DR50 DataRelease
Release Date: December 2023
New Studies: 30
Updated Studies: 95
New Studies
| SDY2367: Maternal immune response and placental antibody transfer by trimester of COVID-19 vaccination | ||||||||||
| Status: | New | |||||||||
| Description: | The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. These results provide novel insight into the impact of platform and trimester of vaccination on maternal humoral immune response and transplacental antibody transfer. | |||||||||
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| DOI: | 10.21430/M3GUZCJM05 | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2370: Flow cytometry data for basophil activation tests to investigate the combination of avidin and CD63 activation markers in diagnosing peanut allergy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | Background: Conventional basophil activation tests (BATs) measure basophil activation by the increased expression of CD63. Previously, fluorophore-labeled avidin, a positively-charged molecule, was found to bind to activated basophils, which tend to expose negatively charged granule constituents during degranulation. This study further compares avidin vs. CD63 as basophil activation biomarkers in classifying peanut allergy. Methods: Seventy subjects with either a peanut allergy (N=47), a food allergy other than peanut (N=6), or no food allergy (N=17) were evaluated. We conducted BATs in response to seven peanut extract (PE) concentrations (0.01 to 10,000 ng/mL) and four control conditions (no stimulant, anti-IgE, fMLP (N-formylmethionine-leucyl-phenylalanine), and anti-FcεRI). We measured avidin binding and CD63 expression on basophils with flow cytometry. We evaluated logistic regression and XGBoost models for peanut allergy classification and feature identification. Results: Avidin binding was correlated with CD63 expression. Both markers discriminated between subjects with and without a peanut allergy. Although small by percentage, an avidin+/CD63- cell subset was found in all allergic subjects tested, indicating that the combination of avidin and CD63 could allow a more comprehensive identification of activated basophils. Indeed, we obtained the best classification accuracy (97.8% sensitivity, 96.7% specificity) by combining avidin and CD63 across seven PE doses. Similar accuracy was obtained by combining PE dose of 10,000 ng/mL for avidin and PE doses of 10 and 100 ng/mL for CD63. Conclusions: Avidin and CD63 are reliable BAT activation markers associated with degranulation. Their combination enhances the identification of activated basophils and improves the classification accuracy of peanut allergy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3SQXEQF5M | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 70 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SDY2412: The post-COVID-19 population has a high prevalence of cross-reactive antibodies to spikes from all Orthocoronavirinae genera | ||||||||||
| Status: | New | |||||||||
| Description: | Here, the investigators report that infection with and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces broadly cross-reactive binding antibodies to spikes from a wide range of coronaviruses. | |||||||||
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| DOI: | 10.21430/M3YZAEH2H6 | |||||||||
| Subjects: | 118 | |||||||||
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| Publications: | None | |||||||||
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| SDY2421: Neutralizing antibody responses elicited by SARS-CoV-2 mRNA vaccination wane over time and are boosted by breakthrough infection | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | The waning efficacy of SARS-CoV-2 vaccines, combined with the continued emergence of variants resistant to vaccine-induced immunity, has reignited debate over the need for booster vaccine doses. To address this, we examined the neutralizing antibody response against the spike protein of five major SARS-CoV-2 variants, D614G, Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529), in health care workers (HCWs) vaccinated with SARS-CoV-2 mRNA vaccines. Serum samples were collected before vaccination, 3 weeks after first vaccination, 1 month after second vaccination, and 6 months after second vaccination. Minimal neutralizing antibody titers were detected against Omicron pseudovirus at all four time points, including for most patients who had SARS-CoV-2 breakthrough infections. Neutralizing antibody titers against all other variant spike protein-bearing pseudoviruses declined markedly from 1 to 6 months after the second mRNA vaccine dose, although SARS-CoV-2 infection boosted vaccine responses. In addition, mRNA-1273-vaccinated HCWs exhibited about twofold higher neutralizing antibody titers than BNT162b2-vaccinated HCWs. Together, these results demonstrate possible waning of antibody-mediated protection against SARS-CoV-2 variants that is dependent on prior infection status and the mRNA vaccine received. They also show that the Omicron variant spike protein can almost completely escape from neutralizing antibodies elicited in recipients of only two mRNA vaccine doses. | ||||||||||||||||||
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| DOI: | 10.21430/M3OD3ZIDCF | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2422: Nanoalum Formulations Containing Aluminum Hydroxide and CpG 1018TM Adjuvants: The Effect on Stability and Immunogenicity of a Recombinant SARS-CoV-2 RBD Antigen | ||||||||||
| Status: | New | |||||||||
| Description: | Aluminum-salt vaccine adjuvants (alum) are commercially available as micron-sized particles with varying chemical composition and crystallinity. There are reports of enhanced adjuvanticity when the alum’s particle size is reduced to the nanometer range. Previously, we demonstrated that a recombinant receptor-binding domain (RBD)-based COVID-19 vaccine candidate (RBD-J; RBD-L452K-F490W) formulated with aluminum hydroxide (Alhydrogel®; AH) and CpG 1018™ (CpG) adjuvants induced potent neutralizing antibody responses in mice yet displayed instability during storage. In this work, we evaluated whether sonication of AH to the nanometer size range (nanoAH) could further enhance immunogenicity or improve storage stability of the above formulation. The addition of CpG to nanoAH (at mouse doses), however, caused re-agglomeration of nanoAH. AH-CpG interactions were evaluated by Langmuir binding isotherms and zeta potential measurements, and stabilized nanoAH + CpG formulations of RBD-J were then designed by (1) optimizing CpG:Aluminum dose ratios or (2) adding a small-molecule polyanion (phytic acid, PA). Compared with the micron-sized AH + CpG formulation, the two stabilized nanoAH + CpG formulations of RBD-J demonstrated no enhancement in SARS-CoV-2 pseudovirus neutralizing titers in mice, but the PA-containing nanoAH + CpG formulation showed improved RBD-J storage stability trends (at 4, 25, and 37 °C). The formulation protocols presented herein can be employed to evaluate the potential benefits of the nanoAH + CpG adjuvant combination with other vaccine antigens in different animal models. | |||||||||
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| DOI: | 10.21430/M3VLCRWJ25 | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2424: Pandemic Experience of First Responders | |||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||
| Description: | Semi-structured interviews with 21 first responders during the COVID-19 pandemic, asking about the impact of COVID-19 | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3IV738S6R | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2425: Determinants of Neutralizing Antibody Response After SARS CoV-2 Vaccination in Patients With Myeloma | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | Purpose: Vaccine-induced neutralizing antibodies (nAbs) play a critical role in protection from SARS CoV-2. Patients with B-cell malignancies including myeloma are at increased risk of COVID-19-related mortality and exhibit variable serologic response to the vaccine. The capacity of vaccine-induced antibodies in these patients to neutralize SARS CoV-2 or its variants is not known. Methods: Sera from 238 patients with multiple myeloma (MM) undergoing SARS CoV-2 vaccination were analyzed. Antibodies against the SARS CoV-2 spike receptor-binding domain (RBD) and viral nucleocapsid were measured to detect serologic response to vaccine and environmental exposure to the virus. The capacity of antibodies to neutralize virus was quantified using pseudovirus neutralization assay and live virus neutralization against the initial SARS CoV-2 strain and the B1.617.2 (Delta) variant. Results: Vaccine-induced nAbs are detectable at much lower rates (54%) than estimated in previous seroconversion studies in MM, which did not monitor viral neutralization. In 33% of patients, vaccine-induced antispike RBD antibodies lack detectable neutralizing capacity, including against the B1.617.2 variant. Induction of nAbs is affected by race, disease, and treatment-related factors. Patients receiving mRNA1273 vaccine (Moderna) achieved significantly greater induction of nAbs compared with those receiving BNT162b2 (Pfizer; 67% v 48%, P = .006). Conclusion: These data show that vaccine-induced antibodies in several patients with MM lack detectable virus-neutralizing activity. Vaccine-mediated induction of nAbs is affected by race, disease, vaccine, and treatment characteristics. These data have several implications for the emerging application of booster vaccines in immunocompromised hosts. | |||||||||||||||||||||
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| DOI: | 10.21430/M3L9Y9XKWD | |||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2427: A public vaccine-induced human antibody for SARS-CoV-2 | |||||||
| Status: | New | ||||||
| Description: | 2C08 is a SARS-CoV-2 mRNA vaccine-induced germinal center B cell-derived human monoclonal antibody that binds to the receptor binding motif within the RBD. 2C08 broadly neutralizes SARS-CoV-2 variants with remarkable potency and reduces lung inflammation, viral load, and morbidity in hamsters challenged with either an ancestral SARS- CoV-2 strain or a recent variant of concern. Clonal analysis identified 2C08-like public clonotypes among B cell clones responding to SARS-CoV-2 infection or vaccination in at least 20 out of 78 individuals. Thus, 2C08-like antibodies can be readily induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern. | ||||||
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| DOI: | 10.21430/M37I59XYLX | ||||||
| Subjects: | 40 | ||||||
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| SDY2429: Relationship between Anti-Spike Antibodies and Risk of SARS-CoV-2 Infection in Infants Born to COVID-19 Vaccinated Mothers | ||||||||||
| Status: | New | |||||||||
| Description: | The goal of this study was to investigate the relationship between anti-SARS-CoV-2-Spike IgG titers passively transferred to the fetus from maternal vaccination during pregnancy and timing of infant SARS-CoV-2 infection. Pregnant, vaccinated individuals (n = 105) and their infants (n = 107) were enrolled in a prospective cohort study from July 2021 to June 2022, linking infant anti-Spike IgG titer at birth to risk of SARS-CoV-2 infection in the first fifteen months of life. Cord blood sera were collected at delivery and infant sera were collected at two and six months of age. Anti-SARS-CoV-2-Spike IgG levels were quantified in cord and infant sera using an enzyme-linked immunosorbent assay. Infants were followed for SARS-CoV-2 infection through fifteen months of age. Anti-SARS-CoV-2-Spike IgG titers in infants declined significantly with increased age (p < 0.001). Infants with higher anti-Spike cord blood levels had significantly longer disease-free intervals prior to infection with SARS-CoV-2 (p = 0.027). While higher anti-Spike IgG titer at two months of age was associated with a longer interval to infection through nine months of age (p = 0.073), infant anti-Spike IgG titers by six months of age had no impact on disease-free interval. This cohort study suggests that passively transferred maternal IgG is protective against infant SARS-CoV-2 infection, with higher antibody levels at birth significantly associated with longer disease-free intervals. Infant antibodies and protection from SARS-CoV-2 infection wane significantly after six months, suggesting that vaccination is needed at this stage to optimize protection against COVID-19. | |||||||||
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| DOI: | 10.21430/M3LSI3ZRX3 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2432: Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death1-4. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters5-7 and nonhuman primates8-10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates11-13. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis. | ||||||||||||||||
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| DOI: | 10.21430/M3P4ALD7A6 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| SDY2433: Ad26.COV2.S and SARS-CoV-2 spike protein ferritin nanoparticle vaccine protect against SARS-CoV-2 Omicron BA.5 challenge in macaques | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines demonstrate reduced protection against acquisition of BA.5 subvariant but are still effective against severe disease. However, immune correlates of protection against BA.5 remain unknown. We report the immunogenicity and protective efficacy of vaccine regimens consisting of the vector-based Ad26.COV2.S vaccine and the adjuvanted spike ferritin nanoparticle (SpFN) vaccine against a high-dose, mismatched Omicron BA.5 challenge in macaques. The SpFNx3 and Ad26 + SpFNx2 regimens elicit higher antibody responses than Ad26x3, whereas the Ad26 + SpFNx2 and Ad26x3 regimens induce higher CD8 T cell responses than SpFNx3. The Ad26 + SpFNx2 regimen elicits the highest CD4 T cell responses. All three regimens suppress peak and day 4 viral loads in the respiratory tract, which correlate with both humoral and cellular immune responses. This study demonstrates that both homologous and heterologous regimens involving Ad26.COV2.S and SpFN vaccines provide robust protection against a mismatched BA.5 challenge in macaques. | ||||||||||||
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| DOI: | 10.21430/M31JVFMED5 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2434: Comparative performance of between-population vaccine allocation strategies with applications for emerging pandemics | |||||||
| Status: | New | ||||||
| Description: | Vaccine allocation decisions during emerging pandemics have proven to be challenging due to competing ethical, practical, and political considerations. Complicating decision making, policy makers need to consider vaccine allocation strategies that balance needs both within and between populations. When vaccine stockpiles are limited, doses should be allocated in locations to maximize their impact. Using a susceptible-exposed-infectious-recovered (SEIR) model we examine optimal vaccine allocation decisions across two populations considering the impact of characteristics of the population (e.g., size, underlying immunity, heterogeneous risk structure, interaction), vaccine (e.g., vaccine efficacy), pathogen (e.g., transmissibility), and delivery (e.g., varying speed and timing of rollout). Across a wide range of characteristics considered, we find that vaccine allocation proportional to population size (i.e., pro-rata allocation) performs either better or comparably to nonproportional allocation strategies in minimizing the cumulative number of infections. These results may argue in favor of sharing of vaccines between locations in the context of an epidemic caused by an emerging pathogen, where many epidemiologic characteristics may not be known. | ||||||
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| DOI: | 10.21430/M34IWWJ4HH | ||||||
| Subjects: | 0 | ||||||
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| SDY2436: Impaired SARS-CoV-2 Variant Neutralization and CD8+ T-cell Responses Following 3 Doses of mRNA Vaccines in Myeloma: Correlation with Breakthrough Infections | |||||||||||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||||||||||
| Description: | Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)-specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells. | ||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3VPZ743F1 | ||||||||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||||||||
| SDY2437: DCVC_0026 | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Two immunogens and a negative control were tested in 7 week old female mice primed on day 0, boosted on day 56, and sacrificed on day 71. | ||||||||||||
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| DOI: | 10.21430/M36E5Z1TNK | ||||||||||||
| Subjects: | 15 | ||||||||||||
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| SDY2438: Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern | |||||||||||
