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Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.
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Anticorpos Neutralizantes , COVID-19 , SARS-CoV-2 , Animais , Cricetinae , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Reações Cruzadas , Evasão da Resposta Imune , Fusão de Membrana , Testes de Neutralização , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Mutação , Células B de Memória/imunologia , Vacinas contra COVID-19/imunologiaRESUMO
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.
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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/genéticaRESUMO
BACKGROUND: Instrumental gait analysis in nephrology is widely neglected, although patients with chronic kidney disease (CKD) show brain changes due to cerebrovascular disease and metabolic disorders that can potentially influence gait quality. Our study assesses the association between CKD stages and gait parameters, to understand the prevalent status of brain related gait parameters (i.e. variability) and of performance related parameters (i.e. gait speed, stride length). We hypothesize that gait changes are detectable already in early stages of CKD. METHODS: Forty-five participants distributed in 5 CKD severity groups underwent an instrumental gait analysis via a triaxial accelerometer affixed to the lower trunk under single- and dual-task conditions. In addition to spatio-temporal parameters, variability and dual-task cost of gait were extracted. A battery of clinical assessments was conducted with the aim of helping to better explain the findings of the gait analysis. A correlation analysis was made to investigate a linear relation between gait parameters and CKD severity. RESULTS: Statistically significant correlations (Pearson correlation coefficient) with CKD severity were found for gait speed (p < 0.01, r = -0.55, 95% CI [-0.73;-0.30]), stride length ( p < 0.01, r = -0.40, 95% CI [-0.62;-0.12]), step length (p < 0.01, r = -0.41, 95% CI [-0.63;-0.13], coefficient of variance (CV) of step length (p = 0.01, r = 0.36, 95% CI [0.08;0.59]), gait regularity (p < 0.01, r = -0.38, 95% CI [-0.61;-0.10]), dual-task cost of gait speed (p < 0.01, r = 0.40, 95% CI [0.13;0.62]) and dual-task cost of stride time (p = 0.03, r = 0.32, 95% CI [0.03;0.57]). Adjustment for age and gender confirmed all results except for gait regularity. With increasing severity of renal failure, Handgrip strength, Time for the Expanded Timed Get Up and Go test, executive functions, haemoglobin, and haematocrit, worsen. CONCLUSIONS: The correlation of CKD severity with spatio-temporal parameters (performance indices mainly relatable to peripheral functionality) and with variability of gait (related to central factors) supported by the results of the clinical assessments, suggests that gait disturbance in CKD patients is not only due to metabolic factors that lead to muscle wasting, but also to brain changes that affect motor control. This suggests that the treatment of renal disease should include cognitive aspects in addition to metabolic and functional factors.
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Disfunção Cognitiva/complicações , Transtornos Neurológicos da Marcha/etiologia , Marcha/fisiologia , Atrofia Muscular/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Análise da Marcha , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: People with Chronic Kidney Disease (CKD) often present with prevalent gait impairment and high fall rates, particularly in advanced CKD stages. Gait impairment and its consequences is associated with increased hospital admission, institutionalization, and greater need for health care. The objective of this systematic review was to evaluate the quality of studies investigating CKD patients' gait characteristics at different CKD stages, to highlight areas of agreement and contradiction between studies reporting aspects of gait in CKD, and to discuss and emphasize gait parameters associated with fall risk. METHODS: We performed a literature search of trials in CINAHL (EBSCO), Cochrane Library, EMBASE, Medline (EBSCO), PEDro, PubMed, and Scopus databases from their inception to June 30th 2018 using a two-stage process for the identification of studies. We retrieved English-, German-, Italian-, Spanish-, Portuguese and Dutch-language articles for review. Methodological quality of randomized and non-randomized studies was assessed with an adapted version of the Downs and Black checklist. RESULTS: Thirty-one studies (22 cross-sectional with 3901 participants) and 9 longitudinal intervention studies (1 randomized control trial, 5 controlled clinical trials and 3 one-group pre-post-test; with 659 participants) were considered. The studies revealed a primary emphasis on gait speed measures within clinical tests, and a neglect of spatiotemporal gait variables. Most of the studies showed that CKD progression is associated with slowing of walking speed. No studies analysed the relation between gait parameters and fall risk. CONCLUSIONS: There was a paucity of studies investigating aspects of gait quality in patients with CKD. In the majority of studies, only gait speed is analysed as a performance indicator. The relation between gait parameters and fall risk in CKD is not investigated. We formulate several recommendations to fill the current research gap, encourage the use of standardized gait analysis protocols that include assessment of spatiotemporal parameters in clinical care of patients with CKD, aimed at prevention of mobility decline and falls risk.
