SeroNet Pooling Project of immunocompromised populations

Introduction: COVID-19 vaccination substantially reduces morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe illness. However, despite effective COVID-19 vaccines many questions remain about the efficacy of vaccines and the durability and robustness of immune responses, especially in immunocompromised persons. The NCI-funded Serological Sciences Network (SeroNet) is a coordinated effort including 11 sites to advance research on the immune response to SARS-CoV-2 infection and COVID-19 vaccination among diverse and vulnerable populations. The goals of the Pooling Project are: (1) to conduct real-world data (RWD) analyses using electronic medical records (EMR) data from four health care systems (Kaiser Permanente Northern California, Northwell Health, Veterans Affairs-Case Western, and Cedars-Sinai) to determine vaccine effectiveness in (a) cancer patients;(b) autoimmune diseases and (c) solid organ transplant recipients (SOTR);(2) to conduct meta-analyses of prospective cohort studies from eight SeroNet institutions (Cedars-Sinai, Johns Hopkins, Northwell Health, Emory University, University of Minnesota, Mount Sinai, Yale University) to determine post-vaccine immune responses in (a) lung cancer patients;(b) hematologic cancers/hematopoietic stem cell transplant (HSCT) recipients;(c) SOTR;(d) lupus. Method(s): For our RWD analyses, data is extracted from EMR using standardized algorithms using ICD-10 codes to identify immunocompromised persons (hematologic and solid organ malignancy;SOTR;autoimmune disease, including inflammatory bowel disease, rheumatoid arthritis, and SLE). We use common case definitions to extract data on demographic, laboratory values, clinical co morbidity, COVID-19 vaccination, SARS-CoV-2 infection and severe COVID-19, and diseasespecific variables. In addition, we pool individual-level data from prospective cohorts enrolling patients with cancer and other immunosuppressed conditions from across network. Surveys and biospecimens from serology and immune profiling are collected at pre-specified timepoints across longitudinal cohorts. Result(s): Currently, we have EMR data extracted from 4 health systems including >715,000 cancer patients, >9,500 SOTR and >180,000 with autoimmune conditions. Prospective cohorts across the network have longitudinal data on >450 patients with lung cancer, >1,200 patients with hematologic malignancies, >400 SOTR and >400 patients with lupus. We will report results examining vaccine effectiveness for prevention of SARS-CoV-2 infection, severe COVID-19 and post-acute sequelae of COVID-19 (PAS-C or long COVID) in cancer patients compared to other immunocompromised conditions. Conclusion(s): Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in immunocompromised populations.

Identifying Similar Questions in the Medical Domain Using a Fine-tuned Siamese-BERT Model

A large number of people search about their health related problems on the web. However, the number of sites with qualified and verified people answering their queries is quite low in comparison to the number of questions being put up. The rate of queries being searched on such sites has further increased due to the COVID-19 pandemic. The main reason people find it difficult to find solutions to their queries is due to ineffective identification of semantically similar questions in the medical domain. For most cases, answers to the queries people ask would be present, the only caveat being the question may be present in a different form than the one asked by the particular user. In this research, we propose a Siamese-based BERT model to detect similar questions using a fine-tuning approach. The network is fine-tuned with medical question-answer pairs and then with question-question pairs to get a better question similarity prediction. © 2022 IEEE.

Severe acute respiratory syndrome coronavirus-2: An era of struggle and discovery leading to the emergency use authorization of treatment and prevention measures based on computational analysis

Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), a novel betacoronavirus, has surprised the world with its disease spread and mortality rate. SARS-CoV-2 is a positive-sense, enveloped RNA virus that can infect various organs of the body, potentially leading to multiple organ dysfunction and eventual death. While various medications have received emergency use authorizations (EUAs) for the treatment of Coronavirus disease-2019 (COVID-19), as of April 30, 2021, only one drug has been Food and Drug Administration (FDA)-approved: remdesivir. Currently, three vaccines have received EUAs in the United States, but none are FDA-approved. This shortage of treatments and prevention measures is extremely problematic. Thus computational approaches would provide important data about drug resistance and variants. Such data will be useful for the development of drugs and vaccines. This chapter is a synopsis of SARS-CoV-2 clinical presentation, COVID-19 symptomology, treatment, prevention mechanisms, and SARS-CoV-2 variants using computational analysis. © 2022 Elsevier Inc. All rights reserved.

