Innate and adaptive immune defects associated with lower SARS-CoV-2 BNT162b2 mRNA vaccine response in elderly people

The immune factors associated with impaired SARS-CoV-2 vaccine response in the elderly are mostly unknown. We studied old and young people vaccinated with SARS-CoV-2 BNT162b2 mRNA before and after the first and second dose. Aging was associated with a lower anti-RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2 specific T cell response. The dramatic decrease in thymic function in the elderly, which fueled alteration in T cell homeostasis, and lower CD161+ T cell levels were associated with decreased T cell response two months after vaccination. Additionally, a deficient dendritic cell (DC) homing, activation and Toll like receptor (TLR)-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the elderly, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.This study was funded by Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades, Junta de Andalucia (CV20-85418 and P20_00906, DOC-01659 and DOC-00963); Consejeria de Salud, Junta de Andalucia (RH-0037-2020), Instituto de Salud Carlos III (CP19/00159, FI17/00186, FI19/00083, PI19/01172, CM20/00243) Fondos FEDER, and National Spanish Research Council (CSIC).N

Immune defects associated with lower SARS-CoV-2 BNT162b2 mRNA vaccine response in aged people

The immune factors associated with impaired SARS-CoV-2 vaccine response in elderly people are mostly unknown. We studied individuals older than 60 and younger than 60 years, who had been vaccinated with SARS-CoV-2 BNT162b2 mRNA, before and after the first and second dose. Aging was associated with a lower anti–RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2–specific T cell response. The dramatic decrease in thymic function in people > 60 years, which fueled alteration in T cell homeostasis, and their lower CD161+ T cell levels were associated with decreased T cell response 2 months after vaccination. Additionally, deficient DC homing, activation, and TLR-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the > 60-year-old group, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.This work was supported by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía grants CV20-85418 and P20_00906 and by research contracts DOC-01659 and DOC-00963, as well as by Consejería de Salud, Junta de Andalucía research contract RH-0037-2020 and Instituto de Salud Carlos III CP19/00159, FI17/00186, FI19/00083, PI19/01127, and CM20/00243 from Fondos FEDER. ERM was supported by the Spanish Research Council (CSIC). We thank all the community volunteers, participants from the IBiS, Chema Niño, and the nursing staff from Virgen del Rocío University Hospital who have taken part in this project. We also thank Alicia Gutierrez and Esperanza Muñoz for reviewing the manuscript. In memoriam Silvio Manuel Pérez Martín.Peer reviewe

Migration and activation marker expressing in monocytes subset in mild and several/critical patients (S/C)

S2 Fig. Migration and activation marker expressing in monocytes subset in mild and several/critical patients (S/C).Peer reviewe

S1 Fig - Clinical, laboratory data and inflammatory biomarkers at baseline as early discharge predictors in hospitalized SARS-CoV-2 infected patients

A, Predictive models for hospital discharge during the first week in mild patients. B, Predictive models for worsening of clinical status during the first week in patients who were admitted mildly ill. AUC, area under the curve.Peer reviewe

Activation, homing and maturation marker expression in different monocyte subsets

Data are expressed by percentage and interquartile range. Medians fluorescence intensitive (MFI) were calculated in those markets that have a high rate of expression.Peer reviewe

Baseline characteristics of the mild patients who were discharged and worsened during the first week

Quantitative variables are expressing as number (percentage) or median (interquartile range). Pa value for differences between patients who were or not discharged. Pb value for differences between patients who who did and did not get wore. SpO2, peripheral capillary oxygen saturation; CRP, C-reactive protein; LDH, Lactate dehydrogenase; NLR, neutrophil/lymphocyte ratio.Peer reviewe

Receiver operating curve (ROC) analyses to evaluate the ability of clinical and laboratory data to predict worse prognosis during the first week

