The ability of SARS-CoV-2 vaccination to prevent infection, also known as sterilizing immunity, is dependent on the ability of vaccine-induced antibodies to block viral entry into cells via viral spike protein. 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. This exciting observation implies that antibody affinity maturation might be more rapid in individuals with B cell malignancies, which leads to a multitude of important mechanistic questions relevant to our understanding of B cell development and vaccine design.

The encounter between naive B cells with B cell receptors (BCR) and their cognate antigens, in this case the spike protein, leads to the migration of activated B cells into B cell follicles and formation of germinal centres2. In the germinal center, activation-induced deaminase (AID) deaminates cytidine to uracil in variable immunoglobulin gene loci to produce point mutations, which increase the diversity and affinity of the BCR for the antigen (in the process of somatic hypermutation). Antigen-activated B cells with higher affinity for antigen are selected for survival, resulting in increasing numbers of B cells with higher antigen avidity with each round of selection and proliferation, a process known as affinity maturation.

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 neutralization3. 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 others4,5, they observed that patients with B cell lymphoma had significantly lower spike IgG antibody levels than healthy controls. However, the hematological malignancy cohort had 13% higher spike IgG avidity to the Wuhan-hu-1 strain at 2–8 weeks and 30% at 4–5 months after the second SARS-CoV-2 vaccine dose, compared to age- and sex-matched healthy controls. Antibody avidity between patient and control cohorts after the third vaccine dose was comparable (87 versus 80%; Fig. 1). The authors further demonstrated that stronger antibody avidity correlated with higher virus neutralization responses across multiple SARS-CoV-2 variants.

Fig. 1
figure 1

Anti-spike IgG antibody level and avidity after second and third doses of SARS-CoV-2 vaccine in healthy individuals compared to participants with hematologic malignancies.

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These findings pose the interesting question of why individuals with B cell malignancies might have higher-avidity antibodies after vaccination than healthy controls. First, these individuals could have accelerated antibody affinity maturation because of reduced B cell competition in the germinal center, as patients with B cell malignancies often have reduced numbers of normal B cells due to the clonal expansion of malignant cells in the bone marrow6. The reduction of naive B cells might lead to the entry of fewer antigen-activated B cells into the germinal centers and, in consequence, less competition and more rapid selection of high-affinity clones. Follicular helper T cells are also critically required for B cell selection and proliferation within the germinal center through their provision of CD40L and IL-212. Coexistent dysfunctional T cell immunity6 in these individuals may result in limited T cell help and more stringent selection of higher-affinity antigen-activated B cells.

An alternative explanation, as raised by the authors, is a difference in the activity of APOBEC family enzymes, notably AID. Constitutive and aberrant AID activity is one of the contributory factors behind the malignant transformation of germinal center B cells7. It is possible that increased AID activity is not limited to malignant B cell clones but also coexistent in normal B cells in the same individual, which might accelerate affinity maturation.

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. However, the interaction disrupted by the chaotropic agent might not be specific to the antigen-binding domain of the antibody. Although this assay is commonly used to estimate antibody avidity to infection and vaccination, the assay is not standardized and is often performed using different chaotropic agents and experimental conditions8. Other methods that may more accurately quantify the affinity or avidity of the antibodies, such as a surface plasmon resonance assay9, could be attempted to validate these observations. The other limitation of this report is the size and heterogeneity of the cohort, which precluded ascertaining whether there is a difference in antibody avidity between disease types or other clinical and treatment factors. Regardless, the authors’ intriguing observation1 warrants further investigation and might deepen our understanding of antibody affinity maturation.

It also important to emphasize that although patients with lymphoma and myeloma might develop higher-quality antibodies more rapidly, this qualitative improvement does not fully compensate for the reduction in antibody levels, and in vitro viral neutralization in these patients is still lower than in healthy individuals. Thus, these patients are likely to remain at increased risk of severe COVID-19 infection compared to healthy people, and other protective measures may be warranted.

Tackling the important point of protective measures against severe COVID-19 from a different angle, another study, by Denkinger et al.10, in the same issue of Nature Cancer investigates the use of SARS-CoV-2-antibody-containing plasma from convalescent or vaccinated individuals. The authors show that this may reduce the risk of progression to severe COVID-19 in patients with hematological malignancies. Specifically, they conducted a randomized trial comparing early plasma administration (median 7.5 days) against standard of care plus crossover to plasma administration 10 days later in 136 high-risk, hospitalized participants. The study consisted of four cohorts: (1) participants with cancer, primarily hematological malignancies; (2) immunosuppressed participants, primarily solid organ transplant (SOT) recipients; and two other high-risk groups based on (3) laboratory risk factors and (4) advanced age. The key finding from the study is that participants with hematological malignancies (cohort 1) who received early plasma administration were 2.5 times more likely to show earlier clinical improvement and to be discharged from hospital and had a 28% lower risk of death than those in the control group. In parallel, a significant increase in pseudoneutralization activity was observed in cohort 1 participants after plasma infusion compared to participants in the control arm. No benefit was observed in the other groups. Cohorts 3 and 4 were reported to have higher pseudoneutralization activity before plasma infusion, suggesting that antibody deficiency was not a contributory factor to the severity of their COVID-19 infection and thus would not have been remedied by plasma administration. Cohort 2 participants had low pseudoneutralization activity at baseline that did not increase with plasma infusions. SOT recipients, particularly those with kidney transplants, are frequently in a protein-losing state11, so we hypothesize that a greater number of more frequent plasma infusions may be required to produce clinical benefit. Apart from the relatively small sample size, a significant limitation of this study is that nearly 90% of the study population was unvaccinated. However, given that many individuals within cohorts 1 and 2 do not develop antibody responses after vaccination, it is conceivable that administration of plasma containing SARS-CoV-2 antibody may still be beneficial in vaccinees in these categories.

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.