Longitudinal Analysis of Memory T-Cell Responses in Survivors of Middle East Respiratory Syndrome

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]: Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a zoonotic betacoronavirus. The development of effective vaccines and control measures requires a thorough understanding of the immune response to this viral infection. METHODS: We investigated cellular immune responses up to 5 years after infection in a cohort of 59 MERS survivors by performing enzyme-linked immunospot assay and intracellular cytokine staining after stimulation of peripheral blood mononuclear cells with synthetic viral peptides. RESULTS: Memory T-cell responses were detected in 82%, 75%, 69%, 64%, and 64% of MERS survivors from 1-5 years post-infection, respectively. Although the frequency of virus-specific interferon gamma (IFN-γ)-secreting T cells tended to be higher in moderately/severely ill patients than in mildly ill patients during the early period of follow-up, there was no significant difference among the different clinical severity groups across all time points. While both CD4+ and CD8+ T cells were involved in memory T-cell responses, CD4+ T cells persisted slightly longer than CD8+ T cells. Both memory CD4+ and CD8+ T cells recognized the E/M/N proteins better than the S protein and maintained their polyfunctionality throughout the period examined. Memory T-cell responses correlated positively with antibody responses during the initial 3-4 years but not with maximum viral loads at any time point. CONCLUSIONS: These findings advance our understanding of the dynamics of virus-specific memory T-cell immunity after MERS-coronavirus infection, which is relevant to the development of effective T cell-based vaccines.N

Effect of the combination of mitiglinide and metformin on glycemic control in patients with type 2 diabetes mellitus

Aims/Introduction: Mitiglinide is the newest drug in the meglitinide family. It increases the early-phase insulin release through rapid association-dissociation kinetics in the pancreatic beta cells. The efficacy and safety of adding meglitinide to metformin monotherapy in patients with type 2 diabetes are unknown. Materials and Methods: We carried out a prospective, randomized, multicenter trial to assess the efficacy and safety of combined treatment with mitiglinide and metformin for patients with type 2 diabetes who showed inadequate glycemic control with metformin monotherapy. Subjects with glycated hemoglobin (HbA(1c)) > 7.0% after an 8-week metformin run-in phase were randomized to a 16-week trial phase with metformin plus mitiglinide (Met + Mit) or metformin plus placebo (Met + Pcb). Results: Compared with the Met + Pcb group, the Met + Mit group showed a greater reduction in HbA(1c) (-0.7 +/- 0.6% vs -0.4 +/- 0.7%, P = 0.002), fasting plasma glucose (-0.77 +/- 1.76 mmol/L vs -0.05 +/- 1.60 mmol/L, P = 0.015) and 2-h postprandial glucose (-3.76 +/- 3.57 mmol/L vs -0.84 +/- 3.07 mmol/L, P < 0.0001). The proportion of the patients who achieved the target HbA(1c) value of < 7% at the end of the study was also higher in the Met + Mit group than the Met + Pcb group (49.3% vs 28.8%, P = 0.016). There were no differences in the adverse event rates between groups. Conclusions: Combination therapy with metformin and mitiglinide is effective and safe for the treatment of patients with type 2 diabetes who have inadequate glycemic control with metformin monotherapy. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00023.x, 2010)Kaku K, 2009, ENDOCR J, V56, P739, DOI 10.1507/endocrj.K09E-023Bolen S, 2007, ANN INTERN MED, V147, P386Ogawa K, 2007, INT HEART J, V48, P337Kumashiro N, 2007, ENDOCR J, V54, P163Yoshihara T, 2006, ENDOCR J, V53, P67Assaloni R, 2005, DIABETOLOGIA, V48, P1919, DOI 10.1007/s00125-005-1849-5Stumvoll M, 2005, LANCET, V365, P1333Leiter LA, 2005, CLIN THER, V27, pS42, DOI 10.1016/j.clinthera.2005.11.020Nakagami T, 2004, DIABETOLOGIA, V47, P385, DOI 10.1007/s00125-004-1334-6Raskin P, 2003, DIABETES CARE, V26, P2063Del Prato S, 2003, DIABETOLOGIA, V46, pM2, DOI 10.1007/s00125-002-0930-6Musi N, 2002, DIABETES, V51, P2074Wright A, 2002, DIABETES CARE, V25, P330MARRE M, 2002, DIABETES OBES METAB, V4, P177Bonora E, 2001, DIABETOLOGIA, V44, P2107Sunaga Y, 2001, EUR J PHARMACOL, V431, P119Zhou GC, 2001, J CLIN INVEST, V108, P1167Reimann F, 2001, BRIT J PHARMACOL, V132, P1542de Souza CJ, 2001, DIABETES OBES METAB, V3, P85HU S, 2001, INT J EXP DIABETES R, V2, P63Horton ES, 2000, DIABETES CARE, V23, P1660Hu SL, 2000, J PHARMACOL EXP THER, V293, P444Laghmich A, 1999, PHARMACOL RES, V40, P475Louchami K, 1999, PHARMACOL RES, V40, P297Moses R, 1999, DIABETES CARE, V22, P119Laghmich A, 1998, EUR J PHARMACOL, V348, P265TURNER NC, 1998, PROG DRUG RES, V51, P33Bailey CJ, 1996, NEW ENGL J MED, V334, P574TURNER RC, 1995, DIABETES, V44, P1249MALAISSE WJ, 1995, GEN PHARMACOL, V26, P1313STUMVOLL M, 1995, NEW ENGL J MED, V333, P550OHNOTA H, 1994, J PHARMACOL EXP THER, V269, P489BAKKALINADI A, 1994, DIABETES RES, V27, P61DEFRONZO RA, 1992, DIABETES CARE, V15, P318CONSOLI A, 1989, DIABETES, V38, P550EFENDIC S, 1984, ENDOCR REV, V5, P395STEINER KE, 1982, DIABETES, V31, P964CERASI E, 1967, DIABETES, V16, P615

Sustained Responses of Neutralizing Antibodies Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Recovered Patients and Their Therapeutic Applicability

Background. Zoonotic coronaviruses have emerged as a global threat by causing fatal respiratory infections. Given the lack of specific antiviral therapies, application of human convalescent plasma retaining neutralizing activity could be a viable therapeutic option that can bridges this gap. Methods. We traced antibody responses and memory B cells in peripheral blood collected from 70 recovered Middle East respiratory syndrome coronavirus (MERS-CoV) patients for 3 years after the 2015 outbreak in South Korea. We also used a mouse infection model to examine whether the neutralizing activity of collected sera could provide therapeutic benefit in vivo upon lethal MERS-CoV challenge. Results. Anti-spike-specific IgG responses, including neutralizing activity and antibody-secreting memory B cells, persisted for up to 3 years, especially in MERS patients who suffered from severe pneumonia. Mean antibody titers gradually decreased annually by less than 2-fold. Levels of antibody responses were significantly correlated with fever duration, viral shedding periods, and maximum viral loads observed during infection periods. In a transgenic mice model challenged with lethal doses of MERS-CoV, a significant reduction in viral loads and enhanced survival was observed when therapeutically treated with human plasma retaining a high neutralizing titer (&gt; 1/5000). However, this failed to reduce pulmonary pathogenesis, as revealed by pathological changes in lungs and initial weight loss. Conclusions. High titers of neutralizing activity are required for suppressive effect on the viral replication but may not be sufficient to reduce inflammatory lesions upon fatal infection. Therefore, immune sera with high neutralizing activity must be carefully selected for plasma therapy of zoonotic coronavirus infection.Y