A distributed digital twin implementation of a hemodialysis unit aimed at helping prevent the spread of the Omicron COVID-19 variant

In order to monitor and assess the spread of the Omicron variant of COVID-19, we propose a Distributed Digital Twin that virtually mirrors a hemodialysis unit in a hospital in Toronto, Canada. Since the solution involves heterogeneous components, we rely on the IEEE HLA distributed simulation standard. Based on the standard, we use an agent-based/discrete event simulator together with a virtual reality environment in order to provide to the medical staff an immersive experience that incorporates a platform showing predictive analytics during a simulation run. This can help professionals monitor the number of exposed, symptomatic, asymptomatic, recovered, and deceased agents. Agents are modeled using a redesigned version of the susceptible-exposed-infected-recovered (SEIR) model. A contact matrix is generated to help identify those agents that increase the risk of the virus transmission within the unit. © 2022 IEEE.

THE T-CELL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE IS OFTEN DEFICIENT IN ANTIBODY-RESPONDERS, AND AUGMENTED BY ANTI-TNF THERAPY

Background: Vaccination against SARS-CoV-2 is a highly effective strategy to protect against infection, which is predominantly mediated by vaccine-induced antibodies. Postvaccination antibodies are robustly produced by those with inflammatory bowel disease (IBD) even on immune-modifying therapies but are blunted by anti-TNF therapy. In contrast, T-cell response which primarily determines long-term efficacy against disease progression, , is less well understood. We aimed to assess the post-vaccination T-cell response and its relationship to antibody responses in patients with inflammatory bowel disease (IBD) on immunemodifying therapies. Methods: We evaluated IBD patients who completed SARS-CoV-2 vaccination using samples collected at four time points (dose 1, dose 2, 2 weeks after dose 2, 8 weeks after dose 2). T-cell clonal analysis was performed by T-cell Receptor (TCR) immunosequencing. The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets and were compared to antibody responses. Results: Overall, 303 subjects were included (55% female;5% with prior COVID) (Table). 53% received BNT262b (Pfizer), 42% mRNA-1273 (Moderna) and 5% Ad26CoV2 (J&J). The Spike-specific clonal response peaked 2 weeks after completion of the vaccine regimen (3- and 5-fold for breadth and depth, respectively);no changes were seen for non-Spike clones, suggesting vaccine specificity. Reduced T-cell clonal depth was associated with chronologic age, male sex, and immunomodulator treatment, and was preserved by nonanti- TNF biologic therapies;augmented clonal depth was associated with anti-TNF treatment (Figure). TCR depth and breadth were associated with vaccine type;after adjusting for age and gender, Ad26CoV2 (J&J) exhibited weaker metrics than mRNA-1273 (Moderna) (p= 0.01 for each) or BNT262b (Pfizer) (p=0.056 for depth). Antibody and T-cell responses were only modestly correlated;while those with robust humoral responses also had robust TCR clonal expansion, a substantial fraction of patients with high antibody levels had only a minimal T-cell clonal response (Figure). Conclusion: Age, sex and select immunotherapies are associated with the T-cell clonal response to SARS-CoV-2 vaccines, and T-cell responses are low in many patients despite high antibody levels. These factors, as well as differences seen by vaccine type may help guide reimmunization vaccine strategy in immune-impaired populations. Further study of the effects of anti-TNF therapy on vaccine responses are warranted. (Table Presented)

SARS-COV-2 VACCINATION INDUCES A PREDOMINENTLY CLASS II (CYTOKINE EFFECTOR) T CELL RESPONSE, BUT THE CLASS I RESPONSE IS AUGMENTED BY ANTI-TNF THERAPY AND VACCINE TYPE

