Randomized Controlled Trial of Adjuvanted Versus Nonadjuvanted Influenza Vaccine in Kidney Transplant Recipients.

BACKGROUND: Influenza vaccine containing an oil-in-water emulsion adjuvant (MF-59) may lead to greater immunogenicity in organ transplant recipients. However, alloimmunization may be a concern with adjuvanted vaccines. METHODS: We conducted a randomized trial comparing the safety and immunogenicity of adjuvanted versus nonadjuvanted influenza vaccine in adult kidney transplant patients. Patients were randomized 1:1 to receive 2012 to 2013 influenza vaccine with or without MF59 adjuvant. Preimmunization and postimmunization sera underwent strain-specific hemagglutination inhibition assay. HLA alloantibody was determined by Luminex single-antigen bead assay. RESULTS: We randomized 68 patients and 60 (29 nonadjuvanted; 31 adjuvanted) had complete samples available at follow-up. Seroconversion to at least 1 of 3 influenza antigens was present in 71.0% versus 55.2% in adjuvanted versus nonadjuvanted vaccine respectively (P = 0.21). Geometric mean titers and seroprotection rates were similar between groups. Seroconversion rates were especially low in those on MMF of 2 g or greater daily (44.4% vs 71.4%; P = 0.047). In the subgroup of patients 18 to 64 years old, seroconversion was significantly greater with adjuvanted vaccine (odds ratio, 6.10; 95% confidence interval, 1.25-28.6). There were no increases in HLA alloantibodies in patients who received adjuvanted vaccine. CONCLUSIONS: Adjuvanted vaccine was safe and had similar immunogenicity to standard vaccine in the overall transplant cohort but did show a potential immunogenicity benefit for the 18 to 64 years age group.

Humoral immune response following seasonal influenza vaccine in islet transplant recipients.

Annual influenza vaccine is recommended for organ transplant recipients, but immunogenicity is known to be suboptimal. Islet transplant recipients receive immunosuppressive therapy, but there are no data on the immunogenicity of influenza vaccine in this population. In this prospective cohort study, adult islet transplant recipients at least 3 months posttransplant were enrolled. All patients received the 2010-2011 seasonal influenza vaccine. Serum was obtained pre- and postvaccination to determine humoral response to each of the three influenza strains included in the vaccine. Adverse effects of vaccine were also noted. A total of 61 islet transplant recipients were enrolled and completed the study protocol. The median time from last transplant was 1.9 years (range 0.26-11.4 years), and most patients had undergone multiple prior islet transplant procedures (90.2%). Overall immunogenicity of the vaccine was poor. Seroconversion rates to H1N1, H3N2, and B antigens were 34.4%, 29.5%, and 9.8%, respectively. In the subset not seroprotected at baseline, a protective antibody titer postvaccination was achieved in 58.6%, 41.9%, and 34.5% of patients, respectively. Patients within the first year of transplant were significantly less likely to seroconvert to at least one antigen (23.5% vs. 54.5%; p = 0.029). Alemtuzumab recipients trended toward lower seroconversion rates (25% vs. 51%; p = 0.11). No vaccine-related safety concerns were identified. Seasonal influenza vaccine had suboptimal immunogenicity in islet transplant recipients especially those who were less than 1 year posttransplant or had received alemtuzumab induction. Novel strategies for protection in this group of patients need further study.

An analysis of regulatory T-cell and Th-17 cell dynamics during cytomegalovirus replication in solid organ transplant recipients.

BACKGROUND: CMV-specific T-cells are crucial to control CMV-replication post-transplant. Regulatory T-cells (T-regs) are associated with a tolerant immune state and may contribute to CMV-replication. However, T-cell subsets such as T-regs and IL-17 producing T-cells (Th-17) are not well studied in this context. We explored T-regs and Th-17 frequencies during CMV-replication after transplantation. METHODS: We prospectively evaluated 30 transplant patients with CMV-viremia. We quantified CMV-specific CD4(+) and CD8(+) T-cells, T-regs (CD4(+)CD25(+)FoxP3(+)) and Th-17 frequencies using flow-cytometry and followed patients requiring anti-viral treatment. Two subsets were compared: anti-viral treatment requirement (n = 20) vs. spontaneous clearance of viremia (n = 10). RESULTS: Higher initial CMV-specific CD4(+) T-cells and lower T-regs were observed in patients with spontaneous clearance (p = 0.043; p = 0.021 respectively). Using a ratio of CMV-specific CD4(+) T-cells to T-regs allowed prediction of viral clearance with 80% sensitivity and 90% specificity (p = 0.001). One month after stop of treatment, the same correlation was observed in patients protected from CMV-relapse. The ratio of CMV-specific CD4(+) T-cells to T-regs allowed prediction of relapse with 85% sensitivity and 86% specificity (p = 0.004). Th-17 responses were not correlated with virologic outcomes. CONCLUSIONS: This study provides novel insights into T-regs and Th-17 subpopulations during CMV-replication after transplantation. These preliminary data suggest that measurement of CMV-specific CD4(+) T-cells together with T-regs has value in predicting spontaneous clearance of viremia and relapse.

