Contrasting Effects of SARS-CoV-2 Vaccination vs. Infection on Antibody and TCR Repertoires (preprint)

Antibodies and helper T cells play important roles in SARS-CoV-2 infection and vaccination. We sequenced B- and T-cell receptor repertoires (BCR/TCR) from the blood of 251 infectees, vaccinees, and controls to investigate whether features of these repertoires could predict subjects' SARS-CoV-2 neutralizing antibody titer (NAbs), as measured by enzyme-linked immunosorbent assay (ELISA). We sequenced recombined immunoglobulin heavy-chain (IGH), TCRbeta (TRB), and TCRdelta (TRD) genes in parallel from all subjects, including select B- and T-cell subsets in most cases, with a focus on their hypervariable CDR3 regions, and correlated this AIRRseq data with demographics and clinical findings from subjects' electronic health records. We found that age affected NAb levels in vaccinees but not infectees. Intriguingly, we found that vaccination, but not infection, has a substantial effect on non-productively recombined IGHs, suggesting a vaccine effect that precedes clonal selection. We found that repertoires' binding capacity to known SARS-CoV-2-specific CD4+ TRBs performs as well as the best hand-tuned fuzzy matching at predicting a protective level of NAbs, while also being more robust to repertoire sample size and not requiring hand-tuning. The overall conclusion from this large, unbiased, clinically well annotated dataset is that B- and T-cell adaptive responses to SARS-CoV-2 infection and vaccination are surprising, subtle, and diffuse. We discuss methodological and statistical challenges faced in attempting to define and quantify such strong-but-diffuse repertoire signatures and present tools and strategies for addressing these challenges.

"Let's Talk About Wellbeing!”: Fostering Interdependence in Doctoral Communities

The Ph.D. genre captures the complexity and plurality of practices generally confronting doctoral scholars, creating challenges and at times contributing to wellbeing concerns. The arrival of COVID-19 has exacerbated such challenges with its associated mandatory self-isolation and other imposed measures, leading to explicit and implicit impact on members of the doctoral community. This autoethnographic study draws upon the collective reflections of a group of researchers as they explored practical ways of fostering and supporting mental health and wellbeing within the doctoral community. Our study highlights three aspects for consideration: (a) a holistic understanding of doctoral wellbeing as key, (b) the interconnection between doctoral scholars' and staff members' well-being, and (c) communities serving as avenues to psychological wellness. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.

SARS-CoV-2 Main Protease Inhibitors: Structure-Based Enhancement to Anti-Viral Pre-Clinical GC376 Encourages Further Development

SARS-CoV-2 Main protease (Mpro) is pivotal in viral replication and transcription. Mpro mediates proteolysis of translated products of replicase genes ORF1a and ORF1ab. Surveying pre-clinical trial Mpro inhibitors suggests potential enhanced efficacy for some moieties. Concordant with promising in vitro and in silico data, the protease inhibitor GC376 was chosen as a lead. Modification of GC376 analogues yielded a series of promising Mpro inhibitors. Design optimization identified compound G59i as lead candidate, displaying a binding energy of −10.54kcal/mol for the complex. Robust interactivity was noted between G59i and Mpro. With commendable ADMET characteristics and enhanced potency, further G59i analysis may be advantageous;moreover, identified key Mpro residues could contribute to the design of neotenic inhibitors. [ FROM AUTHOR]

Pandemic Care Through Collaboration: Lessons From a COVID-19 Field Hospital.

During the surge of Coronavirus Disease 2019 (COVID-19) infections in March and April 2020, many skilled-nursing facilities in the Boston area closed to COVID-19 post-acute admissions because of infection control concerns and staffing shortages. Local government and health care leaders collaborated to establish a 1000-bed field hospital for patients with COVID-19, with 500 respite beds for the undomiciled and 500 post-acute care (PAC) beds within 9 days. The PAC hospital provided care for 394 patients over 7 weeks, from April 10 to June 2, 2020. In this report, we describe our implementation strategy, including organization structure, admissions criteria, and clinical services. Partnership with government, military, and local health care organizations was essential for logistical and medical support. In addition, dynamic workflows necessitated clear communication pathways, clinical operations expertise, and highly adaptable staff.

Identification of a druggable binding pocket in the spike protein reveals a key site for existing drugs potentially capable of combating Covid-19 infectivity.

BACKGROUND: Following the recent outbreak of the new coronavirus pandemic (Covid-19), the rapid determination of the structure of the homo-trimeric spike glycoprotein has prompted the study reported here. The aims were to identify potential "druggable" binding pockets in the protein and, if located, to virtual screen pharmaceutical agents currently in use for predicted affinity to these pockets which might be useful to restrict, reduce, or inhibit the infectivity of the virion. RESULTS: Our analyses of this structure have revealed a key potentially druggable pocket where it might be viable to bind pharmaceutical agents to inhibit its ability to infect human cells. This pocket is found at the inter-chain interface that exists between two domains prior to the virion binding to human Angiotensin Converting Enzyme 2 (ACE2) protein. One of these domains is the highly mobile receptor binding domain, which must move into position to interact with ACE2, which is an essential feature for viral entry to the host cell. Virtual screening with a library of purchasable drug molecules has identified pharmaceuticals currently in use as prescription and over the counter medications that, in silico, readily bind into this pocket. CONCLUSIONS: This study highlights possible drugs already in use as pharmaceuticals that may act as agents to interfere with the movements of the domains within this protein essential for the infectivity processes and hence might slow, or even halt, the infection of host cells by this new coronavirus. As these are existing pharmaceuticals already approved for use in humans, this knowledge could accelerate their roll-out, through repurposing, for affected individuals and help guide the efforts of other researchers in finding effective treatments for the disease.