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Acidentes por Quedas , Marcha/fisiologia , Diálise Renal/tendências , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Acidentes por Quedas/prevenção & controle , Ensaios Clínicos como Assunto/métodos , Estudos Transversais , Humanos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicaçõesRESUMO
BACKGROUND: Hyperammonemia usually results from an inborn error of metabolism or from an advanced liver disease. Individual case reports suggest that both distal renal tubular acidosis and urinary tract infection may also result in hyperammonemia. METHODS: A systematic review of the literature on hyperammonemia secondary to distal renal tubular acidosis and urinary tract infection was conducted. RESULTS: We identified 39 reports on distal renal tubular acidosis or urinary tract infections in association with hyperammonemia published between 1980 and 2017. Hyperammonemia was detected in 13 children with distal renal tubular acidosis and in one adult patient with distal renal tubular acidosis secondary to primary hyperparathyroidism. In these patients a negative relationship was observed between circulating ammonia and bicarbonate levels (P < 0.05). In 31 patients (19 children, 12 adults), an acute urinary tract infection was complicated by acute hyperammonemia and symptoms and signs of acute neuronal dysfunction, such as an altered level of consciousness, convulsions and asterixis, often associated with signs of brain edema, such as anorexia and vomiting. Urea-splitting bacteria were isolated in 28 of the 31 cases. The urinary tract was anatomically or functionally abnormal in 30 of these patients. CONCLUSIONS: This study reveals that both altered distal renal tubular acidification and urinary tract infection may be associated with relevant hyperammonemia in both children and adults.
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Acidose Tubular Renal/complicações , Hiperamonemia/etiologia , Infecções Urinárias/complicações , Feminino , Humanos , Masculino , Sistema Urinário/fisiopatologiaRESUMO
BACKGROUND: Reducing unnecessary laboratory blood testing in the hospital setting represents a challenge to improve the adequacy of healthcare and a tricky task for teaching hospitals. Our hospital network actively participates in the Choosing Wisely Campaign and is engaged in avoiding unnecessary low value interventions and investigations. We aimed to study whether a multi-level approach combining educational and web-system based interventions, could be effective in reducing laboratory testing and related costs. METHODS: Multicenter, proof of concept, prospective, observational, before and after study, in a network of public hospitals in Switzerland. All patients admitted between 1 January 2015 and 31 December 2017 were analyzed. A multi-level strategy based on online continuous monitor benchmarking and educational support was applied in the internal medicine services. The primary outcome was a significant reduction in the number of laboratory tests per patient and per day during the hospital stay. Secondary outcomes were reduction in the blood sample volume taken per patient and per day in laboratory costs. RESULTS: Over the 36 months of the study, 33 309 admissions were analyzed. A significant reduction of laboratory tests per patient and per day of hospitalisation was found:-11%, P-value<0.001; -6%, P-value <0.001. The mean monthly blood volume, per patient and per day of hospital stay and laboratory costs per patient was also significantly reduced: -7%, P-value<0.05; -3%, P-value<0.01, and -17%, P-value<0.01, respectively. CONCLUSIONS: The obtained reduction in the number of laboratory tests, blood volume withdrawn and related costs, support the idea that an open web-based system, involving all health care providers, coupled with educational interventions, can be helpful in generating awareness of prescriber habits and to catalyze changes in their behaviour. The peer pressure related to the unmasked benchmarking process did probably play a determinant role.
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Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.
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Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.
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To assess how many adults remember their own birth weight, an important anamnestic item for cardiovascular and renal disease risk stratification, we conducted an inquiry among all employees of public hospitals of Ente Ospedaliero Cantonale (EOC) in Ticino region (Southern Switzerland). The results show that the vast majority of adults remember their own birth weight. Hence, it is reasonable to include this information in the stratification of risk for cardiovascular and renal diseases.