| Status: | New | ||||||||||
| Description: | 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. | ||||||||||
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| DOI: | 10.21430/M349YMQ9J3 | ||||||||||
| Subjects: | 0 | ||||||||||
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| SDY2439: SARS-CoV-2 spike E484K mutation reduces antibody neutralisation | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | It is concerning that emerging variants of SARS-CoV-2 can evade neutralising antibodies induced by previous infection or vaccination through mutations in the spike protein, including the receptor-binding domain (RBD). The asparagine (N) to tyrosine (Y) substitution at position 501 (N501Y), present in variants of concern belonging to the B.1.1.7, B.1.351, and P.1 lineages, does not seem to affect in-vitro neutralisation of human convalescent or post-vaccination sera. However, additional substitutions, such as E484K present in B.1.351 and P.1 lineages, might allow evasion from neutralising antibodies. | |||||||||||||||
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| DOI: | 10.21430/M3RRW397V4 | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| SDY2440: Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Short- and Mid-term Cardiac Outcomes in Multisystem Inflammatory Syndrome in Children | ||||||||||
| Status: | New | |||||||||
| Description: | Cardiac outcomes of 131 children with multisystem inflammatory syndrome (MIS-C) were examined. The majority of the cohort was male (66.4%) and half were Black (49.6%). Cardiac involvement was evident in 25% of the cohort at diagnosis. Favorable short- and mid-term outcomes were documented on follow-up, irrespective of the severe acute respiratory syndrome coronavirus 2 variants causing the infection. | |||||||||
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| DOI: | 10.21430/M3OB1XR8HS | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2441: Systems approach to define humoral correlates of immunity to Shigella | |||||||
| Status: | New | ||||||
| Description: | Shigella infection is the second leading cause of death due to diarrheal disease in young children worldwide. With the rise of antibiotic resistance, initiatives to design and deploy a safe and effective Shigella vaccine are urgently needed. However, efforts to date have been hindered by the limited understanding of immunological correlates of protection against shigellosis. We applied systems serology to perform a comprehensive analysis of Shigella-specific antibody responses in sera obtained from volunteers before and after experimental infection with S. flexneri 2a in a series of controlled human challenge studies. Polysaccharide-specific antibody responses are infrequent prior to infection and evolve concomitantly with disease severity. In contrast, pre-existing antibody responses to type 3 secretion system proteins, particularly IpaB, consistently associate with clinical protection from disease. Linked to particular Fc-receptor binding patterns, IpaB-specific antibodies leverage neutrophils and monocytes, and complement and strongly associate with protective immunity. IpaB antibody-mediated functions improve with a subsequent rechallenge resulting in complete clinical protection. Collectively, our systems serological analyses indicate protein-specific functional correlates of immunity against Shigella in humans. | ||||||
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| DOI: | 10.21430/M3XDH3OU6I | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2442: The microbiota of pregnant women with SARS-CoV-2 and their infants | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Background: Infants receive their first bacteria from their birthing parent. This newly acquired microbiome plays a pivotal role in developing a robust immune system, the cornerstone of long-term health. Results: We demonstrated that the gut, vaginal, and oral microbial diversity of pregnant women with SARS-CoV-2 infection is reduced, and women with early infections exhibit a different vaginal microbiota composition at the time of delivery compared to their healthy control counterparts. Accordingly, a low relative abundance of two Streptococcus sequence variants (SV) was predictive of infants born to pregnant women with SARS-CoV-2 infection. Conclusions: Our data suggest that SARS-CoV-2 infections during pregnancy, particularly early infections, are associated with lasting changes in the microbiome of pregnant women, compromising the initial microbial seed of their infant. Our results highlight the importance of further exploring the impact of SARS-CoV-2 on the infant's microbiome-dependent immune programming. Video Abstract. | ||||||||||||
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| DOI: | 10.21430/M3ETH127PN | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2444: Development of a universal pentavalent mRNA vaccine against IBVs | |||||||||
| Status: | New | ||||||||
| Description: | Mice were vaccinated intradermally with nucleoside-modified mRNA-LNPs encoding different IBV antigens (monovalent or pentavalent formulation) or an irrelevant formulation. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3I9PXID7K | ||||||||
| Subjects: | 450 | ||||||||
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| Publications: | None | ||||||||
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| SDY2445: A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | The SARS-CoV-2 pandemic has caused extreme human suffering and economic harm. We generated and characterized a new mouse-adapted SARS-CoV-2 virus that captures multiple aspects of severe COVID-19 disease in standard laboratory mice. This SARS-CoV-2 model exhibits the spectrum of morbidity and mortality of COVID-19 disease as well as aspects of host genetics, age, cellular tropisms, elevated Th1 cytokines, and loss of surfactant expression and pulmonary function linked to pathological features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). This model can rapidly access existing mouse resources to elucidate the role of host genetics, underlying molecular mechanisms governing SARS-CoV-2 pathogenesis, and the protective or pathogenic immune responses related to disease severity. The model promises to provide a robust platform for studies of ALI and ARDS to evaluate vaccine and antiviral drug performance, including in the most vulnerable populations (i.e., the aged) using standard laboratory mice. | ||||||||||||||||
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| DOI: | 10.21430/M33HAE2CN9 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2446: Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination | |||||||||||||||||
| Status: | New | ||||||||||||||||
| Description: | Group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. Here, we evaluate the mechanisms of cross-sarbecovirus protective immunity, currently less clear yet important for pan-sarbecovirus vaccine development, using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination does not prevent virus replication, it protects against lethal heterologous disease outcomes in both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clade 2 bat sarbecovirus challenge models. The spike vaccines tested primarily elicit a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. Rather, non-neutralizing antibody functions, mechanistically linked to FcgR4 and spike S2, mediate cross-protection in wild-type mice. Protection is lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs. | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EDQ0ZAF9 | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||
| SDY2447: A homologous or variant booster vaccine after Ad26.COV2.S immunization enhances SARS-CoV-2-specific immune responses in rhesus macaques | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3M4NQO6CB | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2448: Deletion of the SARS-CoV-2 Spike Cytoplasmic Tail Increases Infectivity in Pseudovirus Neutralization Assays | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Pseudotyped viruses are valuable tools for studying virulent or lethal viral pathogens that need to be handled in biosafety level 3 (BSL3) or higher facilities. With the explosive spread of the coronavirus disease 2019 (COVID-19) pandemic, the establishment of a BSL2 adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization assay is needed to facilitate the development of countermeasures. Here, we describe an approach to generate a single-round lentiviral vector-based SARS-CoV-2 pseudovirus, which produced a signal more than 2 logs above background. Specifically, a SARS-CoV-2 spike variant with a cytoplasmic tail deletion of 13 amino acids, termed SΔCT13, conferred enhanced spike incorporation into pseudovirions and increased viral entry into cells compared to that with full-length spike (S). We further compared S and SΔCT13 in terms of their sensitivity to vaccine sera, purified convalescent-phase IgG, human ACE2 (hACE2) murine IgG (mIgG), and the virus entry inhibitor bafilomycin A1 (BafA1). We developed an SΔCT13-based pseudovirus neutralization assay and defined key assay characteristics, including linearity, limit of detection, and intra-assay and intermediate assay precision. Our data demonstrate that the SΔCT13-based pseudovirus shows enhanced infectivity in target cells, which will facilitate the assessment of humoral immunity to SARS-CoV-2 infection, antibody therapeutics, and vaccination. This pseudovirus neutralization assay can also be readily adapted to SARS-CoV-2 variants that emerge. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3M4UA5R2W | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2449: The feasibility of multiple units of convalescent plasma in mechanically ventilated patients with COVID-19: A pilot study | |||||||
| Status: | New | ||||||
| Description: | Early in the pandemic, we were interested in strategies that would increase a patient’s chances of receiving the quantity (i.e.; titer) and type (i.e.; neutralizing) of antibodies needed to suppress SARS-CoV-2 viral injury. We anticipated this could be done safely via serial transfusions of CP given the low risk of plasma transfusion. Based on this premise, we conducted a pilot study to evaluate the feasibility of repeated dosing of anti-SARS-CoV-2 CP in critically ill mechanically ventilated patients. Key parameters included access to CP and provider willingness to transfuse multiple units of CP to profoundly hypoxemic, mechanically ventilated patients. Additional areas of interest included the antibody content of the transfused CP and measures of safety. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3IRBDLZV1 | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2450: Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3IHAJTFXE | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2451: SARS-CoV-2 viral protein ORF3A injures renal tubules by interacting with TRIM59 to induce STAT3 activation | |||||||||||
| Status: | New | ||||||||||
| Description: | Acute kidney injury occurs frequently in COVID-19 patients infected by the coronavirus SARS-CoV-2, and infection of kidney cells by this virus has been reported. However, little is known about the direct impact of the SARS-CoV-2 infection upon the renal tubular cells. We report that SARS-CoV-2 activated signal transducer and activator of transcription 3 (STAT3) signaling and caused cellular injury in the human renal tubular cell line. Mechanistically, the viral protein ORF3A of SARS-CoV-2 augmented both NF-κB and STAT3 signaling and increased the expression of kidney injury molecule 1. SARS-CoV-2 infection or expression of ORF3A alone elevated the protein level of tripartite motif-containing protein 59 (TRIM59), an E3 ubiquitin ligase, which interacts with both ORF3A and STAT3. The excessive TRIM59 in turn dissociated the phosphatase TCPTP from binding to STAT3 and hence inhibited the dephosphorylation of STAT3, leading to persistent STAT3 activation. Consistently, ORF3A induced renal injury in zebrafish and mice. In addition, expression of TRIM59 was elevated in the kidney autopsies of COVID-19 patients with acute kidney injury. Thus, the aberrant activation of STAT3 signaling by TRIM59 plays a significant role in the renal tubular cell injury caused by SARS-CoV-2, which suggests a potential targeted therapy for the renal complications of COVID-19. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3G7JY97PO | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2452: Epidemiological and Immunological Features of Obesity and SARS-CoV-2 | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Obesity is a key correlate of severe SARS-CoV-2 outcomes while the role of obesity on risk of SARS-CoV-2 infection, symptom phenotype, and immune response remain poorly defined. We examined data from a prospective SARS-CoV-2 cohort study to address these questions. Serostatus, body mass index, demographics, comorbidities, and prior COVID-19 compatible symptoms were assessed at baseline and serostatus and symptoms monthly thereafter. SARS-CoV-2 immunoassays included an IgG ELISA targeting the spike RBD, multiarray Luminex targeting 20 viral antigens, pseudovirus neutralization, and T cell ELISPOT assays. Our results from a large prospective SARS-CoV-2 cohort study indicate symptom phenotype is strongly influenced by obesity among younger but not older age groups; we did not identify evidence to suggest obese individuals are at higher risk of SARS-CoV-2 infection; and remarkably homogenous immune activity across BMI categories suggests immune protection across these groups may be similar. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3S1GADOL2 | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | |||||||||||||||
| SDY2453: B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WU4T0N60 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||
| SDY2454: Cross-Neutralization of Emerging SARS-CoV-2 Variants | |||||||
| Status: | New | ||||||
| Description: | Viral variants harboring mutations at K417, E484, and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and variants of concern (VOCs), including B.1.1.7 (alpha), P.1 (gamma), and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting that different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to the first pandemic wave of prototype SARS-CoV-2 possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BTFZRIDV | ||||||
| Subjects: | 10 | ||||||
| Study PI, contact: |
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| Publications: | None | ||||||
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Updated Studies
| SDY78: Antigenic and immunogenic properties of recombinant hemagglutinin proteins when produced in various protein expression systems | |||||||||
| Status: | Updated | ||||||||
| Description: | Assess the immunogenicity and antigenicity of recombinant hemagglutinin proteins produced and purified by various methods | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3EER1F151 | ||||||||
| Subjects: | 178 | ||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||
| SDY111: VZV vaccination in the elderly SLVP020 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Healthy adults (50+ years old) with history of varicella but no history of zoster are vaccinated with Zostavax. Blood and serum are taken prior to vaccination and at several points after. A systems biology approach will be used to identify age-related decreases in immune function and potential predictors and correlates of protection. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3ODYABDL2 | ||||||||||||
| Subjects: | 48 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY112: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2011 (See companion studies SDY311 2010 / SDY312 2009 / SDY314 2008 / SDY315 2012) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M320H8XYFG | ||||||||||||
| Subjects: | 93 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY113: Plasmablast response to inactivated and live attenuated influenza vaccines (TIV3/TIV3 ID/LAIV) SLVP021 2011 | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | To study the plasmablast response to influenza vaccines | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3KPFS7KXI | ||||||||||||||||
| Subjects: | 70 | ||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY202: Heterovariant cross-reactive B-cell responses induced by the 2009 pandemic influenza virus A subtype H1N1 vaccine SLVP021 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | To study the plasmablast response to monovalent inactivated 2009 pandemic pH1N1 vaccine | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3LS2SRM8M | ||||||||||||
| Subjects: | 79 | ||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||
| SDY207: Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8+ T cell phenotypes | |||||||
| Status: | Updated | ||||||
