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Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-334973


It is becoming increasingly clear that individuals recovered from acute coronavirus disease 2019 (COVID-19) can develop into long-term sequelae (post-acute sequala of SARS-CoV-2 infection, PACS). While antibody response kinetics against viral particles is well studied in natural infection and vaccine, the molecular mechanisms governing disease formation remain elusive. We investigated plasma and saliva samples from COVID-19 and healthy control subjects to understand early immune responses globally after exposure to the virus. Antibody analyses showed robust IgA and IgG responses, neutralizing functions to the SARS-CoV-2, and positive correlations between matched plasma and saliva fluids. Shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of neutrophil-fibrinogen axis, and dysregulated immune and clotting functions. Our study suggests saliva as fluid to monitor serology and immune functions to detect early and chronic signs of disease development. Further delineation of the pathophysiology in saliva may lead to discovery of novel biomarkers and therapeutic targets to patients at risk to develop PASC and chronic conditions.

Preprint in English | EMBASE | ID: ppcovidwho-326837


SARS-CoV-2 infection and COVID-19 vaccines elicit memory T cell responses. Here, we report the development of two new pools of Experimentally-defined T cell epitopes derived from the non-spike Remainder of the SARS-CoV-2 proteome (CD4RE and CD8RE). The combination of T cell responses to these new pools and Spike (S) were used to discriminate four groups of subjects with different SARS-CoV-2 infection and COVID-19 vaccine status: non-infected, non-vaccinated (I-V-);infected and non-vaccinated (I+V-);infected and then vaccinated (I+V+);and non-infected and vaccinated (I-V+). The overall classification accuracy based on 30 subjects/group was 89.2% in the original cohort and 88.5% in a validation cohort of 96 subjects. The T cell classification scheme was applicable to different mRNA vaccines, and different lengths of time post-infection/post-vaccination. T cell responses from breakthrough infections (infected vaccinees, V+I+) were also effectively segregated from the responses of vaccinated subjects using the same classification tool system. When all five groups where combined, for a total of 239 different subjects, the classification scheme performance was 86.6%. We anticipate that a T cell-based immunodiagnostic scheme able to classify subjects based on their vaccination and natural infection history will be an important tool for longitudinal monitoring of vaccination and aid in establishing SARS-CoV-2 correlates of protection.

Preprint in English | MEDLINE | ID: ppcovidwho-326687


The emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy 1-7 . Development of broadly effective coronavirus vaccines that can mitigate these threats is needed 8, 9 . Notably, several recent studies have revealed that vaccination of recovered COVID-19 donors results in enhanced nAb responses compared to SARS-CoV-2 infection or vaccination alone 10-13 . Here, we utilized a targeted donor selection strategy to isolate a large panel of broadly neutralizing antibodies (bnAbs) to sarbecoviruses from two such donors. Many of the bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and a substantial fraction also show notable binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against most SARS-CoV-2 VOCs and many neutralize the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in SARS-CoV-2 infection and vaccination 14-18 . Consistent with targeting of conserved sites, select RBD bnAbs exhibited in vivo protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model. The generation of a large panel of potent bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a molecular basis for effective design of pan-sarbecovirus vaccines.

Preprint in English | MEDLINE | ID: ppcovidwho-326636


Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and, importantly, as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a coronavirus disease 2019 (COVID-19)-convalescent donor that exhibits broad reactivity with human beta-coronaviruses (beta-CoVs). Here, we showed that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem-peptide at 1.6 A resolution and found that the peptide adopted a mainly helical structure. Conserved residues in beta-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 infection and therefore their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on beta-CoV spike proteins for protective antibodies that may facilitate the development of pan-beta-CoV vaccines. SUMMARY: A human mAb isolated from a COVID-19 donor defines a protective cross-neutralizing epitope for pan-beta-CoV vaccine design strategies.

Topics in Antiviral Medicine ; 29(1):269-270, 2021.
Article in English | EMBASE | ID: covidwho-1250626


Background: Closing labs to decrease spread of COVID-19 has impacted research progress. Serial testing could supplement other measures to help provide a safe lab environment. Methods: Lab employees who came to work at an academic laboratory at the University of California San Diego (UCSD) were invited and consented to perform their own anterior nasal swab or have a swab collected by an on-site physician. Nasal swabs were combined into one pool for each work shift. Each pool underwent nucleic acid testing (NAT) via qRT-PCR to detect SARS-CoV-2 RNA (FluxErgy). Results were available within one hour. Positive pools were deconvoluted and tested individually. Cost evaluation of the pooling approach was compared to individual NAT and to institutional guidelines for lab occupancy. Results: From Apr 9 to Oct 26, 2020 (28 weeks), 1,199 nasal swab samples collected from lab workers were batched in 194 pools of median size 7 [95%I: 3-11]. A median of 41 tests per week [95%I: 22-67] were performed in a total of 77 participants (Fig 1). 19 core staff were tested a median 54 times [95%I:13-95]. Of the 194 pools, 7 (3.6%, n=47 samples) were considered positive and required repeat testing of all participant samples in the pool as confirmation. One true positive was identified before work started. That participant was referred to their primary care provider. This early detection prevented a 2-week quarantine of 7 employees. Given ∼$65/hour salary per lab worker, this saved 420 hours of work and ∼$26,600 in wages. Current UCSD guidelines recommend decreasing staffing levels to 25% of pre-COVID-19 occupancy. Regular NAT allowed 100% staffing. Screening of lab technicians with the pooled NAT strategy over 6 months cost $25,740 but permitted 2,430 person-hours of additional work ($132,210 in wages), as compared to the recommended 75% reduction without testing. A similar approach with individual NAT would cost $124,020 (thus $98,280 saved by pooling). Conclusion: Regular pooled NAT for SARS-CoV-2 among lab personnel offers a cost-efficient way to maintain a safe lab environment without a reduction in staffing. This approach could be applied in other settings to help ensure safe work environments.