Two approaches to tackle COVID-19 in blood cancer patients

The ability of SARS-CoV-2 vaccination to prevent infection is also known as immune sterilization, in which vaccine-induced antibodies block viral entry into cells via the viral spike protein. depends on the ability to Antibody quantification is frequently used as a proxy for antibody potency, but it ignores the strength (avidity) of antibody binding to its target antigen.In this issue natural cancerKepler-Hafkemeyer et al.¹ Patients with haematological malignancies (lymphoma and myeloma) report producing antibodies with higher avidity than matched healthy controls after a second vaccination. Thus, although these patients develop lower antibody levels than healthy controls after vaccination, the reduction in virus neutralization is better than expected. means that antibody affinity maturation may be more rapid, leading to a number of important mechanistic questions related to understanding B cell development and vaccine design.

Encounter of naive B cells with B cell receptors (BCR) and their cognate antigens (in this case, spike proteins) causes activated B cells to migrate into B cell follicles and form germinal centers.²In germinal centers, activation-induced deaminase (AID) deaminates cytidine to uracil at variable immunoglobulin loci, generating point mutations. This increases the diversity and affinity of the BCR for antigen (in the process of somatic hypermutation). Antigen-activated B cells with higher affinity for antigen are selected for survival, resulting in an increase in the number of B cells with higher antigen avidity with each round of selection and expansion. This is a process known as affinity maturation.

Consistent with our understanding of affinity maturation, anti-spike IgG antibody levels, and increased avidity with each SARS-CoV-2 vaccination in healthy individuals, which correlates with in vitro virus neutralization.³Kepler-Hafkemeyer et al.¹ hematologic malignancies (B-cell lymphomas (n = 38) and myeloma (n = 22)) after 2 and 3 doses of BNT162b2 mRNA vaccine.as others have reported^Four,FiveThey observed that patients with B-cell lymphoma had significantly lower spike IgG antibody levels than healthy controls. However, the hematological malignancies cohort showed spiked IgG binding activity against the Wuhan-hu-1 strain of 13% at 2–8 weeks and 30% at 4–5 months after the second SARS-CoV-2 vaccine dose, with age and increased with age. Gender-matched healthy controls. Antibody avidity was similar between patient and control cohorts after the third dose of vaccine (87 vs. 80%; Figure . 1). The authors further showed that stronger antibody avidity correlated with higher virus-neutralizing responses across multiple SARS-CoV-2 variants.

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

These findings raise an interesting question as to why individuals with B-cell malignancies have higher avidity of antibodies than healthy controls after vaccination. First, patients with B-cell malignancies often have reduced numbers of normal B-cells due to clonal expansion of malignant cells in the bone marrow, thus reducing competition for B-cells in the germinal centers, thus making these individuals may have accelerated antibody affinity maturation.⁶The depletion of naive B cells may lead to less entry of antigen-activated B cells into germinal centers, resulting in less competition and faster selection of high-affinity clones. Follicular helper T cells are also critically required for the selection and expansion of her B cells within germinal centers through the provision of CD40L and IL-21.²Coexisting Dysfunctional T Cell Immunity⁶ In these individuals, T cell help may be limited, resulting in a more stringent selection of higher affinity, antigen-activated B cells.

Another explanation put forward by the authors is the difference in activity of the APOBEC family enzymes, especially AID.Constitutive and aberrant AID activity is one of the contributing factors behind the malignant transformation of germinal center B cells⁷Increased AID activity is not restricted to malignant B-cell clones, but may also co-exist in normal B-cells from the same individual, potentially accelerating affinity maturation.

The study by Keppler-Hafkemeyer et al. has several caveats.¹The authors used a modified ELISA assay to increase antibody avidity by adding a chaotropic agent to break hydrogen bonds between antigen and antibody in order to elute antibodies that bind weakly to the antigen. I rated it. However, interactions disrupted by chaotropic agents may not be unique to the antigen-binding domain of antibodies. This assay is commonly used to estimate antibody affinity for infection and vaccination, but the assay is not standardized and is often performed using different chaotropic agents and conditions. increase.⁸Other methods that can more accurately quantify antibody affinity or avidity, such as surface plasmon resonance assays⁹, we can try to verify these observations.Another limitation of this report was the size and heterogeneity of the cohort, which prevented us from ascertaining whether there were differences in antibody avidity among disease types or other clinical and therapeutic factors. observation¹ Further investigation is needed and may lead to a better understanding of antibody affinity maturation.

Also, although patients with lymphoma and myeloma may develop high-quality antibodies more rapidly, this qualitative improvement does not fully compensate for the reduced antibody levels, and the in vitro viral response of these patients It is also important to emphasize that neutralization is still lower than in healthy individuals. These patients are therefore likely to remain at increased risk of severe her COVID-19 infection compared to healthy individuals and may require other protective measures.

Another study, by Denkinger et al., addresses key points of protective measures against severe COVID-19 from a different angle.^Tenof the same number natural cancer To investigate the use of SARS-CoV-2 antibody-containing plasma from convalescent or vaccinated individuals. The authors show that this may reduce the risk of a patient with hematologic malignancies progressing to her severe COVID-19. Specifically, we conducted a randomized trial comparing initial plasma administration (median 7.5 days) with standard care and crossover to plasma administration after 10 days in 136 high-risk hospitalized participants. bottom. This study consisted of four cohorts. (1) participants with cancer, primarily hematologic malignancies; (2) immunosuppressed participants, primarily solid organ transplant (SOT) recipients; (3) laboratory risk factors and (4) two other high-risk groups based on advanced age. A key finding of this study was that participants with hematologic malignancies who received early plasma administration (cohort 1) showed early clinical improvement, were 2.5 times more likely to be discharged from the hospital, and had a 28-fold higher risk of death. % was low. Control group. In parallel, a significant increase in pseudoneutralizing activity was observed in cohort 1 participants after plasma infusion compared to control group participants. No benefit was observed in other groups. Cohorts 3 and 4 were reported to have higher pseudoneutralizing activity before plasma infusion, suggesting that antibody deficiency was not a contributing factor to the severity of her COVID-19 infection and thus was not ameliorated by plasma infusion. suggesting that Cohort 2 participants had lower pseudoneutralizing activity at baseline, which did not increase with plasma infusion. SOT recipients, especially those who have undergone kidney transplants, are often in a state of protein deprivation.¹¹, therefore, we hypothesize that more and more frequent plasma infusions may be required to obtain clinical benefit. A limitation is that nearly 90% of the study population was unvaccinated. However, given that many individuals within cohorts 1 and 2 do not develop an antibody response after vaccination, administration of plasma containing SARS-CoV-2 antibodies is still beneficial for these categories of vaccinees. It is considered possible.

Despite the vast amount of knowledge gained from COVID-19 research, it remains unclear how to identify the most immunosuppressed individuals and how best to prevent and treat severe COVID-19 infection. not been to Kepler-Hafkemeyer et al.¹ and Denkinger et al.^Ten We highlight the importance of in-depth analysis when profiling immune responses to vaccination and the need for continued investigation of protective measures for immunosuppressed populations.