Search

Your search keyword '"Ignacio Mazzitelli"' showing total 18 results
Start Over Author "Ignacio Mazzitelli"
18 results on '"Ignacio Mazzitelli"'

1. Concomitant inhibition of PPARγ and mTORC1 induces the differentiation of human monocytes into highly immunogenic dendritic cells

Author

Fernando Erra Diaz, Ignacio Mazzitelli, Lucía Bleichmar, Claudia Melucci, Asa Thibodeau, Tomás Dalotto Moreno, Radu Marches, Gabriel A. Rabinovich, Duygu Ucar, and Jorge Geffner

Subjects
CP: Immunology, Biology (General), QH301-705.5
Abstract

Summary: Monocytes can differentiate into macrophages (Mo-Macs) or dendritic cells (Mo-DCs). The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the differentiation of monocytes into Mo-Macs, while the combination of GM-CSF/interleukin (IL)-4 is widely used to generate Mo-DCs for clinical applications and to study human DC biology. Here, we report that pharmacological inhibition of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the presence of GM-CSF and the absence of IL-4 induces monocyte differentiation into Mo-DCs. Remarkably, we find that simultaneous inhibition of PPARγ and the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) induces the differentiation of Mo-DCs with stronger phenotypic stability, superior immunogenicity, and a transcriptional profile characterized by a strong type I interferon (IFN) signature, a lower expression of a large set of tolerogenic genes, and the differential expression of several transcription factors compared with GM-CSF/IL-4 Mo-DCs. Our findings uncover a pathway that tailors Mo-DC differentiation with potential implications in the fields of DC vaccination and cancer immunotherapy.

Published
2023
Full Text
View/download PDF

2. Antibody response against SARS-CoV-2 variants of concern in children infected with pre-Omicron variants: An observational cohort study

Author

Vanesa Seery, Silvina Raiden, Constanza Russo, Mauricio Borda, Largión Herrera, Macarena Uranga, Augusto Varese, María Marcó del Pont, Carina Chirino, Constanza Erramuspe, Laura Silvana Álvarez, Melisa Lenoir, Laura Daniela Morales, Carolina Davenport, Alexsa Alarcón Flores, Soledad Huespe Auchter, Yanina Ruiz, Liliana Monsalvo, Laura Sastoque, Magalí Gavazzi, Ignacio Mazzitelli, Facundo Di Diego, Yesica Longueira, Bianca Mazzitelli, Inés Sananez, Norberto De Carli, Mirna Marcela Biglione, Juan Martín Gómez Penedo, Ana Ceballos, Natalia Laufer, Fernando Ferrero, Jorge Geffner, and Lourdes Arruvito

Subjects
Pediatric COVID-19, SARS-CoV-2, Variants, Vaccines, Antibodies, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Despite that pediatric COVID-19 is usually asymptomatic or mild, SARS-CoV-2 infection typically results in the development of an antibody response. Contradictory observations have been reported when the antibody response of children and adults were compared in terms of strength, specificity and perdurability. Methods: This observational study includes three cohorts infected with SARS-CoV-2 between March 2020-July 2021: unvaccinated infected children (n=115), unvaccinated infected adults (n=62), and vaccinated infected children (n=76). Plasma anti-spike IgG antibodies and neutralising activity against Wuhan, Delta and Omicron variants after 7-17 months post-infection were analysed. Findings: More than 95% of unvaccinated infected children and adults remained seropositive when evaluated at 382-491 and 386-420 days after infection, respectively. Anti-spike IgG titers and plasma neutralising activity against Wuhan, Delta and Omicron variants were higher in children compared to adults. No differences were found when unvaccinated infected children were stratified by age, gender or presence/absence of symptoms in the acute phase of SARS-CoV-2 infection, but a slight decrease in the antibody response was observed in those with comorbidities. Vaccination of previously infected children with two doses of the inactivated BBIBP-CorV or the mRNA vaccines, BNT162b2 and/or mRNA-1273, further increased anti-spike IgG titers and neutralising activity against Wuhan, Delta and Omicron variants. Interpretation: Unvaccinated infected children mount a more potent and sustained antibody response compared with adults, which is significantly increased after vaccination. Further studies including not only the analysis of the immune response but also the effectiveness to prevent reinfections by the different Omicron lineages are required to optimise vaccination strategy in children. Funding: National Agency for Scientific and Technological Promotion from Argentina (PICTO-COVID-SECUELAS-00007 and PMO-BID-PICT2018-2548).

