Elevated sodium concentrations are commonly observed in tumors and sites of inflammation. Previous studies have shown that high salt levels modulate the phenotype and function of CD4+ and CD8+ T cells, regulatory T cells, and macrophages. In this study, we performed transcriptomic studies that revealed profound alterations in the neutrophil transcriptome upon high salt exposure, with changes that significantly exceeded those triggered by conventional agonists. By integrating transcriptomic data with functional assays, our findings suggest that high salt-induced neutrophil activation involves mitochondrial ROS production, which subsequently activates p38 MAPK and engages FOS-, Bruton's tyrosine kinase (BTK)-, and cyclooxygenase 2 (COX2)-dependent pathways. Remarkably, the plasticity of the neutrophil transcriptome in response to high salt was further evidenced by the upregulation of genes typically associated with other cell types, including semenogelin 1 (SEMG1), intercellular adhesion molecule-4 (ICAM4), tripartite motif69 (TRIM69), amphiregulin (AREG), oncostatin (OSM), and transducer of ERBB2-1 (TOB1), suggesting a broader role for neutrophils in different biological processes beyond their participation in innate immunity.

BackgroundMost children in Argentina received only the initial COVID-19 vaccine series, with presumed hybrid immunity after multiple Omicron waves. However, the durability of immune memory, particularly in immunocompromised (IC) children, remains poorly studied.MethodsA cohort of IC (n=45) and healthy children (HC, n=79) was assessed between 13 to 17 months after receiving two or three doses of BBIBP-CorV and/or BNT162b2. Plasma anti-spike IgG, neutralizing activity and antigen-specific CD4+ and CD8+ T cells against Wuhan and Omicron BA.5 variants were assessed.ResultsMost children remained seropositive after two vaccine doses, but compared with HC, IC exhibited lower neutralizing titers against both Wuhan and Omicron BA.5, particularly those vaccinated with BBIBP-CorV. Even after three vaccine doses, IC showed weaker neutralizing antibody response, CD8+ T cell responses and lower IFN-γ production compared with HC. Integrated analysis of neutralizing antibodies, memory CD4+, and CD8+ T cells revealed a weak immune memory among IC with an important compromise in memory CD8+ T cell responses.ConclusionsImmunity can last up to 17 months, but reduced effectiveness against new variants highlights the need for updated COVID-19 vaccines, especially for IC children. Additional efforts are essential to enhance vaccination coverage and protect this vulnerable population.

Monocytes are highly plastic cells and can be used as precursors for the generation of dendritic cell (DC)-based vaccines. Despite the capacity of DC vaccines to elicit antigen-specific T responses, their clinical benefit has been disappointing. Poor phenotypic stability, reduced migratory capacity, and the acquisition of tolerogenic features when injected into patients might explain their limited clinical efficacy. Consequently, tailoring the immunogenic potential of DCs by manipulating their differentiation offers the possibility of improving the efficacy of DC vaccines, especially in combination with immune checkpoint blockade therapies. We have reported that the simultaneous pharmacological inhibition of the mammalian target of rapamycin complex 1 and the peroxisome proliferator-activated receptor γ (PPARγ) in the presence of GM-CSF induces the differentiation of highly immunogenic human monocyte-derived dendritic cells (MoDCs). When compared to the traditional method to generate MoDCs in vitro, using GM-CSF and IL-4, these cells show higher phenotypic stability and stronger immunogenic profile. Here we provide a comprehensive protocol for the generation of these cells and evaluation of their immune functions in vitro.

