DR53 DataRelease
Release Date: September 2024
New Studies: 47
Updated Studies: 10
New Studies
| SDY1252: innate immune responses to AS03 adjuvanted vs. non-adjuvanted H5N1 vaccine | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Study the effect of AS03 adjuvant on the innate/early immune response to H5N1, avian flu, a potentially lethal disease that most subjects are assumed to be naive to. AS03 is an adjuvant oil in water emulsion containing DL-alpha-tocopherol, squalene and the non-ionic detergent Tween 80 that has been widely used as an adjuvant to flu vaccines produced by GlaxoSmithKline(GSK). We therefore propose to randomize up to 60 healthy volunteers into two intervention arms (25 volunteers in each arm with up to 10 total replacements in the event a volunteer does not return for the first vaccine). The first arm will receive a vaccine containing H5N1 with AS03 adjuvant, the second arm will receive H5N1 without AS03 adjuvant. Both arms will receive primary and booster vaccination followed by repeated blood sampling to evaluate the immune responses. We will apply high throughput analytic techniques and use systems biology methods to integrate the collected data and draw a description of the immune system response with and without the adjuvant. The primary objective is to compare multiplex immune response signatures following two (primary and a boost) vaccinations with the GSK AS03 adjuvanted H5N1 influenza vaccine or the non-adjuvanted form of the H5N1 influenza vaccine, at the 3.75 mcg dose and given 21 days apart and identify differences in very early innate immune responses. These immune signatures will also be correlated with the clinical observations especially safety related local and systemic events. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3QQEGKR3V | ||||||||||||
| Subjects: | 40 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2428: Antibodies targeting the neuraminidase active site inhibit influenza H3N2 viruses | |||||||
| Status: | New | ||||||
| Description: | Here, three NA monoclonal antibodies are tested against a panel of H3N2 viruses (DBA/2 J mice challenged with reassortant H6N2 viruses). | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3GFX5MZKQ | ||||||
| Subjects: | 60 | ||||||
| Study PI, contact: |
|
||||||
| Publications: | None | ||||||
| Resources: |
|
||||||
| Assays: | None | ||||||
| Clinical Assessments: |
|
||||||
| SDY2431: Activity of convalescent and vaccine serum against Omicron | ||||||||||
| Status: | New | |||||||||
| Description: | Omicron hosts an unprecedented number of mutations in its spike gene and early reports have provided evidence for extensive immune escape and reduced vaccine effectiveness. Here we investigated the virus-neutralizing and spike protein-binding activity of sera from convalescent, double mRNA-vaccinated, mRNA-boosted, convalescent double-vaccinated and convalescent boosted individuals against wild-type, Beta (B.1.351) and Omicron SARS-CoV-2 isolates and spike proteins. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M39F8QLTJH | |||||||||
| Subjects: | 54 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: | None | |||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: |
|
|||||||||
| SDY2492: CRITICAL | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | Cockroach allergen has been established as one of the leading causative agents for morbidity in inner-city children with asthma. Although the negative effects of cockroach exposure have been known for almost 20 years, eradication and avoidance, which can be impossible to achieve in the housing available to lower socioeconomic urban populations. Given these data, a major goal of the NIAID-funded Inner-City Asthma Consortium (ICAC) is to conduct a large multi-center efficacy trial of cockroach immunotherapy in inner-city asthma. We intend in this study to test the effects of cockroach subcutaneous immunotherapy (SCIT) on asthma control, as well as safety and immunologic biomarkers, in a pediatric population. Provocation testing with cockroach allergen is used to objectively document the response to SCIT. Nasal Allergen Challenge (NAC) is an established type of provocation testing commonly used in the research setting to assess early stage efficacy of nasal allergy treatments, including allergen immunotherapy, and to study the pathophysiology of allergic reactions in an accessible part of the respiratory tract. NAC are not lower airway outcomes, but the purpose of using this form of assessment in the context of this trial is to establish that treatment is effective against mucosal reactions to the allergen in question and not to substitute for asthma outcomes. As the majority of children with allergic asthma also have allergic rhinitis and improvement in upper respiratory control is beneficial in asthma, the nasal challenge may have a direct clinical relevance in a study of allergen immunotherapy for asthma. This study is a randomized, double-blind, placebo-controlled, multicenter trial of non-standardized glycerinated German cockroach (Blattella germanica) allergenic extract or placebo treatment administered by subcutaneous injection. | |||||||||||||||||||||
| Program/Contract: |
|
|||||||||||||||||||||
| DOI: | 10.21430/M3532ZIV6B | |||||||||||||||||||||
| Subjects: | 82 | |||||||||||||||||||||
