RESUMEN
The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.
Asunto(s)
Antígenos Virales/inmunología , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , COVID-19/virología , Cricetinae , Mapeo Epitopo , Variación Genética , Modelos Moleculares , Mutación/genética , Pruebas de Neutralización , Dominios Proteicos , ARN Viral/genética , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/ultraestructuraRESUMEN
SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.
Asunto(s)
COVID-19/inmunología , Aptitud Genética , Evasión Inmune , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Enzima Convertidora de Angiotensina 2/química , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/virología , Humanos , Mutación , Filogenia , SARS-CoV-2/química , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/química , VirulenciaRESUMEN
Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Mapeo Epitopo/métodos , Glicoproteína de la Espiga del Coronavirus/inmunología , Enzima Convertidora de Angiotensina 2 , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Reacciones Antígeno-Anticuerpo , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Betacoronavirus/metabolismo , Sitios de Unión , COVID-19 , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Epítopos/química , Epítopos/inmunología , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Cinética , Simulación de Dinámica Molecular , Pandemias , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/patología , Neumonía Viral/virología , Unión Proteica , Dominios Proteicos/inmunología , Estructura Cuaternaria de Proteína , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.
Asunto(s)
Anticuerpos Antivirales , Especificidad de Anticuerpos , Virus de la Influenza A , Virus de la Influenza B , Vacunas contra la Influenza , Gripe Humana , Imitación Molecular , Neuraminidasa , Animales , Humanos , Ratones , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Especificidad de Anticuerpos/inmunología , Arginina/química , Dominio Catalítico , Hemaglutininas Virales/inmunología , Virus de la Influenza A/clasificación , Virus de la Influenza A/enzimología , Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/enzimología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Virus de la Influenza B/clasificación , Virus de la Influenza B/enzimología , Virus de la Influenza B/inmunología , Vacunas contra la Influenza/química , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/inmunología , Gripe Humana/prevención & control , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Neuraminidasa/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Estaciones del Año , Ácidos Siálicos/químicaRESUMEN
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.
Asunto(s)
Anticuerpos Neutralizantes , COVID-19 , SARS-CoV-2 , Animales , Cricetinae , Humanos , Ratones , Enzima Convertidora de Angiotensina 2/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Reacciones Cruzadas , Evasión Inmune , Fusión de Membrana , Pruebas de Neutralización , SARS-CoV-2/clasificación , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Mutación , Células B de Memoria/inmunología , Vacunas contra la COVID-19/inmunologíaRESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Deriva y Cambio Antigénico/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Pruebas de Neutralización , SARS-CoV-2/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Deriva y Cambio Antigénico/genética , Vacunas contra la COVID-19/inmunología , Línea Celular , Convalecencia , Epítopos de Linfocito B/inmunología , Humanos , Evasión Inmune , Ratones , SARS-CoV-2/química , SARS-CoV-2/clasificación , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vesiculovirus/genéticaRESUMEN
An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse sarbecoviruses4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
Asunto(s)
Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/virología , Reacciones Cruzadas/inmunología , Evasión Inmune , SARS-CoV-2/clasificación , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anciano , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Afinidad de Anticuerpos , Anticuerpos ampliamente neutralizantes/química , COVID-19/inmunología , Vacunas contra la COVID-19/química , Vacunas contra la COVID-19/inmunología , Línea Celular , Cricetinae , Epítopos de Linfocito B/química , Epítopos de Linfocito B/genética , Epítopos de Linfocito B/inmunología , Femenino , Humanos , Evasión Inmune/genética , Evasión Inmune/inmunología , Masculino , Mesocricetus , Persona de Mediana Edad , Modelos Moleculares , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Vacunología , Tratamiento Farmacológico de COVID-19RESUMEN
The recent emergence of SARS-CoV-2 variants of concern1-10 and the recurrent spillovers of coronaviruses11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2/clasificación , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/química , Anticuerpos Antivirales/química , Anticuerpos Antivirales/uso terapéutico , Anticuerpos ampliamente neutralizantes/química , COVID-19/inmunología , COVID-19/virología , Reacciones Cruzadas/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Evasión Inmune/genética , Evasión Inmune/inmunología , Mesocricetus/inmunología , Mesocricetus/virología , Mutación , Pruebas de Neutralización , SARS-CoV-2/química , SARS-CoV-2/genética , Zoonosis Virales/inmunología , Zoonosis Virales/prevención & control , Zoonosis Virales/virologíaRESUMEN
BACKGROUND & AIMS: Chronic hepatitis B is a global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to treat chronic hepatitis B and chronic hepatitis D. METHODS: HBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting 3 weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase). RESULTS: From a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with higher potency than hepatitis B immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and the increase in intrahepatic HBV RNA and covalently closed circular DNA. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs. CONCLUSIONS: The potently neutralizing anti-HBs mAb VIR-3434 reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D. IMPACT AND IMPLICATIONS: Chronic infection with hepatitis B virus and co-infection with hepatitis D virus place approximately 290 million individuals worldwide at risk of severe liver disease and cancer. Available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D.