A randomized, placebo-controlled, crossover, double-blind, phase II/III study was conducted to evaluate the immunogenicity, safety, and tolerability of a recombinant booster vaccine (ARVAC) containing the SARS-CoV-2 spike protein receptor binding domain in three versions: ARVACGamma, ARVACOmicron, and ARVACBivalent in adults with ≤3 previous SARS-CoV-2 booster doses. Primary endpoint was seroconversion rate of neutralizing antibodies compared to placebo and to a > 75 % seroconversion rate to vaccine antigen homologous variants. All vaccine versions significantly increased seroconversion rates to SARS-CoV-2 variants compared to placebo. In participants aged 18-60 years, all versions met the primary endpoint; in those over 60 years old, ARVACOmicron and ARVACBivalent met this endpoint. No vaccine-related serious adverse events were recorded, and most adverse events were mild. Plasma levels of anti-spike-specific IgG and anti-S1-specific IgA in saliva increased in participants receiving any vaccine. The increase in plasma neutralizing antibodies induced by the vaccine was independent of the number of previous booster doses (0, 1 or 2), the primary vaccine platform (adenovirus, single-dose adenovirus, mRNA, inactivated virus, heterologous vaccination, and virus-like particle [VLP]) and the history of previous COVID-19. The neutralizing Ab response induced by the vaccine in healthy participants was similar to that triggered in participants with underlying medical conditions associated with an increased risk of severe COVID-19. ARVACBivalent induced high seroconversion rates (>90 %) against multiple variants and was superior to other ARVAC-versions. It increased neutralizing antibodies against SARS-CoV-2 variants (Ancestral, Gamma, Omicron, XBB and JN.1) and SARS-CoV-1. (NCT05752201).

BackgroundFollicular helper T cells (Tfh) are pivotal in B cell responses. Activation of the purinergic receptor P2X7 on Tfh cells regulates their activity. We investigated the ATP-P2X7R axis in circulating Tfh (cTfh) cells during Respiratory Syncytial Virus (RSV) infection.MethodsWe analyzed two cohorts: children with RSV infection (moderate, n=30; severe, n=21) and healthy children (n=23). We utilized ELISA to quantify the levels of PreF RSV protein-specific IgG antibodies, IL-21 cytokine, and soluble P2X7R (sP2X7R) in both plasma and nasopharyngeal aspirates (NPA). Additionally, luminometry was employed to determine ATP levels in plasma, NPA and supernatant culture. The frequency of cTfh cells, P2X7R expression, and plasmablasts were assessed by flow cytometry. To evaluate apoptosis, proliferation, and IL-21 production by cTfh cells, we cultured PBMCs in the presence of Bz-ATP and/or P2X7R antagonist (KN-62) and a flow cytometry analysis was performed.ResultsIn children with severe RSV disease, we observed diminished titers of neutralizing anti-PreF IgG antibodies. Additionally, severe infections, compared to moderate cases, were associated with fewer cTfh cells and reduced plasma levels of IL-21. Our investigation revealed dysregulation in the ATP-P2X7R pathway during RSV infection. This was characterized by elevated ATP levels in both plasma and NPA samples, increased expression of P2X7R on cTfh cells, lower levels of sP2X7R, and heightened ATP release from PBMCs upon stimulation, particularly evident in severe cases. Importantly, ATP exposure decreased cTfh proliferative response and IL-21 production, while promoting their apoptosis. The P2X7R antagonist KN-62 mitigated these effects. Furthermore, disease severity positively correlated with ATP levels in plasma and NPA samples and inversely correlated with cTfh frequency.ConclusionOur findings indicate that activation of the ATP-P2X7R pathway during RSV infection may contribute to limiting the cTfh cell compartment by promoting cell death and dysfunction, ultimately leading to increased disease severity.