AUC, area under the curve; SE, sensitivity; S, specificity; PPV, positive predictive value; NPV, negative predictive value. SpO2, peripheral capillary oxygen saturation; CRP, C-reactive protein; LDH, Lactate dehydrogenase; NLR, neutrophil/lymphocyte ratio; TNF-α; tumor necrosis factor α; IL-6, interleukine-6; IL-8, interleukine-8; IL-1β, interleukine-1β; MIP-1β, macrophage inflammatory proteins 1β; sCD25, soluble receptor interleukine-2; IP-10, interferon γ-induced protein 10.Peer reviewe

Clinical, laboratory data and inflammatory biomarkers at baseline as early discharge predictors in hospitalized SARS-CoV-2 infected patients

Background The SARS-CoV-2 pandemic has overwhelmed hospital services due to the rapid transmission of the virus and its severity in a high percentage of cases. Having tools to predict which patients can be safely early discharged would help to improve this situation. Methods Patients confirmed as SARS-CoV-2 infection from four Spanish hospitals. Clinical, demographic, laboratory data and plasma samples were collected at admission. The patients were classified into mild and severe/critical groups according to 4-point ordinal categories based on oxygen therapy requirements. Logistic regression models were performed in mild patients with only clinical and routine laboratory parameters and adding plasma pro-inflammatory cytokine levels to predict both early discharge and worsening. Results 333 patients were included. At admission, 307 patients were classified as mild patients. Age, oxygen saturation, Lactate Dehydrogenase, D-dimers, neutrophil-lymphocyte ratio (NLR), and oral corticosteroids treatment were predictors of early discharge (area under curve (AUC), 0.786; sensitivity (SE) 68.5%; specificity (S), 74.5%; positive predictive value (PPV), 74.4%; and negative predictive value (NPV), 68.9%). When cytokines were included, lower interferon-γ-inducible protein 10 and higher Interleukin 1 beta levels were associated with early discharge (AUC, 0.819; SE, 91.7%; S, 56.6%; PPV, 69.3%; and NPV, 86.5%). The model to predict worsening included male sex, oxygen saturation, no corticosteroids treatment, C-reactive protein and Nod-like receptor as independent factors (AUC, 0.903; SE, 97.1%; S, 68.8%; PPV, 30.4%; and NPV, 99.4%). The model was slightly improved by including the determinations of interleukine-8, Macrophage inflammatory protein-1 beta and soluble IL-2Rα (CD25) (AUC, 0.952; SE, 97.1%; S, 98.1%; PPV, 82.7%; and NPV, 99.6%). Conclusions Clinical and routine laboratory data at admission strongly predict non-worsening during the first two weeks; therefore, these variables could help identify those patients who do not need a long hospitalization and improve hospital overcrowding. Determination of pro-inflammatory cytokines moderately improves these predictive capacities.This work was supported by Consejeria de Salud y Familia (research Project COVID-0005-2020 and Research Contract RH-0037-2020 to JV); Consejería de Transformación Económica, Industria, Conocimiento y Universidades (PY20/01276 to APG); Instituto de Salud Carlos III (CP19/00159 to AGV, CP19/00146 to AR, FI19/00304 to EMM, FI19/00083 to MCGC, "a way to make Europe, and COV20/00698 to support COHVID-GS), Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020, RD16/0025/0006 and RD16/0025/0026), Fondos FEDER; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII (CB21/13/00020) Madrid, Spain. ERM was supported by the Spanish Research Council (CSIC). AR is also supported by a grant from IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Receiver operating curve (ROC) analyses to evaluate the ability of clinical and laboratory data to predict discharge during the first week

AUC, area under the curve; SE, sensitivity; S, specificity; PPV, positive predictive value; NPV, negative predictive value. SpO2, peripheral capillary oxygen saturation; CRP, C-reactive protein; LDH, Lactate dehydrogenase; NLR, neutrophil/lymphocyte ratio; TNF-α; tumor necrosis factor α; IL-6, interleukine-6; IL-8, interleukine-8; IL-1β, interleukine-1β; MIP-1β, macrophage inflammatory proteins 1β; sCD25, soluble receptor interleukine-2; IP-10, interferon γ-induced protein 10.Peer reviewe

