maturation, anti-spike IgG antibody levels and avidity increase with each SARS-CoV-2 vaccine dose in healthy individuals, and this correlates with in vitro virus neutralization 3 . Keppler-Hafkemeyer et al 1 analyzed antibody levels, avidity and virus neutralization to SARS-CoV-2 variants in 60 patients with hematological malignancies (B cell lymphoma (n = 38) and myeloma (n = 22)) after two and three doses of BNT162b2 mRNA vaccines. As reported by others 4,5 , they observed that patients News & views vaccinated individuals.…”