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1.
J Infect Dis ; 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36482781

RESUMO

BACKGROUND: Monocyte activation is a driver of inflammation in the course of chronic HIV infection. Prostaglandin E2 (PGE2) is known to mediate anti-inflammatory effects, notably the inhibition of TNF-α production by monocytes. We aim to investigate the effects of PGE2 on the activation of monocytes in the course of chronic HIV infection and the mechanisms through which PGE2 modulates their inflammatory signature. METHODS: We recruited a group of people with HIV (PWH) and matched healthy uninfected persons. Then we compared plasma levels of PGE2, monocyte activation and sensitivity of monocytes to the inhibitory actions mediated by PGE2. RESULTS: We found increased plasma levels of PGE2 in PWH, and an activated phenotype in circulating monocytes, compared with uninfected individuals. Monocytes from PWH showed a significant resistance to the inhibitory actions mediated by PGE2. In fact, the concentration of PGE2 able to inhibit 50% of the production of TNF-α by LPS-stimulated monocytes was 10 times higher in PWH compared with uninfected controls. Furthermore, the expression of phosphodiesterase 4B, a negative regulator of PGE2 activity, was significantly increased in monocytes from PWH. CONCLUSION: Resistance to the inhibitory actions mediated by PGE2 could account, at least in part, to the inflammatory profile of circulating monocytes in PWH.

2.
Sci Immunol ; : eadf1421, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36356052

RESUMO

Numerous safe and effective COVID-19 vaccines have been developed worldwide that utilize various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.

3.
Medicina (B Aires) ; 82(5): 631-640, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36220018

RESUMO

INTRODUCTION: Given the vulnerability of chronic kidney disease individuals to SARS-CoV-2, nephrology 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, observational and analytical study of a prospective cohort of hemodialysis patients from the Ciudad Autónoma 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.


Introducción: Dada la vulnerabilidad al SARS-CoV-2 de las personas con enfermedad renal crónica, las sociedades de nefrología han emitido declaraciones pidiendo priorizar a estos pacientes para la vacunación. Aún no se sabe si las vacunas COVID-19 confieren el mismo nivel de protección en pacientes con enfermedad renal. Los objetivos de este estudio fueron evaluar la seguridad, medida por eventos supuestamente atribuidos a las vacunas (ESAVI) y la efectividad, evaluada por la presencia de anticuerpos en pacientes en diálisis inmunizados con la vacuna COVID-19 Sputnik V. Métodos: estudio multicéntrico, observacional y analítico de una cohorte prospectiva de pacientes en hemodiálisis, en la Ciudad Autónoma de Buenos Aires, con plan de vacunación. Se incluyeron pacientes mayores de 18 años en diálisis que recibieron ambos componentes de la vacuna COVID-19. Resultados: 491 pacientes fueron incluidos en el análisis de seguridad. Se detectó ESAVI con el primer o el segundo componente en 186 (37.9% IC 95%: 33.6%-42.3%). La efectividad medida por presencia de anticuerpos IgG contra SARS-Cov-2 se realizó en 102 pacientes, 98% presentaba IgG contra SARS-CoV-2, 21 días después del segundo componente. En pacientes con COVID-19 previo a la vacunación, los anticuerpos al día 21 del primer componente alcanzaron niveles casi mayores que en aquellos que no habían sufrido COVID-19, aunque el aumento de los niveles a los 21 días del segundo componente fue menor que en los pacientes sin COVID-19 previo. Conclusión: Los pacientes en diálisis constituyen una población vulnerable para la infección por SARS-CoV-2, por lo tanto, más allá de las recomendaciones implementadas por las unidades de diálisis, la vacunación completa es mandatoria. Se ha demostrado que la vacuna Sputnik V es segura y eficaz en esta población de pacientes.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Insuficiência Renal Crônica , Eficácia de Vacinas , Humanos , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Imunoglobulina G , Estudos Prospectivos , Diálise Renal , SARS-CoV-2 , Vacinas de Produtos Inativados , Insuficiência Renal Crônica/complicações , Argentina
4.
Medicina (B.Aires) ; 82(5): 631-640, Oct. 2022. graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1405717

RESUMO

Abstract Introduction: Given the vulnerability of chronic kidney disease individuals to SARS-CoV-2, nephrology 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 Autónoma 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.


Resumen Introducción: Dada la vulnerabilidad al SARS-CoV-2 de las personas con enfermedad renal crónica, las sociedades de nefrología han emitido declaraciones pidiendo priorizar a estos pacientes para la vacunación. Aún no se sabe si las vacunas COVID-19 confieren el mismo nivel de protección en pacientes con enfermedad renal. Los objetivos de este estudio fueron evaluar la seguridad, medida por eventos supuestamente atribuidos a las vacunas (ESAVI) y la efectividad, evaluada por la presencia de anticuerpos en pacientes en diálisis inmuniza dos con la vacuna COVID-19 Sputnik V. Métodos: estudio multicéntrico, observacional y analítico de una cohorte prospectiva de pacientes en hemodiálisis, en la Ciudad Autónoma de Buenos Aires, con plan de vacunación. Se incluyeron pacientes mayores de 18 años en diálisis que recibieron ambos componentes de la vacuna COVID-19. Resultados: 491 pacientes fueron incluidos en el análisis de seguridad. Se detectó ESAVI con el primer o el segundo componente en 186 (37.9% IC 95%: 33.6%-42.3%). La efectividad medida por presencia de anticuerpos IgG contra SARS-Cov-2 se realizó en 102 pacientes, 98% presentaba IgG contra SARS-CoV-2, 21 días después del segundo componente. En pacientes con COVID-19 previo a la vacunación, los anticuerpos al día 21 del primer componente alcanzaron niveles casi mayores que en aquellos que no habían sufrido COVID-19, aunque el aumento de los niveles a los 21 días del segundo componente fue menor que en los pacientes sin COVID-19 previo. Conclusión: Los pacientes en diálisis constituyen una población vulnerable para la infección por SARS-CoV-2, por lo tanto, más allá de las recomendaciones implementadas por las unidades de diálisis, la vacunación completa es mandatoria. Se ha demostrado que la vacuna Sputnik V es segura y eficaz en esta población de pacientes.

