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BACKGROUND: In solid organ transplant (SOT) recipients, the primary vaccination series against Coronavirus Disease 2019 is 3 doses followed by boosters. We determined whether a fourth dose booster induced Omicron BA.4/5 neutralizing antibodies (nAbs) and T cells in a large multicenter cohort study. METHODS: Serum was collected 4-6 weeks post-third and post-fourth doses of messenger RNA vaccine in 222 SOT recipients. nAbs were measured using a pseudovirus neutralization assay that targeted the Omicron BA.4/5 spike protein. A subset underwent T-cell testing. RESULTS: The median age of the cohort was 63 years (interquartile range [IQR], 50-68) with 61.7% men. BA.4/5 nAb detection increased from 26.6% (59 of 222) post-third dose to 53.6% (119 of 222) post-fourth dose (P < .0001). In patients with breakthrough infection prior to the fourth dose (n = 27), nAbs were detected in 77.8% and median nAb titers were significantly higher compared with those with 4 vaccine doses alone (P < .0001). Factors associated with a low BA.4/5 neutralization response after the fourth dose were older age (odds ratio [OR], 0.96; 95% confidence interval [CI], .94-.99), mycophenolate use (OR, 0.39; 95% CI, .20-.77) and prednisone use (OR, 0.34; 95% CI, .18-.63), and vaccine type (OR, 0.72; 95% CI, .51-.99), while breakthrough infection prior to the 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 4 doses and were identified in 76.9% of patients at a median frequency of 213/106 cells (IQR, 98-650). CONCLUSIONS: 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 who are older and on mycophenolate and prednisone need additional preventative strategies.
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COVID-19 , Trasplante de Órganos , Masculino , Humanos , Persona de Mediana Edad , Femenino , Estudios de Cohortes , Prednisona , SARS-CoV-2 , Anticuerpos Neutralizantes , Infección Irruptiva , Inmunosupresores/uso terapéutico , ARN Mensajero , Receptores de Trasplantes , Vacunas de ARNm , Anticuerpos AntiviralesRESUMEN
BACKGROUND: Immune-suppressed solid-organ transplant recipients (SOTRs) display impaired humoral responses to COVID-19 vaccination, but T cell responses are incompletely understood. SARS-CoV-2 variants Omicron BA.4/5 (BA.4/5) and XBB.1.5 escape neutralization by antibodies induced by vaccination or infection with earlier strains, but T cell recognition of these lineages in SOTRs is unclear. METHODS: We characterized Spike-specific T cell responses to ancestral SARS-CoV-2 and BA.4/5 peptides in 42 kidney, liver, and lung transplant recipients throughout a 3- or 4-dose ancestral Spike mRNA vaccination schedule. As the XBB.1.5 variant emerged during the study, we tested vaccine-induced T cell responses in 10 additional participants using recombinant XBB.1.5 Spike protein. Using an optimized activation-induced marker assay, we quantified circulating Spike-specific CD4 + and CD8 + â T cells based on antigen-stimulated expression of CD134, CD69, CD25, CD137, and/or CD107a. RESULTS: Vaccination strongly induced SARS-CoV-2-specific T cells, including BA.4/5- and XBB.1.5-reactive T cells, which remained detectable over time and further increased following a fourth dose. However, responses to BA.4/5 (1.34- to 1.67-fold lower) XBB.1.5 (2.0- to 18-fold lower) were significantly reduced in magnitude compared with ancestral strain responses. CD4 + responses correlated with anti-receptor-binding domain antibodies and predicted subsequent antibody responses in seronegative individuals. Lung transplant recipients receiving prednisone and older adults displayed weaker responses. CONCLUSIONS: Ancestral strain vaccination stimulates BA.4/5 and XBB.1.5-cross-reactive T cells in SOTRs, but at lower magnitudes. Antigen-specific T cells can predict future antibody responses. Our data support monitoring both humoral and cellular immunity in SOTRs to track COVID-19 vaccine immunogenicity against emerging variants.
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COVID-19 , Trasplante de Órganos , Humanos , Anciano , SARS-CoV-2 , Vacunas contra la COVID-19 , Receptores de Trasplantes , COVID-19/prevención & control , Trasplante de Órganos/efectos adversos , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
Background: Solid organ transplant (SOT) recipients are at risk for severe coronavirus disease 2019 (COVID-19), despite vaccination. Our study aimed to elucidate COVID-19 vaccine immunogenicity and evaluate adverse events such as hospitalization, rejection, and breakthrough infection in a SOT cohort. Methods: We performed a prospective, observational study on 539 adult SOT recipients (age ≥18â years old) recruited from 7 Canadian transplant centers. Demographics including transplant characteristics, vaccine types, and immunosuppression and events such as hospitalization, infection, and rejection were recorded. Follow ups occurred every 4-6 weeks postvaccination and at 6 and 12 months from first dose. Serum was processed from whole blood to measure anti-receptor binding domain (RBD) antibodies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to assess immunogenicity. Results: The COVID-19 vaccines were found to be safe in SOT recipients with low rates of rejection requiring therapy (0.7%). Immunogenicity improved after the third vaccine dose, yet 21% developed no anti-RBD response. Factors such as older age, lung transplantation, chronic kidney disease, and shorter duration from transplant were associated with decreased immunogenicity. Patients with at least 3 doses were protected from hospitalization when experiencing breakthrough infections. Significantly increased anti-RBD levels were observed in patients who received 3 doses and had breakthrough infection. Conclusions: Three or four doses of COVID-19 vaccines were safe, increased immunogenicity, and protected against severe disease requiring hospitalization. Infection paired with multiple vaccinations significantly increased anti-RBD response. However, SOT populations should continue to practice infection prevention measures, and they should be prioritized for SARS-CoV-2 pre-exposure prophylactics and early therapeutics.
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Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%. Kidney injury molecule 1 (KIM-1), encoded by the HAVCR1 gene, is a proximal tubule cell-surface glycoprotein and a biomarker for early detection of RCC, but its pathophysiological significance in RCC remains unclear. We generated human and murine RCC cell lines either expressing or lacking KIM-1, respectively, and compared their growth and metastatic properties using validated methods. Surprisingly, KIM-1 expression had no effect on cell proliferation or subcutaneous tumour growth in immune deficient (Rag1-/-) Balb/c mice, but inhibited cell invasion and formation of lung metastasis in the same model. Further, we show that the inhibitory effect of KIM-1 on metastases was observed in both immune deficient and immune competent mice. Transcriptomic profiling identified the mRNA for the pro-metastatic GTPase, Rab27b, to be downregulated significantly in KIM-1 expressing human and murine RCC cells. Finally, analysis of The Cancer Genome Atlas (TCGA) data revealed that elevated HAVCR1 mRNA expression in the two most common types of RCC, clear cell and papillary RCC, tumours correlated with significantly improved overall patient survival. Our findings reveal a novel role for KIM-1 in inhibiting metastasis of RCC and suggests that tumour-associated KIM-1 expression may be a favourable prognostic factor.