| Description: | High dimensional analysis of CD8+ T cell phenotype and function | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M33C1GNCXF | ||||||
| Subjects: | 6 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY215: TIV 2008 vaccination of CD95-/- mice and ELISA for detection of influenza-specific antibodies | |||||||
| Status: | Updated | ||||||
| Description: | Evaluation of the mouse immune response to influenza vaccination. ELISA was used to examine the immune response of mutant mice (MRL/Mpj-Faslpr/J (Mpj/lpr), B6.MRL-Faslpr/J (B6/lpr), MRL/MpJ (Mpj) and C57BL/6L (B6)) to a single dose of the trivalent 2008 seasonal influenza vaccine | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M38JPMTP8S | ||||||
| Subjects: | 17 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY232: Determinants of human NK cell diversity by mass cytometry | |||||||
| Status: | Updated | ||||||
| Description: | Natural Killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 35 parameters, including 28 NK cell receptors, on peripheral blood NK cells from five sets of monozygotic twins and twelve unrelated donors of defined HLA and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6,000-30,000 phenotypic populations within an individual and >100,000 phenotypes in this population. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors, while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3J7Z67HEA | ||||||
| Subjects: | 22 | ||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||
| SDY305: Plasmablast response to inactivated and live attenuated influenza vaccines (TIV3/TIV3 ID) SLVP021 2012 | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | To study the plasmablast response to 2012 seasonal inactivated influenza vaccine | ||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U2R9IV87 | ||||||||||||||||
| Subjects: | 25 | ||||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||||
| SDY311: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2010 (See companion studies SDY315 2012 / SDY312 2009 / SDY314 2008 / SDY112 2011) | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33MSDRJ55 | ||||||||||||||
| Subjects: | 76 | ||||||||||||||
| Study PI, contact: |
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| Clinical Assessments: | None | ||||||||||||||
| SDY312: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2009 (See companion studies SDY315 2012 / SDY314 2008 / SDY311 2010 / SDY112 2011) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3G230OYOM | ||||||||||||
| Subjects: | 84 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY314: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination (TIV) SLVP015 2008 (See companion studies SDY315 2012 / SDY312 2009 / SDY311 2010 / SDY112 2011) | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WZ7XK2GG | ||||||||||||
| Subjects: | 92 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY406: Immune Responses to Influenza-Like Illness SLVP022 2013 | |||||||||
| Status: | Updated | ||||||||
| Description: | To investigate the nasal transcriptional response and peripheral plasmablast response in acute influenza infection | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3U4SDFNWN | ||||||||
| Subjects: | 83 | ||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY478: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination SLVP015 2013 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3YEJTSS29 | ||||||||||
| Subjects: | 71 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY514: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2009 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Evaluate the variation in immune response between individuals and assess whether it changes as a function of age and similarity in genetic and environmental background (by comparing differences between monozygotic and dizygotic twin pairs of different ages). | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3M6BADC48 | ||||||||||
| Subjects: | 74 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY515: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2010 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Evaluate the variation in immune response between individuals and assess whether it changes as a function of age and similarity in genetic and environmental background (by comparing differences between monozygotic and dizygotic twin pairs of different ages). | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3RDGZH60O | ||||||||||||
| Subjects: | 84 | ||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||||
| SDY519: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2011 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Evaluate the variation in immune response between individuals and assess whether it changes as a function of age and similarity in genetic and environmental background (by comparing differences between monozygotic and dizygotic twin pairs of different ages). | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3TI6PGH9Q | ||||||||||
| Subjects: | 63 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY675: Heritable influence on the B and T cell receptor repertoire | |||||||
| Status: | Updated | ||||||
| Description: | The adaptive immune systems capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is frequently underestimated. By leveraging the unique characteristics of B, CD4+ T, and CD8+ T lymphocyte subsets isolated from monozygotic twins, we have elucidated the impact of heritable factors on the V(D)J recombination process and have shown that the repertoires of both naive and antigen experienced cells are subject to biases resulting from initial recombination differences. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with approximately 1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that bias exists on a chromosome-wide level. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XMYVQI9X | ||||||
| Subjects: | 10 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY887: Defective signaling in aging, influenza vaccination 2007 SLVP015 | |||||||||
| Status: | Updated | ||||||||
| Description: | Pilot year. Despite the importance of the immune system in many diseases, there are currently no objective benchmarks of immunological health. In an effort to indentify benchmarks of immunological health, influenza vaccination was used in 10 young (20-30 years) and 19 older subjects (60 to 89 years) as models for strong and weak immune responses, respectively. Serological responses to influenza strains as well as a wide variety of other parameters, including gene expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset phenotypes and in vitro cytokine stimulation were measured. Using machine learning, nine variables predicting antibody response with 84% accuracy were identified. Two of these variables are involved in apoptosis, which positively associated with the response to vaccination and was confirmed to be a contributor to vaccine responsiveness in mice. The identification of these biomarkers provides new insights into what immune features may be most important for immune health. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33JMYFLF1 | ||||||||
| Subjects: | 29 | ||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY1464: T cell responses to H1N1v and a longitudinal study of seasonal influenza vaccination SLVP015 2014 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3AUKDIXFI | ||||||||||
| Subjects: | 101 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1466: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2013 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Evaluate the variation in immune response between individuals and assess whether it changes as a function of age and similarity in genetic and environmental background (by comparing differences between monozygotic and dizygotic twin pairs of different ages). | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33B64BQUE | ||||||||||
| Subjects: | 22 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1467: B-cell Immunity to Influenza SLVP017 2009 | |||||||
| Status: | Updated | ||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3BNBGK39S | ||||||
| Subjects: | 51 | ||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||
| SDY1468: B-cell Immunity to Influenza (SLVP017) 2010 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M30IB1ZZDJ | ||||||||||
| Subjects: | 71 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY1471: B-cell Immunity to Influenza (SLVP017) 2013 | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WEPI1HA3 | ||||||||||
| Subjects: | 10 | ||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||||
| SDY2193: MoTrPAC 6-month rat endurance training | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The MoTrPAC program is supported by the NIH Common Fund and is managed by a trans-agency working group representing multiple NIH institutes and centers, led by the NIH Office of Strategic Coordination, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, and National Institute of Biomedical Imaging and Bioengineering. | ||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3XZN09QFF | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||||||||
| Resources: |
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| Assays: | None | ||||||||||||||
| Clinical Assessments: | None | ||||||||||||||
| SDY2209: CD8 Depletion | |||||||||
| Status: | Updated | ||||||||
| Description: | Cell-mediated immunity is critical for control of M. tuberculosis infection. Although the importance of CD4 T cells in control of tuberculosis is well-established, the importance of CD8+ lymphocytes is less clear. Here, we investigated the requirement for all CD8+ lymphocytes (innate and adaptive) or just CD8 alpha/beta adaptive T cells in control of initial and early infection in cynomolgus macaques, using anti-CD8alpha or anti-CD8beta depleting antibodies in vivo. Flow cytometry and single-cell RNA-sequencing analysis of lung granulomas from control (undepleted) macaques at 6 weeks post-infection revealed a rich landscape of cytotoxic CD8+ lymphocytes. Anti-CD8alpha antibody resulted in susbstantial loss of all CD8+ lymphocytes from granulomas, while anti-CD8beta antibody selectively depleted classical CD8alpha beta T cells. In CD8-depleted granulomas, CD4 T cells and gamma delta T cells had increased expression of certain cytotoxic effectors, such as granzymes. However, these cells had reduced expression of perforin, granulysin, and/or CCL5, and thus displayed an incomplete cytotoxic profile. At 6 weeks post-infection, CD8 alpha depleted macaques had increased granuloma numbers, lung inflammation, and total thoracic bacterial burden, while CD8beta-depleted macaques showed increased lymph node bacterial burden. Mtb barcode analysis revealed that depletion of all CD8+ lymphocytes resulted in greater initial establishment of Mtb in the lungs, indicating a loosening of the airway bottleneck for infection, and increased dissemination of Mtb within lungs, to lymph nodes and to extrapulmonary sites. These data suggest that the total CD8+ lymphocyte population is critical for early control of Mtb infection in macaques and support the importance of targeting CD8+ lymphocytes in a vaccine strategy. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3TEVRE64X | ||||||||
| Subjects: | 0 | ||||||||
| Study PI, contact: |
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| Publications: | None | ||||||||
| Resources: |
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| Assays: |
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| Clinical Assessments: | None | ||||||||
| SDY2228: COVID-19 Vaccinations in EMS Professionals: Prevalence and Predictors | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Background: Immunizations for emergency medical services (EMS) professionals during pandemics are an important tool to increase the safety of the workforce as well as their patients. The purpose of this study was to better understand EMS professionals' decisions to receive or decline a COVID-19 vaccine.Methods: We conducted a cross-sectional analysis of nationally certified EMS professionals (18-85 years) in April 2021. Participants received an electronic survey asking whether they received a vaccine, why or why not, and their associated beliefs using three validated scales: perceived risk of COVID-19, medical mistrust, and confidence in the COVID-19 vaccine. Data were merged with National Registry dataset demographics. Analyses included descriptive analysis and multivariable logistic regression (OR, 95% CI). Multivariate imputation by chained equations was used for missingness.Results: A total of 2,584 respondents satisfied inclusion criteria (response rate = 14%). Overall, 70% of EMS professionals were vaccinated. Common reasons for vaccination among vaccinated respondents were to protect oneself (76%) and others (73%). Common reasons for non-vaccination among non-vaccinated respondents included concerns about vaccine safety (53%) and beliefs that vaccination was not necessary (39%). Most who had not received the vaccine did not plan to get it in the future (84%). Hesitation was most frequently related to wanting to see how the vaccine was working for others (55%). Odds of COVID-19 vaccination were associated with demographics including age (referent <28 years; 39-50 years: 1.56, 1.17-2.08; >51 years: 2.22, 1.64-3.01), male sex (1.26, 1.01-1.58), residing in an urban/suburban area (referent rural; 1.36, 1.08-1.70), advanced education (referent GED/high school and below; bachelor's and above: 1.72, 1.19-2.47), and working at a hospital (referent fire-based agency; 1.53, 1.04-2.24). Additionally, vaccination odds were significantly higher with greater perceived risk of COVID-19 (2.05, 1.68-2.50), and higher vaccine confidence (2.84, 2.40-3.36). Odds of vaccination were significantly lower with higher medical mistrust (0.54, 0.46-0.63).Conclusion: Despite vaccine availability, not all EMS professionals had been vaccinated. The decision to receive a COVID-19 vaccine was associated with demographics, beliefs regarding COVID-19 and the vaccine, and medical mistrust. Efforts to increase COVID-19 vaccination rates should emphasize the safety and efficacy of vaccines. | ||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M397IY0TSF | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2229: An Opportunity to Understand Concerns about COVID-19 Vaccination: Perspectives from EMS Professionals | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | Some healthcare professionals, including emergency medical service (EMS) professionals, remain hesitant about receiving COVID-19 vaccines. This study sought to understand EMS professionals' perspectives regarding COVID-19 vaccination. Using open-ended comments from a national survey deployed electronically to over 19,000 EMS professionals in April of 2021, we examined perspectives about acceptance of and hesitancy toward COVID-19 vaccines. Survey comments revealed differences in perspectives between vaccinated and unvaccinated EMS professionals regarding their personal role in improving public health through COVID-19 vaccination as well as vaccine benefits and the protection conferred by vaccination. Unvaccinated individuals also expressed concerns over the research and development of the COVID-19 vaccines that led to their decision not to get vaccinated. Individuals who were vaccinated suggested ways to increase uptake of the vaccine including having healthcare professionals serve as leaders for vaccination and educating individuals about COVID-19 vaccination through credible resources. Vaccine hesitancy remains a challenge to achieving herd immunity to COVID-19 through vaccination, even among healthcare professionals. Understanding the perspectives of those who have chosen not to be vaccinated can help direct strategies to reduce confusion and concerns. The perspectives of vaccinated individuals may also be valuable in identifying opportunities to promote vaccination in the professional setting. | |||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3154E9F43 | |||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2230: Closing the Gap on COVID-19 Vaccinations in First Responders and Beyond: Increasing Trust | |||||||||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||||||||