BACKGROUND: In response to COVID-19 vaccination, cytotoxic and cytokine effector T cell immune responses are elicited in the T-cell compartment, based on recognition of epitopes presented by Class I or Class II MHC molecules, respectively. The levels of these distinct T-cell responses may have significant implications for immunization strategies and risk assessment. Knowledge of these two responses after vaccination is still largely unknown, especially in the context of immunomodulatory treatment regimens. METHODS: We performed T-cell receptor (TCR) immunosequencing (Adaptive Biotechnologies, Seattle WA) of IBD patients (N=303) and health care worker controls (HCW, N=224) at up to four time points (prior to dose 1, prior to dose 2, 2 weeks after dose 2, 8 weeks after dose 2). Two metrics of TCR response, breadth (# of unique antigen-specific sequences) and depth (expansion of antigen-specific sequences), were calculated for all sequences and Class I- and Class II-specific sequences, and compared to demographics, IBD treatment, and vaccine type. Subjects with exceptional Class I or Class II responses were calculated as significant residuals relative to the Class I vs. Class II regression line. Similar associations were observed for both breadth and depth: breadth is presented here for brevity. RESULTS: Both Class I- and Class II-specific T-cell responses peaked 2 weeks after dose 2, and significantly correlated with lower age, female gender, and mRNA vaccine type (mRNA-1273/Moderna and BNT262b/Pfizer, versus vector vaccine AD26CoV2/J&J) (FIGURE). Class II responses comprised ~85% of detected TCR response in both IBD and HCW subjects. Among IBD patients, there was a significant elevation of the class I response with anti-TNF treatment (p=0.04). This effect was most pronounced at later timepoints, suggesting that anti-TNF permitted a more persistent Class I-specific response. Among patients with exceptionally high or low Class I TCR response, there were significant differences in TCR metrics across vaccine types (p=0.0035). 21% of AD26CoV2 patients were highly Class I-biased (Zscore>1, 9.4% and 7.3% for BNT162 and mRNA-1273, respectively), and this was correlated with lower anti-spike serology 2 and 8 weeks after vaccination (p<1E-10). Conversely, mRNA- 1273 patients were Class I-deficient, representing 25.3% of patients but 44.1% of highly Class I-deficient patients (Zscore<1, 0% for AD26CoV2). CONCLUSION: The T-cell clonal response to SARS-CoV-2 vaccine is Class II-predominant, but the Class I-response is augmented by anti-TNF therapy and vector vaccine type. These factors may help guide reimmunization vaccine strategy in immune-impaired populations, and warrant further study of the effects of anti-TNF therapies on vaccine efficacy.(Figure Presented)Figure: TCR response time course (left);effect of anti-TNF (middle);effect of vaccine type (right). Breadth was predominantly Class II for most patients, with maximum response at 2 weeks after full vaccination (left). The balance of Class I vs. Class II response was significantly biased towards Class I at 8 weeks after full vaccination for patients receiving anti-TNF treatment for IBD (asterisk, p=0.036). Patients receiving AD26CoV2 vaccines were significantly increased in Class I responses, while patients receiving mRNA-1273 vaccines were significantly reduced for Class I responses (t-tests: p=0.0036 at 8 weeks [asterisk], p=0.051 at 2 weeks).

POST-VACCINATION SYMPTOMS AFTER A THIRD DOSE OF SARS-COV-2 MRNA VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Background:Symptoms after SARS-CoV-2 primary vaccination among patients with inflammatory bowel disease (IBD) are generally similar to the general population,although symptoms after the second dose are more frequent and severe than after the first dose.Postvaccination symptoms after a 3rd mRNA vaccine dose in the predominantly immune-compromised IBD population is unknown.Methods:Adults with IBD participating in the prospective Coronavirus Risk Associations and Longitudinal Evaluation in IBD (CORALE-IBD) vaccine registry who received a 3rd mRNA vaccine dose were asked to complete a detailed symptom survey 1 week after vaccination.Symptoms were assessed across 11 organ systems,and graded as mild,moderate,or severe,or requiring hospitalization.“Severe+” referred to those with severe symptoms or who required hospitalization.We stratified by age (<or> 50 years) given prior distinct symptom profiles after dose 2 (D2).We also evaluated whether severe+ symptoms after D2 predicted severe+ symptoms after dose 3 (D3).Results:We included 524 participants (70% female, mean age 45 years) who received a 3rd mRNA vaccine through October 11, 2021.Most had Crohn's disease (71%), and 89% were on biologic therapies.Most (58%) had received primary vaccination with BNT562b2,and only 3.5% reported prior COVID infection at the time of initial vaccination.Overall, 97% of subjects received a 3rd dose with the same mRNA vaccine as in their initial series with the remainder receiving the other mRNA vaccine type.No participants received a 3rd dose with the Ad26.CoV.2 (J&J) vaccine. Overall, 41% reported symptoms after a 3rd dose,with symptoms generally more frequent and severe among those <55 years (Table).The most frequent postvaccination symptom was injection site pain (39%).Common systemic symptoms included fatigue/malaise (34%),headache (23%),and muscle, bone or joint symptoms (13%).These were all less frequent after D3 than after D2 (Figure).Gastrointestinal symptoms were reported by 8.8%, which was slightly more frequent than after D2 (7.8%).Among those with postvaccination symptoms, the proportion with severe symptoms after D3 was lower than D2 for fatigue/ malaise, headache, dizziness and lightheadedness, fever/chills, and rheumatologic symptoms, but was slightly higher than D2 for gastrointestinal symptoms.Severe+ symptoms were seen in 17% after D2 and in 14% after D3. Of those with severe+ symptoms after D2, 34% had severe+ symptoms after D3.In contrast, about 22% had severe+ symptoms after D3 but did not report severe+ symptoms after D2.Conclusion:The frequency and severity of symptoms after a 3rd mRNA vaccine dose are generally similar or lower than those after a second dose.Furthermore, prior severe+ symptoms after D2 do not necessarily predict severe+ symptoms after D3. Further evaluation of postvaccination gastrointestinal symptoms in this population is warranted. (Figure Presented) (Table Presented)

