European soybean to benefit people and the environment.

Europe imports large amounts of soybean that are predominantly used for livestock feed, mainly sourced from Brazil, USA and Argentina. In addition, the demand for GM-free soybean for human consumption is project to increase. Soybean has higher protein quality and digestibility than other legumes, along with high concentrations of isoflavones, phytosterols and minerals that enhance the nutritional value as a human food ingredient. Here, we examine the potential to increase soybean production across Europe for livestock feed and direct human consumption, and review possible effects on the environment and human health. Simulations and field data indicate rainfed soybean yields of 3.1 ± 1.2 t ha-1 from southern UK through to southern Europe (compared to a 3.5 t ha-1 average from North America). Drought-prone southern regions and cooler northern regions require breeding to incorporate stress-tolerance traits. Literature synthesized in this work evidenced soybean properties important to human nutrition, health, and traits related to food processing compared to alternative protein sources. While acknowledging the uncertainties inherent in any modelling exercise, our findings suggest that further integrating soybean into European agriculture could reduce GHG emissions by 37-291 Mt CO2e year-1 and fertiliser N use by 0.6-1.2 Mt year-1, concurrently improving human health and nutrition.

Clinical outcomes and adverse events of bariatric surgery in adults with severe obesity in Scotland: the SCOTS observational cohort study.

Background: Bariatric surgery is a common procedure worldwide for the treatment of severe obesity and associated comorbid conditions but there is a lack of evidence as to medium-term safety and effectiveness outcomes in a United Kingdom setting. Objective: To establish the clinical outcomes and adverse events of different bariatric surgical procedures, their impact on quality of life and the effect on comorbidities. Design: Prospective observational cohort study. Setting: National Health Service secondary care and private practice in Scotland, United Kingdom. Participants: Adults (age >16 years) undergoing their first bariatric surgery procedure. Main outcome measures: Change in weight, hospital length of stay, readmission and reoperation rate, mortality, diabetes outcomes (HbA1c, medications), quality of life, anxiety, depression. Data sources: Patient-reported outcome measures, hospital records, national electronic health records (Scottish Morbidity Record 01, Scottish Care Information Diabetes, National Records Scotland, Prescription Information System). Results: Between December 2013 and February 2017, 548 eligible patients were approached and 445 participants were enrolled in the study. Of those, 335 had bariatric surgery and 1 withdrew from the study. Mean age was 46.0 (9.2) years, 74.7% were female and the median body mass index was 46.4 (42.4; 52.0) kg/m2. Weight was available for 128 participants at 3 years: mean change was -19.0% (±14.1) from the operation and -24.2% (±12.8) from the start of the preoperative weight-management programme. One hundred and thirty-nine (41.4%) participants were readmitted to hospital in the same or subsequent 35 months post surgery, 18 (5.4% of the operated cohort) had a reoperation or procedure considered to be related to bariatric surgery gastrointestinal complications or revisions. Fewer than five participants (<2%) died during follow-up. HbA1c was available for 93/182 and diabetes medications for 139/182 participants who had type 2 diabetes prior to surgery; HbA1c mean change was -5.72 (±16.71) (p = 0.001) mmol/mol and 65.5% required no diabetes medications (p < 0.001) at 3 years post surgery. Physical quality of life, available for 101/335 participants, improved in the 3 years post surgery, mean change in Rand 12-item Short Form Survey physical component score 8.32 (±8.95) (p < 0.001); however, there was no change in the prevalence of anxiety or depression. Limitations: Due to low numbers of bariatric surgery procedures in Scotland, recruitment was stopped before achieving the intended 2000 participants and follow-up was reduced from 10 years to 3 years. Conclusions: Bariatric surgery is a safe and effective treatment for obesity. Patients in Scotland, UK, appear to be older and have higher body mass than international comparators, which may be due to the small number of procedures performed. Future work: Intervention studies are required to identify the optimal pre- and post surgery pathway to maximise safety and cost-effectiveness. Study registration: This study is registered as ISRCTN47072588. Funding details: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 10/42/02) and is published in full in Health Technology Assessment; Vol. 28, No. 7. See the NIHR Funding and Awards website for further award information.

