Role of mTOR inhibitor in the cellular and humoral immune response to a booster dose of SARS-CoV-2 mRNA-1273 vaccine in kidney transplant recipients.

Background: Immunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved. Methods: Prospective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination. Results: Among COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p<0.001) and the percentage of S-protein-specific IFNγ-producing CD8-T cells (r=0.198, p=0.049) was observed. Factors related to the humoral response in naïve KTR were: lymphocytes count pre-vaccination >1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001). Conclusions: KTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.

Evidence of exhausted lymphocytes after the third anti-SARS-CoV-2 vaccine dose in cancer patients.

Introduction: Evidence is scant regarding the long-term humoral and cellular responses Q7 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in cancer patients after repeated booster doses. The possibility of T-cell exhaustion following these booster doses in this population has not yet been fully studied and remains uncertain. Methods: In this single-center prospective observational study, we explored the specific humoral and cellular response to S1 antigen in 36 patients with solid malignancies at baseline, and after the second and third doses of the mRNA-1273 vaccine. Results: A dual behavior was observed: 24 (66.7%) patients showed partial specific IFN-γ response after the second dose that was further enhanced after the third dose; and 11 (30.5%) already showed an optimal response after the second dose and experienced a marked fall-off of specific IFN-γ production after the third (4 patients negativization), which might suggest T cell exhaustion due to repetitive priming to the same antigen. One (2.8%) patient had persistently negative responses after all three doses. Seroconversion occurred in all patients after the second dose. We then studied circulating exhausted CD8+ T-cells in 4 patients from each of the two response patterns, those with increase and those with decrease in cellular response after the third booster. The patients with decreased cellular response after the booster had a higher expression of PD1+CD8+ and CD57+PD1+CD8+ exhausted T cells compared with those with an increased cellular response both in vivo and in vitro. The proportion of PD1+CD8+ and CD57+PD1+CD8+ exhausted T cells inversely correlated with IFN-γ production. Discussion: Our preliminary data show that the two-dose SARS-CoV-2 vaccine regimen was beneficial in all cancer patients of our study. An additional booster seems to be beneficial in suboptimal vaccine seroconverters, in contrast to maximal responders that might develop exhaustion. Our data should be interpreted with caution given the small sample size and highlight the urgent need to validate our results in other independent and larger cohorts. Altogether, our data support the relevance of immunological functional studies to personalize preventive and treatment decisions in cancer patients.

A Prospective Study of the Serological, Clinical, and Epidemiological Features of a SARS-CoV-2 Positive Pediatric Cohort.

BACKGROUND: SARS-CoV-2 was a global pandemic. Children develop a mild disease and may have a different rate of seroconversion compared to adults. The objective was to determine the number of seronegative patients in a pediatric cohort. We also reviewed the clinical-epidemiological features associated with seroconversion. METHODS: A multicenter prospective observational study during September-November 2020, of COVID-19, confirmed by reverse transcription-polymerase chain reaction. Data were obtained 4-8 weeks after diagnosis. Blood samples were collected to investigate the humoral response, using three different serological methods. RESULTS: A total of 111 patients were included (98 symptomatic), 8 were admitted to hospital, none required an Intensive Care Unit visit. Median age: 88 months (IQR: 24-149). Median time between diagnosis and serological test: 37 days (IQR: 34-44). A total of 19 patients were non-seroconverters when using three serological techniques (17.1%; 95% CI: 10.6-25.4); most were aged 2-10 years (35%, p < 0.05). Univariate analysis yielded a lower rate of seroconversion when COVID-19 confirmation was not present amongst household contacts (51.7%; p < 0.05). CONCLUSIONS: There was a high proportion of non-seroconverters. This is more commonly encountered in childhood than in adults. Most seronegative patients were in the group aged 2-10 years, and when COVID-19 was not documented in household contacts. Most developed a mild disease. Frequently, children were not the index case within the family.

Clinical characteristics of children hospitalized for COVID-19.