PATIENTS WITH INFLAMMATORY BOWEL DISEASE HAVE IMPAIRED HUMORAL BUT PRESERVED CELLULAR RESPONSES TO SARS-COV-2 MRNA VACCINATION

Background: Vaccine-induced protection against SARS-CoV-2 infection is predominantly mediated by humoral immunity;protection against disease progression is primarily determined by cellular immunity. Patients with inflammatory bowel disease (IBD) have high rates of post-vaccination anti-Spike IgG [IgG(S)] seroconversion, but postvaccination immune responses relative to non-IBD controls have not been well described. We aimed to assess post-vaccination humoral (antibody) and cellular (T-cell) responses in IBD relative to healthcare worker (HCW) controls. Methods: We evaluated IBD patients enrolled in a US registry referred from 26 centers at 2, 8, and 16 weeks after completing 2 doses of SARSCoV- 2 mRNA vaccination and compared results to non-IBD non-immunosuppressed HCW participating in a parallel study. We analyzed plasma antibodies to the receptor binding domain of the viral spike protein using the SARS-CoV-2 IgG-II assay (Abbott Labs, Abbott Park, IL);IgG(S) > 50 AU/mL was defined as positive. Those with prior COVID were excluded. We also performed T-cell clonal analysis by T-cell receptor (TCR) immunosequencing at 8 weeks (Adaptive Biotechnologies, Seattle, WA). The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets. Analyses were adjusted for age, sex and vaccine type. Results: Overall, 1805 subjects were included (IBD n=1074 (65% Crohn's disease, 35% ulcerative colitis);HCW n=731). Age and sex were similar between both cohorts;Hispanic ethnicity and Asian race were less common among IBD than HCW (Table). Vaccine type included BNT162b2 (Pfizer) (75% of IBD, 98% of HCW) and the remainder mRNA-1274 (Moderna). IBD treatments included anti- TNF (46%), other biologics (33%), other immune suppressing therapy (9%), and no immune suppression (12%). Postvaccination antibody levels were lower among IBD than HCW both before and after adjusting for vaccine type (p<0.0001 each timepoint;Figure). After further restricting the IBD cohort to those on no immune-suppressive therapies, antibodies remained lower in IBD vs HCW at 2w (p=0.008) and 8w (p<0.0001), but not 16w (p=0.07). Among 321 subjects with available whole cell samples at 8 weeks (IBD n=163, HCW =158), Spikespecific TCR responses were similar between IBD and HCW for both clonal breadth and depth in both unadjusted and adjusted analyses;sub-analyses of those on biologics yielded similar results. Conclusion: Patients with IBD have dampened humoral responses, but similar cellular responses, after SARS-CoV-2 mRNA vaccination relative to HCW. These findings suggest a potentially greater risk of infection, but not of disease progression, among those with IBD, and should be considered to help guide booster dosing strategies for the IBD population. (Figure Presented) (Figure Presented) Figure: Post-vaccination immune responses: (A) Antibody responses are lower in IBD relative to non-IBD healthcare workers at 2, 8, and 16 weeks (p<0.0001 at each timepoint). In contrast, post-vaccination Spike-specific T-cell receptor clonal breadth (B1) and clonal depth (B2) at 8 weeks are similar in IBD compared to healthcare workers.