Bariatric surgery is performed on the stomach and small bowel to help people living with obesity lose weight. Our research study has looked at who is getting bariatric surgery, if they are having problems afterwards, how much weight they lose and if their medical conditions improve. A total of 444 people who were attending bariatric surgery services in Scotland, UK, agreed to take part and 336 had surgery. One hundred and eighty-nine of them completed a questionnaire before their surgery and 85 of them after 3 years, to tell us about how they were feeling physically and mentally. We looked at their computer hospital records to see how long they spent in hospital, any medical problems and changes to diabetes medicines and tests. One in five people taking part did not have surgery after all; they changed their mind or the hospital teams did not think it would be safe or work well for the patient. Those who had surgery lost 19% of their body weight and those with type 2 diabetes needed less or no medication 3 years after the surgery. The effect of physical symptoms on day-to-day activities improved but mental health did not. Compared to other countries, the people taking part were older, heavier and sicker. They spent longer in hospital after surgery and were more likely to be readmitted to hospital. How many appointments they had or what type of health professional they saw before or after surgery did not change these results. We had hoped to have far more people in this study and be able to answer more questions, but not enough people were getting bariatric surgery in Scotland for us to ask them to take part. Further research is needed to find the best ways to care for people living with obesity who would benefit from bariatric surgery.

Risk of Subsequent Respiratory Virus Detection After Primary Virus Detection in a Community Household Study-King County, Washington, 2019-2021.

BACKGROUND: The epidemiology of respiratory viral infections is complex. How infection with one respiratory virus affects risk of subsequent infection with the same or another respiratory virus is not well described. METHODS: From October 2019 to June 2021, enrolled households completed active surveillance for acute respiratory illness (ARI), and participants with ARI self-collected nasal swab specimens; after April 2020, participants with ARI or laboratory-confirmed severe acute respiratory syndrome coronavirus 2 and their household members self-collected nasal swab specimens. Specimens were tested using multiplex reverse-transcription polymerase chain reaction for respiratory viruses. A Cox regression model with a time-dependent covariate examined risk of subsequent detections following a specific primary viral detection. RESULTS: Rhinovirus was the most frequently detected pathogen in study specimens (406 [9.5%]). Among 51 participants with multiple viral detections, rhinovirus to seasonal coronavirus (8 [14.8%]) was the most common viral detection pairing. Relative to no primary detection, there was a 1.03-2.06-fold increase in risk of subsequent virus detection in the 90 days after primary detection; risk varied by primary virus: human parainfluenza virus, rhinovirus, and respiratory syncytial virus were statistically significant. CONCLUSIONS: Primary virus detection was associated with higher risk of subsequent virus detection within the first 90 days after primary detection.

Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern.

While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protection. Moreover, whether anamnestic correlates are conserved across variants of concern (VOC), including the Delta and more distant Omicron VOC, remains unclear. To define the anamnestic correlates of immunity, across VOCs, we deeply profiled the humoral immune response in individuals infected with sequence-confirmed Delta or Omicron VOC after completing the vaccination series. While limited acute N-terminal domain and receptor-binding domain (RBD)-specific immune expansion was observed following breakthrough infection, a significant immunodominant expansion of opsonophagocytic Spike-specific antibody responses focused largely on the conserved S2-domain of SARS-CoV-2 was observed. This S2-specific functional humoral response continued to evolve over 2-3 weeks following Delta or Omicron breakthrough, targeting multiple VOCs and common coronaviruses. Strong responses were observed on the fusion peptide (FP) region and the heptad repeat 1 (HR1) region adjacent to the RBD. Notably, the FP is highly conserved across SARS-related coronaviruses and even non-SARS-related betacoronavirus. Taken together, our results point to a critical role of highly conserved, functional S2-specific responses in the anamnestic antibody response to SARS-CoV-2 infection across VOCs. These humoral responses linked to virus clearance can guide next-generation vaccine-boosting approaches to confer broad protection against future SARS-related coronaviruses. IMPORTANCE The Spike protein of SARS-CoV-2 is the primary target of antibody-based recognition. Selective pressures, be it the adaption to human-to-human transmission or evasion of previously acquired immunity, have spurred the emergence of variants of the virus such as the Delta and Omicron lineages. Therefore, understanding how antibody responses are expanded in breakthrough cases of previously vaccinated individuals can provide insights into key correlates of protection against current and future variants. Here, we show that vaccinated individuals who had documented COVID-19 breakthrough showed anamnestic antibody expansions targeting the conserved S2 subdomain of Spike, particularly within the fusion peptide region. These S2-directed antibodies were highly leveraged for non-neutralizing, phagocytic functions and were similarly expanded independent of the variant. We propose that through deep profiling of anamnestic antibody responses in breakthrough cases, we can identify antigen targets susceptible to novel monoclonal antibody therapy or vaccination-boosting strategies.