Published
2022
Full Text
View/download PDF

3. High Salt Induces a Delayed Activation of Human Neutrophils

Author

Ignacio Mazzitelli, Lucía Bleichmar, Claudia Melucci, Pehuén Pereyra Gerber, Agustina Toscanini, María Luján Cuestas, Fernando Erra Diaz, and Jorge Geffner

Subjects
inflammation, IL-8 (CXCL8), oxygen reactive intermediates, sodium chloride, innate immunity, Immunologic diseases. Allergy, RC581-607
Abstract

High salt (NaCl) concentrations are found in a number of tissues under physiological and pathological conditions. Here, we analyzed the effects induced by high salt on the function of human neutrophils. The culture of neutrophils in medium supplemented with high salt (50 mM NaCl) for short periods (30-120 min) inhibited the ability of conventional agonists to induce the production of IL-8 and the activation of respiratory burst. By contrast, exposure to high salt for longer periods (6-18 h) resulted in the activation of neutrophils revealed by the production of high levels of IL-8, the activation of the respiratory burst, and a marked synergistic effect on the production of TNF-α induced by LPS. Increasing osmolarity of the culture medium by the addition of sorbitol or mannitol (100 mM) was shown to be completely unable to stimulate neutrophil responses, suggesting that high sodium but not an increased osmolarity mediates the activation on neutrophils responses. A similar biphasic effect was observed when the function of monocytes was analyzed. Short term exposure to high salt suppressed IL-8 and TNF-α production induced by LPS while culture for longer periods triggered the production of IL-8 but not TNF-α in the absence of LPS stimulation. Contradictory results have been published regarding how high salt modulates neutrophil function. Our results suggest that the modulation of neutrophil function by high salt is strongly dependent on the exposure time.

Published
2022
Full Text
View/download PDF

4. Immunogenicity induced by the use of alternative vaccine platforms to deal with vaccine shortages in a low- to middle-income country: Results of two randomized clinical trials

Author

Alejandro Macchia, Daniel Ferrante, María Belén Bouzas, Patricia Angeleri, Cristián Biscayart, Jorge Geffner, Lilia Mammana, Inés Zapiola, Eduardo Luis López, Angela Gentile, Augusto Varese, Ignacio Mazzitelli, Facundo Di Diego García, Deborah Sharff, Verónica Lucconi, Paula Sujansky, Javier Mariani, and Fernán González Bernaldo de Quirós

Subjects
COVID-19, Randomised clinical trial, Public health, Vaccines, Public aspects of medicine, RA1-1270
Abstract

Summary: Background: Shortages of component two of Sputnik V vaccine (rAd5) are delaying the possibility of achieving full immunisation. The immunogenic response associated with the use of alternative schemes to complete the scheme was not explored. Methods: We did two non-inferiority randomized clinical trials with outcomes measures blinded to investigators on adults aged 21–65 years, vaccinated with a single dose of rAd26 ≥ 30 days before screening and no history of SARS-CoV-2. Participants were assigned (1:1:1:1:1) to receive either rAd5; ChAdOx1; rAd26; mRNA-1273 or BBIBP-CorV. The primary endpoint was the geometric mean ratio (GMR) of SARS-CoV-2 anti-spike IgG concentration at 28 days after the second dose, when comparing rAd26/rAd5 with rAd26/ChAdOx1, rAd26/rAd26, rAd26/mRNAmRNA-1273 and rAd26/BBIBP-CorV. Serum neutralizing capacity was evaluated using wild type SARS-CoV-2 reference strain 2019 B.1. The safety outcome was 28-day rate of serious adverse. The primary analysis included all participants who received ≥ 1 dose. The studies were registered with NCT04962906 and NCT05027672. Both trials were conducted in Buenos Aires, Argentina. Findings: Between July 6 and August 3, 2021, 540 individuals (age 56·7 [SD 7·3]; 243 (45%) women) were randomly assigned to received rAd5 (n=150); ChAdOx1 (n=150); rAd26 (N=87); mRNAmRNA-1273 (n=87) or BBIBP-CorV (n=65). 524 participants completed the study. As compared with rAd26/rAd5 (1·00), the GMR (95%CI) at day 28 was 0·65 (0·51–0·84) among those who received ChAdOx1; 0·47 (0·34–0·66) in rAd5; 3·53 (2·68–4·65) in mRNA-1273 and 0·23 (0·16–0·33) in BBIBP-CorV. The geometric mean (IU/ml) from baseline to day 28 within each group increased significantly with ChAdOx1 (4·08 (3·07–5·43)); rAd26 (2·69 (1·76–4·11)); mRNA-1273 (21·98 (15·45–31·08)) but not in BBIBP-CorV (1·22 (0·80–1·87)). Interpretation: Except for mRNA-1273 which proved superior, in all other alternatives non-inferiority was rejected. Antibody concentration increased in all non-replicating viral vector and RNA platforms. Funding: The trials were supported (including funding, material support in the form of vaccines and testing supplies) by the Buenos Aires City Government.