Background This study (ARVAC-F2-3-002) assessed the immunogenicity, safety, and tolerability of a recombinant booster vaccine (ARVAC) containing the receptor binding domain of the SARS-CoV-2 Spike protein in three different versions: Gamma (ARVACGamma), Omicron BA.4/5 (ARVACOmicron), and Gamma/Omicron Bivalent (ARVACBivalent). Methods Randomized, double-blind, crossover, placebo-controlled, multicenter (11 centers in Argentina) Phase II/III trial including adult volunteers previously vaccinated against SARS-CoV-2 with ≤3 booster doses. Participants were randomized to receive ARVACGamma (50 µg)+placebo and vice-versa (1:1 ratio) (Phase II), and ARVACGamma (50 µg)+placebo, ARVACOmicron (50 µg)+placebo, and ARVACBivalent (Gamma/Omicron 25 µg/25 µg)+placebo and vice-versa (Phase III) (1:1:1:1:1:1 ratio) 28 days apart. The primary endpoint was the seroconversion rate of neutralizing antibodies compared to placebo. The vaccine immunogenicity was considered acceptable at >75% seroconversion rate to variants homologous to the antigen contained in the vaccine (prespecified primary endpoint). Results Participants (n=2012) (mean 48.2 years, SD 16.7; 48.1% women) were randomized and allocated to ARVACGamma (n=232 in Phase II and n=592 in Phase III), ARVACOmicron (n=594), and ARVACBivalent (n=594); 232 in Phase II and 370 in each Phase III group were included in the immunogenicity subset. Seroconversion rates to all SARS-CoV-2 variants were significantly higher after receiving any vaccine than placebo. All vaccine versions met the prespecified primary endpoint in all participants and in those 18−60 years old. In participants >60 years, the ARVACOmicron and the ARVACBivalent met the prespecified primary endpoint, whereas the ARVACGamma did not. The ARVACBivalent induced seroconversion rates were significantly higher than 75% across all tested SARS- CoV-2 variants (homologous and heterologous) and age groups. No vaccine-related serious adverse events were recorded; most local and systemic adverse events were grade 1-2. Conclusion Booster vaccination with Gamma, Omicron BA.4/5, and Bivalent protein subunit recombinant ARVAC vaccine versions elicited protective neutralizing antibody responses to several SARS-CoV-2 variants, with very low reactogenicity and a favorable safety profile. Trial registration: [NCT05752201][1] ### Competing Interest Statement J.M.R., L.P.C. Group, F.M.O., J.C.V. and JoC are employees of Laboratorio Pablo Cassará S.R.L., which developed the vaccine. M.E.L. and J.F. are external consultants and received honoraria from Laboratorio Pablo Cassará S.R.L. G.PM has received a research grant from Merck and G.PM, A.B., V.M.B., A.Ch, S.C., M.C.D., L.DN., T.B.N., R.LP., C.G.M., LP, V.M.TU, C.J.W, and R.Z. conduct clinical trials for Pfizer, Merck, Sanofi, and Moderna, Inc. P.B. was investigator in clinical trials of Sinopharm and Janssen COVID-19 vaccines and was Advisory Board Participant for Moderna and Raffo. M.F.A. received honoraria for clinical research from Astra Zeneca, Pfizer, Dompé and Red Insight. N.I. received honoraria for clinical research GSK, Celcuity, Novartis, Genentech, Astra Zeneca, MSD, and Chiesi. S.A.N. received honoraria for clinical research from: GSK, AstraZeneca, Sanofi Aventis, Eli Lilly, NIAID, ATEA Pharmaceuticals and financial help to assist meetings and conferences from GSK, MSD, and Sanofi. O.R. was principal investigator in a clinical study of Merck. R.M.G. and F.B. are employees from Nobeltri S.R.L that offers services to Laboratorio Pablo Cassará S.R.L. All other authors declare no competing interests. ### Clinical Trial NCT05752201 ### Funding Statement The trial was funded by the National ministry of Science and Technology and the National Agency for promotion of Science and Technology of Argentina. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants signed the informed consent form. The National Administration of Drugs, Food, and Medical Technology (Administración Nacional de Medicamentos, Alimentación y Tecnología Médica, ANMAT), the CABA Local Ethics Committee (PRIISA, Plataforma de Registro Informatizado de Investigaciones en Salud de Buenos Aires), and the Ethics Committee on Clinical Research (CEIC) of the Infectious Studies Center S.A. (Centro de Estudios Infectológicos, CEI) Stamboulián approved the protocol, which was prospectively registered at ANMAT, PRIISA, and [clinicaltrials.gov][2] ([NCT05752201][1]). The local Ethics Committees that approved the study protocol are: 1 Ethics Committee on Clinical Research (CEIC) of the Infectious Studies Center S.A. Comité de ética en Investigación Clínica (CEIC) del Centro de Estudios Infectologicos S.A. CEI Stamboulián. 2 Ethics Committee of the Medical Education and Clinical Investigations Center. Comité de ética en Investigación de CEMIC. 3 Research Ethics Committee. Clinical Research Institute Dr. Jesus Vazquez. DiMe Foundation. 4 Provincial Biomedical Research Commission. Comisión Provincial de Investigaciones Biomédicas. 5 Research Ethics Committee of the Platense Medical Institute. Comité de ética en Investigación Instituto Médico Platense (CEDIMP). 6 Institutional Medical Research Ethics Committee Fabiola Queen Fabiola. University Clinic. Comité Institucional de ética en Investigación en Salud CIEIS Fabiola. Clínica Universitaria Reina Fabiola. 7 Bioethics Committee (Research Ethics Committee) of the Huesped Foundation. Comite de Bioética de la Fundación Huésped. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [clinicaltrials.gov][2]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05752201&atom=%2Fmedrxiv%2Fearly%2F2024%2F05%2F06%2F2024.05.06.24306575.atom [2]: http://clinicaltrials.gov