Clinical utility of cytomegalovirus cell-mediated immunity in transplant recipients with cytomegalovirus viremia.

BACKGROUND: A CD8+ T-cell response to cytomegalovirus (CMV) has been associated with control of viral replication. Assessment shortly after the onset of asymptomatic viremia could help significantly refine preemptive strategies. METHODS: We conducted a prospective study of organ transplant recipients who developed asymptomatic low-level viremia not initially requiring antiviral therapy. Cell-mediated immunity (CMI) was measured shortly after viremia onset and longitudinally using the Quantiferon-CMV assay. The primary outcome was the ability to predict spontaneous clearance versus virologic and/or clinical progression. RESULTS: We enrolled 42 transplant patients, of which 37 were evaluable. Viral load at onset was 1140 copies/mL (interquartile range 655-1542). Spontaneous viral clearance occurred in 29 of 37 (78.4%) patients and 8 of 37(21.6%) had clinical and/or virologic progression requiring antivirals. At baseline, a positive CMI test (interferon-γ≥0.2 IU/mL) was present in 26 of 37(70.3%) patients. In patients with a positive CMI, the incidence of subsequent spontaneous viral clearance was 24 of 26 (92.3%) compared with 5 of 11 (45.5%) in patients with a negative CMI at onset (P=0.004). The absolute interferon-γ production was higher in patients with spontaneous clearance versus progression at all time points tested. Analysis of different cutoffs for defining a positive test suggested that the best threshold was 0.1 or 0.2 IU/mL of interferon-γ. CONCLUSIONS: CMI assessment shortly after the onset of CMV viremia may be useful to predict progression versus spontaneous viral clearance, thereby helping guide the need for antiviral therapy and refining current preemptive strategies.

Long term immune responses to pandemic influenza A/H1N1 infection in solid organ transplant recipients.

In solid organ transplant (SOT) recipients it is unknown if natural infection with influenza confers protection from re-infection with the same strain during the next influenza season. The purpose of this study was to determine if infection with pandemic influenza A/H1N1 (pH1N1) resulted in a long-term immunologic response. Transplant recipients with microbiologically proven pH1N1 infection in 2009/2010 underwent humoral and cell-mediated immunity (CMI) testing for pH1N1 just prior to the next influenza season. Concurrent testing for A/Brisbane/59/2007 was done to rule-out cross-reacting antibody. We enrolled 22 adult transplant patients after pH1N1 infection. Follow up testing was done at a median of 7.4 months (range 5.8-15.4) after infection. After excluding those with cross-reactive antibody, 7/19 (36.8%) patients were seroprotected. Detectable pH1N1-specific CD4+ and CD8+ interferon-γ producing T-cells were found in 11/22 (50%) and 8/22 (36.4%) patients respectively. Humoral immunity had a significant correlation with a CD4 response. This is the first study in transplant patients to evaluate long-term humoral and cellular response after natural influenza infection. We show that a substantial proportion of SOT recipients with previous pH1N1 infection lack long-term humoral and cellular immune responses to pH1N1. These patients most likely are at risk for re-infection.

Renal function and vasomotor activity in mice lacking the Cyp4a14 gene.

The production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney is thought to be involved in the control of renal vascular tone and tubular sodium and chloride reabsorption. Cytochrome (Cyp) P-450 enzymes of the Cyp4a family in the mouse, namely 4a10, -12 and 14, are involved in 20-HETE synthesis. Recent advances in the molecular genetics of the mouse have produced mice in which Cyp4a isoforms have been disrupted and the consequence of such an approach is examined. This study evaluated the effect of deletion of the Cyp4a14 gene on blood pressure, renal vascular responses and tubular function. When compared with the wild-type (WT) litter mates, systolic blood pressure was greater in Cyp4a14 null (KO) mice as were renal vascular responses to angiotensin II or phenyephrine, G protein-coupled receptor (GPCR) agonists, but not KCl, a non-GPCR agonist. Renal vascular responses to guanosine 5'-O-(gamma-thio)triphosphate, a non-hydrolyzable GTP analog, or NaF(4), an activator of G-proteins, were also enhanced. However, vasodilation to bradykinin or apocynin but not sodium nitroprusside was blunted in Cyp4a14 null (KO) kidneys. These changes in KO mice were accompanied by increased 20-HETE synthesis, reduced renal production of nitric oxide (NO), increased lipid hydroperoxides and increased apocynin-inhibitable vascular NADPH oxidase activity that was prevented by administration of NO synthase (NOS) inhibitor, suggesting endothelial nitric oxide synthase (eNOS) uncoupling. Cyp4a14 KO mice also exhibited a diminished capacity to excrete an acute sodium load (0.9% NaCl, 2.5 mL/kg). These data suggest that deletion of the Cyp4a gene conferred a prohypertensive status via mechanisms involving increased 20-HETE synthesis and eNOS uncoupling leading to increased oxidative stress, enhanced vasoconstriction but diminished vasodilation as well as a defect in the renal excretory capacity in Cyp4a14 KO mice. These mechanisms suggest that the Cyp4a14-deficient mouse may be a useful model for evaluation of NO/20-HETE interactions.