Published
2022
Full Text
View/download PDF

5. Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape to Neutralization over Time

Author

María M. Gonzalez Lopez Ledesma, Lautaro Sanchez, Diego S. Ojeda, Santiago Oviedo Rouco, Andrés H. Rossi, Augusto Varese, Ignacio Mazzitelli, Carla A. Pascuale, Esteban A. Miglietta, Pamela E. Rodríguez, Horacio M. Pallarés, Guadalupe S. Costa Navarro, Julio J. Caramelo, Paul W. Rothlauf, Zhuoming Liu, Louis-Marie Bloyet, Marjorie Cornejo Pontelli, Natali B. Rasetto, Shirley D. Wenker, Lila Y. Ramis, Magalí G. Bialer, María Jose de Leone, C. Esteban Hernando, Luciana Bianchimano, Antonella S. Ríos, María Soledad Treffinger Cienfuegos, Diana R. Rodriguez García, Yesica Longueira, Natalia Laufer, Diego Alvarez, Ana Ceballos, Valeria Ochoa, Cecilia Monzani, Gariela Turk, Melina Salvatori, Jorge Carradori, Katherine Prost, Alejandra Rima, Claudia Varela, Regina Ercole, Rosana I. Toro, Sebastian Gutierrez, Martín Zubieta, Dolores Acuña, Mercedes S. Nabaes Jodar, Carolina Torres, Laura Mojsiejczuk, Mariana Viegas, Pilar Velazquez, Clarisa Testa, Nicolas Kreplak, Marcelo Yanovsky, Sean Whelan, Jorge Geffner, Marina Pifano, and Andrea V. Gamarnik

Subjects
COVID-19, SARS CoV-2, Sputnik V, viral variants, Microbiology, QR1-502
Abstract

ABSTRACT Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOC; Alpha, Beta, Gamma, and Delta), and to a local variant of interest (VOI; Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. Longitudinal serum samples (N = 536) collected from 118 volunteers obtained between January and October 2021 were used. The analysis indicates that while anti-spike IgG levels significantly wane over time, the neutralizing capacity for the Wuhan-related lineages of SARS-CoV-2 and VOC is maintained within 6 months of vaccination. In addition, an improved antibody cross-neutralizing ability for circulating variants of concern (Beta and Gamma) was observed over time postvaccination. The viral variants that displayed higher escape to neutralizing antibodies with respect to the original virus (Beta and Gamma variants) were the ones showing the largest increase in susceptibility to neutralization over time after vaccination. Our observations indicate that serum neutralizing antibodies are maintained for at least 6 months and show a reduction of VOC escape to neutralizing antibodies over time after vaccination. IMPORTANCE Vaccines have been produced in record time for SARS-CoV-2, offering the possibility of halting the global pandemic. However, inequalities in vaccine accessibility in different regions of the world create a need to increase international cooperation. Sputnik V is a recombinant adenovirus-based vaccine that has been widely used in Argentina and other developing countries, but limited information is available about its elicited immune responses. Here, we examined longitudinal antibody levels and viral neutralizing capacity elicited by Sputnik V vaccination. Using a cohort of 118 volunteers, we found that while anti-spike antibodies wane over time, the neutralizing capacity to viral variants of concern and local variants of interest is maintained within 4 months of vaccination. In addition, we observed an increased cross-neutralization activity over time for the Beta and Gamma variants. This study provides valuable information about the immune response generated by a vaccine platform used in many parts of the world.

Published
2022
Full Text
View/download PDF

6. A Novel Bacterial Protease Inhibitor Adjuvant in RBD-Based COVID-19 Vaccine Formulations Containing Alum Increases Neutralizing Antibodies, Specific Germinal Center B Cells and Confers Protection Against SARS-CoV-2 Infection in Mice

Author

Lorena M. Coria, Lucas M. Saposnik, Celeste Pueblas Castro, Eliana F. Castro, Laura A. Bruno, William B. Stone, Paula S. Pérez, Maria Laura Darriba, Lucia B. Chemes, Julieta Alcain, Ignacio Mazzitelli, Augusto Varese, Melina Salvatori, Albert J. Auguste, Diego E. Álvarez, Karina A. Pasquevich, and Juliana Cassataro

Subjects
adjuvant, protease inhibitor, SARS- CoV-2, U-Omp19, germinal center cells, Immunologic diseases. Allergy, RC581-607
Abstract

In this work, we evaluated recombinant receptor binding domain (RBD)-based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus alum, AddaS03, AddaVax, or the combination of alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and alum as adjuvants has a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus alum, AddaVax, or AddaS03. Antibodies induced with the formulation containing U-Omp19 and alum not only increased their neutralization capacity against the ancestral virus but also cross-neutralized alpha, lambda, and gamma variants with similar potency. Furthermore, the addition of U-Omp19 to alum vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+alum formulation induced RBD-specific Th1 and CD8+ T-cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge of K18-hACE2 mice.

