Prior vaccination enhances immune responses during SARS-CoV-2 breakthrough infection with early activation of memory T cells followed by production of potent neutralizing antibodies (preprint)

SARS-CoV-2 infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened Spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific CD4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production, and primary responses to non-Spike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection.

How to Prepare for the Next Pandemic -- Investigation of Correlation Between Food Prices and COVID-19 From Global and Local Perspectives (preprint)

The coronavirus disease (COVID-19) has caused enormous disruptions to not only the United States, but also the global economy. Due to the pandemic, issues in the supply chain and concerns about food shortage drove up the food prices. According to the U.S. Bureau of Labor Statistics, the prices for food increased 4.1% and 3.7% over the year ended in August 2020 and August 2021, respectively, while the amount of annual increase in the food prices prior to the COVID-19 pandemic is less than 2.0%. Previous studies show that such kinds of exogenous disasters, including the 2011 Tohoku Earthquake, 9/11 terrorist attacks, and major infectious diseases, and the resulted unusual food prices often led to subsequent changes in people's consumption behaviors. We hypothesize that the COVID-19 pandemic causes food price changes and the price changes alter people's grocery shopping behaviors as well. To thoroughly explore this, we formulate our analysis from two different perspectives, by collecting data both globally, from China, Japan, United Kingdom, and United States, and locally, from different groups of people inside the US. In particular, we analyze the trends between food prices and COVID-19 as well as between food prices and spending, aiming to find out their correlations and the lessons for preparing the next pandemic.

Rapid Clinical Screening and Staging for COVID-19 Severe Outcome - A Hospitalization Study in New York City (preprint)

Background: We aimed to evaluate the risk factors for Coronavirus disease 2019 (COVID-19) related severe outcome (in-hospital death) among the hospitalized patients in New York State (NYS) and proposed a method that could be used to inform future work to develop clinical algorithms and predict resource needs for hospitalized COVID-19 patients. Methods: We analyzed covid-19 related hospitalization in NYS from April 1st to November 17th, 2020, using Statewide Planning and Research Cooperative System (SPARCS) discharge dataset. Logistic regression was performed to evaluate the risk factors for COVID-19 related in-hospital death using demographic variables, symptom, rapid clinical examination, and medical history of chronic co-morbid conditions. Receiver operating characteristic (ROC) curve was calculated, and cut-off points for predictors were selected to stage the risk of COVID-19 related fatal outcome. Results: Logistic regression analysis showed age was the greatest risk factor for COVID-19 related fatal outcome among the hospitalized patients, which by itself achieved the diagnostic accuracy of 0.78 represented by the area under the ROC curve. By adding other demographic variables, dyspnea or hypoxemia and multiple chronic co-morbid conditions, the diagnostic accuracy was improved to 0.85. We selected cut-off points for predictors and provided a general recommendation to categorize the levels of risk for COVID-19 related fatal outcome. Conclusions: We assessed risk factors associated with in-hospital COVID-19 mortality and identified cut-off points that might be used to categorize the level of risk. Further studies are warranted to evaluate laboratory tests and develop laboratory biomarkers to improve the diagnostic accuracy for early intervention.

Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19 (preprint)

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon in vitro stimulation. Correlating clinical features to the ability of plasma from COVID-19 patients to stimulate control platelets identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the Fc{gamma}RIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions, thus identifying these potentially actionable pathways as central for platelet activation and/or vascular complications in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect. These studies have implications for the role of platelet hyperactivation in complications associated with SARS-CoV-2 infection.

Student-Led Curricular Approaches in Medical Education: The Value-Added Effects of a Virtual Fundamentals of COVID-19 Course (preprint)

Background As the field of education was adapting to virtual learning during the COVID-19 pandemic, a need quickly emerged for a course to prepare medical students for future clinical practice. This call to action was answered by creating an innovative Fundamentals of COVID-19 course at the Indiana University School of Medicine (IUSM). As a group of medical student leaders at IUSM, we developed this online course in order to support our fellow students and the community. The course was implemented in May 2020 and enrolled a total of 724 third- and fourth-year medical students. Subsequently, we carried out a research study about this student-led curricular approach and its implications for medical education. Methods The study examined the value-added educational effects of completing the Fundamentals of COVID-19 course. In order to examine these effects, the study asked enrolled students to complete both a pre- and post-course self-assessment survey. Students were asked an identical set of questions on each survey about their knowledge (7), skills (5), and abilities (5) (KSA) regarding COVID-19. Composite scores were created for each KSA learning domain. Responses were provided using a five-point Likert scale ranging from 1 = strongly disagree to 5 = strongly agree. Results Out of the 724 students enrolled, 645 students completed both the pre- and post-course assessment surveys. Findings show that there were both meaningful and statistically significant differences in students’ responses to the pre- and post-course surveys. Results show 1.) a significant mean increase in the knowledge composite score of 1.01, 95% CI [0.95, 1.06], t(644) = 36.4 , p <.001, d = 1.43; 2.) a significant mean increase in the skills composite score of .55, 95% CI [0.50, 0.60], t(644) = 20.70, p <.001, d = 0.81. and 3.) a significant mean increase of the abilities composite score of 1.02, 95% CI [.97, 1.07], t(644) = 36.56, p <.001, d = 1.44. Conclusions These findings demonstrate that the student-developed, online Fundamentals of COVID-19 course resulted in value-added educational effects. Overall, this study provides evidence to support virtually delivered, student-led curricular approaches in medical education. 

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the COVID-19 pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 204 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 252 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that [~]23% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically these hCoV cross-reactive antibodies were boosted upon SARS-CoV-2 infection.

Deep Immune Profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19 (preprint)

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions (preprint)

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of [~]200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.