RESUMEN
The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mgâ kg-1 , and p < 0.001 at 1 mgâ kg-1 and 10 mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mgâ kg-1 and 3 mgâ kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.
Asunto(s)
Narcolepsia , Orexinas , Vigilia , Animales , Método Doble Ciego , Narcolepsia/tratamiento farmacológico , Orexinas/farmacología , Primates , Somnolencia , Resultado del Tratamiento , Vigilia/efectos de los fármacos , Humanos , MasculinoRESUMEN
BACKGROUND: Early in the COVID-19 pandemic, reports about a possible protective effect of nicotine on COVID-19 conflicted with messaging by public health organizations about increased risks of COVID-19 due to smoking. The ambiguous information the public received, combined with COVID-19-induced anxiety, may have led to changes in tobacco or other nicotine product use. This study examined changes in use of combustible cigarettes (CCs), nargila (hookah/waterpipe), e-cigarettes, and IQOS and home-smoking behaviors. We also assessed COVID-19 related anxiety and perceptions regarding changes in risk of COVID-19 severity due to smoking. METHODS: We used cross-sectional data from a population telephone survey that was conducted in Israel in the early phase of the COVID-19 pandemic (May-June 2020) and included 420 adult (age 18+) individuals who reported having ever used CCs (n = 391), nargila (n = 193), and/or electronic cigarettes (e-cigarettes)/heated tobacco products (e.g., IQOS) (n = 52). Respondents were asked about the effect that COVID-19 had on their nicotine product use (quit/reduced use, no change, increased use). We assessed changes in product use, risk perceptions, and anxiety using adjusted multinomial logistic regression analyses. RESULTS: Most respondents did not change their frequency of product use (CCs: 81.0%, nargila: 88.2%, e-cigarettes/IQOS: 96.8%). A small percentage either decreased use (CCs: 7.2%, nargila: 3.2%, e-cigarettes/IQOS:2.4%) or increased use (CCs:11.8%, nargila:8.6%, e-cigarettes/IQOS:+ 0.9%). 55.6% of respondents used a product in the home prior to COVID-19; but during the first lockdown COVID-19 period, a greater percentage increased (12.6%) than decreased (4.0%) their home use. Higher levels of anxiety due to COVID-19 were associated with increased home smoking (aOR = 1.59, 95% CI:1.04-2.42, p = 0.02). Many respondents believed that increased severity of COVID-19 illness was associated with CCs (62.0%) and e-cigarettes/vaping (45.3%), with uncertainty about the association being lower for CCs (20.5%) than for vaping (41.3%). CONCLUSIONS: While many respondents believed that nicotine product use (particularly CCs and e-cigarettes) was associated with increased risk of COVID-19 disease severity, the majority of users did not change their tobacco/nicotine use. The confusion about the relationship between tobacco use and COVID-19 calls for clear evidence-based messaging from governments. The association between home smoking and increased COVID-19-related stress suggests the need for campaigns and resources to prevent smoking in the home, particularly during times of stress.
Asunto(s)
COVID-19 , Sistemas Electrónicos de Liberación de Nicotina , Productos de Tabaco , Adulto , Humanos , Adolescente , Nicotina/efectos adversos , Autoinforme , Israel/epidemiología , Estudios Transversales , Pandemias , COVID-19/epidemiología , Control de Enfermedades Transmisibles , Ansiedad/epidemiologíaRESUMEN
BACKGROUND: Designing the home environment can promote well-being. Social networks provide learning opportunities to improve health. OBJECTIVE: This study aimed to develop and evaluate a Facebook intervention called Design for Wellness (DWELL). The program was created to improve knowledge, engagement, and self-efficacy in the creation of healthy home environments. METHODS: A randomized controlled trial was conducted to assess the effects of the intervention program DWELL. Content was uploaded to the Facebook group and gave the participants practical solutions for how to design their home environment for wellness. The intervention addressed multiple components of health behaviors, such as healthy eating, physical activity, tobacco-free environment, hygiene, family conversations regarding wellness issues, and stress reduction. The main outcome was the participants' overall score on the DWELL index, which we developed to assess the elements of our intervention: knowledge, awareness, engagement, and self-efficacy regarding home design for wellness. The intervention was conducted in Israel and lasted 6 weeks during the third wave of the COVID-19 pandemic. The primary analysis included a multivariable model to assess the DWELL score at the end of the study while controlling for baseline characteristics. The waitlist control group did not receive an intervention between the 2 administrations of the questionnaire. RESULTS: In total, 643 participants began the program: 322 (50.1%) in the intervention group and 321 (49.9%) in the control group. Of the 643 participants, 476 (74%) completed the study. At the end of the study, there was a statistically significant benefit of the intervention as assessed using a one-way analysis of covariance: there was a mean difference of 8.631 (SD 1.408) points in the DWELL score in favor of the intervention group (intervention: mean 61.92, SD 14.30; control: mean 53.29, SD 16.374; P<.001). Qualitative feedback from participants in the intervention group strengthened the positive results as most of them found the group beneficial. The Facebook group was very active. Being more engaged in the group correlated with having a higher DWELL score, but this relationship was weak (r=0.37; P<.001). The mean significant difference of 26.281 (SD 19.24) points between the overall DWELL score and the overall engagement score indicated that participants who were not active in the group still followed the posts and benefited. We found no improvements in the secondary outcome regarding participants' well-being. The COVID-19 lockdown may have prevented this. CONCLUSIONS: DWELL was found to be a beneficial intervention for improving perceptions of the design of home environments to foster wellness. Facebook was an effective platform to deliver this intervention. DWELL may become a prototype for other health promotion interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03736525; https://clinicaltrials.gov/study/NCT03736525?term=DWELL&rank=1.