Published
2022
Full Text
View/download PDF

7. Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells

Author

Fernando Erra Díaz, Valeria Ochoa, Antonela Merlotti, Ezequiel Dantas, Ignacio Mazzitelli, Virginia Gonzalez Polo, Juan Sabatté, Sebastián Amigorena, Elodie Segura, and Jorge Geffner

Subjects
Monocytes, dendritic cells, differentiation, acidosis, low pH, metabolism, Biology (General), QH301-705.5
Abstract

Summary: During inflammation, recruited monocytes can differentiate either into macrophages or dendritic cells (DCs); however, little is known about the environmental factors that determine this cell fate decision. Low extracellular pH is a hallmark of a variety of inflammatory processes and solid tumors. Here, we report that low pH dramatically promotes the differentiation of monocytes into DCs (monocyte-derived DCs [mo-DCs]). This process is associated with a reduction in glucose consumption and lactate production, the upregulation of mitochondrial respiratory chain genes, and the inhibition of mTORC1 activity. Interestingly, we also find that both serum starvation and pharmacological inhibition of mTORC1 markedly promote the differentiation of mo-DCs. Our study contributes to better understanding the mechanisms that govern the differentiation of monocytes into DCs and reveals the role of both extracellular pH and mTORC1 as master regulators of monocyte cell fate.

Published
2020
Full Text
View/download PDF

8. Immune Maturation Effects on Viral Neutralization and Avidity of Hyperimmunized Equine Anti-SARS-CoV-2 Sera

Author

Myriam Belén González Viacava, Augusto Varese, Ignacio Mazzitelli, Laura Lanari, Lucía Ávila, María Julia García Vampa, Jorge Geffner, Osvaldo Cascone, José Christian Dokmetjian, Adolfo Rafael de Roodt, and Matías Fingermann

Subjects
COVID-19, anti-SARS-CoV-2, hyperimmunization, therapeutics, immune maturation, hyperimmune equine, Immunologic diseases. Allergy, RC581-607
Abstract

Mass-vaccination against COVID-19 is still a distant goal for most low-to-middle income countries. The experience gained through decades producing polyclonal immunotherapeutics (such as antivenoms) in many of those countries is being redirected to develop similar products able to neutralize SARS-CoV-2 infection. In this study we analyzed the biological activity (viral neutralization or NtAb) and immunochemical properties of hyperimmune horses’ sera (HHS) obtained during initial immunization (I) and posterior re-immunization (R) cycles using the RBD domain of the SARS-CoV-2 spike protein as antigen. HHS at the end of the R cycle showed higher NtAb titers when compared to those after the I cycle (35,585 vs. 7000 mean NtAb, respectively). Moreover, this increase paralleled an increase in avidity (95.2% to 65.2% mean avidity units, respectively). The results presented herein are relevant for manufacturers of these therapeutic tools against COVID-19.

Published
2022
Full Text
View/download PDF

9. Platelets modulate CD4 + T‐cell function in COVID‐19 through a PD‐L1 dependent mechanism

Author

Ana Paletta, Facundo Di Diego García, Augusto Varese, Fernando Erra Diaz, Julián García, Juan Carlos Cisneros, Guillermina Ludueña, Ignacio Mazzitelli, Andrea Pisarevsky, Gonzalo Cabrerizo, Álvaro López Malizia, Alejandra G. Rodriguez, Nicolás Lista, Yesica Longueira, Juan Sabatté, Jorge Geffner, Federico Remes Lenicov, and Ana Ceballos

Subjects
Hematology
Published
2022

10. Immunogenicity and reactogenicity of heterologous immunization against SARS CoV-2 using Sputnik V, ChAdOx1-S, BBIBP-CorV, Ad5-nCoV, and mRNA-1273

Author

Carla A. Pascuale, Augusto Varese, Diego S. Ojeda, Marina E. Pasinovich, Laura Lopez, Andres H. Rossi, Pamela E. Rodriguez, Esteban A. Miglietta, Ignacio Mazzitelli, Facundo Di Diego Garcia, Lautaro Sanchez, Santiago Oviedo Rouco, María Mora Gonzalez Lopez Ledesma, Juan Pablo Zurano, Bianca Mazzitelli, Graciela Scruzzi, Paula Barbero, Diego Cardozo, Sandra Gallego, Mariel Borda, Miguel Diaz, Francisco Ridao, Angela Brigido Rosales, Jorge Bhon, Juan M. Talia, María E. Diangelo, María A. Lacaze, Balanzino Aime, Sebastian Isaac Gutierrez, Regina Ercole, Rosana Toro, Lorena Tau, Laura Delaplace, Malena Ferreyra Compagnucci, Celeste Sartori, Isabel Desimone, Cecilia Echegoyen, Pilar Velazquez, Clarisa Testa, Daniela Hozbor, Guillermo Docena, Carlos H. Laino, Nicolas Kreplak, Marina Pifano, Gabriela Barbas, Analía Rearte, Carla Vizzotti, Juan M. Castelli, Jorge Geffner, and Andrea V. Gamarnik