| Study PI, contact: |
|
|||||||||||||||||||||
| Publications: | None | |||||||||||||||||||||
| Resources: |
|
|||||||||||||||||||||
| Assays: | None | |||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2540: RITUX-SW | |||||||
| Status: | New | ||||||
| Description: | Multi-modal biological datasets provide rich information from different scales or aspects of complex biological systems that can be analyzed to highlight the critical multi-scale interactions underlying specific biological phenomena. However, identifying the strongest associations between features and desired outputs can be beset by a high degree of intra-dataset correlation and spurious connections due to indirect impacts of multiple immune features propagating through an unmapped biological network. Here, we applied a probabilistic graphical modeling approach, Markov Fields, to empirically dissect correlations between all features from a public multi-modal dataset (antibody titers, antibody-dependent functions, cytokines, cytometry) from macaques undergoing intravenous BCG vaccination—a promising vaccine strategy against the major public health threat tuberculosis. This yielded an interaction network that interprets the collection of multi-scale paths by which vaccine effects propagate through the immune network to eventually protect against tuberculosis infection. Importantly, the models shows that the vast majority of correlations between features arise indirectly due to multiple interactions connecting distant immune features to each other. We next conducted experimental depletion of B cells during BCG IV vaccination in macaques--which did not reduce BCG IV-mediated protection against tuberculosis—and validated that our Markov Field models can predict subtle systems-wide shifts across the immune system in response to this perturbation. Finally, we also apply our model to highlight immune changes in the network that are predicted to have strong effects on IV-BCG efficacy, showing that probabilistic graphical models increase the interpretability and value of multi-scale datasets for identifying new targets in disease. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M38IT61DK0 | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: |
|
||||||
| Clinical Assessments: | None | ||||||
| SDY2614: Advancement in mice blood based flow cytometry assay | |||||||
| Status: | New | ||||||
| Description: | Optimization of procedure to assess the antigen-specific responses from the blood of mice either immunized with Tuberculosis vaccine candidates or infected with Mycobacterium tuberculosis by an intracellular cytokine staining (ICS) flow cytomtery assay is described. C57BL/6 mice were immunized intramuscularly with saline or ID93, a fusion of M.tb proteins consisting of Rv2608, Rv3620, Rv1813 and Rv3619, admixed with glucopyranosyl lipid adjuvant in a squalene emulsion (GLA-SE), a synthetic TLR4 agonist, twice at an eight-week interval, or once with 104 CFU BCG intradermally at the base of the tail. In some experiments, naïve mice were used as controls for antigen-specific responses. C57BL/6 and IL-21Rko male mice were infected with a low dose aerosol (LDA) of M.tb HN878 using an aerosol exposure chamber calibrated to deliver 50-100 CFU into the lung. Four weeks after infection, blood, lung, and spleen were harvested for ICS. For comparison, organs of uninfected mice were also assayed. Samples from immunized mice were cultured with a pool of overlapping 15-mer peptides of ID93. Samples from IL-21Rko and matched C57BL/6 mice were cultured with CFP-10 or ESAT-6, or a pool of 300 MTB-specific epitopes minus ID93 epitopes (MTB300-ID93). RBC lysed whole blood was stained with different immune markers and run on cytometer for analyzing cell population. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M349GKKYA4 | ||||||
| Subjects: | 8 | ||||||
| Study PI, contact: |
|
||||||
| Publications: | None | ||||||
| Resources: |
|
||||||
| Assays: |
|
||||||
| Clinical Assessments: | None | ||||||
| SDY2740: Universal influenza virus neuraminidase vaccine elicits protective immune responses against human seasonal and pre-pandemic strains | ||||||||||
| Status: | New | |||||||||
| Description: | In this study, computationally optimized broadly reactive antigen (COBRA) methodology was used to generate the N1-I NA vaccine antigen that was designed to cross-react with avian, swine, and human influenza viruses of the N1 NA subtype. The elicited antibodies bound to NA proteins derived from A/California/07/2009 (H1N1)pdm09, A/Brisbane/59/2007 (H1N1), A/Swine/North Carolina/154074/2015 (H1N1), and A/Viet Nam/1203/2004 (H5N1) influenza viruses, with NA-neutralizing activity against a broad panel of HXN1 influenza strains. Mice vaccinated with the N1-I COBRA NA vaccine were protected from mortality and viral lung titers were lower when challenged with four different viral challenges (A/California/07/2009, A/Brisbane/59/2007, A/Swine/North Carolina/154074/2015, and A/Viet Nam/1203/2004). Vaccinated mice had little to no weight loss against both homologous, but also cross-NA, genetic clade challenges. Lung viral titers were lower than the mock-vaccinated mice and, at times, equivalent to the homologous control. Thus, the N1-I COBRA NA antigen has the potential to be a complementary component in a multiantigen universal influenza virus vaccine formulation that also contains HA antigens. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M38ZNYUCM1 | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2741: Protective activity of mRNA vaccines | ||||||||||