5.
Cell Rep Med ; 3(8): 100706, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35926505

RESUMO

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.


Assuntos
COVID-19 , Vacinas Virais , Vacina de mRNA-1273 contra 2019-nCoV , Anticorpos Antivirais , COVID-19/prevenção & controle , Humanos , Imunização , RNA Mensageiro/genética , SARS-CoV-2 , Vacinação
6.
EBioMedicine ; 83: 104230, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35988465

RESUMO

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).


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Formação de Anticorpos , Vacina BNT162 , Criança , Estudos de Coortes , Humanos , Imunoglobulina G
7.
Science ; 377(6608): 890-894, 2022 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-35857529

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Imunização Secundária , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
9.
J Infect Dis ; 226(10): 1717-1720, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-35723970

RESUMO

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is usually asymptomatic or mild and appears to be poorly immunogenic at least in unvaccinated individuals. Here, we found that health care workers vaccinated with 2 doses of Sputnik V and a booster dose of ChAdOx1 mount a vigorous neutralizing-antibody response after Omicron breakthrough infection.


Assuntos
Formação de Anticorpos , COVID-19 , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinação , Anticorpos Neutralizantes , Anticorpos Antivirais
10.
Front Immunol ; 13: 831844, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720394

RESUMO

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.


Assuntos
Neutrófilos , Fator de Necrose Tumoral alfa , Humanos , Interleucina-8/farmacologia , Lipopolissacarídeos/farmacologia , Neutrófilos/patologia , Cloreto de Sódio/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
11.
Front Cell Infect Microbiol ; 12: 893044, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663467

RESUMO

Severe COVID-19 in children is rare, but the reasons underlying are unclear. Profound alterations in T cell responses have been well characterized in the course of adult severe COVID-19, but little is known about the T cell function in children with COVID-19. Here, we made three major observations in a cohort of symptomatic children with acute COVID-19: 1) a reduced frequency of circulating FoxP3+ regulatory T cells, 2) the prevalence of a TH17 polarizing microenvironment characterized by high plasma levels of IL-6, IL-23, and IL17A, and an increased frequency of CD4+ T cells expressing ROR-γt, the master regulator of TH17 development, and 3) high plasma levels of ATP together with an increased expression of the P2X7 receptor. Moreover, that plasma levels of ATP displayed an inverse correlation with the frequency of regulatory T cells but a positive correlation with the frequency of CD4+ T cells positive for the expression of ROR-γt. Collectively, our data indicate an imbalance in CD4+ T cell profiles during pediatric COVID-19 that might favor the course of inflammatory processes. This finding also suggests a possible role for the extracellular ATP in the acquisition of an inflammatory signature by the T cell compartment offering a novel understanding of the involved mechanisms.


Assuntos
COVID-19 , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Trifosfato de Adenosina/metabolismo , Adulto , Linfócitos T CD4-Positivos/metabolismo , Criança , Humanos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores , Células Th17
12.
J Cell Biochem ; 123(7): 1197-1206, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35538691

RESUMO

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.


Assuntos
Acidose , Neoplasias da Mama , Neoplasias da Mama/metabolismo , Proteína Tirosina Quinase CSK , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Microambiente Tumoral
13.
bioRxiv ; 2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35313570

RESUMO

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.

16.
Lancet Reg Health Am ; 9: 100196, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35128512

RESUMO

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.

18.
Br J Haematol ; 197(3): 283-292, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35076084

RESUMO

Severe COVID-19 is associated with a systemic inflammatory response and progressive CD4+ T-cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4+ T-cell dysfunction in COVID-19. We observed a high frequency of CD4+ T cell-platelet aggregates in COVID-19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID-19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)-α production by CD4+ T cells. In addition, interferon (IFN)-γ production was increased by platelets from HD but not from COVID-19 inpatients. A high expression of PD-L1 was found in platelets from COVID-19 patients to be inversely correlated with IFN-γ production by activated CD4+ T cells cocultured with platelets. We also found that a PD-L1-blocking antibody significantly restored platelets' ability to stimulate IFN-γ production by CD4+ T cells. Our study suggests that platelets might contribute to disease progression in COVID-19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+ T cells functionality.


Assuntos
Antígeno B7-H1 , COVID-19 , Antígeno B7-H1/metabolismo , Plaquetas/metabolismo , Linfócitos T CD4-Positivos , Humanos , Interferon gama
19.
Antibodies (Basel) ; 11(1)2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35076465

RESUMO

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.

20.
Nature ; 602(7898): 664-670, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35016195

RESUMO

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Deriva e Deslocamento Antigênicos/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Testes de Neutralização , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Deriva e Deslocamento Antigênicos/genética , Vacinas contra COVID-19/imunologia , Linhagem Celular , Convalescença , Epitopos de Linfócito B/imunologia , Humanos , Evasão da Resposta Imune , Camundongos , SARS-CoV-2/química , SARS-CoV-2/classificação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Vesiculovirus/genética
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