El Documento de posición sobre vacunación COVID-19 en pacientes inmunosuprimidos en todas las etapas de la vida, redactado por diferentes representantes de prestigiosas sociedades e instituciones científicas, intenta dar una respuesta a un complejo universo a fin de que todo el espectro de actores pueda contar con una herramienta de calidad, fruto del debate entre especialistas de indiscutible nivel, y adaptada a la realidad espe- cífica de nuestro país. El Comité Editorial de Actualizaciones en SIDA e Infectología considera que este documento debe ser difundido a fin de que en todos los centros sanitarios del país se pueda brindar una atención médica de primer nivel, como lo merecen todos y cada uno de nuestros pacientes. Es por eso que lo presentamos en este suplemento especial del número 114 de nuestra revista, para que todos nuestros lectores cuenten con esta importante herramienta y nos ayuden con su difusión.

Objectives: Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. Methods: This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. Results: At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. Conclusions: One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation.

The SARS-CoV-2 pandemic caused millions of deaths around the world. This dramatic balance requires governments, international organizations, vaccine manufacturers, and the scientific community itself to take stock of what has been done and what could have been done better. In this sense, the tremendous inequity in access to vaccines, the main tool to deal with the pandemic, deserves deep reflection and a set of actions to be carried out by low-and middle-income countries. Among them, the construction of a joint effort to produce their own vaccines and the reconsideration of the bases that govern the intellectual property rights of vaccines and medicines, which harmed equitable access to health, with the consequent loss of many lives that could have been saved.

Introducción: el objetivo de este estudio fue analizar la relación entre los valores de IL13 y su pronóstico en pacientes con artritis reumatoidea (AR) y enfermedad pulmonar intersticial (EPI). Materiales y métodos: estudio de cohorte prospectiva. Se midió IL13 en suero y se dividió la cohorte en dos grupos con la mediana de IL13 como punto de corte. Se estudió el tiempo hasta una caída de la capacidad vital forzada (CVF) mayor o igual al 5% con el método de Kaplan Meier (KM) y regresión de Cox. Resultados: se incluyeron 47 pacientes. La media (DE) de tiempo de seguimiento fue de 12,7 (12,5) meses. El estimador de KM a 15 meses fue de 0,48 (IC 95% 0,13-0,76) en el grupo con valores elevados de IL13 y de 0,86 (IC 95% 0,54-0,93) en el otro grupo (p=0,037). En el análisis de Cox multivariado los valores elevados de IL13 se asociaron con una caída de la CVF mayor o igual al 5% en el seguimiento (HR 17.64 [IC 95% 1,89-164,1] p=0,012). Conclusiones: los valores elevados de IL13 se asociaron con peor evolución funcional en esta cohorte prospectiva de pacientes con AR y EPI.

Substantial efforts have been made to understand the immune response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, in order to identify and characterize risk factors, immune mechanisms responsible for the induction of tissue injury and potential therapeutic targets. Purinergic signaling pathway has shown to modulate the inflammatory processes in the course of several infectious diseases, but its role in the coronavirus disease 2019 (COVID-19) has not been clearly defined. Inflammation is usually associated to the release of ATP from different cell types, starting a cascade of events through the activation of a set of different purinergic receptors. This review summarizes the evidence showing the involvement of the purinergic system in the inflammatory condition that characterizes severe COVID-19.