| Status: | New | |||||||||
| Description: | Mice were immunized with either high-dose or low-dose formulations of the mRNA vaccines, where low-dose vaccination modeled suboptimal immune responses. Immunization with formulations at either dose induced neutralizing antibodies in serum against ancestral SARS-CoV-2 WA1/2020 and several virus variants, although serum titers were lower against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. However, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, showed breakthrough lung infections with B.1.617.2 and development of pneumonia in K18-hACE2 mice. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3NT600QA9 | |||||||||
| Subjects: | 680 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: |
|
|||||||||
| SDY2743: SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters | |||||||
| Status: | New | ||||||
| Description: | We evaluated the ability of several B.1.1.529 isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. Despite modelling data indicating that B.1.1.529 spike can bind more avidly to mouse ACE2 (refs. 3,4), we observed less infection by B.1.1.529 in 129, C57BL/6, BALB/c and K18-hACE2 transgenic mice than by previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease and pathology with B.1.1.529 were also milder than with historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3QEPYG5NS | ||||||
| Subjects: | 206 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: |
|
||||||
| Clinical Assessments: |
|
||||||
| SDY2744: Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses | |||||||||
| Status: | New | ||||||||
| Description: | To assess the immunogenicity and protective efficacy of nucleoside-modified mRNA-LNP vaccines that contain four influenza A group 2 virus antigens | ||||||||
| Program/Contract: |
|
||||||||
| DOI: | 10.21430/M3UYBQD3CU | ||||||||
| Subjects: | 270 | ||||||||
| Study PI, contact: |
|
||||||||
| Publications: |
|
||||||||
| Resources: |
|
||||||||
| Assays: |
|
||||||||
| Clinical Assessments: |
|
||||||||
| SDY2745: Structural analysis of COBRA protection | |||||||
| Status: | New | ||||||
| Description: | Not Provided | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3DD8R6RI0 | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2746: A Virion-Based Combination Vaccine Protects against Influenza and SARS-CoV-2 Disease in Mice | ||||||||||
| Status: | New | |||||||||
| Description: | Vaccines targeting SARS-CoV-2 have been shown to be highly effective; however, the breadth against emerging variants and the longevity of protection remains unclear. Postimmunization boosting has been shown to be beneficial for disease protection, and as new variants continue to emerge, periodic (and perhaps annual) vaccination will likely be recommended. New seasonal influenza virus vaccines currently need to be developed every year due to continual antigenic drift, an undertaking made possible by a robust global vaccine production and distribution infrastructure. To create a seasonal combination vaccine targeting both influenza viruses and SARS-CoV-2 that is also amenable to frequent reformulation, we have developed an influenza A virus (IAV) genetic platform that allows the incorporation of an immunogenic domain of the SARS-CoV-2 spike (S) protein onto IAV particles. Vaccination with this combination vaccine elicited neutralizing antibodies and provided protection from lethal challenge with both pathogens in mice. This approach may allow the leveraging of established influenza vaccine infrastructure to generate a cost-effective and scalable seasonal vaccine solution for both influenza and coronaviruses. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3Y1UZJBP5 | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2751: Multi-subtype protection N1 Vaccination | |||||||
| Status: | New | ||||||
| Description: | Protection induced by vaccination with the computationally optimized broadly reactive NA antigen (N1-I COBRA NA) was characterized in both influenza serologically naive and pre-immune ferret models following H1N1 viral challenge. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3QYG9MI3P | ||||||
| Subjects: | 195 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2752: Concomitant administration of seasonal influenza and COVID-19 mRNA vaccines | |||||||
| Status: | New | ||||||
| Description: | The authors aimed to understand the impact of mRNA COVID-19 vaccines administered concomitantly on the immune response to influenza vaccines. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3N0YZN1L0 | ||||||
| Subjects: | 128 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: |
|
||||||
| Clinical Assessments: | None | ||||||
| SDY2762: XBB.1.5 monovalent vaccine induces lasting cross-reactive responses to SARS-CoV-2, HV.1, JN.1 and SARS-CoV-1, but limited XBB.1.5 specific antibodies | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Here, the investigators assessed sera collected before, 1-month and 3-months following administration of an updated XBB.1.5 monovalent vaccine to individuals with diverse infection and vaccination histories. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3HZI08OZI | ||||||||||||