| Description: | Although COVID-19 vaccines are widely available in the U.S. and much of the world, many have chosen to forgo this vaccination. Emergency medical services (EMS) professionals, despite their role on the frontlines and interactions with COVID-positive patients, are not immune to vaccine hesitancy. Via a survey conducted in April 2021, we investigated the extent to which first responders in the U.S. trusted various information sources to provide reliable information about COVID-19 vaccines. Those vaccinated generally trusted healthcare providers as a source of information, but unvaccinated first responders had fairly low trust in this information source-a group to which they, themselves, belong. Additionally, regardless of vaccination status, trust in all levels of government, employers, and their community as sources of information was low. Free-response explanations provided some context to these findings, such as preference for other COVID-19 management options, including drugs proven ineffective. A trusted source of COVID-19 vaccination information is not readily apparent. Individuals expressed a strong desire for the autonomy to make vaccination decisions for themselves, as opposed to mandates. Potential reasons for low trust, possible solutions to address them, generalizability to the broader public, and implications of low trust in official institutions are discussed. | ||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3AGU15EQU | ||||||||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | ||||||||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||||||||
| SDY2231: Symptomology following mRNA vaccination against SARS-CoV-2. | ||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||
| Description: | Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination | |||||||||||||||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3A8F4A3NU | |||||||||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: | None | |||||||||||||||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||||||||||||||
| SDY2232: Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2. | ||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||
| Description: | In a cohort of BNT162b2 (Pfizer-BioNTech) mRNA vaccine recipients (n = 1,090), we observed that spike-specific IgG antibody levels and ACE2 antibody binding inhibition responses elicited by a single vaccine dose in individuals with prior SARS-CoV-2 infection (n = 35) were similar to those seen after two doses of vaccine in individuals without prior infection (n = 228). Post-vaccine symptoms were more prominent for those with prior infection after the first dose, but symptomology was similar between groups after the second dose. | |||||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3K6396YAI | |||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||
| Study PI, contact: |
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| Publications: |
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| Resources: |
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| Assays: |
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| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2233: Practice Patterns and Patient Outcomes After Widespread Adoption of Remote Heart Failure Care | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background : An unprecedented shift to remote heart failure outpatient care occurred during the coronavirus disease 2019 (COVID-19) pandemic. Given challenges inherent to remote care, we studied whether remote visits (video or telephone) were associated with different patient usage, clinician practice patterns, and outcomes. Methods : We included all ambulatory cardiology visits for heart failure at a multisite health system from April 1, 2019, to December 31, 2019 (pre-COVID) or April 1, 2020, to December 31, 2020 (COVID era), resulting in 10 591 pre-COVID in-person, 7775 COVID-era in-person, 1009 COVID-era video, and 2322 COVID-era telephone visits. We used multivariable logistic and Cox proportional hazards regressions with propensity weighting and patient clustering to study ordering practices and outcomes. Results : Compared with in-person visits, video visits were used more often by younger (mean 64.7 years [SD 14.5] versus 74.2 [14.1]), male (68.3% versus 61.4%), and privately insured (45.9% versus 28.9%) individuals (P<0.05 for all). Remote visits were more frequently used by non-White patients (35.8% video, 37.0% telephone versus 33.2% in-person). During remote visits, clinicians were less likely to order diagnostic testing (odds ratio, 0.20 [0.18–0.22] video versus in-person, 0.18 [0.17–0.19] telephone versus in-person) or prescribe β-blockers (0.82 [0.68–0.99], 0.35 [0.26–0.47]), mineralocorticoid receptor antagonists (0.69 [0.50–0.96], 0.48 [0.35–0.66]), or loop diuretics (0.67 [0.53–0.85], 0.45 [0.37–0.55]). During telephone visits, clinicians were less likely to prescribe ACE (angiotensin-converting enzyme) inhibitor/ARB (angiotensin receptor blockers)/ARNIs (angiotensin receptor-neprilysin inhibitors; 0.54 [0.40–0.72]). Telephone visits but not video visits were associated with higher rates of 90-day mortality (1.82 [1.14–2.90]) and nonsignificant trends towards higher rates of 90-day heart failure emergency department visits (1.34 [0.97–1.86]) and hospitalizations (1.36 [0.98–1.89]). Conclusions : Remote visits for heart failure care were associated with reduced diagnostic testing and guideline-directed medical therapy prescription. Telephone but not video visits were associated with increased 90-day mortality. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3C2Q25ENQ | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2234: Optimizing prevalence estimates for a novel pathogen by reducing uncertainty in test characteristics | |||||||
| Status: | Updated | ||||||
| Description: | Emergence of a novel pathogen drives the urgent need for diagnostic tests that can aid in defining disease prevalence. The limitations associated with rapid development and deployment of these tests result in a dilemma: In efforts to optimize prevalence estimates, would tests be better used in the lab to reduce uncertainty in test characteristics or to increase sample size in field studies? Here, we provide a framework to address this question through a joint Bayesian model that simultaneously analyzes lab validation and field survey data, and we define the impact of test allocation on inferences of sensitivity, specificity, and prevalence. In many scenarios, prevalence estimates can be most improved by apportioning additional effort towards validation rather than to the field. The joint model provides superior estimation of prevalence, sensitivity, and specificity, compared with typical analyses that model lab and field data separately, and it can be used to inform sample allocation when testing is limited. | ||||||
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| DOI: | 10.21430/M3O5E1Q8JY | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2236: SARS-CoV-2 Serosurveys: How antigen, isotype and threshold choices affect the outcome | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | Background: Evaluating the performance of SARS-CoV-2 serological assays and clearly articulating the utility of selected antigen, isotypes and thresholds is crucial to understanding the prevalence of infection within selected communities. Methods: This cross-sectional study, implemented in 2020, screened PCR-confirmed COVID-19 patients (n = 86), banked pre-pandemic and negative donors (n = 96), health care workers and family members (n = 552), and university employees (n = 327) for anti-SARS-CoV-2 receptor-binding domain (RBD), trimeric spike protein (S), and nucleocapsid protein (N) IgG and IgA antibodies with a laboratory developed Enzyme-Linked Immunosorbent Assay (ELISA) and tested how antigen, isotype and threshold choices affected the seroprevalence. The following threshold methods were evaluated: (i) mean + 3 standard deviations of the negative controls; (ii) 100% specificity for each antigen/isotype combination; and (iii) the maximal Youden index. Results: We found vastly different seroprevalence estimates depending on selected antigens, isotypes and the applied threshold method, ranging from 0.0% to 85.4% . Subsequently, we maximized specificity and reported a seroprevalence, based on more than one antigen, ranging from 9.3% to 25.9%. Conclusions: This study revealed the importance of evaluating serosurvey tools for antigen, isotype, and threshold-specific sensitivity and specificity, in order to interpret qualitative serosurvey outcomes reliably and consistently across studies. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M38M5AU5PJ | |||||||||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||||||||||||||
| SDY2239: SARS-CoV-2 -specific immune responses in boosted vaccine recipients with breakthrough infections during the Omicron variant surge | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | BACKGROUND. Breakthrough SARS-CoV-2 infections in vaccinated individuals have been previously associated with suboptimal humoral immunity. However, less is known about breakthrough infections with the Omicron variant. METHODS. We analyzed SARS-CoV-2 specific antibody and cellular responses in healthy vaccine recipients who experienced breakthrough infections a median of 50 days after receiving a booster mRNA vaccine with an ACE2 binding inhibition assay and an ELISpot assay respectively. Results: We found high levels of antibodies that inhibited vaccine strain spike protein binding to ACE2 but lower levels that inhibited Omicron variant spike protein binding to ACE2 in four boosted vaccine recipients prior to infection. The levels of antibodies that inhibited vaccine strain and Omicron spike protein binding after breakthrough in 18 boosted vaccine recipients were similar to levels seen in COVID-19 negative boosted vaccine recipients. In contrast, boosted vaccine recipients had significantly stronger T cells responses to both vaccine strain and Omicron variant spike proteins at the time of breakthrough. CONCLUSIONS. Our data suggest that breakthrough infections with the Omicron variant can occur despite robust immune responses to the vaccine strain spike protein. | ||||||||||||
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| DOI: | 10.21430/M3Q3C0UDD8 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2240: Neutralization of SARS-CoV-2 Omicron sub-lineages BA.1, BA.1.1, and BA.2 | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta-infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants and provide insight into the immunity from natural infection against Omicron sub-lineages. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M32EKWILLC | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2241: Neutralization of the SARS-CoV-2 Deltacron and BA.3 Variants | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | We used a pseudotyped virus neutralization assay to examine neutralizing-antibody titers in serum samples obtained from vaccinated health care workers at the Wexner Medical Center at Ohio State University as well as from patients with confirmed Covid-19 during the delta and omicron waves in the Columbus, Ohio, area. We evaluated neutralizing-antibody titers against the ancestral SARS-CoV-2 strain bearing the D614G mutation, along with the understudied BA.3 and deltacron variants, and compared the responses with previously reported results for the BA.1, BA.2, and delta variants. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3WD13IVPV | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2242: Perspectives of Volunteer Firefighters during the COVID-19 Pandemic: Stumbling Blocks and Silver Linings | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | The COVID-19 pandemic has profoundly affected the lives of almost every individual in every nation, with numbers of infections continuing to grow. Across these nations, first responders are essential in their roles addressing emergencies, despite their risk of exposure to COVID-19 in the course of their work. We sought to understand the impacts of the COVID-19 pandemic on the lives of volunteer firefighters in the United States, an understudied group of these first responders. Interviews were conducted with volunteer firefighters between September and November 2021. Interviews were analyzed using deductive dominant thematic analysis. Thirty-three firefighters were interviewed who had an average of 22 years of service and a mean age of 52 years. Interviewees described pandemic-related challenges including the fear of COVID exposure and frustrations with work and personal relationships. They also identified unexpected work-related benefits including a deepened commitment to serve and improvements to training and safety. Further, some volunteers noted personal benefits such as developing stronger connections with others, having a new outlook on life, and observing goodwill. Our findings provide insight into the multifaceted and complex impact of the COVID-19 pandemic on volunteer firefighters. | ||||||||||||||||||
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| DOI: | 10.21430/M3743KKGHE | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Assays: | None | ||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2243: Ultrasensitive detection of salivary SARS-CoV-2 IgG antibodies in individuals with natural and COVID-19 vaccine-induced immunity | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | We assessed the feasibility of a highly sensitive immunoassay method based on single molecule array (Simoa) technology to detect IgG and IgA antibodies against SARS-CoV-2 spike protein receptor binding domain (RBD) in saliva from individuals with natural or vaccine-induced COVID-19 immunity. The performance of the method was compared to a laboratory-developed SARS-CoV-2 RBD total antibody enzyme-linked immunosorbent assay (ELISA). Paired serum and saliva specimens were collected from individuals (n = 40) prior to and 2 weeks after receiving an initial prime COVID-19 vaccine dose (Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273). Saliva was collected using a commercially available collection device (OraSure Inc.) and SARS-CoV-2 RBD IgG antibodies were measured by an indirect ELISA using concentrated saliva samples and a Simoa immunoassay using unconcentrated saliva samples. The IgG results were compared with paired serum specimens that were analyzed for total RBD antibodies using the ELISA method. The analytical sensitivity of the saliva-based Simoa immunoassay was five orders of magnitude higher than the ELISA assay: 0.24 pg/mL compared to 15 ng/mL. The diagnostic sensitivity of the saliva ELISA method was 90% (95% CI 76.3-97.2%) compared to 91.7% (95% CI 77.5-98.2%) for the Simoa immunoassay without total IgG-normalization and 100% (95% CI 90.3-100%) for the Simoa immunoassay after total IgG-normalization when compared to the serum ELISA assay. When analyzed using the SARS-CoV-2 RBD IgG antibody ELISA, the average relative increase in antibody index (AI) between the saliva of the post- and pre-vaccinated individuals was 8.7 (AIpost/pre). An average relative increase of 431 pg/mL was observed when the unconcentrated saliva specimens were analyzed using the Simoa immunoassay (SARS-CoV-2 RBD IgGpost/pre). These findings support the suitability of concentrated saliva specimens for the measurement of SARS-CoV-2 RBD IgG antibodies via ELISA, and unconcentrated saliva specimens for the measurement of SARS-CoV-2 RBD IgG and IgA using an ultrasensitive Simoa immunoassay | ||||||||||||
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| DOI: | 10.21430/M3VWJ6W5M3 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2244: Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for <10 days were eligible. Participants received either CCP with nAb titers of >1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray's P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher's P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507). IMPORTANCE In this study, in a high-risk population of patients admitted for COVID-19, we found an earlier time to hospital discharge among participants receiving CCP with nAb titers of >1:640 compared with participants receiving CCP with a lower nAb titer and no CCP-related AEs. The significance of our research is in identifying a dose response of CCP and clinical outcomes based on nAb titer. Although limited by a small study size, these findings support further study of high-nAb-titer CCP defined as >1:640 in the treatment of COVID-19. | ||||||||||||||||||
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| DOI: | 10.21430/M37S4576ZH | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2247: Preserved recognition of Omicron spike following COVID-19 messenger RNA vaccination in pregnancy | |||||||
| Status: | Updated | ||||||
| Description: | This study aims to test whether vaccine-induced antibodies raised during pregnancy continue to bind to and leverage Fc receptors to protect against variants of concern including the Omicron variant. The receptor binding domain or whole spike-specific antibody isotype binding titers and Fc gamma receptor binding directed toward variants of concern, including the Omicron variant, were analyzed in pregnant women after receiving the full dose regimen of either the Pfizer/BioNTech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay. Reduced isotype recognition of the Omicron receptor binding domain was observed following administration of either vaccine with relatively preserved, albeit reduced, recognition of the whole Omicron spike by immunoglobulin M and G antibodies. Despite the near complete loss of Fc receptor binding to the Omicron receptor binding domain, Fc receptor binding to the Omicron spike was more variable but largely preserved. Reduced binding titers to the Omicron receptor binding domain aligns with the observed loss of neutralizing activity. Despite the loss of neutralization, preserved, albeit reduced, Omicron spike recognition and Fc receptor binding potentially continue to attenuate disease severity in pregnant women. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SQTEAH4V | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2314: Estimating Vaccine Efficacy Against Transmission via Effect on Viral Load | ||||||||||