Asunto(s)
COVID-19 , Medios de Comunicación Sociales , Humanos , Femenino , Ambiente en el Hogar , Pandemias , Autoeficacia , MadresRESUMEN
Designing home environments for health and wellness is a crucial strategy for disease prevention and health promotion. Yet, there is not a tool to evaluate perceptions regarding home design for health and wellness. This study aimed to develop and validate a new instrument to measure people's perceptions regarding the concept of DWELL: Design for WELLness in the home environment. We developed a short 5-item online questionnaire to detect changes in knowledge, awareness, engagement and self-efficacy regarding DWELL. The instrument was validated in an online study. Of the 613 mothers who answered the questionnaire initially, 397 answered the questionnaire a second time. Factor analysis and Cronbach's alpha indicated that all five DWELL questions load into one single factor (the model explained 61.84% of total variance), and measure a reliable scale of the same construct, with high levels of internal consistency (Cronbach's α = 0.85) at both first and second administrations. Spearman correlations between DWELL first and second administrations of the questionnaire indicated moderate-to-high test-retest reliability (0.55-0.70, p < 0.001). DWELL was found to be a valid tool which fills a gap in the public health literature. This measure serves as a free and convenient online instrument to gain insights regarding the effect of modifying environments for disease prevention and health promotion. The tool may be used to assess perceptions in the conditions leading wellness promotion in the home.
Asunto(s)
Promoción de la Salud , Madres , Femenino , Humanos , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Análisis Factorial , PsicometríaRESUMEN
AIMS: TAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071. METHODS: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect. RESULTS: TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition. CONCLUSIONS: PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.
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Electroencefalografía , Receptor Muscarínico M1 , Donepezilo/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Receptor Muscarínico M1/agonistasRESUMEN
The aim of this paper is to overview progress made with respect to the adoption of plain (or standardised) packaging, key challenges faced, evaluative evidence and opportunities for extending this policy. It has been a decade since Australia became the first country to require tobacco products to be sold in plain packaging; after slow initial uptake, 16 countries have now fully implemented this policy. Since 2020, plain packaging laws have become more comprehensive in some countries, expanding coverage beyond traditional tobacco products to include heated tobacco, tobacco accessories (rolling papers) and other nicotine-containing products (e-cigarettes). Laws have also become more innovative: some now ban non-biodegradable filters, include provision for a periodic change of the pack colour or require both plain packaging and health-promoting pack inserts. The tobacco industry has and will continue to use multi-jurisdictional strategies to oppose this policy. Evaluations suggest that plain packaging has improved health outcomes and has not burdened retailers, although research is limited to early policy adopters and important gaps in the literature remain. While the power of packaging as a sales tool has diminished in markets with plain packaging, tobacco companies have exploited loopholes to continue to promote their products and have increasingly focused on filter innovations. Opportunities exist for governments to strengthen plain packaging laws.
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Sistemas Electrónicos de Liberación de Nicotina , Industria del Tabaco , Productos de Tabaco , Humanos , Embalaje de Productos , NicotianaRESUMEN
Outcomes from studies assessing exposure often use multiple measurements. In previous work, using a model first proposed by Buonoccorsi (1991), we showed that combining direct (eg, biomarkers) and indirect (eg, self-report) measurements provides a more accurate picture of true exposure than estimates obtained when using a single type of measurement. In this article, we propose a tool for efficient design of studies that include both direct and indirect measurements of a relevant outcome. Based on data from a pilot or preliminary study, the tool, which is available online as a shiny app at https://michalbitan.shinyapps.io/shinyApp/, can be used to compute: (1) the sample size required for a statistical power analysis, while optimizing the percent of participants who should provide direct measures of exposure (biomarkers) in addition to the indirect (self-report) measures provided by all participants; (2) the ideal number of replicates; and (3) the allocation of resources to intervention and control arms. In addition we show how to examine the sensitivity of results to underlying assumptions. We illustrate our analysis using studies of tobacco smoke exposure and nutrition. In these examples, a near-optimal allocation of the resources can be found even if the assumptions are not precise.