| Subjects: | 25 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2773: Robust induction of functional humoral response by a plant-derived Coronavirus-like particle vaccine candidate for COVID-19. | ||||||||||
| Status: | New | |||||||||
| Description: | Despite the success of existing COVID-19 vaccine platforms, the persistent limitations in global deployment of vaccines and waning immunity exhibited by many of the currently deployed vaccine platforms have led to perpetual outbreaks of SARS-CoV-2 variants of concern. Thus, there is an urgent need to develop new durable vaccine candidates, to expand the global vaccine pipeline, and provide safe and effective solutions for every country worldwide. Here we deeply profiled the functional humoral response induced by two doses of AS03-adjuvanted and non-adjuvanted plant-derived Coronavirus-like particle (CoVLP) vaccine candidate from the phase 1 clinical trial, at peak immunogenicity and six months post-vaccination. AS03-adjuvanted CoVLP induced robust and durable SARS-CoV-2 specific humoral immunity, marked by strong IgG1antibody responses, potent FcγR binding, and antibody effector function. Contrary to a decline in neutralizing antibody titers, the FcγR2A-receptor binding capacity and antibody-mediated effector functions, such as opsonophagocytosis, remained readily detectable for at least six months. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3DTJ2HG1T | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2776: Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The COVID-19 pandemic continues to be a health crisis with major unmet medical needs. The early responses fromairway epithelial cells, the first target of the virus regulating the progression toward severe disease, are not fully understood. Primary human air-liquid interface cultures representing the broncho-alveolar epithelia were used to study the kinetics and dynamics of SARS-CoV-2 variants infection. The infection measured by nucleoprotein expression, was a late event appearing between day 4–6 post infection for Wuhan-like virus. Other variants demonstrated increasingly accelerated timelines of infection. All variants triggered similar transcriptional signatures, an ‘‘early’’ inflammatory/immune signature preceding a ‘‘late’’ type I/III IFN, but differences in the quality and kinetics were found, consistent with the timing of nucleoprotein expression. Response to virus was spatially organized: CSF3 expression in basal cells and CCL20 in apical cells. Thus, SARS-CoV-2 virus triggers specific responses modulated over time to engage different arms of immune response. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3JBPQ0SP8 | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2777: Targeted electronic health record-based recruitment strategy to enhance COVID-19 vaccine response clinical research study enrollment | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Efficient recruitment of eligible participants is a significant challenge for clinical research studies. This challenge was exacerbated during the COVID-19 pandemic when in-person recruitment was not an option. In 2020, the University of Minnesota was tasked, as part of the National Cancer Institute's Serological Sciences Network for COVID-19 (SeroNet), to recruit participants for a longitudinal serosurveillance clinical research study with a goal of characterizing the COVID-19 vaccine-elicited immune response among immunocompromised individuals, which necessitated reliance on non-traditional strategies for participant recruitment. To meet our enrollment target of 300 transplant patients, 300 cancer patients, 100 persons living with HIV, and 200 immunocompetent individuals, we utilized targeted electronic health record (EHR)-based recruitment in addition to traditional recruitment tools, which was an effective combination of recruitment strategies. A significant advantage of patient portal messaging or other digital recruitment strategies such as email communication is timing. We reached 85 % (769 out of 900) of our enrollment target within one year with a 14.3 % response rate to invitations to participate in our study. This achievement is perhaps more salient given the COVID-19 pandemic-related constraints within which we were operating. We demonstrated that the EHR can be leveraged to quickly identify potentially eligible study participants either via EHR communication or mail. We also illustrate how the online portal MyChart can be used to efficiently send targeted recruitment messages. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3OFED88WB | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2778: Selective SARS-CoV2 BA.2 escape of antibody Fc/Fc-receptor interactions | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | The number of mutations in the omicron (B.1.1.529) BA.1 variant of concern led to an unprecedented evasion of vaccine induced immunity. However, despite rise in global infections, severe disease did not increase proportionally and is likely linked to persistent recognition of BA.1 by T cells and non-neutralizing opsonophagocytic antibodies. Yet, the emergence of new sublineage BA.2, which is more transmissible than BA.1 despite relatively preserved neutralizing antibody responses, has raised the possibility that BA.2 may evade other vaccine-induced responses. Here, we comprehensively profiled the BNT162b2 vaccine-induced response to several VOCs, including omicron BA.1 and BA.2. While vaccine-induced immune responses were compromised against both omicron sublineages, vaccine-induced antibody isotype titers, and non-neutralizing Fc effector functions were attenuated to the omicron BA.2 spike compared to BA.1. Conversely, FcγR2a and FcγR2b binding was elevated to BA.2, albeit lower than BA.1 responses, potentially contributing to persistent protection against severity of disease. | |||||||||||||||