| Status: | Updated | |||||||||
| Description: | Determining policies to end the SARS-CoV-2 pandemic will require an understanding of the efficacy and effectiveness (hereafter, efficacy) of vaccines. Beyond the efficacy against severe disease and symptomatic and asymptomatic infection, understanding vaccine efficacy against virus transmission, including efficacy against transmission of different viral variants, will help model epidemic trajectory and determine appropriate control measures. Recent studies have proposed using random virologic testing in individual randomized controlled trials to improve estimation of vaccine efficacy against infection. We propose to further use the viral load measures from these tests to estimate efficacy against transmission. This estimation requires a model of the relationship between viral load and transmissibility and assumptions about the vaccine effect on transmission and the progress of the epidemic. We describe these key assumptions, potential violations of them, and solutions that can be implemented to mitigate these violations. Assessing these assumptions and implementing this random sampling, with viral load measures, will enable better estimation of the crucial measure of vaccine efficacy against transmission. | |||||||||
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| DOI: | 10.21430/M3NE47YVTE | |||||||||
| Subjects: | 0 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2315: Seasonal COVID-19 surge related hospital volumes and case fatality rates | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Background: Seasonal and regional surges in COVID-19 have imposed substantial strain on healthcare systems. Whereas sharp inclines in hospital volume were accompanied by overt increases in case fatality rates during the very early phases of the pandemic, the relative impact during later phases of the pandemic are less clear. We sought to characterize how the 2020 winter surge in COVID-19 volumes impacted case fatality in an adequately-resourced health system. Methods: We performed a retrospective cohort study of all adult diagnosed with COVID-19 in a large academic healthcare system between August 25, 2020 to May 8, 2021, using multivariable logistic regression to examine case fatality rates across 3 sequential time periods around the 2020 winter surge: pre-surge, surge, and post-surge. Subgroup analyses of patients admitted to the hospital and those receiving ICU-level care were also performed. Additionally, we used multivariable logistic regression to examine risk factors for mortality during the surge period. Results: We studied 7388 patients (aged 52.8 ± 19.6 years, 48% male) who received outpatient or inpatient care for COVID-19 during the study period. Patients treated during surge (N = 6372) compared to the pre-surge (N = 536) period had 2.64 greater odds (95% CI 1.46-5.27) of mortality after adjusting for sociodemographic and clinical factors. Adjusted mortality risk returned to pre-surge levels during the post-surge period. Notably, first-encounter patient-level measures of illness severity appeared higher during surge compared to non-surge periods. Conclusions: We observed excess mortality risk during a recent winter COVID-19 surge that was not explained by conventional risk factors or easily measurable variables, although recovered rapidly in the setting of targeted facility resources. These findings point to how complex interrelations of population- and patient-level pandemic factors can profoundly augment health system strain and drive dynamic, if short-lived, changes in outcomes. | ||||||||||||
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| DOI: | 10.21430/M3JSHP7C23 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2316: Seroprevalence of antibodies to SARS-CoV-2 in healthcare workers: a cross-sectional study | |||||||||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||||||||
| Description: | Objective: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers. Design: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires. Settings: A multisite healthcare delivery system located in Los Angeles County. Participants: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions. Main outcomes: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection. Results: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors. Conclusion and relevance: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19. | ||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M3OARX7MTO | ||||||||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||||||||
| SDY2317: Infection and Vaccine-Induced Neutralizing-Antibody Responses to the SARS-CoV-2 B.1.617 Variants | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The B.1.617.1 (or kappa) and B.1.617.2 (or delta) variants were first identified in India and have rapidly spread to several countries throughout the world. These variants contain mutations within the spike protein locat- ed in antigenic sites recognized by antibodies with potent neutralizing activity. We used serum samples obtained from infected and vaccinated persons to assess neutralizing activity against the SARS-CoV-2 variants in a live-virus assay. | ||||||||||||
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| DOI: | 10.21430/M3MY26YEQB | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2319: Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Study shows that the BA.2.12.1, BA.4, and BA.5 subvariants substantially escape neutralizing antibodies induced by both vaccination and infection. | |||||||||
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| DOI: | 10.21430/M3ELUY0H0W | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2321: Humoral profiling of pediatric patients with cancer reveals robust immunity following anti-SARS-CoV-2 vaccination superior to natural infection | |||||||
| Status: | Updated | ||||||
| Description: | Background: Pediatric patients with cancer infected with COVID-19 may be at higher risk of severe disease and may be unable to mount an adequate response to the virus due to compromised immunity secondary to their cancer therapy. Procedure: This study presents immunologic analyses of 20 pediatric patients with cancer, on active chemotherapy or having previously received chemotherapy, and measures their immunoglobulin titers and activation of cellular immunity response to acute SARS-CoV-2 infection and COVID-19 vaccination compared with healthy pediatric controls. Results: Forty-three patients were enrolled, of which 10 were actively receiving chemotherapy, 10 had previously received chemotherapy, and 23 were healthy controls. Pediatric patients with cancer had similar immunoglobulin titers, antibody binding capacity, and effector function assay activity after vaccination against COVID-19 compared with healthy controls, though more variability in response was noted in the cohort actively receiving chemotherapy. Compared with acute infection, vaccination against COVID-19 produced superior immunoglobulin responses, particularly IgA1, IgG1, and IgG3, and elicited superior binding capacity and effector function in children with cancer and healthy controls. Conclusions: Pediatric patients receiving chemotherapy and those who had previously received chemotherapy had adequate immune activation after both vaccination and acute infection compared to healthy pediatric controls, although there was a demonstrated variability in response for the patients on active chemotherapy. Vaccination against COVID-19 produced superior immune responses compared to acute SARS-CoV-2 infection in pediatric patients with cancer and healthy children, underscoring the importance of vaccination even in previously infected individuals. | ||||||
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| DOI: | 10.21430/M33P8B9NUW | ||||||
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| SDY2323: BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection. | ||||||||||||||||||
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| DOI: | 10.21430/M3F5BNG7XB | ||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||
| SDY2325: COVID-19 Booster Uptake among First Responders and Their Household Members May Be Lower than Anticipated | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Background: COVID-19 vaccination status varies widely among law enforcement and emergency medical services professionals. Though at high risk of exposure, these first responders have demonstrated significant vaccine hesitancy, with only 70% reportedly vaccinated. We sought to understand whether similar vaccine hesitancy exists for first responders and their household contacts around COVID-19 boosters. Methods: In a prospective longitudinal cohort of first responders and their household contacts, survey data was collected, including demographics, medical history, COVID-19 exposure risks, and vaccination and/or booster status. The statistical analysis focused on primary vaccination and booster rates of both the first responders and their household contacts. Results: Across 119 study participants, 73% reported having received some combination of vaccine and/or booster, and 26% were unvaccinated. Vaccinated individuals were older, reported less prior exposure to COVID-19 and had more comorbidities. Only 23% reported having received a COVID-19 booster. Pairing of the data for household contacts demonstrated a 60% agreement to receive primary vaccination but only a 20% agreement for boosters within households. Conclusions: This study provides insight into the vaccination and booster rates of first responders and household contacts. Focused efforts to enhance vaccinations is essential for the protection and maintenance of this critical workforce. | ||||||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3V9IIIKI3 | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
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| Assays: | None | ||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2326: Mucosal nanobody IgA as inhalable and affordable prophylactic and therapeutic treatment against SARS-CoV-2 and emerging variants | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Anti-COVID antibody therapeutics have been developed but not widely used due to their high cost and escape of neutralization from the emerging variants. Here, we describe the development of VHH-IgA1.1, a nanobody IgA fusion molecule as an inhalable, affordable and less invasive prophylactic and therapeutic treatment against SARS-CoV-2 Omicron variants. VHH-IgA1.1 recognizes a conserved epitope of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) and potently neutralizes major global SARS-CoV-2 variants of concern (VOC) including the Omicron variant and its sub lineages BA.1.1, BA.2 and BA.2.12.1. VHH-IgA1.1 is also much more potent against Omicron variants as compared to an IgG Fc fusion construct, demonstrating the importance of IgA mediated mucosal protection for Omicron infection. Intranasal administration of VHH-IgA1.1 prior to or after challenge conferred significant protection from severe respiratory disease in K18-ACE2 transgenic mice infected with SARS-CoV-2 VOC. More importantly, for cost-effective production, VHH-IgA1.1 produced in Pichia pastoris had comparable potency to mammalian produced antibodies. Our study demonstrates that intranasal administration of affordably produced VHH-IgA fusion protein provides effective mucosal immunity against infection of SARS-CoV-2 including emerging variants. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3I8SDCBK5 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2327: mRNA-1273 vaccine-induced antibodies maintain Fc effector functions across SARS-CoV-2 variants of concern | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | SARS-CoV-2 mRNA vaccines confer robust protection against COVID-19, but the emergence of variants has generated concerns regarding the protective efficacy of the currently approved vaccines, which lose neutralizing potency against some variants. Emerging data suggest that antibody functions beyond neutralization may contribute to protection from the disease, but little is known about SARS-CoV-2 antibody effector functions. Here, we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs). Although the neutralizing responses to VOCs decreased in both groups, the Fc-mediated responses were distinct. In convalescent individuals, although antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued to interact with Fc-receptors and mediate antibody effector functions. These data point to a resilience in the mRNA-vaccine-induced humoral immune response that may continue to offer protection from SARS-CoV-2 VOCs independent of neutralization. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3LZ41HGX6 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2328: The Kinetics of SARS-CoV-2 Antibody Development Is Associated with Clearance of RNAemia | ||||||||||
| Status: | Updated | |||||||||
| Description: | Persistent SARS-CoV-2 replication and systemic dissemination are linked to increased COVID-19 disease severity and mortality. However, the precise immune profiles that track with enhanced viral clearance, particularly from systemic RNAemia, remain incompletely defined. To define whether antibody characteristics, specificities, or functions that emerge during natural infection are linked to accelerated containment of viral replication, we examined the relationship of SARS-CoV-2-specific humoral immune evolution in the setting of SARS-CoV-2 plasma To define whether antibody characteristics, specificities, or functions that emerge during natural infection are linked to accelerated containment of viral replication, we examined the relationship of SARS-CoV-2-specific humoral immune evolution in the setting of SARS-CoV-2 plasma RNAemia, which is tightly associated with disease severity and death. On presentation to the emergency department, S-specific IgG3, IgA1, and Fc-γ-receptor (Fcγ R) binding antibodies were all inversely associated with higher baseline plasma RNAemia. Importantly, the rapid development of spike (S) and its subunit (S1/S2/receptor binding domain)-specific IgG, especially FcγR binding activity, were associated with clearance of RNAemia. These results point to a potentially critical and direct role for SARS-CoV-2-specific humoral immune clearance on viral dissemination, persistence, and disease outcome, providing novel insights for the development of more effective therapeutics to resolve COVID-19. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M31UN2QQ3Z | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2329: Serological Markers of SARS-CoV-2 Reinfection | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | As public health guidelines throughout the world have relaxed in response to vaccination campaigns against SARS-CoV-2, it is likely that SARS-CoV-2 will remain endemic, fueled by the rise of more infectious SARS-CoV-2 variants. Moreover, in the setting of waning natural and vaccine immunity, reinfections have emerged across the globe, even among previously infected and vaccinated individuals. As such, the ability to detect reexposure to and reinfection by SARS-CoV-2 is a key component for global protection against this virus and, more importantly, against the potential emergence of vaccine escape mutations. Accordingly, there is a strong and continued need for the development and deployment of simple methods to detect emerging hot spots of reinfection to inform targeted pandemic response and containment, including targeted and specific deployment of vaccine booster campaigns. In this study, we identify simple, rapid immune biomarkers of reinfection in rhesus macaques, including IgG3 antibody levels against nucleocapsid and FcγR2A receptor binding activity of anti-RBD antibodies, that are recapitulated in human reinfection cases. As such, this cross-species analysis underscores the potential utility of simple antibody titers and function as price-effective and scalable markers of reinfection to provide increased resolution and resilience against new outbreaks. IMPORTANCE As public health and social distancing guidelines loosen in the setting of waning global natural and vaccine immunity, a deeper understanding of the immunological response to reexposure and reinfection to this highly contagious pathogen is necessary to maintain public health. Viral sequencing analysis provides a robust but unrealistic means to monitor reinfection globally. The identification of scalable pathogen-specific biomarkers of reexposure and reinfection, however, could significantly accelerate our capacity to monitor the spread of the virus through naive and experienced hosts, providing key insights into mechanisms of disease attenuation. Using a nonhuman primate model of controlled SARS-CoV-2 reexposure, we deeply probed the humoral immune response following rechallenge with various doses of viral inocula. We identified virus-specific humoral biomarkers of reinfection, with significant increases in antibody titer and function upon rechallenge across a range of humoral features, including IgG1 to the receptor binding domain of the spike protein of SARS-CoV-2 (RBD), IgG3 to the nucleocapsid protein (N), and FcγR2A receptor binding to anti-RBD antibodies. These features not only differentiated primary infection from reexposure and reinfection in monkeys but also were recapitulated in a sequencing-confirmed reinfection patient and in a cohort of putatively reinfected humans that evolved a PCR-positive test in spite of preexisting seropositivity. As such, this cross-species analysis using a controlled primate model and human cohorts reveals increases in antibody titers as promising cross-validated serological markers of reinfection and reexposure. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M363FLUDZ8 | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2330: Compromised Humoral Functional Evolution Tracks with SARS-CoV-2 Mortality | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | The urgent need for an effective SARS-CoV-2 vaccine has forced development to progress in the absence of well-defined correlates of immunity. While neutralization has been linked to protection against other pathogens, whether neutralization alone will be sufficient to drive protection against SARS-CoV-2 in the broader population remains unclear. Therefore, to fully define protective humoral immunity, we dissected the early evolution of the humoral response in 193 hospitalized individuals ranging from moderate to severe. Although robust IgM and IgA responses evolved in both survivors and non-survivors with severe disease, non-survivors showed attenuated IgG responses, accompanied by compromised Fcɣ receptor binding and Fc effector activity, pointing to deficient humoral development rather than disease-enhancing humoral immunity. In contrast, individuals with moderate disease exhibited delayed responses that ultimately matured. These data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection and the need for early functional humoral immunity. | |||||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3Z7DQQQCT | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| Clinical Assessments: | None | |||||||||||||||
| SDY2331: SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children | |||||||||
| Status: | Updated | ||||||||
| Description: | Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings, have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Here we aimed to deeply profile the vaccine-induced humoral immune response in 6 to 11 year old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children that experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100 μg dose, but more variable immunity at a 50 μg dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain-binding, but robustly preserved omicron spike protein-binding. Fc-receptor binding capabilities were also preserved in a dose dependent manner. These data indicate that both the 50 μg and 100 μg doses of mRNA vaccination in children elicits robust cross-VOC antibody responses and that 100 μg doses in children results in highly preserved omicron-specific functional humoral immunity. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3CGGNTLBL | ||||||||
| Subjects: | 0 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2332: Selective transfer of maternal antibodies in preterm and fullterm children | |||||||
| Status: | Updated | ||||||
| Description: | Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether maternal-fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3MPZ42LIC | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY2333: Humoral signatures of protective and pathological SARS-CoV-2 infection in children | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M33P84EYFU | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2334: Case-Control Study of Individuals with Discrepant Nucleocapsid and Spike Protein SARS-CoV-2 IgG Results | ||||||||||
| Status: | Updated | |||||||||
| Description: | Laboratory-based methods for SARS- CoV-2 antibody detection vary widely in performance. However, there are limited prospectively-collected data on assay performance, and minimal clinical information to guide interpretation of discrepant results. Over a 2-week period, 1080 consecutive plasma samples submitted for clinical SARS-CoV-2 IgG testing were tested in parallel for anti-nucleocap- sid IgG (anti-N, Abbott) and anti-spike IgG (anti-S1, EUROIMMUN). Chart review was conducted for samples testing positive or borderline on either assay, and for an age/sex-matched cohort of samples negative by both assays. CDC surveillance case definitions were used to determine clinical sensitivity/specificity and conduct receiver operating characteristics curve analysis. There were 52 samples positive by both meth- ods, 2 positive for anti-N only, 34 positive for anti-S1 only, and 27 borderline for anti-S1. Of the 34 individu- als positive for anti-S1 alone, 8 (24%) had confirmed COVID-19. No anti-S1 borderline cases were positive for anti-N or had confirmed/probable COVID-19. The anti-N assay was less sensitive (84.2% [95% CI 72.1- 92.5%] vs 94.7% [95% CI 85.4-98.9%]) but more spe- cific (99.2% [95% CI 95.5-100%] vs 86.9% [95% CI 79.6-92.3%]) than anti-S1. Abbott anti-N sensitivity could be improved to 96.5% with minimal effect on specificity if the index threshold was lowered from 1.4 to 0.6. Real-world concordance between differ- ent serologic assays may be lower than previously described in retrospective studies. These findings have implications for the interpretation of SARS-CoV-2 IgG results, especially with the advent of spike antigen- targeted vaccination, as a subset of patients with true infection are anti-N negative and anti-S1 positive. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3DS84ZIC4 | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2335: Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response | |||||||||
| Status: | Updated | ||||||||
| Description: | Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody titer, Fc-receptor binding, and Fc-mediated functional assays in CP units, as well as in plasma from hospitalized COVID-19 patients before and after CP administration. The profiling results show that, although all recipients exhibit expanded SARS-CoV-2-specific humoral immune responses, CP units contain more functional antibodies than recipient plasma. Meanwhile, CP functional profiles influence the evolution of recipient humoral immunity in conjuncture with the recipient's pre-existing SARS-CoV2-specific antibody titers: CP-derived SARS-CoV-2 nucleocapsid-specific antibody functions are associated with muted humoral immune evolution in patients with high titer anti-spike IgG. Our data thus provide insights into the unexpected impact of CP-derived functional anti-spike and anti-nucleocapsid antibodies on the evolution of SARS-CoV-2-specific response following severe infection. | ||||||||
| Program/Contract: |
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| DOI: | 10.21430/M35T1O3RCQ | ||||||||
| Subjects: | 0 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY2336: Evaluation of SARS-CoV-2 total antibody detection via a lateral flow nanoparticle fluorescence immunoassay | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: The coronavirus disease 2019 (COVID-19) endgame may benefit from simple, accurate antibody testing to characterize seroprevalence and immunization coverage. Objectives: To evaluate the performance of the lateral flow QIAreach anti-SARS-CoV-2 Total rapid nanoparticle fluorescence immunoassay compared to reference isotype-specific IgG, IgM, and IgA SARS-CoV-2 ELISA using S1 or receptor binding domain (RBD) as antigens. Study design: A diagnostic comparison study was carried out using 154 well-characterized heparin plasma samples. Agreement between assays was assessed by overall, positive, and negative percent agreement and Cohen's kappa coefficient. Results: Overall agreement between the QIAreach anti-SARS-CoV-2 Total and any anti-spike domain (S1 or RBD) antibody isotype was 96.0 % (95 % CI 89.8-98.8), the positive percent agreement was 97.6 % (95 % CI 91.0-99.9), the negative percent agreement was 88.2 % (95 % CI 64.4-98.0). The kappa coefficient was 0.86 (95 % CI 0.72 to 0.99). Conclusion: The QIAreach anti-SARS-CoV-2 Total rapid antibody test provides comparable performance to high-complexity, laboratory-based ELISA. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3I852KR2U | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2337: Compromised SARS-CoV-2-specific placental antibody transfer | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design. | ||||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3VD2DZFRS | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY2338: Mouse Adapted SARS-CoV-2 (MA10) Viral Infection Induces Neuroinflammation in Standard Laboratory Mice | ||||||||||
| Status: | Updated | |||||||||
| Description: | Increasing evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacts neurological function both acutely and chronically, even in the absence of pronounced respiratory distress. Developing clinically relevant laboratory mouse models of the neuropathogenesis of SARS-CoV-2 infection is an important step toward elucidating the underlying mechanisms of SARS-CoV-2-induced neurological dysfunction. Although various transgenic models and viral delivery methods have been used to study the infection potential of SARS-CoV-2 in mice, the use of commonly available laboratory mice would facilitate the study of SARS-CoV-2 neuropathology. Herein we show neuroinflammatory profiles of immunologically intact mice, C57BL/6J and BALB/c, as well as immunodeficient (Rag2−/−) mice, to a mouse-adapted strain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 (MA10)). Our findings indicate that brain IL-6 levels are significantly higher in BALB/c male mice infected with SARS-CoV-2 MA10. Additionally, blood-brain barrier integrity, as measured by the vascular tight junction protein claudin-5, was reduced by SARS-CoV-2 MA10 infection in all three strains. Brain glial fibrillary acidic protein (GFAP) mRNA was also elevated in male C57BL/6J infected mice compared with the mock group. Lastly, immune-vascular effects of SARS-CoV-2 (MA10), as measured by H&E scores, demonstrate an increase in perivascular lymphocyte cuffing (PLC) at 30 days post-infection among infected female BALB/c mice with a significant increase in PLC over time only in SARS-CoV-2 MA10) infected mice. Our study is the first to demonstrate that SARS-CoV-2 (MA10) infection induces neuroinflammation in laboratory mice and could be used as a novel model to study SARS-CoV-2-mediated cerebrovascular pathology. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3MGIPQRJW | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2340: Reduced antibody activity against SARS-CoV-2 B.1.617.2 delta virus in serum of mRNA-vaccinated individuals receiving tumor necrosis factor-α inhibitors | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Background: Although vaccines effectively prevent coronavirus disease 2019 (COVID-19) in healthy individuals, they appear to be less immunogenic in individuals with chronic inflammatory disease (CID) or receiving chronic immunosuppression therapy. Methods: Here we assessed a cohort of 77 individuals with CID treated as monotherapy with chronic immunosuppressive drugs for antibody responses in serum against historical and variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses after immunization with the BNT162b2 mRNA vaccine. Findings: Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with tumor necrosis factor alpha (TNF-α) inhibitors (TNFi), and this pattern appeared to be worse against the B.1.617.2 delta virus. Within 5 months of vaccination, serum neutralizing titers of all TNFi-treated individuals tested fell below the presumed threshold correlate for antibody-mediated protection. However, TNFi-treated individuals receiving a third mRNA vaccine dose boosted their serum neutralizing antibody titers by more than 16-fold. Conclusions: Vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) will likely be required to prevent SARS-CoV-2 infection in this susceptible population. Funding: This study was supported by grants and contracts from the NIH (R01 AI157155, R01AI151178, and HHSN75N93019C00074; NIAID Centers of Excellence for Influenza Research and Response (CEIRR) contracts HHSN272201400008C and 75N93021C00014; and Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051). | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M367HK3SG8 | ||||||||||
| Subjects: | 0 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY2341: Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness | ||||||||||
| Status: | Updated | |||||||||
| Description: | The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness. | |||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3FFX45TTD | |||||||||
| Subjects: | 0 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2342: Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines | |||||||
| Status: | Updated | ||||||
| Description: | Despite the successes of current coronavirus disease 2019 (COVID-19) vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infections and diseases among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following Pfizer/BNT162b2, Moderna mRNA-1273, ChadOx1/AZD1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1 domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2. | ||||||
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| DOI: | 10.21430/M3SRNQ6IU1 | ||||||
| Subjects: | 0 | ||||||
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| SDY2343: Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M vaccination | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants. | ||||||||||||||||
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| DOI: | 10.21430/M3U21VQOCM | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| SDY2344: Durable protection against the SARS-CoV-2 Omicron variant is induced by an adjuvanted subunit vaccine | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Despite the remarkable efficacy of COVID-19 vaccines, waning immunity and the emergence of SARS-CoV-2 variants such as Omicron represents a global health challenge. Here, we present data from a study in nonhuman primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, which was recently authorized for use in individuals 18 years or older. Vaccination induced neutralizing antibody (nAb) titers that were maintained at high concentrations for at least 1 year after two doses, with a pseudovirus nAb geometric mean titer (GMT) of 1978 and a live virus nAb GMT of 1331 against the ancestral strain but not against the Omicron BA.1 variant. However, a booster dose at 6 to 12 months with RBD-Wu or RBD-β (RBD from the Beta variant) displayed on I53-50 elicited high neutralizing titers against the ancestral and Omicron variants. In addition, we observed persistent neutralization titers against a panel of sarbecoviruses, including SARS-CoV. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Vaccination resulted in protection against Omicron infection in the lung and suppression of viral burden in the nares at 6 weeks after the final booster immunization. Even at 6 months after vaccination, we observed protection in the lung and rapid control of virus in the nares. These results highlight the durable and cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine. | ||||||||||||