Subjects
SARS-CoV-2, Vaccination, COVID-19, Humans, Immunization, Viral Vaccines, RNA, Messenger, Antibodies, Viral, General Biochemistry, Genetics and Molecular Biology, 2019-nCoV Vaccine mRNA-1273
Abstract

Heterologous vaccination against coronavirus disease 2019 (COVID-19) provides a rational strategy to rapidly increase vaccination coverage in many regions of the world. Although data regarding messenger RNA (mRNA) and ChAdOx1 vaccine combinations are available, there is limited information about the combination of these platforms with other vaccines widely used in developing countries, such as BBIBP-CorV and Sputnik V. Here, we assess the immunogenicity and reactogenicity of 15 vaccine combinations in 1,314 participants. We evaluate immunoglobulin G (IgG) anti-spike response and virus neutralizing titers and observe that a number of heterologous vaccine combinations are equivalent or superior to homologous schemes. For all cohorts in this study, the highest antibody response is induced by mRNA-1273 as the second dose. No serious adverse events are detected in any of the schedules analyzed. Our observations provide rational support for the use of different vaccine combinations to achieve wide vaccine coverage in the shortest possible time.

Published
2022

11. Platelets modulate CD4

Author

Ana, Paletta, Facundo, Di Diego García, Augusto, Varese, Fernando, Erra Diaz, Julián, García, Juan Carlos, Cisneros, Guillermina, Ludueña, Ignacio, Mazzitelli, Andrea, Pisarevsky, Gonzalo, Cabrerizo, Álvaro, López Malizia, Alejandra G, Rodriguez, Nicolás, Lista, Yesica, Longueira, Juan, Sabatté, Jorge, Geffner, Federico, Remes Lenicov, and Ana, Ceballos

Subjects
Blood Platelets, CD4-Positive T-Lymphocytes, Interferon-gamma, COVID-19, Humans, B7-H1 Antigen
Abstract

Severe COVID-19 is associated with a systemic inflammatory response and progressive CD4

Published
2022

12. A Novel Bacterial Protease Inhibitor Adjuvant in RBD-Based COVID-19 Vaccine Formulations Containing Alum Increases Neutralizing Antibodies, Specific Germinal Center B Cells and Confers Protection Against SARS-CoV-2 Infection in Mice

Author

Lorena M. Coria, Lucas M. Saposnik, Celeste Pueblas Castro, Eliana F. Castro, Laura A. Bruno, William B. Stone, Paula S. Pérez, Maria Laura Darriba, Lucia B. Chemes, Julieta Alcain, Ignacio Mazzitelli, Augusto Varese, Melina Salvatori, Albert J. Auguste, Diego E. Álvarez, Karina A. Pasquevich, and Juliana Cassataro

Subjects
B-Lymphocytes, Mice, Inbred BALB C, COVID-19 Vaccines, SARS-CoV-2, Immunology, COVID-19, Antibodies, Viral, Germinal Center, Antibodies, Neutralizing, Brucella, Mice, Inbred C57BL, Mice, Adjuvants, Immunologic, Antibody Formation, Spike Glycoprotein, Coronavirus, Immunology and Allergy, Alum Compounds, Animals, Humans, Female, Bacterial Outer Membrane Proteins, Disease Resistance
Abstract

In this work, we evaluated recombinant receptor binding domain (RBD)-based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus alum, AddaS03, AddaVax, or the combination of alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and alum as adjuvants has a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus alum, AddaVax, or AddaS03. Antibodies induced with the formulation containing U-Omp19 and alum not only increased their neutralization capacity against the ancestral virus but also cross-neutralized alpha, lambda, and gamma variants with similar potency. Furthermore, the addition of U-Omp19 to alum vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+alum formulation induced RBD-specific Th1 and CD8+ T-cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge of K18-hACE2 mice.

Published
2021

13. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Author

Elisabetta Cameroni, Christian Saliba, John E. Bowen, Laura E. Rosen, Katja Culap, Dora Pinto, Laura A. VanBlargan, Anna De Marco, Samantha K. Zepeda, Julia di Iulio, Fabrizia Zatta, Hannah Kaiser, Julia Noack, Nisar Farhat, Nadine Czudnochowski, Colin Havenar-Daughton, Kaitlin R. Sprouse, Josh R. Dillen, Abigail E. Powell, Alex Chen, Cyrus Maher, Li Yin, David Sun, Leah Soriaga, Jessica Bassi, Chiara Silacci-Fregni, Claes Gustafsson, Nicholas M. Franko, Jenni Logue, Najeeha Talat Iqbal, Ignacio Mazzitelli, Jorge Geffner, Renata Grifantini, Helen Chu, Andrea Gori, Agostino Riva, Olivier Giannini, Alessandro Ceschi, Paolo Ferrari, Pietro Cippà, Alessandra Franzetti-Pellanda, Christian Garzoni, Peter J. Halfmann, Yoshihiro Kawaoka, Christy Hebner, Lisa A. Purcell, Luca Piccoli, Matteo Samuele Pizzuto, Alexandra C. Walls, Michael S. Diamond, Amalio Telenti, Herbert W. Virgin, Antonio Lanzavecchia, David Veesler, Gyorgy Snell, and Davide Corti

