A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have been used as antiviral therapeutics; however, these therapeutics have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs) and in deployment by the need for high doses. In this study, we leveraged the multi-specific, multi-affinity antibody (Multabody, MB) platform, derived from the human apoferritin protomer, to enable the multimerization of antibody fragments. MBs were shown to be highly potent, neutralizing SARS-CoV-2 at lower concentrations than their corresponding mAb counterparts. In mice infected with SARS-CoV-2, a tri-specific MB targeting three regions within the SARS-CoV-2 receptor binding domain was protective at a 30-fold lower dose than a cocktail of the corresponding mAbs. Furthermore, we showed in vitro that mono-specific MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding mAbs lose their ability to neutralize potently, and that tri-specific MBs expanded the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.

The future of work in shaping the employment inclusion of young adults with disabilities: a qualitative study

PurposeThe world of work is changing and creating challenges and opportunities for the employment inclusion of young people with disabilities. In this article, the perceptions held by young adults with disabilities regarding participation in the future of work are examined.Design/methodology/approachOne-on-one interviews were conducted with Canadian young adults (ages 18–36 years) living with a disability. Participants were asked about their thoughts regarding the impact of the changing nature of work on their labor market involvement and career aspirations. A thematic analysis was performed to identify and examine emergent salient themes.FindingsIn total, 22 young adults were interviewed;over half held secure employment. Career aspirations and work-related decisions were primarily shaped by a participant's health needs. The future of work was seen as a more proximal determinant to employment. Digital technologies were expected to impact working conditions and create barriers and facilitators to employment. Participants who indicated being securely employed held positive expectations regarding the impact of digital technology on their work. Participants working precariously held negative appraisals regarding the impact of digital technologies on employment opportunities. The role of technological and soft skills was critical to participating in a labor market reliant on advanced technology. Participants reported barriers to developing job skills related to their disability and their work arrangements.Originality/valueThis research highlights the importance of considering changes in the future of work, especially the digital transformation of the economy, in the design of initiatives which promote the employment inclusion of young adults with disabilities. Despite the significance of the changing nature of work, supporting health needs and encouraging access to secure work arrangements also remain paramount.

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses.

Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses

Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a SARS-CoV-2 subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor binding domain (RBD) to antigen presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant. Graphical Kassardjian et al. engineer and characterize a modular vaccine scaffold for the delivery of antigen to MHC class II on antigen-presenting cells. This protein vaccine induces broad sarbecovirus neutralizing antibody responses and protects from SARS-CoV-2 viral challenge independently of adjuvant co-administration.

Inclusion of young people with disabilities in the future of work: forecasting workplace, labour market and community-based strategies through an online and accessible Delphi survey protocol.

INTRODUCTION: The future of work is expected to transform the nature of work, create unique employment barriers for young people living with disabilities and disrupt pathways to better health. We present a Delphi survey protocol through which we aim to obtain future-oriented strategies that can improve the accessibility and inclusion of young people with disabilities in the future of work. METHODS AND ANALYSIS: The Delphi survey will be conducted primarily online, over two rounds and in a format that is accessible to people living with disabilities. A diverse sample of subject matter experts (eg, policy makers, employment service providers, labour market experts) and participants with lived experience of a disability will be recruited using a purposive sampling strategy. All participants will be asked to complete both rounds of the Delphi survey. In the first round, open-ended questions will be asked about workplace, community-based or policy supports that can foster the inclusion of young people with disabilities in the labour market and that can also address specific future of work trends which span sociopolitical, economic, environmental and technological domains. In the second round of the survey, we will aim to build consensus; participants will be provided with a summary of specific strategies that correspond to the different future of work trends emerging from round one and will be asked to rank-order strategies according to their importance. Following the completion of the second round, consensus-based and future-focused recommendations will be generated that can support young people with disabilities in the world of work over the coming decades. ETHICS AND DISSEMINATION: The study protocol has been cleared by the University of Toronto's research ethics board (#40727). The study will identify future-focused support strategies that will be shared with people living with disabilities, policy makers and disability employment service providers through an integrated knowledge transfer and exchange approach.

Precarious work among personal support workers in the Greater Toronto Area: a respondent-driven sampling study.

