ABSTRACT
Purpose: Kidney transplant recipients taking belatacept (KTR-B) have poor immune response to two-dose SARS-CoV-2 vaccination. We sought to characterize the impact of an additional vaccine dose on plasma neutralizing capacity and cellular responses as compared to that of KTRs controls (KTR-C) not taking belatacept. Method(s): Within an observational cohort, we tested 26 KTR-Bs and 27 KTR-Cs for anti-spike antibody responses before and after a third SARS-CoV-2 vaccine dose (D3) using two clinical assays (Roche Elecsys anti-S Ig and EUROIMMUN anti-S1 IgG). For a subset of 5 KTR-Bs and for all KTR-Cs we used a research assay (Meso Scale Diagnostics V-Plex [MSD]) to further assess anti-spike and RBD IgG, as well as surrogate plasma neutralizing activity (% ACE2 inhibition) versus the ancestral and delta variants. For 3 KTR-Bs, post D3 T cell response was assessed via IFN-y ELISpot and deemed positive if spot forming units > 20 per million PBMC and stimulation index > 3. Result(s): KTR-Bs had significant lower clinical anti-spike seroconversion than KTR-Cs (31% vs 74%, p=0.001) after D3 despite similar demographics, clinical factors, and vaccines administered (Table 1). No KTR-B (0/5) was seropositive by MSD anti-spike or anti-RBD IgG (Figure 1). % ACE2 inhibition versus the ancestral variant was significantly lower in KTR-Bs than in KTR-Cs (Median [IQR] 5.2 [2.8, 6.5] vs 12.5 [7.7, 23.9], p<0.01);all KTR-Bs were below a level consistent with detectable neutralizing antibody. All tested KTR-Bs (3/3) had a negative ELISpot, consistent with negligible cellular response. Conclusion(s): These results suggest minimal humoral or cellular immunogenicity of additional vaccine doses for KTR-Bs and indicates the need for alternative strategies to improve vaccine response such as immunosuppression alteration or use of passive immunoprophylaxis with monoclonal anti-spike antibody to improve protection versus SARS-CoV-2.
ABSTRACT
Background: Recent studies have shown that vaccinated individuals harbor cross-reactive T cell responses that can cross-recognize SARS-CoV-2 and endemic human common cold coronaviruses (HCoVs). However, it is still unknown whether CD4+ T cells from vaccinated individuals recognize peptides from bat coronaviruses that may have the potential of causing future pandemics. In this study, we identified a SARS-CoV-2 spike protein epitope (S815-827) that is conserved in coronaviruses from different genera and subgenera including SARS-CoV, MERS-CoV, multiple bat coronaviruses and a feline coronavirus. We hypothesized that S815-827 is recognized by vaccinated individuals, and that S815-827-reactive T cells can cross-recognize homologues bat coronaviruses. Methods: To evaluate CD4+ T cell responses, we isolated CD8 depleted PBMCs from COVID-19 vaccinated individuals and performed IFN-γ ELISPOT assays. To assess T cell cross-reactivity, S815-827-reactive T cell lines were re-stimulated with homologous coronavirus peptides and cytokine production was assessed with flow cytometry. Additionally, the Vira-FEST assay (which utilizes TCR Vβ CDR3 sequencing) was performed to identify cross-reactive CD4+ T cell clones. Statistical comparisons were done using Mann-Whitney test, Wilcoxon matched-pairs signed rank test or Friedman test with Dunn's multiple comparison as appropriate. Results: Our results show that 16 out of 38 (42%) of vaccinated participants in our study who received the Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) COVID-19 vaccines had robust CD4+ T cell responses to S815-827. All responders also recognized homologous peptides from at least 2 other coronaviruses, and 8 out of 11 responders recognized peptides from at least 6 out of the 9 other coronaviruses tested. To determine T cell cross-reactivity, we re-stimulated S815-827 specific T cell lines with homologous coronavirus peptides. We found that S815-827 specific T cells had a robust increase in IFN-γ+ TNF-α+ expression upon re-stimulation with other peptides. We next used the Vira-FEST assay to confirm cross-reactivity by assessing if the same CD4+ T receptor clonotypes recognize both S815-827 and homologous bat coronavirus peptides. In all 3 participants tested, we identified multiple cross-reactive T cell receptors that recognize both S815-827 and homologous bat coronavirus peptides. Conclusion: Our results suggest that current mRNA vaccines elicit T cell responses that can cross-recognize bat coronaviruses, and thus might induce protection.