Subjects
COVID-19 Vaccines, Multidisciplinary, SARS-CoV-2, Antibodies, Monoclonal, Convalescence, Vesiculovirus, Antibodies, Monoclonal, Humanized, Antibodies, Viral, Antibodies, Neutralizing, Article, Cell Line, Mice, Neutralization Tests, Spike Glycoprotein, Coronavirus, Animals, Epitopes, B-Lymphocyte, Humans, Angiotensin-Converting Enzyme 2, Antigenic Drift and Shift, Broadly Neutralizing Antibodies, Immune Evasion
Abstract

SUMMARYThe recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Published
2021

14. A novel bacterial protease inhibitor adjuvant in RBD-based COVID-19 vaccine formulations increases neutralizing antibodies, specific germinal center B cells and confers protection against SARS-CoV-2 infection

Author

Lorena M. Coria, Lucas M. Saposnik, Celeste Pueblas Castro, Eliana F. Castro, Laura A. Bruno, William B. Stone, Paula S. Pérez, M. Laura Darriba, Lucia B. Chemes, Julieta Alcain, Ignacio Mazzitelli, Augusto Varese, Melina Salvatori, Albert J. Auguste, Diego E Álvarez, Karina A. Pasquevich, and Juliana Cassataro

Abstract

In this work we evaluated recombinant receptor binding domain (RBD) based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus Alum, AddaS03, AddaVax or the combination of Alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and Alum as adjuvants have a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus Alum, AddaVax or AddaS03. Antibodies induced with the formulation containing U-Omp19 not only increased their neutralization capacity against the wild-type virus but also cross neutralized alpha, lambda and gamma variants with similar potency. Also, addition of U-Omp19 to vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+Alum formulation induced RBD-specific Th1 and CD8+ T cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal SARS-CoV-2 challenge of K18-hACE2 mice.

Published
2021

15. Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape over Time

Author

Sebastian Gutierrez, Carla A. Pascuale, Guadalupe S. Costa Navarro, Natali B. Rasetto, Carolina Torres, Paul W. Rothlauf, Esteban Alberto Miglietta, Natalia Laufer, Claudia Varela, Valeria Ocho, Zhouming Liu, Pilar Velazquez, Diego E. Alvarez, Jorge Carradori, Laura Noelia Mojsiejczuk, Katherine Prost, Pamela E. Rodriguez, Gabriela Turk, Augusto Varesse, Diana Rosa Rodriguez Garcia, Cecilia Monzani, Marjorie Cornejo Pontelli, Andrea V. Gamarnik, Julio J. Caramelo, Regina Ercole, Horacio M. Pallarés, Ignacio Mazzitelli, Dolores Acuna, Louis Marie Bloyet, Marcelo J. Yanovsky, María José de Leone, Shirley D. Wenker, Martin Zubieta, Magalí G. Bialer, Maria Soledad Treffinger Cienfuegos, Yesica Longueira, Liloa Y. Ramis, Rasana I. Toro, María Mora González López Ledesma, Ana Ceballos, Mariana Viegas, Lautaro Sanchez, Santiago Oviedo Rouco, Jorge Geffner, Sean P. J. Whelan, C. Esteban Hernando, Andrés Hugo Rossi, Nicolás Kreplak, Alejandra Rima, Clarisa Testa, Luciana Bianchamino, Marina Pifano, Melina Salvatori, Mercedes Soledad Nabaes Jodar, Diego Sebastian Ojeda, and Antonella S. Rios

Subjects
Vaccination, biology, biology.protein, Alpha (ethology), Potency, Antibody, Beta (finance), Neutralizing antibody, Virology, Neutralization, Virus
Abstract

Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOCs: Alpha, Beta, Gamma, and Delta) and a local variant of interest (VOI: Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. A collection of 472 serum samples obtained between January and September 2021 was used. The analysis indicates that while anti-spike IgG levels significantly wane over time, the neutralizing capacity to the first-wave linages of SARS-CoV-2 and VOC are maintained within four months of vaccination. In addition, an improved antibody cross-neutralizing ability to circulating variants of concern (Beta, Gamma and Delta) was observed over time of vaccination. The viral variants that displayed higher escape to neutralizing antibodies with respect to the original virus (Beta and Gamma variants) were the ones showing the largest increase in susceptibility to neutralization over time after vaccination. Our observations indicate that serum neutralizing antibodies are maintained for at least four month and show a reduction of VOC escape over time of vaccination.