BACKGROUND: The COVID-19 pandemic has highlighted the role of personal support workers (PSWs) in health care, as well as their work conditions. Our study aimed to understand the characteristics of the PSW workforce, their work conditions and their job security, as well as to explore the health of PSWs and the impact of precarious employment on their health. METHODS: Our community-based participatory action research focused on PSWs in the Greater Toronto Area. We administered an online, cross-sectional survey between June and December 2020 using respondent-driven sampling. Data on sociodemographics, employment precarity, worker empowerment and health status were collected. We assessed the association between precarious employment and health using multivariable logistic regression models. RESULTS: We contacted 739 PSWs, and 664 consented to participate. Overall, 658 (99.1%) completed at least part of the survey. Using data adjusted for our sampling approach, the participants were predominantly Black (76.5%, 95% confidence interval [CI] 68.2%-84.9%), women (90.1%, 95% CI 85.1%-95.1%) and born outside of Canada (97.4%, 95% CI 94.9%-99.9%). Most worked in home care (43.9%, 95% CI 35.2%-52.5%) or long-term care (34.5%, 95% CI 27.4%-42.0%). Although most participants had at least some postsecondary education (unadjusted proportion = 83.4%, n = 529), more than half were considered low income (55.1%, 95% CI 46.3%-63.9%). Most participants were precariously employed (86.5%, 95% CI 80.7%-92.4%) and lacked paid sick days (89.5%, 95% CI 85.8%-93.3%) or extended health benefits (74.1%, 95% CI 66.8%-81.4%). Nearly half of the participants described their health as less than very good (46.7%, 95% CI 37.9%-55.5%). Employment precarity was significantly associated with higher risk of depression (odds ratio 1.02, 95% CI 1.01-1.03). INTERPRETATION: Despite being key members of health care teams, most PSWs were precariously employed with low wages that keep them in poverty; the poor work conditions they faced could be detrimental to their physical and mental health. Equitable strategies are needed to provide decent work conditions for PSWs and to improve their health.

The working conditions for personal support workers in the Greater Toronto Area during the COVID-19 pandemic: a mixed-methods study.

OBJECTIVE: During the height of the COVID-19 pandemic, personal support workers (PSWs) were heralded as healthcare 'heroes' as many of them cared for high-risk, vulnerable older populations, and worked in long-term care, which experienced a high number of COVID-19 outbreaks and deaths. While essential to the healthcare workforce, there is little understanding of PSW working conditions during the pandemic. The aim of our study was to examine the working conditions (including job security, work policies, and personal experiences) for PSWs in the Greater Toronto Area during the COVID-19 pandemic from the perspectives of PSWs. METHODS: This study used a mixed-methods design. From June to December 2020, we conducted a survey of 634 PSWs to understand their working conditions during the COVID-19 pandemic. Semi-structured interviews with 31 survey respondents were conducted from February to May 2021 to understand in greater depth how working conditions were impacting the well-being of PSWs. RESULTS: We found PSWs faced a range of challenges related to COVID-19, including anxiety about contracting COVID-19, reduced work hours, taking leaves of absences, concerns about job security, and losing childcare. While the COVID-19 pandemic highlighted the PSW workforce and their importance to the healthcare system (especially in the long-term care system), pre-existing poor work conditions of insecure jobs with no paid sick days and benefits exacerbated COVID-19-related challenges. Despite these hardships, PSWs were able to rely on their mental resilience and passion for their profession to cope with challenges. CONCLUSION: Significant changes need to be made to improve PSW working conditions. Better compensation, increased job security, decreased workload burden, and mental health supports are needed.

