RESUMO
The impact of SARS-CoV2 vaccination in cancer patients remains incompletely understood given the heterogeneity of cancer and cancer therapies. We assessed vaccine-induced antibody response to the SARS-CoV2 Omicron (B.1.1.529) variant in 57 patients with B cell malignancies with and without active B cell-targeted therapy. Ancestral- and Omicron-reactive antibody levels were determined by ELISA and neutralization assays. In over one third of vaccinated patients at the pre-booster timepoint, there were no ELISA-detectable antibodies against either the ancestral strain or Omicron variant. The lack of vaccine-induced antibodies was predominantly in patients receiving active therapy such as anti-CD20 monoclonal antibody (mAb) or Brutons tyrosine kinase inhibitors (BTKi). While booster immunization was able to induce detectable antibodies in a small fraction of seronegative patients, the benefit was disproportionately evident in patients not on active therapy. Importantly, in patients with post-booster ELISA-detectable antibodies, there was a positive correlation of antibody levels against the ancestral strain and Omicron variant. Booster immunization increased overall antibody levels, including neutralizing antibody titers against the ancestral strain and Omicron variant; however, predominantly in patients without active therapy. Furthermore, ancestral strain neutralizing antibody titers were about 5-fold higher in comparison with those to Omicron, suggesting that even with booster administration, there may be reduced protection against the Omicron variant. Interestingly, in almost all patients regardless of active therapy, including those unable to generate detectable antibodies against SARS-CoV2 spike, we observed comparable levels of EBV, influenza, and common cold coronavirus reactive antibodies demonstrating that B cell-targeting therapies primarily impair de novo but not pre-existing antibody levels. These findings suggest that patients with B cell malignancies on active therapy may be at disproportionately higher risk to new versus endemic viral infection and suggest utility for vaccination prior to B cell-targeted therapy.
RESUMO
BACKGROUNDSARS-CoV-2 causes COVID-19 through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns (DAMPs) and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) is able to blunt the broad inflammatory response induced by DAMPs in multiple models. A recent randomized phase III trial evaluating the impact of CD24Fc in patients with severe COVID-19 demonstrated encouraging clinical efficacy. METHODSWe studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial (NCT04317040) collected before and after treatment with CD24Fc or placebo. We performed high dimensional spectral flow cytometry analysis of peripheral blood mononuclear cells and measured the levels of a broad array of cytokines and chemokines. A systems analytical approach was used to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. FINDINGSTwenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found systemic hyper-activation of multiple cellular compartments in the placebo group, including CD8+ T cells, CD4+ T cells, and CD56+ NK cells. By contrast, CD24Fc-treated patients demonstrated blunted systemic inflammation, with a return to homeostasis in both NK and T cells within days without compromising the ability of patients to mount an effective anti-Spike protein antibody response. A single dose of CD24Fc significantly attenuated induction of the systemic cytokine response, including expression of IL-10 and IL-15, and diminished the coexpression and network connectivity among extensive circulating inflammatory cytokines, the parameters associated with COVID-19 disease severity. INTERPRETATIONOur data demonstrates that CD24Fc treatment rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19. FUNDINGNIH