Published
2021

16. Sputnik V vaccine elicits seroconversion and neutralizing capacity to SARS-CoV-2 after a single dose

Author

Dariana Pedrozza, Diego Sebastian Ojeda, Guadalupe S. Costa Navarro, Natali B. Rasetto, Diego E. Alvarez, Natalia Laufer, Santiago Sosa, Maria Soledad Treffinger Cienfuegos, Paula Gelpi, Antonella S. Rios, Magalí G. Bialer, María Mora González López Ledesma, Augusto Varese, Ignacio Mazzitelli, Lautaro Sanchez, Regina Ercole, Jorge Carradori, Guillermo Horacio Docena, Jorge Geffner, C. Esteban Hernando, Shirley D. Wenker, Santiago Oviedo Rouco, Andrea V. Gamarnik, Andrés Hugo Rossi, Alejandra Rima, Anabel Alvarez Juliá, Horacio M. Pallarés, Luciana Bianchimano, Marina Pifano, Susana Marchetti, Yesica Longueira, Nicolás Kreplak, Julio J. Caramelo, Marcelo J. Yanovsky, María José de Leone, Lila Y. Ramis, Martin Zubieta, Cecilia Echegoyen, and Corina I. García

Subjects
COVID-19 Vaccines, Health Personnel, COVIDAR IGG, Argentina, Antibodies, Viral, General Biochemistry, Genetics and Molecular Biology, Virus, NEUTRALIZING ANTIBODIES, Sputnik V, Report, Pandemic, Chlorocebus aethiops, SEROCONVERSION, Global health, Medicine, Animals, Humans, neutralizing antibodies, SARS-COV-2 VACCINATION, Seroconversion, Pandemics, Vero Cells, Vaccines, Vaccines, Synthetic, biology, business.industry, SARS-CoV-2, COVIDAR IgG, Vaccination, COVID-19, purl.org/becyt/ford/3.1 [https], Antibodies, Neutralizing, Titer, SARS-CoV-2 vaccination, HEK293 Cells, Cohort, Immunology, Spike Glycoprotein, Coronavirus, Ciencias Médicas, SPUTNIK V, biology.protein, WHO SARS-COV-2 ANTIBODY INTERNATIONAL STANDARD, purl.org/becyt/ford/3 [https], Antibody, business, WHO SARS-CoV-2 antibody International Standard
Abstract

Massive vaccination offers great promise for halting the global COVID-19 pandemic. However, the limited supply and uneven vaccine distribution create an urgent need to optimize vaccination strategies. We evaluate SARS-CoV-2-specific antibody responses after Sputnik V vaccination of healthcare workers in Argentina, measuring IgG anti-spike titers and neutralizing capacity after one and two doses in a cohort of naive or previously infected volunteers. By 21 days after receiving the first dose of the vaccine, 94% of naive participants develop spike-specific IgG antibodies. A single Sputnik V dose elicits higher antibody levels and virus-neutralizing capacity in previously infected individuals than in naive ones receiving the full two-dose schedule. The high seroconversion rate after a single dose in naive participants suggests a benefit of delaying administration of the second dose to increase the number of people vaccinated. The data presented provide information for guiding public health decisions in light of the current global health emergency., Graphical abstract, Rossi et al. provide data on antibody responses to Sputnik V vaccine in naive and previously infected volunteers. This study shows a high seroconversion rate following the first dose in naive individuals. In seropositive participants, a single dose of Sputnik V elicits a fast and robust antibody response without apparent benefit from a second dose.

Published
2021

17. IgG immune complexes may contribute to neutrophil activation in the course of severe COVID-19

Author

Ignacio Mazzitelli, Lucia Bleichmar, Santiago N Piombi Adanza, Verónica Chiaradia, Ana Luz Paletta, Francisco Paulin, Macarena Hormanstorfer, Paola Finocchieto, Fernando Erra Díaz, Andrea Pisarevsky, Claudia Melucci, Ana Ceballos, Jorge Geffner, María Guillermina Ludueña, Mariana Labato, María Noel Parodi, María Constanza Baretto, Martin Alberto Ragusa, and Facundo Di Diego