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| DOI: | 10.21430/M3FBIXLU6O | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2345: Phosphatidylserine receptors enhance SARS-CoV-2 infection | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | Phosphatidylserine (PS) receptors enhance infection of many enveloped viruses through virion-associated PS binding that is termed apoptotic mimicry. Here we show that this broadly shared uptake mechanism is utilized by SARS-CoV-2 in cells that express low surface levels of ACE2. Expression of members of the TIM (TIM-1 and TIM-4) and TAM (AXL) families of PS receptors enhance SARS-CoV-2 binding to cells, facilitate internalization of fluorescently-labeled virions and increase ACE2-dependent infection of SARS-CoV-2; however, PS receptors alone did not mediate infection. We were unable to detect direct interactions of the PS receptor AXL with purified SARS-CoV-2 spike, contrary to a previous report. Instead, our studies indicate that the PS receptors interact with PS on the surface of SARS-CoV-2 virions. In support of this, we demonstrate that: 1) significant quantities of PS are located on the outer leaflet of SARS-CoV-2 virions, 2) PS liposomes, but not phosphatidylcholine liposomes, reduced entry of VSV/Spike pseudovirions and 3) an established mutant of TIM-1 which does not bind to PS is unable to facilitate entry of SARS-CoV-2. As AXL is an abundant PS receptor on a number of airway lines, we evaluated small molecule inhibitors of AXL signaling such as bemcentinib for their ability to inhibit SARS-CoV-2 infection. Bemcentinib robustly inhibited virus infection of Vero E6 cells as well as multiple human lung cell lines that expressed AXL. This inhibition correlated well with inhibitors that block endosomal acidification and cathepsin activity, consistent with AXL-mediated uptake of SARS-CoV-2 into the endosomal compartment. We extended our observations to the related betacoronavirus mouse hepatitis virus (MHV), showing that inhibition or ablation of AXL reduces MHV infection of murine cells. In total, our findings provide evidence that PS receptors facilitate infection of the pandemic coronavirus SARS-CoV-2 and suggest that inhibition of the PS receptor AXL has therapeutic potential against SARS-CoV-2. | ||||||||||||||
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| DOI: | 10.21430/M3R54VI9B8 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| SDY2346: Early cross-coronavirus reactive signatures of humoral immunity against COVID-19 | ||||||||||
| Status: | Updated | |||||||||
| Description: | The introduction of vaccines has inspired hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against SARS-CoV-2, thus we profiled the earliest humoral signatures in a large cohort of acutely ill (survivors and nonsurvivors) and mild or asymptomatic individuals with COVID-19. Although a SARS-CoV-2–specific immune response evolved rapidly in survivors of COVID-19, nonsurvivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibodies. Given the conservation of S2 across β-coronaviruses, we found that the early development of SARS-CoV-2–specific immunity occurred in tandem with preexisting common β-coronavirus OC43 humoral immunity in survivors, which was also selectively expanded in individuals that develop a paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19. | |||||||||
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| DOI: | 10.21430/M3NEC9ABZ2 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2347: COVID-19 booster dose induces robust antibody response in pregnant, lactating, and nonpregnant women | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Although emerging data during the SARS-CoV-2 pandemic have demonstrated robust messenger RNA vaccine-induced immunogenicity across populations, including pregnant and lactating individuals, the rapid waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of messenger RNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known. Objective: This study aimed to profile the humoral immune response to a COVID-19 messenger RNA booster dose in a cohort of pregnant, lactating, and nonpregnant age-matched women. Study design: This study characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating, and 20 nonpregnant age-matched controls who received a BNT162b2 or messenger RNA-1273 booster dose after primary COVID-19 vaccination. In addition, this study examined the vaccine-induced antibody profiles of 15 maternal-to-cord dyads at delivery. Results: Receiving a booster dose during pregnancy resulted in increased immunoglobulin G1 levels against Omicron Spike (postprimary vaccination vs postbooster dose; P=.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total immunoglobulin G1, immunoglobulin M, and immunoglobulin A levels and neutralizing titers against Omicron compared with nonpregnant women. Subtle differences in Fc receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant vs nonpregnant individuals. The analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific immunoglobulin G1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (P=.002), consistent with the preferential transfer of highly functional immunoglobulin. Spike-specific immunoglobulin G1 levels in the cord were positively correlated with the time elapsed since receiving the booster dose (Spearman R, .574; P=.035). Conclusion: Study data suggested that receiving a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester of pregnancy, higher Spike-specific cord immunoglobulin G1 levels are achieved with greater time elapsed between receiving the booster and delivery. Receiving a booster dose has the potential to augment maternal and neonatal immunity. | |||||||||
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| DOI: | 10.21430/M3ZR1DTL20 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2348: Immunogenicity and protective efficacy of a rhesus adenoviral vaccine targeting conserved COVID-19 replication transcription complex | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | The COVID-19 pandemic marks the third coronavirus pandemic this century (SARS-CoV-1, MERS, SARS-CoV-2), emphasizing the need to identify and evaluate conserved immunogens for a pan-sarbecovirus vaccine. Here we investigate the potential utility of a T-cell vaccine strategy targeting conserved regions of the sarbecovirus proteome. We identified the most conserved regions of the sarbecovirus proteome as portions of the RNA-dependent RNA polymerase (RdRp) and Helicase proteins, both of which are part of the coronavirus replication transcription complex (RTC). Fitness constraints suggest that as SARS-CoV-2 continues to evolve these regions may better preserve cross-reactive potential of T-cell responses than Spike, Nucleocapsid, or Membrane proteins. We sought to determine if vaccine-elicited T-cell responses to the highly conserved regions of the RTC would reduce viral loads following challenge with SARS-CoV-2 in mice using a rhesus adenovirus serotype 52 (RhAd52) vector. The RhAd52.CoV.Consv vaccine generated robust cellular immunity in mice and led to significant reductions in viral loads in the nasal turbinates following challenge with a mouse-adapted SARS-CoV-2. These data suggest the potential utility of T-cell targeting of conserved regions for a pan-sarbecovirus vaccine. | |||||||||||||||
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| DOI: | 10.21430/M3R6ELP1QB | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| SDY2355: Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling | |||||||||||||||||
| Status: | Updated | ||||||||||||||||
| Description: | Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice. | ||||||||||||||||
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| DOI: | 10.21430/M35CKYIPBS | ||||||||||||||||
| Subjects: | 0 | ||||||||||||||||
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| SDY2356: The Serological Sciences Network (SeroNet) for COVID-19: Depth and Breadth of Serology Assays and Plans for Assay Harmonization | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description: | In October 2020, the National Cancer Institute (NCI) Serological Sciences Network (SeroNet) was established to study the immune response to COVID-19, and ""to develop, validate, improve, and implement serological testing and associated technologies"" (https://www.cancer.gov/research/key-initiatives/covid-19/coronavirus-research-initiatives/serological-sciences-network). SeroNet is comprised of 25 participating research institutions partnering with the Frederick National Laboratory for Cancer Research (FNLCR) and the SeroNet Coordinating Center. Since its inception, SeroNet has supported collaborative development and sharing of COVID-19 serological assay procedures and has set forth plans for assay harmonization. To facilitate collaboration and procedure sharing, a detailed survey was sent to collate comprehensive assay details and performance metrics on COVID-19 serological assays within SeroNet. In addition, FNLCR established a protocol to calibrate SeroNet serological assays to reference standards, such as the U.S. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology standard reference material and first WHO international standard (IS) for anti-SARS-CoV-2 immunoglobulin (20/136), to facilitate harmonization of assay reporting units and cross-comparison of study data. SeroNet institutions reported development of a total of 27 enzyme-linked immunosorbent assay (ELISA) methods, 13 multiplex assays, and 9 neutralization assays and use of 12 different commercial serological methods. FNLCR developed a standardized protocol for SeroNet institutions to calibrate these diverse serological assays to reference standards. In conclusion, SeroNet institutions have established a diverse array of COVID-19 serological assays to study the immune response to SARS-CoV-2 and vaccines. Calibration of SeroNet serological assays to harmonize results reporting will facilitate future pooled data analyses and study cross-comparisons. IMPORTANCE SeroNet institutions have developed or implemented 61 diverse COVID-19 serological assays and are collaboratively working to harmonize these assays using reference materials to establish standardized reporting units. This will facilitate clinical interpretation of serology results and cross-comparison of research data. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| DOI: | 10.21430/M33Q07AHU9 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SDY2357: Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells. | ||||||||||||||
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| DOI: | 10.21430/M3D5OJ0CDJ | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
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| SDY2372: Sex and Gender Differences in Testing, Hospital Admission, Clinical Presentation, and Drivers of Severe Outcomes From COVID-19 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear. Methods: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5-8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect. Results: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males (P < .001). Among 18-49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18-49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness. Conclusions: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes. | |||||||||
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| DOI: | 10.21430/M3GXSGMPEX | |||||||||
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| SDY2373: Neutralization Escape by SARS-CoV-2 Omicron Subvariant BA.4.6 | ||||||||||
| Status: | Updated | |||||||||
| Description: | The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has splintered into multiple subvariants with increased transmissibility and immune escape.1 At the time of this report, omicron subvariant BA.5 is the dominant global virus and has shown substantial immune escape as compared with previous omicron subvariants.2-5 BA.4.6 is a sublineage of BA.4 with two additional mutations in the spike protein (R346T and N658S) (Figure 1A) and has recently increased in prevalence in certain regions currently dominated by BA.5, including in the United States. The ability of BA.4.6 to evade neutralizing antibodies that were induced by infection or vaccination remains to be determined. | |||||||||
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| DOI: | 10.21430/M3Y1WRSJZ6 | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2374: Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants | |||||||||
| Status: | Updated | ||||||||
| Description: | The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced S1 shedding of their reversion mutants K547T and Y655H in viral producer cells. Importantly, the H655Y mutation also determines the low fusogenicity and enhanced dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5, and BA.2.75. Together, these results uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis. IMPORTANCE Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and reduced disease severity; however, the underlying mechanism is not fully understood. In addition, whether the most recent Omicron subvariants, including BA.5 and BA.2.75, use the same pathway as their ancestor for entry is currently not known. In this study, we show that T547K and H655Y mutations in the C terminus of the S1 subunit critically determine the enhanced dependence on the endosomal entry pathway as well as the reduced cell-cell fusion activity of Omicron BA.1, BA.1.1, and other subvariants. Further experiments and molecular modeling suggest that H655Y and K547T stabilize the spike trimer conformation, likely contributing to the decreased fusogenicity and endosomal entry. Our work uncovers novel mechanisms underlying the distinct entry pathway of Omicron subvariants and advances our understanding of their biological characteristics. | ||||||||
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| DOI: | 10.21430/M3PPVGC75E | ||||||||
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| SDY2375: SARS-CoV-2 Delta variant genomic variation associated with breakthrough infection in Northern California: A retrospective cohort study | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: The association between SARS-CoV-2 genomic variation and breakthrough infection is not well-defined among persons with Delta variant SARS-CoV-2 infection. Methods: In a retrospective cohort we assessed whether individual non-lineage defining mutations and overall genomic variation (including low frequency alleles) were associated with breakthrough infection defined as SARS-CoV-2 infection after COVID-19 primary vaccine series. We identified all non-synonymous single nucleotide polymorphisms, insertions and deletions in SARS-CoV-2 genomes with ≥5% allelic frequency and population frequency of ≥5% and ≤95%. Using Poisson regression, we assessed the association with breakthrough infection for each individual mutation and a viral genomic risk score. Results: Thirty-six mutations met our inclusion criteria. Among 12,744 persons infected with Delta variant SARS-CoV-2, 5,949 (47%) were vaccinated and 6,795 (53%) were unvaccinated. Viruses with a viral genomic risk score in the highest quintile were 9% more likely to be associated with breakthrough infection than viruses in the lowest quintile, but including the risk score improved overall predictive model performance (measured by c-statistic) by only +0.0006. Conclusions: Genomic variation within SARS-CoV-2 Delta variant was weakly associated with breakthrough infection, however several potential non-lineage defining mutations were identified that might contribute to immune evasion by SARS-CoV-2. | |||||||||
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| DOI: | 10.21430/M3CTYNVL3V | |||||||||
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| SDY2376: Coronavirus Disease 2019 Messenger RNA Vaccine Immunogenicity in Immunosuppressed Individuals | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals. | ||||||||||||||||||
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| DOI: | 10.21430/M3XAUTDG0K | ||||||||||||||||||
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| SDY2377: Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | Importance: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these populations are therefore limited. Objective: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern. Design, setting, and participants: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection. Main outcomes and measures: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants. Results: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. Conclusion and relevance: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern. | |||||||||||||||
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| DOI: | 10.21430/M39GU9W1LH | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
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| SDY2378: Characterization of immune responses in fully vaccinated individuals after breakthrough infection with the SARS-CoV-2 delta variant | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been reported frequently in vaccinated individuals with waning immunity. In particular, a cluster of over 1000 infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. In this study, vaccinated individuals who tested positive for SARS-CoV-2 (n = 16) demonstrated substantially higher serum antibody responses than vaccinated individuals who tested negative for SARS-CoV-2 (n = 23), including 32-fold higher binding antibody titers and 31-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed higher mucosal antibody responses in nasal secretions and higher spike protein-specific CD8+ T cell responses in peripheral blood than did vaccinated individuals who tested negative. These data demonstrate that fully vaccinated individuals developed robust anamnestic antibody and T cell responses after infection with the SARS-CoV-2 delta variant. Moreover, these findings suggest that population immunity will likely increase over time by a combination of widespread vaccination and breakthrough infections. | ||||||||||||