No Fear Nor Grief: Employing Islamic Wisdom to Address Contemporary Spiritual Challenges

Muslim chaplains face a plethora of challenges. Notably, two directly focused on the chaplain are: (1) attuning to and triaging the spiritual and emotional needs of Muslims they are serving and, then, (2) accompanying them on their spiritual journey. These challenges are amplified even more during the COVID-19 pandemic when people are turning to spirituality for coping. In addition, communities that are disproportionately burdened by disease morbidity and mortality, as one study of Black Americans showed. This paper seeks to critically examine the difference between Islamic spiritual gnosis and spiritual bypassing. For chaplains, this differentiation is essential to provide effective and meaningful Islamic pastoral care because it helps the client to powerfully leverage sacred beliefs and regulate while trying to navigate challenging experiences rather than glossing over or avoiding dealing with these challenges. I believe a potential solution to both is found in humility.

A Distributed Simulation Approach to Integrate AnyLogic and Unity for Virtual Reality Applications: Case of COVID-19 Modelling and Training in a Dialysis Unit

Different heterogeneous simulation components can be integrated to produce a more effective complex global system. The IEEE High-Level Architecture (HLA) is an international standard that promotes interoperability and reusability for distributed simulation (DS). This paper proposes a DS system that integrates an agent-based and discrete-event simulator with a 3D game engine to build virtual reality (VR) applications that replicate real environments. In this case study, AnyLogic is used as an agent-based and discrete event simulator to simulate the process flow and COVID-19 transmission inside the University Health Network dialysis unit, Toronto, Canada. Unity game engine delivers the 3D modelling replicating the real architecture and environment of the dialysis unit. The HLA standard plays a major role in the integration of AnyLogic and Unity to produce a more effective and powerful DS system for VR applications. © 2021 IEEE.

Health-related quality of life, vaccine uptake and immune response among cancer patients undergoing treatment during the COVID-19 pandemic

Background: Cancer patients are at increased risk of severe COVID-19 illness because of their systemic immunosuppressive state. The potential effects of cancer and/or anticancer treatments on COVID-19 vaccine response, adverse events and progression are unknown. Moreover, the impacts of financial, familial and societal stressors during the pandemic on health-related quality of life are unclear. To address these concerns, we report data from the ongoing U.S. NCI-funded SeroNet COVID-19 Risk Associations and Longitudinal Evaluation Study (CORALE) at a large health care system in Los Angeles. Methods: Cancer patients are invited to complete questionnaires, donate blood specimens and engage in long-term follow-up with repeat questionnaires and biosampling. Patient-reported outcomes are assessed at baseline, post-vaccination, 6, 12 and 24 months. Clinical information on cancer type, stage, treatment, dates, medications and outcomes (adverse events, SARS-CoV-2 infection, COVID-19 vaccination and cancer-related outcomes) are extracted from electronic medical records. Results: From December 2019-May 2020, we enrolled 317 patients with malignancies or hematologic disorders (70.0% response rate). The median age was 63 (interquartile range (IQR)=54-73) years, 47% were women, 30% self-identified as non-White minorities and 18% were unable to work due to health status. 3% were known to been infected with SARS-CoV-2. An overall COVID-19 vaccine acceptance rate of 80% was reported. Among unvaccinated patients, women expressed more hesitancy than men (p=0.045). Concerns about adverse events (56%), rushed vaccine development (44%), and insufficient knowledge (44%) were reported. Self-reported symptoms after the first dose included injection site pain (21%) and fatigue (11%). We observed low levels of depression and high emotional support. Enrollment is ongoing. Conclusions: Individuals with cancer are a complex and extremely diverse population with a multitude of considerations for both immediate clinical care and long-term survivorship. Updated results including findings on antibody response to vaccination across cancer types/treatment protocols will be presented. Legal entity responsible for the study: Cedars-Sinai Medical Center. Funding: U.S. National Cancer Institute. Disclosure: All authors have declared no conflicts of interest.