The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

BACKGROUND: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. METHODS: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score-composed of factors related to hematopoietic reserve and baseline inflammatory state-was determined prior to lymphodepleting chemotherapy. RESULTS: At lymphodepletion, 63 patients were HTlow (score 0-1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). CONCLUSIONS: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.

Nausea, Vomiting, and Diarrhea Are Common in Community-Acquired Acute Viral Respiratory Illness.

BACKGROUND: Gastrointestinal (GI) symptoms are recognized sequelae of acute respiratory illness (ARI), but their prevalence is not well documented. Our study aim was to assess the incidence of GI symptoms in community ARI cases for persons of all ages and their association with clinical outcomes. METHODS: We collected mid-nasal swabs, clinical, and symptom data from Seattle-area individuals during the 2018-2019 winter season as part of a large-scale prospective community surveillance study. Swabs were tested by polymerase chain reaction (PCR) for 26 respiratory pathogens. Likelihood of GI symptoms given demographic, clinical, and microbiological covariates were analyzed with Fisher's exact, Wilcoxon-rank-sum, and t-tests and multivariable logistic regression. RESULTS: In 3183 ARI episodes, 29.4% had GI symptoms (n = 937). GI symptoms were significantly associated with pathogen detection, illness interfering with daily life, seeking care for the illness, and greater symptom burden (all p < 0.05). Controlling for age, > 3 symptoms, and month, influenza (p < 0.001), human metapneumovirus (p = 0.004), and enterovirus D68 (p = 0.05) were significantly more likely to be associated with GI symptoms than episodes with no pathogen detected. Seasonal coronaviruses (p = 0.005) and rhinovirus (p = 0.04) were significantly less likely to be associated with GI symptoms. CONCLUSION: In this community-surveillance study of ARI, GI symptoms were common and associated with illness severity and respiratory pathogen detection. GI symptoms did not track with known GI tropism, suggesting GI symptoms may be nonspecific rather than pathogen-mediated. Patients presenting with GI and respiratory symptoms should have respiratory virus testing, even if the respiratory symptom is not the primary concern.

The implications of defining obesity as a disease: a report from the Association for the Study of Obesity 2021 annual conference.

Unlike various countries and organisations, including the World Health Organisation and the European Parliament, the United Kingdom does not formally recognise obesity as a disease. This report presents the discussion on the potential impact of defining obesity as a disease on the patient, the healthcare system, the economy, and the wider society. A group of speakers from a wide range of disciplines came together to debate the topic bringing their knowledge and expertise from backgrounds in medicine, psychology, economics, and politics as well as the experience of people living with obesity. The aim of their debate was not to decide whether obesity should be classified as a disease but rather to explore what the implications of doing so would be, what the gaps in the available data are, as well as to provide up-to-date information on the topic from experts in the field. There were four topics where speakers presented their viewpoints, each one including a question-and-answer section for debate. The first one focused on the impact that the recognition of obesity could have on people living with obesity regarding the change in their behaviour, either positive and empowering or more stigmatising. During the second one, the impact of defining obesity as a disease on the National Health Service and the wider economy was discussed. The primary outcome was the need for more robust data as the one available does not represent the actual cost of obesity. The third topic was related to the policy implications regarding treatment provision, focusing on the public's power to influence policy. Finally, the last issue discussed, included the implications of public health actions, highlighting the importance of the government's actions and private stakeholders. The speakers agreed that no matter where they stand on this debate, the goal is common: to provide a healthcare system that supports and protects the patients, strategies that protect the economy and broader society, and policies that reduce stigma and promote health equity. Many questions are left to be answered regarding how these goals can be achieved. However, this discussion has set a good foundation providing evidence that can be used by the public, clinicians, and policymakers to make that happen.

Perspectives in weight control in diabetes - SGLT2 inhibitors and GLP-1-glucagon dual agonism.

Treatment of people with type 2 diabetes mellitus (T2D) and obesity should include glycemic control and sustained weight loss. However, organ protection and/or risk reduction for co-morbidities have also emerged as important goals. Here, we define this combined treatment approach as 'weight loss plus' and describe it as a metabolic concept where prolonged periods of energy consumption is central to outcomes. We suggest there are currently two drug classes - sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1)-glucagon dual agonists - that can facilitate this 'weight loss plus' approach. We describe evidence supporting that both classes address the underlying pathophysiology of T2D and facilitate normalization of metabolism through increased periods with a catabolic type of energy consumption, which effect other organ systems and may facilitate long-term cardio-renal benefits. These benefits have been demonstrated in trials of SGLT2is, and appear, to some degree, to be independent of glycemia and substantial weight loss. The combined effect of caloric restriction and metabolic correction facilitated by SGLT2i and GLP-1-glucagon dual agonists can be conceptualized as mimicking dietary restriction and physical activity, a phenomenon not previously observed with drugs whose benefits predominantly arise from absolute weight loss, and which may be key to achieving a 'weight loss plus' approach to treatment.