| Program/Contract: |
|
|||||||||||||||
| DOI: | 10.21430/M3K6FF5PJ2 | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
| Study PI, contact: |
|
|||||||||||||||
| Publications: |
|
|||||||||||||||
| Resources: |
|
|||||||||||||||
| Assays: |
|
|||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2783: Concordance of SARS-CoV-2 Antibody Results during a Period of Low Prevalence | ||||||||||
| Status: | New | |||||||||
| Description: | Accurate, highly specific immunoassays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to evaluate seroprevalence. This study investigated the concordance of results across four immunoassays targeting different antigens for sera collected at the beginning of the SARS-CoV-2 pandemic in the United States. Specimens from All of Us participants contributed between January and March 2020 were tested using the Abbott Architect SARS-CoV-2 IgG (immunoglobulin G) assay (Abbott) and the EuroImmun SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) (EI). Participants with discordant results, participants with concordant positive results, and a subset of concordant negative results by Abbott and EI were also tested using the Roche Elecsys anti-SARS-CoV-2 (IgG) test (Roche) and the Ortho-Clinical Diagnostics Vitros anti-SARS-CoV-2 IgG test (Ortho). The agreement and 95% confidence intervals were estimated for paired assay combinations. SARS-CoV-2 antibody concentrations were quantified for specimens with at least two positive results across four immunoassays. Among the 24,079 participants, the percent agreement for the Abbott and EI assays was 98.8% (95% confidence interval, 98.7%, 99%). Of the 490 participants who were also tested by Ortho and Roche, the probability-weighted percentage of agreement (95% confidence interval) between Ortho and Roche was 98.4% (97.9%, 98.9%), that between EI and Ortho was 98.5% (92.9%, 99.9%), that between Abbott and Roche was 98.9% (90.3%, 100.0%), that between EI and Roche was 98.9% (98.6%, 100.0%), and that between Abbott and Ortho was 98.4% (91.2%, 100.0%). Among the 32 participants who were positive by at least 2 immunoassays, 21 had quantifiable anti-SARS-CoV-2 antibody concentrations by research assays. The results across immunoassays revealed concordance during a period of low prevalence. However, the frequency of false positivity during a period of low prevalence supports the use of two sequentially performed tests for unvaccinated individuals who are seropositive by the first test. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3ZJ820TCE | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2784: Prime-Pull Immunization of Mice with a BcfA-Adjuvanted Vaccine Elicits Sustained Mucosal Immunity That Prevents SARS-CoV-2 Infection and Pathology | |||||||||||||||
| Status: | New | ||||||||||||||
| Description: | Vaccines against SARS-CoV-2 that induce mucosal immunity capable of preventing infection and disease remain urgently needed. In this study, we demonstrate the efficacy of Bordetella colonization factor A (BcfA), a novel bacteria-derived protein adjuvant, in SARS-CoV-2 spike-based prime-pull immunizations. We show that i.m. priming of mice with an aluminum hydroxide- and BcfA-adjuvanted spike subunit vaccine, followed by a BcfA-adjuvanted mucosal booster, generated Th17-polarized CD4+ tissue-resident memory T cells and neutralizing Abs. Immunization with this heterologous vaccine prevented weight loss following challenge with mouse-adapted SARS-CoV-2 (MA10) and reduced viral replication in the respiratory tract. Histopathology showed a strong leukocyte and polymorphonuclear cell infiltrate without epithelial damage in mice immunized with BcfA-containing vaccines. Importantly, neutralizing Abs and tissue-resident memory T cells were maintained until 3 mo postbooster. Viral load in the nose of mice challenged with the MA10 virus at this time point was significantly reduced compared with naive challenged mice and mice immunized with an aluminum hydroxide-adjuvanted vaccine. We show that vaccines adjuvanted with alum and BcfA, delivered through a heterologous prime-pull regimen, provide sustained protection against SARS-CoV-2 infection. | ||||||||||||||
| Program/Contract: |
|
||||||||||||||
| DOI: | 10.21430/M3LVQBHHQA | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
| Study PI, contact: |
|
||||||||||||||
| Publications: |
|
||||||||||||||
| Resources: |
|
||||||||||||||
| Assays: |
|
||||||||||||||
| Clinical Assessments: | None | ||||||||||||||
| SDY2785: COVID-19 hospitalization risk after outpatient nirmatrelvir/ritonavir use, January to August 2022, North Carolina | ||||||||||
| Status: | New | |||||||||