SUMMARY Background In view of the emergence of SARS-CoV-2 immune escape variants and evidence of waning immunity, new immunisation strategies and variant-adapted vaccines are needed. Based on preclinical proof of concept studies and requirement of variant-adapted and booster vaccines, the Gamma Variant RBD-based ARVAC-CG vaccine was selected for a first clinical trial in humans. Methods Eighty participants (healthy adults, 18-55 years-old) were sequentially assigned to receive two (28 days apart) intramuscular doses of 25-μg (n=60) or 50-μg (n=20) of a Gamma RBD-based subunit vaccine adjuvanted with aluminium hydroxide. The primary endpoint was safety. The secondary objective was to describe the neutralising antibody response against the SARS-CoV-2 Ancestral strain and several variants of concern (Gamma, Delta, Omicron BA.1 and Omicron BA.5) measured by a live virus-based neutralisation assay. Cellular immune responses were studied as an exploratory objective by an enzyme-linked immunospot (ELISpot) assay. This trial is registered in ClinicalTrials.gov ( NCT05656508 ). Findings The interim results from the ongoing phase 1 study are described. ARVAC-CG exhibited a satisfactory safety profile, a robust and broad booster response of neutralising antibodies against the Ancestral strain of SARS-CoV-2, the Gamma variant, and other VOCs (Delta, Omicron BA.1 and Omicron BA.5) and a booster effect on T cell immunity. Interpretation ARVAC-CG is safe and highly immunogenic when used as booster in individuals previously immunised with different COVID-19 vaccine platforms. These results warrant further clinical evaluation of this vaccine candidate for boosting other COVID-19 vaccines. Funding Laboratorio Pablo Cassará S.R.L. (Argentina). Research in context Evidence before this study Next-generation COVID-19 vaccines are based on a variant-adapted approach, using a strain other than the parental strain of SARS-CoV-2 (Wuhan or D614G strain). It has been suggested that the use of vaccines containing Beta spike protein may be an interesting strategy to acquire wider protection against SARS-CoV-2 variants. The Beta variant has been tested as booster in different monovalent or bivalent vaccine platforms. Indeed, Sanofi and GSK VidPrevtyn® Beta has recently been approved in Europe representing the first protein-based next-generation COVID-19 booster vaccine. While the receptor binding domain (RBD) of the spike protein of Gamma and Beta SARS-CoV-2 variants are very similar, no clinical data on Gamma variant-based COVID-19 vaccines has been published so far. Preclinical data in mice indicate that the Gamma variant-based vaccine is more immunogenic and induces a broader nAb response than the ancestral RBD-based vaccine. Added value of this study To our knowledge, these is the first clinical trial reported from any monovalent Gamma variant RBD protein adjuvanted vaccine used as heterologous booster of different primary series vaccine platforms. Two different vaccine doses were tested, and both exhibited a good profile of safety, tolerability and reactogenicity. ARVAC-CG as a single heterologous booster induced a significant increase of broad-spectrum neutralising antibodies against Ancestral, Gamma, Delta, Omicron BA.1 and Omicron BA.5 variants of concern (VOCs), binding antibodies, and IFN-γ producing cells. All these immune responses were significantly boosted in individuals primed with vaccines from different platforms. Plasma from vaccinees receiving a heterologous booster with ARVAC-CG was superior to plasma from BTN16b2 boosted individuals in neutralising Omicron BA.1 and BA.5 SARS-CoV-2 VOCs. Implications of all the available evidence Here, we present the available data from the phase I study of ARVAC-CG vaccine, involving healthy adults who had previously received a complete primary vaccination schedule with a COVID-19 vaccine. The positive safety and immunogenicity results of the ARVAC-CG vaccine candidate presented here justify further evaluation of its immunogenicity against currently circulating SARS-CoV-2 VOCs in a comprehensive Phase 2/3 trial. Further research is required to assess the antibody persistence over time after a booster dose of ARVAC-CG.