Cytotoxic T Cells Targeting Spike Glycoprotein Are Associated with Hybrid Immunity to SARS-CoV-2.

mRNA vaccination of individuals with prior SARS-CoV-2 infection provides superior protection against breakthrough infections with variants of concern compared with vaccination in the absence of prior infection. However, the immune mechanisms by which this hybrid immunity is generated and maintained are unknown. Whereas genetic variation in spike glycoprotein effectively subverts neutralizing Abs, spike-specific T cells are generally maintained against SARS-CoV-2 variants. Thus, we comprehensively profiled human T cell responses against the S1 and S2 domains of spike glycoprotein in a cohort of SARS-CoV-2-naive (n = 13) or -convalescent (n = 17) individuals who received two-dose mRNA vaccine series and were matched by age, sex, and vaccine type. Using flow cytometry, we observed that the overall functional breadth of CD4 T cells and polyfunctional Th1 responses was similar between the two groups. However, polyfunctional cytotoxic CD4 T cell responses against both S1 and S2 domains trended higher among convalescent subjects. Multimodal single-cell RNA sequencing revealed diverse functional programs in spike-specific CD4 and CD8 T cells in both groups. However, convalescent individuals displayed enhanced cytotoxic and antiviral CD8 T cell responses to both S1 and S2 in the absence of cytokine production. Taken together, our data suggest that cytotoxic CD4 and CD8 T cells targeting spike glycoprotein may partially account for hybrid immunity and protection against breakthrough infections with SARS-CoV-2.

Are there inequalities in the attendance and effectiveness of behavioural weight management interventions for adults in the UK? Protocol for an individual participant data (IPD) meta-analysis.

INTRODUCTION: It is important to identify whether behavioural weight management interventions work well across different groups in the population so health inequalities in obesity are not widened. Previous systematic reviews of inequalities in the attendance and effectiveness of behavioural weight management interventions have been limited because few trials report relevant analyses and heterogeneity in the categorisation of inequality characteristics prevents meta-analysis. An individual participant data meta-analysis (IPD-MA) allows us to reanalyse all trials with available data in a uniform way. We aim to conduct an IPD meta-analysis of UK randomised controlled trials to examine whether there are inequalities in the attendance and effectiveness of behavioural weight interventions. METHODS AND ANALYSIS: In a recently published systematic review, we identified 17 UK-based randomised controlled trials of primary care-relevant behavioural interventions, conducted in adults living with overweight or obesity and reporting weight outcomes at baseline and 1-year follow-up. The corresponding author of each trial will be invited to contribute data to the IPD-MA. The outcomes of interest are weight at 12-months and intervention attendance (number of sessions offered vs number of sessions attended). We will primarily consider whether there is an interaction between intervention group and characteristics where inequalities occur, such as by gender/sex, socioeconomic status or age. The IPD-MA will be conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses of IPD guidelines. ETHICS AND DISSEMINATION: No further ethical approval was required as ethical approval for each individual study was obtained by the original trial investigators from appropriate ethics committees. The completed IPD-MA will be disseminated at conferences, in a peer-reviewed journal and contribute to the lead author's PhD thesis. Investigators of each individual study included in the final IPD-MA will be invited to collaborate on any publications that arise from the project.

Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants.

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.

A systematic review of the association of diet quality with the mental health of university students: implications in health education practice.

University students are at risk of experiencing mental health problems during the transition from home to university. This transition can also adversely affect their diet quality. This review aims to examine bidirectional associations from observational studies regarding the influence of diet quality on the mental health of university students, and vice versa. The databases PubMed, CINAHL, EMBASE, PsycINFO, The Cochrane Library and Web of Science were searched using relevant search terms. The searches were last updated on 15 July 2022. Majority of studies (36 out of 45) found that good diet quality of students was associated with better mental health in terms of depression, anxiety, stress and overall general mental well-being. Moreover, majority of studies (19 out of 23) found that stress and anxiety of students were associated with poorer diet quality. The effect sizes observed were generally small-moderate. Healthy diets of students have been associated with better mental health in terms of depression, anxiety, stress or other mental health issues. Stress experienced by university students has been associated with unhealthy diets. There are implications for health education research, as interventions to improve diet quality at the university level could reduce mental health issues; additionally, interventions to support students under stress may lead to healthier dietary habits when living on campuses. Randomized controlled trials and intervention studies are needed to further investigate these implications.

SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines.

Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S as compared with vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity, and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by receptor binding domain-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages.

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.

Can We Deliver Person-Centred Obesity Care Across the Globe?

PURPOSE OF REVIEW: This article discusses what person-centred care is; why it is critically important in providing effective care of a chronic, complex disease like obesity; and what can be learnt from international best practice to inform global implementation. RECENT FINDINGS: There are four key principles to providing person-centred obesity care: providing care that is coordinated, personalised, enabling and delivered with dignity, compassion and respect. The Canadian 5AsT framework provides a co-developed person-centred obesity care approach that addresses complexity and is being tested internationally. Embedding person-centred obesity care across the globe will require a complex system approach to provide a framework for healthcare system redesign, advances in people-driven discovery and advocacy for policy change. Additional training, tools and resources are required to support local implementation, delivery and evaluation. Delivering high-quality, effective person-centred care across the globe will be critical in addressing the current obesity epidemic.

Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2.

Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on details of the experimental assay. Here we systematically assess how ACE2 expression in target cells affects neutralization by antibodies to different spike epitopes in lentivirus pseudovirus neutralization assays. For high ACE2-expressing target cells, receptor binding domain (RBD) antibodies account for nearly all neutralizing activity in polyclonal human sera. But for lower ACE2-expressing target cells, antibodies targeting regions outside the RBD make a larger (although still modest) contribution to serum neutralization. These serum-level results are mirrored for monoclonal antibodies: N-terminal domain (NTD) antibodies and RBD antibodies that do not compete for ACE2 binding incompletely neutralize on high ACE2-expressing target cells, but completely neutralize on cells with lower ACE2 expression. Our results show that ACE2 expression level in the target cells is an important experimental variable, and that high ACE2 expression emphasizes the role of a subset of RBD-directed antibodies.

Receptor-Binding Domain (RBD) Antibodies Contribute More to SARS-CoV-2 Neutralization When Target Cells Express High Levels of ACE2.

Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on the details of the experimental assay. Here, we systematically assess how ACE2 expression in target cells affects neutralization by antibodies to different spike epitopes in lentivirus pseudovirus neutralization assays. For high ACE2-expressing target cells, receptor-binding domain (RBD) antibodies account for nearly all neutralizing activity in polyclonal human sera. However, for lower ACE2-expressing target cells, antibodies targeting regions outside the RBD make a larger (although still modest) contribution to serum neutralization. These serum-level results are mirrored for monoclonal antibodies: N-terminal domain (NTD) antibodies and RBD antibodies that do not compete for ACE2 binding incompletely neutralize on high ACE2-expressing target cells, but completely neutralize on cells with lower ACE2 expression. Our results show that the ACE2 expression level in the target cells is an important experimental variable, and that high ACE2 expression emphasizes the role of a subset of RBD-directed antibodies.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

A multifaceted high-throughput assay for probing antigen-specific antibody-mediated primary monocyte phagocytosis and downstream functions.

Monocytes are highly versatile innate immune cells responsible for pathogen clearance, innate immune coordination, and induction of adaptive immunity. Monocytes can directly and indirectly integrate pathogen-destructive instructions and contribute to disease control via pathogen uptake, presentation, or the release of cytokines. Indirect pathogen-specific instructions are conferred via Fc-receptor signaling and triggered by antibody opsonized material. Given the tremendous variation in polyclonal humoral immunity, defining the specific antibody-responses able to arm monocytes most effectively remains incompletely understood. While monocyte cell line-based assays have been used previously, cell lines may not faithfully recapitulate the full biology of monocytes. Thus, here we describe a multifaceted antigen-specific method for probing antibody-dependent primary monocyte phagocytosis (ADMP) and secondary responses. The assay not only reliably captures phagocytic uptake of immune complexes, but also detects unique changes in surface markers and cytokine secretions profiles, poorly detected by monocytic cell lines. The assay captures divergent polyclonal-monocyte recruiting activity across subjects with varying SARS-CoV-2 disease severity and also revealed biological nuances in Fc-mutant monoclonal antibody activity related to differences in Fc-receptor binding. Thus, the ADMP assay is a flexible assay able to provide key insights into the role of humoral immunity in driving monocyte phenotypic transitions and downstream functions across many diseases.

Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines.

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