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Introduction: Physical exercise showed to be beneficial for frail older adults on haemodialysis (HD). However, there are several obstacles hindering the regular practice of exercise, such as transportation difficulties, lack of time, fatigue and comorbidities. E-health in this regard has many potential advantages and could be useful for motivating HD patients to increase their level of physical activity. The aim of this study was to evaluate the feasibility of a blended e-health intervention for elderly HD patients who individually exercise at home while under remote supervision of a physiotherapist. Material and methods: Patients over 60 years of age with sufficient cognitive and motoric resources to perform a simple physical test battery and to use a tablet-computer were recruited from four HD outpatient facilities. Following baseline assessment at home, the participants were visited by a physiotherapist (PT). The PT set an individual exercise programme and explained how to use the web-based interface. During the 12 weeks of training, the PTs remotely supervised the patients' progress. At 12 weeks follow-up a second assessment took place. Results: Twenty-two patients were recruited to participate in the study. Seven patients dropped out of the blended programme and 15 patients concluded the programme. The average training frequency of the 15 participants concluding the study was 1.5 times a week [range 0.2-5.8]. The duration of a training session was between 20 and 40â min. The usability of the system was deemed positive. Regarding the efficacy of the intervention, no significant improvement of any measured parameter was found, and effect sizes were small to medium. Conclusion: A blended e-health intervention supported by a web-based application for exercising at home under remote supervision of a PT is feasible in a HD population including older patients. However, before planning a randomized controlled trial, strategies to increase the recruitment rate and the adherence to such a blended intervention should be further developed, e.g., to improve the recruitment procedures and lower the expectable drop-out rate. Furthermore, the dosage of the blended programme should be adapted to the patients' physical performance levels in future trials.The study was registered on the website clinicaltrials.gov with ID NCT04076488.
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BACKGROUND: Patients with end-stage renal disease are known to be particularly frail, and the cause is still widely seen as being directly related to specific factors in renal replacement therapy. However, a closer examination of the transitional phase from predialysis to long-term hemodialysis leads to controversial explanations, considering that the frailty process is already well-described in the early stages of renal insufficiency. This study aims to describe longitudinally and multifactorially changes in the period extending from the decision to start the replacement therapy through to the end of 2 years of hemodialysis. We hypothesized that frailty is pre-existent in the predialysis phase and does not worsen with the beginning of the replacement therapy. Between 2015 and 2018 we recruited 25 patients (72.3 ± 5.7 years old) in a predialysis program, with the expectation that replacement therapy would begin within the coming few months. METHODS: The patients underwent a baseline visit before starting hemodialysis, with 4 follow-up visits in the first 2 years of treatment. Health status, physical performance, cognitive functioning, hematology parameters, and adverse events were monitored during the study period. RESULTS: At baseline, our sample had a high variability with patients ranging from extremely frail to very fit. In the 14 participants that did not drop out of the study, out of 32 clinical and functional measures, a statistically significant worsening was only observed in the Short Physical Performance Battery (SPPB) score (p < 0.01, F = 8.50) and the number of comorbidities (p = 0.01, F = 3.94). A careful analysis, however, reveals a quite stable situation in the first year of replacement therapy, for both frail and fit participants and a deterioration in the second year that in frail participants could lead to death. CONCLUSION: Our results should stimulate a reassessment about the role of a predialysis program in reducing complications during the transitional phase, but also about frailty prevention programs once hemodialysis has begun, for both frail and fit patients, to maintain satisfactory health status.
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Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month timeframe. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both pre- and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sub-lineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly-reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.
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Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.
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Anticorpos Neutralizantes/imunologia , Testes de Neutralização , Diálise Renal , SARS-CoV-2/imunologia , Vacinação , Animais , Anticorpos Neutralizantes/sangue , Afinidade de Anticorpos , Células CHO , Vacinas contra COVID-19/imunologia , Estudos de Casos e Controles , Cricetulus , Relação Dose-Resposta Imunológica , Seguimentos , Células HEK293 , Humanos , Imunoglobulina G/sangue , Fatores de Risco , Vacinas de mRNA/imunologiaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Formação de Anticorpos , COVID-19 , Evasão da Resposta Imune , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Testes de Neutralização , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Memória Imunológica , Células B de Memória/imunologiaRESUMO
SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.