Dendritic cells (DCs) play a key role in the induction of the adaptive immune response. They capture antigens in peripheral tissues and prime naïve T lymphocytes, triggering the adaptive immune response. In the course of inflammatory processes DCs face stressful conditions including hypoxia, low pH and high concentrations of reactive oxygen species (ROS), among others. How DCs survive under these adverse conditions remain poorly understood. Clusterin is a protein highly expressed by tumors and usually associated with bad prognosis. It promotes cancer cell survival by different mechanisms such as apoptosis inhibition and promotion of autophagy. Here, we show that, upon maturation, human monocyte-derived DCs (MoDCs) up-regulate clusterin expression. Clusterin protects MoDCs from ROS-mediated toxicity, enhancing DC survival and promoting their ability to induce T cell activation. In line with these results, we found that clusterin is expressed by a population of mature LAMP3+ DCs, called mregDCs, but not by immature DCs in human cancer. The expression of clusterin by intratumoral DCs was shown to be associated with a transcriptomic profile indicative of cellular response to stress. These results uncover an important role for clusterin in DC physiology.

A Gamma Variant RBD-based aluminum hydroxide adjuvanted vaccine called ARVAC CG was selected for a first in human clinical trial. Healthy male and female participants (18-55 years old) with a complete COVID-19-primary vaccine scheme were assigned to receive two intramuscular doses of either a low-dose or a high-dose of ARVAC CG. The primary endpoint was safety. The secondary objective was humoral immunogenicity. Cellular immune responses were studied as an exploratory objective. The trial was prospectively registered in PRIISA.BA (Registration Code 6564) and ANMAT and retrospectively registered in ClinicalTrials.gov (NCT05656508). Samples from participants of a surveillance strategy implemented by the Ministry of Health of the Province of Buenos Aires that were boosted with BNT162b2 were also analyzed to compare with the booster effect of ARVAC CG. ARVAC CG exhibits a satisfactory safety profile, a robust and broad booster response of neutralizing antibodies against the Ancestral strain of SARS-CoV-2 and the Gamma, Delta, Omicron BA.1 and Omicron BA.5 variants of concern and a booster effect on T cell immunity in individuals previously immunized with different COVID-19 vaccine platforms.

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.

Introduction: Coronavirus 19 disease (COVID-19) in solid organ transplant recipients (SOT) is associated with increased morbidity and mortality. The WHO recommends vaccination as a primary prevention tool. We evaluate the safety and generation of Ab Anti-Spike in SOT patients at 28 and 90 days after Covid 19 vaccination schedule. Methods: This is a Multicenter prospective study in SOT with a complete vaccination schedule who agreed to participate in the study. Demographic, vaccination schedule, adverse events and transplant variables were collected. Anti-spike antibodies were evaluated by the COVIDAR-IgG method at the Universidad de Buenos Aires School of Medicine. Results: 244 SOT patients were included from September 2021 to February 2022. Median age was 50 (IQR 41-61, women 47%).Transplant type: 62.1% kidney, 14.8% cardiac, 15.6% liver, 0.6% pancreas, kidney-pancreas 5.3% and 1.6% lung. Deceased donors 70%. The median time since transplantation to vaccination was 72.3 months (IQR 30.6 -140). Only 10.3% of patients had developed rejection one year prior to vaccination and 3.3% of patients rejected post-vaccination. 146 ptes (60.3%) had triple immunosuppressive maintenance regimen (steroids +calcineurin inhibitors (ICN) + antiproliferatives), 46ptes19.8% (received double regimen without steroids and 12 ptes 5.2% monotherapy with ICN. Vaccination scheme was: Sputnik 33%, Sputnik-AstraZeneca 5.4%, Sputnik-Moderna 19.6%, Sinopharm 6.7%, AstraZeneca 35%. The eGFR (CKD-EPI Cr) in patients who had a positive anti-Spike antibody response was higher than in those with no response: 60 ml/min/1.73 m2 (IQR 41.65 - 78.15) vs 49.4 ml/min/1.73 m2 (IQR 35.60 - 65.40) (p=0.010). Vaccine-related adverse events were observed in 22.3% of patients, 76% were mild. Patients with no response at 28 days had triple immunosuppressive regimen (p < 0.001, RR 0.419 (0.26 -0.66) and lower time post-transplant 55 vs 107 months (p < 0.001). Patients infected with Covid-19 prior to vaccine (13%), had a higher response rate: p <0.0001 RR 2.58 (1.90-3.51). Patients previously infected with Covid-19 and Anti-Spike Ab + at 28 days had a higher response at 90 days. 16% of patients were infected with COVID-19 after vaccination. Conclusion: In our SOT population, a lower generation rate of anti-spike Ab was observed, compared to the reported in the general population. Lower eGFR and the triple IS regimen were associated with a lower response rate. Covid-19 prior to vaccination was associated with a higher antibody response to the vaccine.