| Description: | Background: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12 years of age, at high risk for progression to severe COVID-19. Objectives: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system. Methods: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods. Results: Among 44 671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28 days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28 day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area. Conclusions: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M30XIL800Q | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2786: Activation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust upregulation of these pathways on days 15-19 following initial Ad26.COV2.S vaccination. Meanwhile, a second immunization or a reduced initial dose of Ad26.COV2.S induces lower activation of these pathways than does the full initial dose. Our data suggest a role of coagulation and proinflammatory pathways in TTS pathogenesis, which may help optimize vaccination regimens to reduce TTS risk. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M38AY9P4LP | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2787: Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Inpatient Clinical Outcome | ||||||||||
| Status: | New | |||||||||
| Description: | Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes. Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11-1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59-.88) and compared with ancestral lineages was .94 (.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30-.54), but no significant outcome difference by variant. Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M39FBI6YOB | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2788: An ELISA-Based Method to Measure Mucosal Antibody Responses Against SARS-CoV-2 in Human Saliva | |||||||
| Status: | New | ||||||
| Description: | The primary mode of transmission for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is infection of the respiratory tract through droplets and/or aerosols. Therefore, immune responses at respiratory mucosal surfaces play a significant role in the prevention of infection. Greater emphasis is now being placed on mucosal immunity induced by exposure to SARS-CoV-2 antigens through infection or vaccination. In concert with cellular immunity, humoral responses at mucosal surfaces, especially the secretory version of immunoglobulin A (sIgA), can be instrumental in preventing respiratory infections. A better understanding of mucosal immune responses can further our knowledge of immunity to SARS-CoV-2 and help inform vaccine design. Here we describe a detailed protocol for an in vitro assay based on the enzyme-linked immunosorbent assay (ELISA) to assess mucosal antibody response to SARS-CoV-2 spike protein in human saliva. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: ELISA measurement of mucosal antibodies to SARS-CoV-2 spike protein in human saliva. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3UDFCJOZB | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: |
|
||||||
| Clinical Assessments: | None | ||||||
| SDY2789: Immune evasion and membrane fusion of SARS-CoV-2 XBB subvariants EG.5.1 and XBB.2.3 | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Immune evasion by SARS-CoV-2 paired with immune imprinting from monovalent mRNA vaccines has resulted in attenuated neutralizing antibody responses against Omicron subvariants. In this study, we characterized two new XBB variants rising in circulation – EG.5.1 and XBB.2.3, for their neutralization and syncytia formation. We determined the neutralizing antibody titers in sera of individuals that received a bivalent mRNA vaccine booster, BA.4/5-wave infection, or XBB.1.5-wave infection. Bivalent vaccination-induced antibodies neutralized ancestral D614G efficiently, but to a much less extent, two new EG.5.1 and XBB.2.3 variants. In fact, the enhanced neutralization escape of EG.5.1 appeared to be driven by its key defining mutation XBB.1.5-F456L. Notably, infection by BA.4/5 or XBB.1.5 afforded little, if any, neutralization against EG.5.1, XBB.2.3 and previous XBB variants – especially in unvaccinated individuals, with average neutralizing antibody titers near the limit of detection. Additionally, we investigated the infectivity, fusion activity, and processing of variant spikes for EG.5.1 and XBB.2.3 in HEK293T-ACE2 and CaLu-3 cells but found no significant differences compared to earlier XBB variants. Overall, our findings highlight the continued immune evasion of new Omicron subvariants and, more importantly, the need to reformulate mRNA vaccines to include XBB spikes for better protection. | |||||||||||||||
| Program/Contract: |
|
|||||||||||||||
| DOI: | 10.21430/M3PBPRLTHD | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
| Study PI, contact: |
|
|||||||||||||||
| Publications: |
|
|||||||||||||||
| Resources: |
|
|||||||||||||||
| Assays: |
|