Introduction: Most SARS-CoV2 infections in the pediatric population are asymptomatic or with mild symptoms, with a minimal proportion of severe cases described as SARS-CoV2-associated multi-system inflammatory syndrome (MIS-C).The objective was to describe the clinical and epidemiological characteristics of pediatric patients admitted with confirmed diagnosis of SARS-CoV2 infection from the beginning of the pandemic until May 2021. Methods: Retrospective observational study of pediatric patients hospitalized with confirmed COVID-19, in a tertiary hospital. Epidemiological and clinical data, additional tests, treatments administered and evolution were collected. Results: 30 patients were included, classified into 3 groups according to diagnosis: respiratory infection, MIS-C and compatible symptoms. The patients with pneumonia were associated with age older, comorbidities and lymphopenia. MIS-C were more serious patients, with marked laboratory involvement and greater admission to PICU. Most of these were secondary cases of contact in the family environment. Discussion: The most frequent clinical manifestations of COVID-19 in children are mild-moderate respiratory with good evolution. MIS-C is another form of expression of SARS-COV2 infection of greater severity, but usually with good prognosis after early diagnosis and frequent PICU admission.

Introducción: La mayoría de infecciones por SARS-CoV2 en población pediátrica cursan asintomáticas o con síntomas leves, con porcentaje mínimo de casos graves descritos como síndrome inflamatorio multisistémico asociado al SARS-CoV2 (SIM-PEDs).El objetivo fue describir las características clínico epidemiológicas de aquellos pacientes pediátricos ingresados, con diagnóstico confirmado de SARS-CoV2 desde el inicio de la pandemia hasta mayo 2021. Métodos: Estudio retrospectivo observacional de pacientes pediátricos ingresados con diagnóstico de COVID-19, de un hospital terciario. Se recogieron datos demográficos, clínicos, pruebas complementarias, tratamiento administrado y evolución. Resultados: Se incluyeron 30 pacientes, clasificándose en 3 grupos según diagnóstico: Infección respiratoria, SIM-PEDs y síntomas compatibles. Los pacientes con neumonía asociaban mayor edad, comorbilidades y linfopenia. SIM-PEDs fueron pacientes más graves, con afectación analítica marcada y mayor ingreso en UCIP. La mayoría eran casos secundarios de contacto en el entorno familiar. Discusión: Los cuadros clínicos de COVID-19 más frecuentes en niños son respiratorios leves-moderados con buena evolución. SIM-PEDs es otra forma de expresión de infección por SARS-COV2 de mayor gravedad, pero habitualmente con buen pronóstico tras diagnóstico precoz y requiriendo frecuentemente ingreso en UCIP.

Clinical characteristics of children hospitalized for COVID-19⋆ Características clínicas de los niños hospitalizados por COVID-19

Introduction Most SARS-CoV2 infections in the pediatric population are asymptomatic or with mild symptoms, with a minimal proportion of severe cases described as SARS-CoV2-associated multi-system inflammatory syndrome (MIS-C). The objective was to describe the clinical and epidemiological characteristics of pediatric patients admitted with confirmed diagnosis of SARS-CoV2 infection from the beginning of the pandemic until May 2021. Methods Retrospective observational study of pediatric patients hospitalized with confirmed COVID-19, in a tertiary hospital. Epidemiological and clinical data, additional tests, treatments administered and evolution were collected. Results 30 patients were included, classified into 3 groups according to diagnosis: respiratory infection, MIS-C and compatible symptoms. The patients with pneumonia were associated with age older, comorbidities and lymphopenia. MIS-C were more serious patients, with marked laboratory involvement and greater admission to PICU. Most of these were secondary cases of contact in the family environment. Discussion The most frequent clinical manifestations of COVID-19 in children are mild-moderate respiratory with good evolution. MIS-C is another form of expression of SARS-COV2 infection of greater severity, but usually with good prognosis after early diagnosis and frequent PICU admission.