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Proyectos de Investigación , Humanos , Tamaño de la MuestraRESUMEN
AIMS: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069). METHODS: Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]). RESULTS: TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide. CONCLUSION: The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.
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Epigénesis Genética , Lisina , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , MasculinoRESUMEN
Smoking cessation medications (SCMs) are an evidence-based cornerstone of comprehensive tobacco control programs globally. However, the impact of SCMs on population smoking prevalence is controversial, with inconsistencies between randomized controlled trials (RCTs) and population-based observational studies. We estimated SCM impact on permanent cessation and population smoking prevalence by extrapolating efficacy estimates from meta-analyses of RCTs, using the standard population impact formula: efficacy*reach. We calculated the potential SCM impact under a range of assumptions for permanent cessation (20%,14%), behavioral support (yes/no), reach (40%-2%), and underlying smoking prevalence. Assuming behavioral support for all, depending on reach, 8%-0.3% of smokers are expected to quit permanently. Without behavioral support, permanent cessation is estimated to be 6.4%-0.2%. Assuming an underlying population smoking prevalence of 14%, (current U.S. prevalence), the maximum impact on population smoking prevalence is 1.12%. Impact on prevalence increases with increasing underlying country-specific levels of prevalence. With current U.S. levels of reach, behavioral support and smoking prevalence, we estimate that, based on a single course of treatment, 2.3% of smokers would quit permanently, contributing to a 0.3% decrease in population level smoking prevalence. Even under ideal conditions, the potential of current first-line SCMs to increase cessation in a substantial proportion of smokers, and reduce population smoking prevalence, is limited. In order to avert the predicted billion tobacco-caused deaths in this century, "safe and effective" medications are not sufficient: SCMs with high population impact are urgently needed. Policies to ensure the availability and accessibility of highly efficacious SCMs, with behavioral support, are crucial.
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Cese del Hábito de Fumar , Humanos , Fumadores , Fumar , Prevención del Hábito de Fumar , Dispositivos para Dejar de Fumar TabacoRESUMEN
INTRODUCTION: Young children are vulnerable to harm from tobacco smoke exposure (TSE). This study assessed the effect of Project Zero Exposure-an intervention program designed to help parents protect children from TSE-on children's exposure. METHODS: Randomized controlled trial of a home-based, theory-driven intervention. Parents of young children (<8 y) in families with a smoking parent were eligible. The intervention included feedback on child TSE (hair nicotine), and home air quality (PM2.5), with motivational interviewing. Families were randomized to: intervention group (IG, N = 69), regular control group (RCG, N = 70), or to a secondary enhanced control group, (ECG, N = 20). Child hair samples were taken at baseline and follow-up. We report on child TSE in the IG versus RCG at six months. RESULTS: Most enrolled families completed the trial (IG: 98.6%[68/69], RCG: 97.1%[68/70]). Log hair nicotine (LHN [ng/mg]) decreased in both the IG (Baseline: -1.78 ± 1.91, Follow-up: -2.82 ± 1.87, p = .003) and RCG (Baseline: -1.79 ± 1.54, Follow-up: -2.85 ± 1.73, p = .002), but did not differ between groups at study end (p = .635). Three of five parentally-reported outcomes showed improvement over time in the IG, and one in the RCG. Among IG participants, 90% found hair nicotine feedback useful. CONCLUSIONS: No difference between the intervention and control groups was found on the objective biomarker, LHN. Child TSE decreased during the trial in intervention and control groups. Trial participation, which included hair nicotine monitoring, may have contributed to decreasing exposure in both groups. Concurrent control group improvements may partially explain lack of proven intervention benefit. Biomarker monitoring warrants further investigation for reduction of child TSE. IMPLICATIONS: Project Zero Exposure is an intervention program designed to help parents protect their children from TSE. Results from the randomized controlled trial of the program showed no difference between groups at study end, but a clear and substantial reduction in child exposure to tobacco smoke from beginning to end of the trial, in both intervention and control groups. Biomarker monitoring, a key element of the trial, was used with all participants. Biomarker monitoring of child exposure to tobacco smoke may help parents become aware of their child's exposure and better protect them, and should be explored as a means to reduce child TSE. Clinical Trial Registration: NCT02867241.