|||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2790: Infants and young children generate more durable antibody responses to SARS-CoV-2 infection than adults | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | As SARS-CoV-2 becomes endemic, it is critical to understand immunity following early-life infection. We evaluated humoral responses to SARS-CoV-2 in 23 infants/young children. Antibody responses to SARS-CoV-2 spike antigens peaked approximately 30 days after infection and were maintained up to 500 days with little apparent decay. While the magnitude of humoral responses was similar to an adult cohort recovered from mild/moderate COVID-19, both binding and neutralization titers to WT SARS-CoV-2 were more durable in infants/young children, with spike and RBD IgG antibody half-life nearly 4X as long as in adults. IgG subtype analysis revealed that while IgG1 formed the majority of the response in both groups, IgG3 was more common in adults and IgG2 in infants/young children. These findings raise important questions regarding differential regulation of humoral immunity in infants/young children and adults and could have broad implications for the timing of vaccination and booster strategies in this age group. | ||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||
| DOI: | 10.21430/M3KKTYGZOH | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||
| Publications: |
|
||||||||||||||||||
| Resources: |
|
||||||||||||||||||
| Assays: |
|
||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2791: Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis | |||||||||||||||||||||
| Status: | New | ||||||||||||||||||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) is a worldwide health concern, and new treatment strategies are needed. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4) and its mouse homolog, caspase-11 (CASP11), are up-regulated in SARS–CoV-2 infections and that CASP4 expression correlates with severity of SARS–CoV-2 infection in humans. SARS–CoV-2–infected Casp11−/− mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) mice and mice lacking the caspase downstream effector gasdermin-D (Gsdmd−/−). Notably, viral titers were similar regardless of CASP11 knockout. Global transcriptomics of SARS–CoV-2–infected WT, Casp11−/−, and Gsdmd−/− lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11−/− mice. We confirmed that protein levels of inflammatory mediators interleukin (IL)-1β, IL-6, and CXCL1, as well as neutrophil functions, were reduced in Casp11−/− lungs. Additionally, Casp11−/− lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11 promotes detrimental SARS–CoV-2–induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19. | ||||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||||
| DOI: | 10.21430/M32M0KZBOA | ||||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||||
| Publications: |
|
||||||||||||||||||||
| Resources: |
|
||||||||||||||||||||
| Assays: |
|
||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||
| SDY2792: Immunogenicity of BA.5 Bivalent mRNA Vaccine Boosters | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Waning immunity after messenger RNA (mRNA) vaccination and the emergence of variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have led to reduced mRNA vaccine efficacy against symptomatic infection and severe disease. Bivalent mRNA boosters (manufactured by Pfizer–BioNTech and Moderna) expressing the spike protein of the B.1.1.529 (omicron) BA.5 sublineage and the ancestral WA1/2020 strain have been developed because BA.5 substantially evades neutralizing antibodies. However, the immunogenicity of the BA.5-containing bivalent mRNA boosters remains unknown. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3GSREONEE | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2793: Neutralization escape, infectivity, and membrane fusion of JN.1-derived SARS-CoV-2 SLip, FLiRT, and KP.2 variants | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | We investigate JN.1-derived subvariants SLip, FLiRT, and KP.2 for neutralization by antibodies in vaccinated individuals, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients, or class III monoclonal antibody S309. Compared to JN.1, SLip, KP.2, and especially FLiRT exhibit increased resistance to bivalent-vaccinated and BA.2.86/JN.1-wave convalescent human sera. XBB.1.5 monovalent-vaccinated hamster sera robustly neutralize FLiRT and KP.2 but have reduced efficiency for SLip. All subvariants are resistant to S309 and show decreased infectivity, cell-cell fusion, and spike processing relative to JN.1. Modeling reveals that L455S and F456L in SLip reduce spike binding for ACE2, while R346T in FLiRT and KP.2 strengthens it. These three mutations, alongside D339H, alter key epitopes in spike, likely explaining the reduced sensitivity of these subvariants to neutralization. Our findings highlight the increased neutralization resistance of JN.1 subvariants and suggest that future vaccine formulations should consider the JN.1 spike as an immunogen, although the current XBB.1.5 monovalent vaccine could still offer adequate protection. | ||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||
| DOI: | 10.21430/M3QDAI95RY | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||
| Publications: |
|
||||||||||||||||||
| Resources: |
|
||||||||||||||||||
| Assays: |
|