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

Virgen del Rocío Hospital COVID-19 Working Team José Miguel Cisneros, Sonsoles Salto-Alejandre, Judith Berastegui-Cabrera, Pedro Camacho-Martínez, Carmen Infante-Domínguez, Marta Carretero-Ledesma, Juan Carlos Crespo-Rivas, Eduardo Márquez, José Manuel Lomas, Claudio Bueno, Rosario Amaya, José Antonio Lepe, Jerónimo Pachón, Elisa Cordero, Javier Sánchez-Céspedes, Manuela Aguilar-Guisado, Almudena Aguilera, Clara Aguilera, Teresa Aldabo-Pallas, Verónica Alfaro-Lara, Cristina Amodeo, Javier Ampuero, María Dolores Avilés, Maribel Asensio, Bosco Barón-Franco, Lydia Barrera-Pulido, Rafael Bellido-Alba, Máximo Bernabeu-Wittel, Candela Caballero-Eraso, Macarena Cabrera, Enrique Calderón, Jesús Carbajal-Guerrero, Manuela Cid-Cumplido, Yael Corcia-Palomo, Juan Delgado, Antonio Domínguez-Petit, Alejandro Deniz, Reginal Dusseck-Brutus, Ana Escoresca-Ortega, Fátima Espinosa, Nuria Espinosa, Michelle Espinoza, Carmen Ferrándiz-Millón, Marta Ferrer, Teresa Ferrer, Ignacio Gallego-Texeira, Rosa Gámez-Mancera, Emilio García, Horacio García-Delgado, Manuel García-Gutiérrez, María Luisa Gascón-Castillo, Aurora González-Estrada, Demetrio González, Carmen Gómez-González, Rocío González-León, Carmen Grande-Cabrerizo, Sonia Gutiérrez, Carlos Hernández-Quiles, Inmaculada Concepción Herrera-Melero, Marta Herrero-Romero, Luis Jara, Carlos Jiménez-Juan, Silvia Jiménez-Jorge, Mercedes Jiménez-Sánchez, Julia Lanseros-Tenllado, Carmina López, Isabel López, Álvaro López-Barrios, Luis F. López-Cortés, Rafael Luque-Márquez, Daniel Macías-García, Guillermo Martín-Gutiérrez, Luis Martín-Villén, José Molina, Aurora Morillo, María Dolores Navarro-Amuedo, Dolores Nieto-Martín, Francisco Ortega, María Paniagua-García, Amelia Peña-Rodríguez, Esther Pérez, Manuel Poyato, Julia Praena-Segovia, Rafaela Ríos, Cristina Roca-Oporto, Jesús F. Rodríguez, María Jesús Rodríguez-Hernández, Santiago Rodríguez-Suárez, Ángel Rodríguez-Villodres, Nieves Romero-Rodríguez, Ricardo Ruiz, Zida Ruiz de Azua, Celia Salamanca, Sonia Sánchez, Víctor Manuel Sánchez-Montagut, César Sotomayor, Alejandro Suárez Benjumea & Javier ToralSevere Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.This work was supported by Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades Junta de Andalucia (research Project CV20-85418), Consejeria de salud Junta de Andalucia (Research Contract RH-0037-2020 to JV) the Instituto de Salud Carlos III (CP19/00159 to AGV, FI17/00186 to MRJL, FI19/00083 to MCGC, CM20/00243 to APG, and COV20/00698 to support COHVID-GS) and the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020 and RD16/0025/0026), which is included in the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, 2008 to 2011 and 2013 to 2016, Instituto de Salud Carlos III, Fondos FEDER. ERM was supported by the Spanish Research Council (CSIC).Peer reviewe