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Background: The frailty status of hemodialysis patients is well-known, but the role of the therapy in the frailty process is not yet clear. Nowadays gait analysis in nephrology is neglected, although gait performance is known to be related to frailty and kidney function. We hypothesized that gait quality and physical activity level is already affected before, and does not change because of the start of hemodialysis. Methods: Fourteen patients (72.3 ± 5.7 years old) in a pre-dialysis program underwent an instrumental gait analysis and their physical activity was monitored for a week. This protocol was repeated 3, 6, 12, and 24 months after the first hemodialysis session. Results: At baseline, our sample showed a conservative gait with pathologic gait variability, high dual-task cost, and a sedentary lifestyle. No statistically significant change was found in any parameter in the analyzed period, but there was a tendency toward an improvement of gait quality and physical activity in the first year of treatment, and a decline in the second year. Conclusion: Elderly patients in the pre-dialysis stage show a conservative gait, however variability was in a pathological range and did not change post-hemodialysis. This hints toward changes in the central nervous system due to the kidney disease. This finding suggests the importance of gait analysis in the early stages of renal disease in the diagnosis of changes in the nervous system due to kidney failure that affect gait. Early detection of these changes would potentially allow a prevention program tailored to this population to be developed.
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BACKGROUND: Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population. METHODS: Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions. FINDINGS: Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9-16.5)) compared to other hospital areas at medium (10.7% (7.6-14.6)) or low risk exposure (7.3% (6.4-8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91-2.22), P = 0.119, and 1.98 (1.55-2.53), P<0.001 for high vs. low wards risk exposure. The same was for true for doctors and nurses (10.1% (9.0-11.3)) compared to other employees at medium (7.1% (4.8-10.0)) or low risk exposure (6.6% (5.0-8.4)). OR for high vs. medium profession risk exposure was 1.37 (0.89-2.11), P = 0.149, and 1.75 (1.28-2.40), P = 0.001 for high vs. low profession risk exposure. Moreover, seropositivity was higher among HCWs who had household exposure to COVID-19 cases compared to those without (18.7% (15.3-22.5) vs. 7.7% (6.9-8.6), OR 2.80 (2.14-3.67), P<0.001). INTERPRETATION: SARS-CoV-2 antibodies are detectable in up to 10% of HCWs from acute care hospitals in a region with high incidence of COVID-19 in the weeks preceding the study. HCWs with exposure to COVID-19 patients have only a slightly higher absolute risk of seropositivity compared to those without, suggesting that the use of PPE and other measures aiming at reducing nosocomial viral transmission are effective. Household contact with known COVID-19 cases represents the highest risk of seropositivity. FUNDING: Henry Krenter Foundation, Ente Ospedaliero Cantonale and Vir Biotechnology.
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The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.
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Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Betacoronavirus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/imunologia , Internalização do Vírus , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/isolamento & purificação , Convalescença , Cricetinae , Reações Cruzadas , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Células Jurkat , Pulmão/imunologia , Fusão de Membrana/imunologia , Testes de Neutralização , Mapeamento de Peptídeos , Conformação Proteica em alfa-Hélice , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Carga Viral/imunologiaRESUMO
The 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 mAb 1 , retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab 2 , S2X259 3 and S2H97 4 , 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.
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Recent data demonstrate that patients affected with hypokalemic salt-losing tubulopathies are prone to acute cardiac arrhythmias and rhabdomyolysis. The tendency to these potentially fatal complications is especially high if chronic hypokalemia is severe, in patients with diarrhea, vomiting or a prolonged QT interval on standard electrocardiography, in patients on drug management with compounds prolonging the electrocardiographic QT interval (including antiarrhythmic agents, some antihistamines, macrolides, antifungals, psychotropics, beta2-adrenergic agonists or cisapride), following acute alcohol abuse and during exercise. Cardiac arrhythmias and rhabdomyolysis occur with sufficient frequency in hypokalemic salt-losing tubulopathies to merit wider awareness of their presence and the preparation of specific prevention and management recommendations.