Omicron BA.4/5 Neutralization and T-Cell Responses in Organ Transplant Recipients After Booster Messenger RNA Vaccine: A Multicenter Cohort Study

Abstract

Background In solid organ transplant (SOT) recipients, the primary vaccination series against COVID-19 is three doses followed by boosters. We determined whether a fourth dose booster induced Omicron BA.4/5 neutralizing antibodies and T-cells in a large multicenter cohort study. Methods Serum was collected 4-6 weeks post third and fourth dose of mRNA vaccine in 222 SOT recipients. Neutralizing antibodies (nAb) were measured using a pseudovirus neutralization assay targeting the Omicron BA.4/5 spike protein. A subset underwent T-cell testing. Results Median age of the cohort was 63 years (IQR 50-68) with 61.7% men. BA.4/5 nAb detection increased from 26.6%(59/222) post third dose to 53.6%(119/222) post fourth dose (p<0.0001). In patients with breakthrough infection prior to fourth dose (n=27), nAb were detected in 77.8% and median nAb titers were significantly higher compared to those with four vaccine doses alone (p<0.0001). Factors associated with a low BA.4/5 neutralization response after fourth dose were older age (OR 0.96, 95%CI 0.94-0.99), mycophenolate use (OR 0.39, 95%CI 0.20-0.77) and prednisone use (OR 0.34, 95%CI 0.18-0.63), and vaccine type (OR 0.72, 95%CI 0.51-0.99) while breakthrough infection prior to fourth dose (OR 3.6, 95%CI 1.3-9.9) was associated with a greater nAb response. Polyfunctional BA.4/5-specific CD4+ T-cells significantly increased after four doses and were identified in 76.9% of patients at a median frequency of 213 per 106 cells (IQR 98-650). Conclusion In summary, a booster significantly increases BA.4/5-specific neutralization and polyfunctional CD4+ T-cell responses, suggesting protection from severe disease even with new Omicron variants. However, SOT recipients that are older, on mycophenolate and prednisone need further preventative strategies.

SARS-CoV-2 Variants Omicron BA.4/5 and XBB.1.5 Significantly Escape T Cell Recognition in Solid-organ Transplant Recipients Vaccinated Against the Ancestral Strain

“…We also identified clinical factors associated with BA.4/5-specific T cell responses to vaccination. Although responses in lung transplant recipients and patients taking prednisone were decreased, consistent with studies of BA.4/5 neutralization in SOTRs, 9 these effects were confounded as all lung recipients in our cohort, and no liver recipients, were receiving prednisone in accordance with regional guidelines. 52 It was therefore not possible to separate the effects of prednisone from lung transplantation.…”

“…[57][58][59] As CD4 + T cells promote high-affinity humoral responses and B-cell memory, 60 we analyzed correlations of BA.4/5specific AIM responses with anti-RBD and nAb titers. 9 Correlations between CD4 + AIM responses and anti-RBD titers were nonsignificant before a second dose, but increased in strength and significance with subsequent vaccinations, and over time even without additional vaccinations. At the 6-mo timepoint or after 3 doses, patients who developed antibody responses generally showed strong CD4 + AIM responses, suggesting that a third dose is necessary to optimally stimulate both immune compartments and that the relationship between cellular and humoral immunity may also strengthen with time.…”

“…5-8 However, a third or fourth “booster” dose significantly increases seropositivity and nAbs in SOTRs. 6,9,10…”

“…A recent study assessed T cell responses to a fourth mRNA vaccine dose by intracellular cytokine staining (ICS) in a small cohort of SOTRs, finding that a fourth dose significantly increased frequencies of IFN-γ+/ IL-2+ BA.4/5-specific CD4 + , but not CD8 + , T cells. 9 Only 1 study has directly compared ancestral SARS-CoV-2-and BA.4/5-specific T cell responses in SOTRs, showing no differences in magnitude by ICS. 30 As an alternative method, activation-induced marker (AIM) assays leverage surface protein upregulation following antigen-specific stimulation [31][32][33][34] and are increasingly used to assess T cell responses to SARS-CoV-2 infection and vaccination.…”

“…[5][6][7][8] However, a third or fourth "booster" dose significantly increases seropositivity and nAbs in SOTRs. 6,9,10 As SARS-CoV-2 continues to evolve, emerging variants, including Omicron lineages and their derivatives, continue to challenge global SARS-CoV-2 immunity. [11][12][13][14][15] The Omicron BA.4 and BA.5 (henceforth BA.4/5) subvariants display over 40 Spike protein mutations and enhanced affinity for the ACE2 receptor.…”