ABSTRACT
Background: Hybrid immunity is more protective than vaccination or prior infection alone. To understand the formation of hybrid immunity, we studied how SARS-CoV-2 mRNA vaccines interact with T cell memory by tracking spike (S) specific T cells in cohorts of hospitalized (n = 19) or non-hospitalized (n = 34) COVID-19 convalescents. We hypothesized that S-reactive CD4 and CD8 T cells would increase in response to serial vaccine doses and reflect prior immune exposure at the clonal level. Method(s): After vaccination, we stimulated PBMCs from 12 participants (8M/4F) with peptides spanning S. Activated cells (CD69+CD137+) were sorted and CD4/CD8 phenotype linked with paired TRB-TRA sequences at single cell resolution. S-reactive TRB sequences were mapped within 4-6 serial blood and post-booster nasal TRB repertoires to evaluate S-reactive CD4 and CD8 T cell clonotypic kinetics spanning convalescence to boost. PBMCs from 53 participants were sequenced with the ImmunoSEQ assay to evaluate S-reactive TRB breadth using a database of S-assigned TRB sequences (Adaptive Biotechnologies), comparing S-reactive TRB diagnostic breadth by hospitalization status (Wilcoxon test). Result(s): SARS-CoV-2 mRNA vaccination provoked strong T cell clonal expansion in most participants. At 8-12 months after infection, each primary mRNA dose increased the abundance and diversity of S-specific T cells. Clonal and integrated expansions were larger in CD8 than in CD4 T cells. At the convalescent time point, we observed greater diagnostic S-reactive CD4 T cell breadth in hospitalized vs. non-hospitalized patients (p< 0.01). CD4 T cell S breadth was again higher in previously hospitalized persons after the 2nd primary (p=0.02) and booster (p< 0.01) doses, suggesting that diverse CD4 T cell memory after severe infection leads to increased repertoire diversity after vaccination. S-specific T cells with identical TCRs were detectable in blood and the nasal mucosa, with specificity confirmed using a TRA/TRB transgenic T cell with the matching receptor. Conclusion(s): Although both S-specific CD8 and CD4 T cell memory are established by prior infection, S-specific CD8 T cells predominated in blood after primary vaccination, with some clonotypes showing up to 1000-fold expansion across 1-2 mRNA doses. Vaccine-reactive CD8 clonotypes were present at the barrier nasal site after booster mRNA dosing. Severe disease imprinted a highly diverse S-reactive CD4 repertoire persisting through vaccination.
ABSTRACT
Background. In the United States, booster vaccines for persons 18 years and older were approved under Emergency Use Authorization (EUA) in September 2021. Waning immunity following SARS-CoV-2 primary vaccination series led to recommendations for booster vaccination. Emerging data suggest that providing boosters different from the primary series (heterologous vaccination) may provide a broader immune response than boosting with the same vaccine (homologous vaccination). CDC recommended the Pfizer-BioNTech BNT162b2 30-mug mRNA booster vaccine to clinical trial participants >6 months post study vaccines if not planned for boosting within the study. Methods. We conducted an observational study of persons who received 2 doses of Novavax protein-based NVX-CoV2373 vaccine 21 days apart, in a Phase 3 clinical trial, and subsequently received a Pfizer BNT162b2 booster vaccine under EUA. Serologic assays, including the Roche anti-nucleocapsid (N) IgG and anti-Spike (S) IgG, were performed on blood collected pre-booster (D0) and on days 18 (D18) and 34 (D34) post-booster vaccine. The anti-S IgG geometric means (GMTs) were calculated over study time points. Wilcoxon signed rank test was performed to compare anti-S IgG response between D0 and D18 and D0 and D34. Results. Of 26 participants enrolled, 16 (57%) were women;the median age was 47 years (range 29-67). Roche anti-N antibodies were negative at all visits. Time from second NVX-CoV2373 vaccine to Pfizer BNT162b2 booster was a median of 10.4 months in 54% of participants and 7 months in 46% of participants. Anti-S IgG GMTs were 222 BAU/ml D0, 24,723 BAU/ml D18, and 24,584 BAU/ml D34 (p< 0.0001 for comparisons of D0 with D18 & D34). Overall, participants tolerated the booster vaccine without significant adverse events. Cell mediated immunity and D614G pseudovirus neutralizing antibody assays are in progress. Figure 1. Anti-S IgG titers pre and post-booster vaccine 16 participants included with all 3-time study time points for comparison. Conclusion. Two doses of NVX-CoV2373 vaccine followed by the Pfizer BNT162b2 booster vaccine resulted in ~100-fold increase in anti-S IgG against SARS-CoV-2. No participant had evidence of prior SARS-CoV-2 infection by anti-N IgG. Two doses of NVX-CoV2373 vaccine followed by one dose of Pfizer BNT162b2 vaccine is an effective and well-tolerated regimen for boosting anti-S IgG against SARS-CoV-2.
ABSTRACT
Background: Initial studies have shown that patients with inflammatory bowel disease (IBD) have a humoral immune response rate of 95–99% to a two-dose SARS-CoV-2 mRNA vaccine series. A third mRNA vaccine dose has been recommended for the IBD population. The aim of our study was to evaluate the humoral immunogenicity a third SARS-CoV-2 mRNA vaccine dose in patients with IBD. Methods: This was a multicenter, prospective, nonrandomized study comprised of patients with IBD and healthy controls (HC) in the HERCULES cohort. IBD subject eligibility criteria included a diagnosis of IBD, stable doses of maintenance therapy (≥ 2 months), and completion of a two-dose mRNA vaccines series. IBD subjects may have received a third mRNA vaccine dose. HC eligibility criteria included absence of immunosuppressive therapy and completion of a two-dose mRNA vaccine series. HC did not receive a third dose. Those with prior COVID-19 infection were excluded. The primary outcome was total serum SARS-CoV-2 anti-spike IgG antibody concentrations following a third dose compared to antibody concentrations following the two-dose series in IBD subjects. In IBD subjects, we measured antibody concentrations at 28–35 days following completion of the two-dose series and 28–65 days following the third dose. In HC, we measured antibody concentrations at 180 days following completion of the twodose series. Antibody concentrations between groups were compared using Mann-Whitney U tests. Results: One hundred thirty-nine IBD subjects and 46 HC were enrolled. Eightyfive IBD subjects received a third dose (Table 1). One hundred thirty-five IBD subjects (97.1%) had detectable antibody concentrations post-two-dose series, while 85 IBD subjects (100%) had detectable antibody concentrations post-third dose. For IBD subjects that received a third dose, antibody concentrations were significantly higher post-third dose compared to post-two-dose series (median 68 (IQR 32–147) vs 31 (IQR 16–61), p<0.001) (Figure 1). Post-third dose, IBD subjects on systemic corticosteroids or anti-TNF combination therapy had significantly lower antibody concentrations than IBD subjects that were not (median 29 (IQR 10–39) vs 72 (IQR 37–164), p<0.001). For HC, antibody concentrations were significantly lower 180 days compared to 30 days post-two-dose series (median 17 (IQR 11–22) vs 120 (IQR 88–190), p<0.001). HC had lower antibody concentrations 180 days post-two-dose series compared to IBD subjects post-third dose (median 17 (IQR 11– 22) vs 68 (IQR 32–147), p<0.001). Conclusion: All patients with IBD receiving a third SARS-CoV-2 mRNA vaccine dose were seropositive, and median antibody concentrations were higher than those measured after the two-dose series. Patients on corticosteroids and anti-TNF combination therapy had lower antibody concentrations than patients not on such therapy following a third dose. (Table Presented) (Figure Presented)