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| DOI: | 10.21430/M3EK86TJV6 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2379: Neutralization escape of Omicron XBB, BR.2, and BA.2.3.20 subvariants | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | New Omicron subvariants continue to emerge throughout the world. In particular, the XBB subvariant, which is a recombinant virus between BA.2.10.1.1 and BA.2.75.3.1.1.1, as well as the BA.2.3.20 and BR.2 subvariants that contain mutations distinct from BA.2 and BA.2.75, are currently increasing in proportion of variants sequenced. Here we show that antibodies induced by 3-dose mRNA booster vaccination as well as BA.1- and BA.4/5-wave infection effectively neutralize BA.2, BR.2, and BA.2.3.20 but have significantly reduced efficiency against XBB. In addition, the BA.2.3.20 subvariant exhibits enhanced infectivity in the lung-derived CaLu-3 cells and in 293T-ACE2 cells. Overall, our results demonstrate that the XBB subvariant is highly neutralization resistant, which highlights the need for continued monitoring of the immune escape and tissue tropism of emerging Omicron subvariants. | |||||||||||||||||||||||||||
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| DOI: | 10.21430/M36HJYNY0B | |||||||||||||||||||||||||||
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| SDY2380: Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | As shown in previous studies,the BNT162b2 and mRNA-1273 vaccines were characterized by high peak antibody responses that declined sharply by 6 months; these responses declined further by 8 months. Antibody titers in recipients of the mRNA-1273 vaccine were generally higher than those in recipients of the BNT162b2 vaccine. The Ad26.COV2.S vaccine induced lower initial antibody responses, but these responses were relatively stable over the 8-month follow-up period, with minimal-to-no evidence of decline. | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3DT6LU7EW | ||||||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY2381: Right Ventricular Abnormality in Patients Hospitalized With COVID-19 Infection During Omicron Variant Surge. | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | We aimed at studying the association of in-hospital mortality with echocardiographic measures of RV performance during the COVID-19 infection surge in New York City attributed to the spread of the Omicron variant. | ||||||||||||
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| DOI: | 10.21430/M3YP5OULP0 | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2382: Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study | ||||||||||
| Status: | Updated | |||||||||
| Description: | Background: Pregnant and lactating women were excluded from initial coronavirus disease 2019 vaccine trials; thus, data to guide vaccine decision making are lacking. Objective: This study aimed to evaluate the immunogenicity and reactogenicity of coronavirus disease 2019 messenger RNA vaccination in pregnant and lactating women compared with: (1) nonpregnant controls and (2) natural coronavirus disease 2019 infection in pregnancy. Study Design: A total of 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 nonpregnant women) were enrolled in a prospective cohort study at 2 academic medical centers. Titers of severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin G, immunoglobulin A, and immunoglobulin M were quantified in participant sera (n=131) and breastmilk (n=31) at baseline, at the second vaccine dose, at 2 to 6 weeks after the second vaccine, and at delivery by Luminex. Umbilical cord sera (n=10) titers were assessed at delivery. Titers were compared with those of pregnant women 4 to 12 weeks from the natural infection (n=37) by enzyme-linked immunosorbent assay. A pseudovirus neutralization assay was used to quantify neutralizing antibody titers for the subset of women who delivered during the study period. Postvaccination symptoms were assessed via questionnaire. Kruskal-Wallis tests and a mixed-effects model, with correction for multiple comparisons, were used to assess differences among groups. | |||||||||
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| DOI: | 10.21430/M3E2GTI9WO | |||||||||
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| SDY2383: Methodological approaches to optimize multiplex oral fluid SARS-CoV-2 IgG assay performance and correlation with serologic and neutralizing antibody responses | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Background: Oral fluid (hereafter, saliva) is a non-invasive and attractive alternative to blood for SARS-CoV-2 IgG testing; however, the heterogeneity of saliva as a matrix poses challenges for immunoassay performance. Objectives: To optimize performance of a magnetic microparticle-based multiplex immunoassay (MIA) for SARS-CoV-2 IgG measurement in saliva, with consideration of: i) threshold setting and validation across different MIA bead batches; ii) sample qualification based on salivary total IgG concentration; iii) calibration to U.S. SARS-CoV-2 serological standard binding antibody units (BAU); and iv) correlations with blood-based SARS-CoV-2 serological and neutralizing antibody (nAb) assays. Methods: The salivary SARS-CoV-2 IgG MIA included 2 nucleocapsid (N), 3 receptor-binding domain (RBD), and 2 spike protein (S) antigens. Gingival crevicular fluid (GCF) swab saliva samples were collected before December 2019 (n = 555) and after molecular test-confirmed SARS-CoV-2 infection from 113 individuals (providing up to 5 repeated-measures; n = 398) and used to optimize and validate MIA performance (total n = 953). Combinations of IgG responses to N, RBD and S and total salivary IgG concentration (μg/mL) as a qualifier of nonreactive samples were optimized and validated, calibrated to the U.S. SARS-CoV-2 serological standard, and correlated with blood-based SARS-CoV-2 IgG ELISA and nAb assays. Results: The sum of signal to cutoff (S/Co) to all seven MIA SARS-CoV-2 antigens and disqualification of nonreactive saliva samples with ≤15 μg/mL total IgG led to correct classification of 62/62 positives (sensitivity [Se] = 100.0%; 95% confidence interval [CI] = 94.8%, 100.0%) and 108/109 negatives (specificity [Sp] = 99.1%; 95% CI = 97.3%, 100.0%) at 8-million beads coupling scale and 80/81 positives (Se = 98.8%; 95% CI = 93.3%, 100.0%] and 127/127 negatives (Sp = 100%; 95% CI = 97.1%, 100.0%) at 20-million beads coupling scale. Salivary SARS-CoV-2 IgG crossed the MIA cutoff of 0.1 BAU/mL on average 9 days post-COVID-19 symptom onset and peaked around day 30. Among n = 30 matched saliva and plasma samples, salivary SARS-CoV-2 MIA IgG levels correlated with corresponding-antigen plasma ELISA IgG (N: ρ = 0.76, RBD: ρ = 0.83, S: ρ = 0.82; all p < 0.001). Correlations of plasma SARS-CoV-2 nAb assay area under the curve (AUC) with salivary MIA IgG (N: ρ = 0.68, RBD: ρ = 0.78, S: ρ = 0.79; all p < 0.001) and with plasma ELISA IgG (N: ρ = 0.76, RBD: ρ = 0.79, S: ρ = 0.76; p < 0.001) were similar. Conclusions: A salivary SARS-CoV-2 IgG MIA produced consistently high Se (> 98.8%) and Sp (> 99.1%) across two bead coupling scales and correlations with nAb responses that were similar to blood-based SARS-CoV-2 IgG ELISA data. This non-invasive salivary SARS-CoV-2 IgG MIA could increase engagement of vulnerable populations and improve broad understanding of humoral immunity (kinetics and gaps) within the evolving context of booster vaccination, viral variants and waning immunity. | ||||||||||||
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| DOI: | 10.21430/M369ETTADW | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| SDY2384: Dissecting strategies to tune the therapeutic potential of SARS-CoV-2–specific monoclonal antibody CR3022 | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross–SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection. | |||||||||||||||
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| DOI: | 10.21430/M3NWOS0BYJ | |||||||||||||||
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| SDY2385: Significant Reduction in Vaccine Induced Antibody Levels and Neutralization Activity Among Healthcare Workers and Nursing Home Residents 6 Months Following Coronavirus Disease 2019 BNT162b2 mRNA Vaccination | |||||||
| Status: | Updated | ||||||
| Description: | Antibody decline occurred from 2 weeks to 6 months post-BNT162b2 mRNA vaccination in nursing home (NH) residents and healthcare workers. Antispike, receptor-binding domain, and neutralization levels dropped >81% irrespective of prior infection. Notably, 69% of infection-naive NH residents had neutralizing antibodies at or below the assay’s limit of detection. | ||||||
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| DOI: | 10.21430/M3ET0ZGOYY | ||||||
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| SDY2386: A Machine Learning Algorithm Predicts Duration of hospitalization in COVID-19 patients. | ||||||||||
| Status: | Updated | |||||||||
| Description: | The COVID-19 pandemic has placed unprecedented strain on the healthcare system, particularly hospital bed capacity in the setting of large variations in patient length of stay (LOS). Using electronic health record data from 966 COVID-19 patients at a large academic medical center, we developed three machine learning algorithms to predict the likelihood of prolonged LOS, defined as >8 days. The models included 353 variables and were trained on 80% of the cohort, with 20% used for model validation. The three models were created on hospital days 1, 2 and 3, each including information available at or before that point in time. The models' predictive capabilities improved sequentially over time, reaching an accuracy of 0.765, with an AUC of 0.819 by day 3. These models, developed using readily available data, may help hospital systems prepare for bed capacity needs, and help clinicians counsel patients on their likelihood of prolonged hospitalization. | |||||||||
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| DOI: | 10.21430/M36U7RSKAO | |||||||||
| Subjects: | 0 | |||||||||
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| SDY2387: Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters | |||||||||||
| Status: | Updated | ||||||||||
| Description: | To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model. | ||||||||||
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| DOI: | 10.21430/M3P39UDC8C | ||||||||||
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| SDY2388: 124I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Purpose: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with 124I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection. Procedures: Pulmonary 124I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues. Results: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased 124I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary 124I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02). Conclusion: 124I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, 124I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19. | ||||||||||
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| DOI: | 10.21430/M3GXF3V8PA | ||||||||||
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| SDY2389: Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (β2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ≤ 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFNγ staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naïve CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naïve CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available. CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients. | ||||||||||
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| DOI: | 10.21430/M3PV8VPKP0 | ||||||||||
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| SDY2390: Conflict in the EMS Workforce: An Analysis of an Open-Ended Survey Question Reveals a Complex Assemblage of Stress, Burnout, and Pandemic-Related Factors Influencing Well-Being | ||||||||||
| Status: | Updated | |||||||||
| Description: | Emergency Medical Services (EMS) clinicians provide patient care within a high-stakes, unpredictable, and complex work environment in which conflict is inevitable. Our objective was to explore the extent to which added stressors of the pandemic exacerbated EMS workplace conflict. We administered our survey to a sample of U.S. nationally certified EMS clinicians during the COVID-19 pandemic in April 2022. Out of 1881 respondents, 46% (n = 857) experienced conflict and 79% (n = 674) provided free-text descriptions of their experience. The responses were analyzed for themes using qualitative content analysis, and they were then sorted into codes using word unit sets. Code counts, frequencies, and rankings were tabulated, enabling quantitative comparisons of the codes. Of the fifteen codes to emerge, stress (a precursor of burnout) and burnout-related fatigue were the key factors contributing to EMS workplace conflict. We mapped our codes to a conceptual model guided by the National Academies of Sciences, Engineering, and Medicine (NASEM) report on using a systems approach to address clinician burnout and professional well-being to explore implications for addressing conflict within that framework. Factors attributed to conflict mapped to all levels of the NASEM model, lending empirical legitimacy to a broad systems approach to fostering worker well-being. Our findings lead us to propose that active surveillance (enhanced management information and feedback systems) of frontline clinicians' experiences during public health emergencies could increase the effectiveness of regulations and policies across the healthcare system. Ideally, the contributions of the occupational health discipline would become a mainstay of a sustained response to promote ongoing worker well-being. The maintenance of a robust EMS workforce, and by extension the health professionals in its operational sphere, is unquestionably essential to our preparedness for the likelihood that pandemic threats may become more commonplace. | |||||||||
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| DOI: | 10.21430/M3E361589T | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2398: Mucosal antibody responses to SARS-CoV-2 booster vaccination and breakthrough infection | ||||||||||
| Status: | Updated | |||||||||
| Description: | Here, the investigators analyzed samples from the PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2) study and measured serum IgG, saliva IgG and saliva secretory IgA responses in individuals who experienced breakthrough infections and who received COVID-19 mRNA booster vaccinations. | |||||||||
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| DOI: | 10.21430/M3JDI4T17W | |||||||||
| Subjects: | 111 | |||||||||
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| Publications: | None | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY2399: Preconception Genetic Carrier Screening for Miscarriage Risk Assessment: A Bioinformatic Approach to Identifying Candidate Lethal Genes and Variants | |||||||
| Status: | Updated | ||||||
| Description: | Purpose: Miscarriage, due to genetically heterogeneous etiology, is a common outcome of pregnancy. Preconception genetic carrier screening (PGCS) currently identifies at-risk partners for newborn genetic disorders; however, miscarriage-related genes are currently not part of the PGCS panels. Here we assessed the theoretical impact of known and candidate genes on prenatal lethality and the PGCS among diverse populations. Methods: We used a bioinformatic approach to define genes essential for human fetal survival (lethal genes), identify variants that are absent in a homozygous state in healthy human population, and to estimate heterozygous carrier rates for known recessive lethal Mendelian conditions and candidate lethal genes. Results: A total of 3080 known and candidate lethal genes were identified. Allele carrier frequencies were evaluated for 20398 pathogenic/likely pathogenic and loss-of-function (LoF) variants in 468 known human lethal genes, and 62815 LoF variants in 2612 candidate genes. In 163 genes, potential lethal variants are present in the general population with high frequency of at least 0.1%. Conclusion: This study identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The diversity of these genes amongst the various ethnic groups underscores the importance of designing a pan-ethnic PGCS panel comprising miscarriage-related genes. Keywords: population carrier screening, lethal genes, intolerome, pregnancy loss, miscarriage. | ||||||
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| DOI: | 10.21430/M32PG4UUJV | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||