RéSUMé: OBJECTIF: Au plus fort de la pandémie de COVID-19, les préposés aux bénéficiaires (PAB) étaient salués comme les « héros ¼ des soins de santé, car beaucoup s'occupaient de populations vulnérables et âgées à risque élevé et travaillaient dans le milieu des soins de longue durée, qui était aux prises avec un grand nombre d'éclosions de COVID-19 et de décès. Malgré l'importance névralgique des PAB dans la main-d'œuvre des soins de santé, leurs conditions de travail durant la pandémie sont peu connues. Nous avons cherché à examiner les conditions de travail (sécurité d'emploi, régimes de travail et expériences personnelles) des PAB dans la région du Grand Toronto durant la pandémie de COVID-19 selon la perspective de ces PAB. MéTHODE: Nous avons utilisé un plan d'étude à méthodes mixtes. De juin à décembre 2020, nous avons sondé 634 PAB pour connaître leurs conditions de travail durant la pandémie de COVID-19. Des entretiens semi-directifs ont été menés auprès de 31 répondants et répondantes entre les mois de février et de mai 2021 pour approfondir notre compréhension de l'impact des conditions de travail des PAB sur leur bien-être. RéSULTATS: Nous avons constaté que les PAB ont connu de nombreuses difficultés en lien avec la COVID-19, dont l'anxiété à l'idée de transmettre la COVID-19, les heures de travail réduites, la prise de congés, les craintes pour leur sécurité d'emploi et la perte de services de garde. Bien que la pandémie de COVID-19 ait braqué les projecteurs sur les PAB et leur importance pour le système de soins de santé (surtout dans le système de soins de longue durée), leurs mauvaises conditions de travail préexistantes ­ des emplois précaires sans congés de maladie payés ni avantages sociaux ­ ont exacerbé les problèmes posés par la COVID-19. Malgré ces épreuves, les PAB ont pu compter sur leur résilience mentale et leur passion pour la profession pour faire face aux difficultés. CONCLUSION: D'importants changements doivent être apportés pour améliorer les conditions de travail des PAB. De meilleurs salaires, une plus grande sécurité d'emploi, une charge de travail allégée et des mesures d'appui à la santé mentale sont nécessaires.

Impacts of the COVID-19 pandemic on health, financial worries, and perceived organizational support among people living with disabilities in Canada.

BACKGROUND: Individuals with physical or mental health disabilities may be particularly vulnerable to the impact of COVID-19 on their health and employment. OBJECTIVES: We examined COVID-19-related concerns for health, finances, and organizational support among workers with no disability, a physical, mental health, or both physical and mental health disability, and factors associated with COVID-19 perceptions. METHODS: An online, cross-sectional survey was administered to a sample of Canadians in the first wave of the COVID-19 pandemic. Questions asked about COVID-19 perceptions, demographics (gender, age, education), work context (e.g., sector, contract work) and employment conditions (e.g., job stress, control, accommodation needs). Descriptive, multivariable, and nested regression analyses examined factors associated with COVID-19 perceptions. RESULTS: A total of 3066 participants completed the survey. Workers with both a physical and mental health disability reported significantly greater health and financial concerns and less organizational support than those with no disability. Workers with a physical disability reported more health concerns and those with a mental health disability reported more financial concerns and less organizational support. Respondents with disabilities also reported significant differences in employment conditions (e.g., more contract work, stress, unmet accommodation needs) than those with no disability. Employment conditions were consistently significant predictors of COVID-19 perceptions and attenuated the significance of disability type in analyses. CONCLUSIONS: Concerns about the impact of COVID-19 on one's health, finances, and organizational support reflected existing disability inequities in employment conditions and highlight the importance of creating more inclusive employment opportunities for people living with physical and mental health disabilities.

Impact of the COVID-19 Pandemic on the Employment of Canadian Young Adults With Rheumatic Disease: Findings From a Longitudinal Survey.

OBJECTIVE: The COVID-19 pandemic has had considerable economic repercussions for young workers. The current study was undertaken to examine the impact of the pandemic on the employment of young adults with rheumatic disease and on perceptions of work and health. METHODS: Surveys were administered to young adults with rheumatic disease prior to and following the onset of the COVID-19 pandemic. Surveys asked about employment status and collected information on sociodemographic, disease/health, and work-context factors. Items also asked about the perceived impact of the COVID-19 pandemic on work and health. A generalized estimating equation model was fitted to examine the effect of the pandemic on employment. RESULTS: In total, 133 young adults completed the pre-COVID-19 pandemic survey (mean age 28.9 years, 82% women). When compared to the pre-COVID-19 pandemic period, employment decreased from 86% to 71% following the pandemic, but no other changes were identified in sociodemographic, disease/health, or work-context factors. The time period following the COVID-19 pandemic was associated with a 72% lower odds of employment compared to the pre-pandemic period (odds ratio 0.28 [95% confidence interval 0.11-0.71]). Those with a postsecondary education or who reported more mental job demands were more likely to be employed following the onset of the pandemic. Also, a majority of participants reported that the pandemic affected health care (83%), treatment access (54%), working conditions (92%), and occupational health and safety (74%). CONCLUSION: The onset of the COVID-19 pandemic had socioeconomic implications for young people with rheumatic disease. To support economic recovery for individuals with rheumatic disease, strategies to promote employment should be designed that account for the young adult life phase and occupational characteristics.