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.

The SARS-CoV-2 Omicron variant of concern comprises three sublineages designated BA.1, BA.2, and BA.3, with BA.2 steadily replacing the globally dominant BA.1. We show that the large number of BA.1 and BA.2 spike mutations severely dampen plasma neutralizing activity elicited by infection or seven clinical vaccines, with cross-neutralization of BA.2 being consistently more potent than that of BA.1, independent of the vaccine platform and number of doses. Although mRNA vaccines induced the greatest magnitude of Omicron BA.1 and BA.2 plasma neutralizing activity, administration of a booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1 and BA.2 across all vaccines evaluated. Our data suggest that although BA.1 and BA.2 evade polyclonal neutralizing antibody responses, current vaccine boosting regimens may provide sufficient protection against Omicron-induced disease.

A reduction in extracellular pH (pHe) is a characteristic of most malignant tumors. The aryl hydrocarbon receptor (AhR) is a transcription factor localized in a cytosolic complex with c-Src, which allows it to trigger nongenomic effects through c-Src. Considering that the slightly acidic tumor microenvironment promotes breast cancer progression in a similar way to the AhR/c-Src axis, our aim was to evaluate whether this pathway could be activated by low pHe. We examined the effect of pHe 6.5 on AhR/c-Src axis using two breast cancer cell lines (MDA-MB-231 and LM3) and mammary epithelial cells (NMuMG) and found that acidosis increased c-Src phosphorylation only in tumor cells. Moreover, the presence of AhR inhibitors prevented c-Src activation. Low pHe reduced intracellular pH (pHi), while amiloride treatment, which is known to reduce pHi, induced c-Src phosphorylation through AhR. Analyses were conducted on cell migration and metalloproteases (MMP)-2 and -9 activities, with results showing an acidosis-induced increase in MDA-MB-231 and LM3 cell migration and MMP-9 activity, but no changes in NMuMG cells. Moreover, all these effects were blocked by AhR and c-Src inhibitors. In conclusion, acidosis stimulates the AhR/c-Src axis only in breast cancer cells, increasing cell migration and MMP-9 activity. Although the AhR activation mechanism still remains elusive, a reduction in pHi may be thought to be involved. These findings suggest a critical role for the AhR/c-Src axis in breast tumor progression stimulated by an acidic microenvironment.

Introduction: Given the vulnerability of chronic kidney disease individuals to SARS-CoV-2, nephrol-ogy societies have issued statements calling for prioritization of these patients for vaccination. It is not yet known whether COVID-19 vaccines grant the same high level of protection in patients with kidney disease compared to the non-dialysis population. The aims of this study were to evaluate the safety -measured by the adverse events potentially attributed to vaccines (ESAVI) -and the effectiveness -evaluated by the presence of antibodies -in dialysis patients immunized with the COVID-19 Sputnik V vaccine. Methods: multicenter, ob-servational and analytical study of a prospective cohort of hemodialysis patients from the Ciudad Autonoma de Buenos Aires participating in an official vaccination program. Dialysis requiring individuals older than 18 years, who received both components of the COVID-19 vaccine were included. Results: Data from 491 patients were included in the safety analysis. ESAVI with either the first or second component was detected in 186 (37.9%, 95% CI 33.6%-42.3%). Effectiveness analysis measuring antibodies levels against SARS-CoV-2 were performed in 102 patients; 98% presented these IgG antibodies at day 21 after the second component. In patients with COVID-19 prior to vaccination, antibodies at day 21 after the first component reached almost the highest levels compared to patients without previous COVID-19, but IgG rise among patients with previous COVID-19 was lower than in those without this previous disease. Conclusion: The Sputnik V vaccine has been shown to be safe and effective in this patient's population.