Subjects
Male, 0301 basic medicine, CD32, Antigen-Antibody Complex, 030204 cardiovascular system & hematology, Antibodies, Viral, medicine.disease_cause, Neutrophil Activation, Immunoglobulin G, immune complexes, purl.org/becyt/ford/1 [https], 0302 clinical medicine, neutrophils, Immunology and Allergy, Coronavirus, CD11b Antigen, biology, purl.org/becyt/ford/3.1 [https], Middle Aged, Infectious Diseases, AcademicSubjects/MED00290, CXCL8, Female, purl.org/becyt/ford/3 [https], medicine.symptom, Antibody, Adult, Inflammation, GPI-Linked Proteins, Proinflammatory cytokine, Young Adult, 03 medical and health sciences, Immune system, INFLAMMATION, Antigens, CD, medicine, Major Article, Humans, Interleukin 8, purl.org/becyt/ford/1.6 [https], Aged, SARS-CoV-2, business.industry, Interleukin-8, Receptors, IgG, COVID-19, 030104 developmental biology, inflammation, Immunology, SARS-CoV2, biology.protein, business, Cell Adhesion Molecules
Abstract

Severe coronavirus disease 2019 (COVID-19) is associated with an overactive inflammatory response mediated by macrophages. Here, we analyzed the phenotype and function of neutrophils in patients with COVID-19. We found that neutrophils from patients with severe COVID-19 express high levels of CD11b and CD66b, spontaneously produce CXCL8 and CCL2, and show a strong association with platelets. Production of CXCL8 correlated with plasma concentrations of lactate dehydrogenase and D-dimer. Whole blood assays revealed that neutrophils from patients with severe COVID-19 show a clear association with immunoglobulin G (IgG) immune complexes. Moreover, we found that sera from patients with severe disease contain high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Interestingly, when integrated in immune complexes, anti-severe acute respiratory syndrome coronavirus 2 IgG antibodies from patients with severe COVID-19 displayed a higher proinflammatory profile compared with antibodies from patients with mild disease. Our study suggests that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils, worsening the course of COVID-19. Fil: Mazzitelli, Ignacio Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Bleichmar, Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ludueña, María Guillermina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Pisarevsky, Andrea. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Labato, Mariana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Chiaradia, Verónica. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Finocchieto, Paola. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Paulin, Francisco. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Hormanstorfer, Macarena. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Baretto, María Constanza. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Adanza, Santiago Piombi. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Parodi, María Noel. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Ragusa, Martín. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Melucci Ganzarain, Claudia del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Erra Diaz, Fernando Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Paletta, Ana Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Di Diego García, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ceballos, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2021

18. Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells

Author

Ezequiel Dantas, Virginia Gonzalez Polo, Antonela Merlotti, Juan Sabatté, Elodie Segura, Valeria Ochoa, Fernando Erra Díaz, Sebastian Amigorena, Jorge Geffner, and Ignacio Mazzitelli

Subjects
0301 basic medicine, CIENCIAS MÉDICAS Y DE LA SALUD, INFLAMATION, Inmunología, Inflammation, mTORC1, Cell fate determination, DENDRITIC CELLS, Monocytes, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Extracellular, medicine, low pH, Humans, MONOCYTE, MTOR INHIBITION, lcsh:QH301-705.5, PI3K/AKT/mTOR pathway, Chemistry, Macrophages, TOR Serine-Threonine Kinases, Monocyte, Cell Differentiation, purl.org/becyt/ford/3.1 [https], differentiation, Dendritic Cells, Cell biology, Medicina Básica, 030104 developmental biology, medicine.anatomical_structure, Mitochondrial respiratory chain, lcsh:Biology (General), Cytokines, purl.org/becyt/ford/3 [https], acidosis, medicine.symptom, metabolism, 030217 neurology & neurosurgery
Abstract

During inflammation, recruited monocytes can differentiate either into macrophages or dendritic cells (DCs); however, little is known about the environmental factors that determine this cell fate decision. Low extracellular pH is a hallmark of a variety of inflammatory processes and solid tumors. Here, we report that low pH dramatically promotes the differentiation of monocytes into DCs (monocyte-derived DCs [mo-DCs]). This process is associated with a reduction in glucose consumption and lactate production, the upregulation of mitochondrial respiratory chain genes, and the inhibition of mTORC1 activity. Interestingly, we also find that both serum starvation and pharmacological inhibition of mTORC1 markedly promote the differentiation of mo-DCs. Our study contributes to better understanding the mechanisms that govern the differentiation of monocytes into DCs and reveals the role of both extracellular pH and mTORC1 as master regulators of monocyte cell fate. Fil: Erra Díaz, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ochoa, Andrea Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Merlotti Ippólito, Antonela. PSL Research University; Francia. Inserm; Francia Fil: Dantas, Ezequiel Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Mazzitelli, Ignacio Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Gonzalez Polo, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Sabatte, Juan Atilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Amigorena, Sebastián. Psl Research University; Francia. Inserm; Francia Fil: Segura, Elodie. Psl Research University; Francia. Inserm; Francia Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2020

Catalog

Books, media, physical & digital resources
See catalog results