||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2794: Heterologous versus homologous boosting elicits qualitatively distinct, BA.5-cross-reactive T cells in transplant recipients | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | The SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical.We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting).Homologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21+ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting.ConclusionBoosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8+ T cell responses. | |||||||||||||||
| Program/Contract: |
|
|||||||||||||||
| DOI: | 10.21430/M3FE995T1C | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
| Study PI, contact: |
|
|||||||||||||||
| Publications: |
|
|||||||||||||||
| Resources: |
|
|||||||||||||||
| Assays: |
|
|||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2795: Neutralizing activity and 3-month durability of tixagevimab and cilgavimab prophylaxis against Omicron sublineages in transplant recipients | ||||||||||
| Status: | New | |||||||||
| Description: | Neutralizing antibody (nAb) responses are attenuated in solid organ transplant recipients (SOTRs) despite severe acute respiratory syndrome-coronavirus-2 vaccination. Preexposure prophylaxis (PrEP) with the antibody combination tixagevimab and cilgavimab (T+C) might augment immunoprotection, yet in vitro activity and durability against Omicron sublineages BA.4/5 in fully vaccinated SOTRs have not been delineated. Vaccinated SOTRs, who received 300 + 300 mg T+C (ie, full dose), within a prospective observational cohort submitted pre and postinjection samples between January 31, 2022, and July 6, 2022. The peak live virus nAb was measured against Omicron sublineages (BA.1, BA.2, BA.2.12.1, and BA.4), and surrogate neutralization (percent inhibition of angiotensin-converting enzyme 2 receptor binding to full length spike, validated vs live virus) was measured out to 3 months against sublineages, including BA.4/5. With live virus testing, the proportion of SOTRs with any nAb increased against BA.2 (47%-100%; P < .01), BA.2.12.1 (27%-80%; P < .01), and BA.4 (27%-93%; P < .01), but not against BA.1 (40%-33%; P = .6). The proportion of SOTRs with surrogate neutralizing inhibition against BA.5, however, fell to 15% by 3 months. Two participants developed mild severe acute respiratory syndrome-coronavirus-2 infection during follow-up. The majority of fully vaccinated SOTRs receiving T+C PrEP achieved BA.4/5 neutralization, yet nAb activity commonly waned by 3 months postinjection. It is critical to assess the optimal dose and interval of T+C PrEP to maximize protection in a changing variant climate. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M353UJVXZ5 | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2796: mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations | ||||||||||||||||
| Status: | New | |||||||||||||||
| Description: | Two messenger RNA (mRNA)-based vaccines are widely used globally to prevent coronavirus disease 2019 (COVID-19). Both vaccine formulations contain PEGylated lipids in their composition, in the form of polyethylene glycol [PEG] 2000 dimyristoyl glycerol for mRNA-1273, and 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide for BNT162b2. It is known that some PEGylated drugs and products for human use which contain PEG are capable of eliciting immune responses that lead to to detectable PEG-specific antibodies in serum. In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). We detected an increase in the reactivity to mRNA vaccine formulations in mRNA-1273 but not BNT162b2 vaccinees' sera in a prime-boost dependent manner. Furthermore, we observed the same pattern of reactivity against irrelevant lipid nanoparticles from an influenza virus mRNA formulation and found that the reactivity of such antibodies correlated well with antibody levels against high and low molecular weight PEG. Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. Overall, our data shows a differential induction of anti-PEG antibodies by mRNA-1273 and BNT162b2. The clinical relevance of PEG reactive antibodies induced by administration of the mRNA-1273 vaccine, and the potential interaction of these antibodies with other PEGylated drugs remains to be explored. | |||||||||||||||
| Program/Contract: |
|
|||||||||||||||
| DOI: | 10.21430/M383CP13ZL | |||||||||||||||
| Subjects: | 0 | |||||||||||||||
| Study PI, contact: |
|
|||||||||||||||
| Publications: |
|
|||||||||||||||
| Resources: |
|
|||||||||||||||
| Assays: |
|
|||||||||||||||
| Clinical Assessments: | None | |||||||||||||||
| SDY2797: Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3-7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections. | ||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||
| DOI: | 10.21430/M34KDLBCOO | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||
| Publications: |
|
||||||||||||||||||
| Resources: |
|
||||||||||||||||||
| Assays: |
|
||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2798: Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Interferon-induced transmembrane protein 3 (IFITM3) is an antiviral protein that alters cell membranes to block fusion of viruses. Conflicting reports identified opposing effects of IFITM3 on SARS-CoV-2 infection of cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with SARS-CoV-2 experience extreme weight loss and lethality compared to mild infection in wild-type (WT) mice. KO mice have higher lung viral titers and increases in inflammatory cytokine levels, immune cell infiltration, and histopathology. Mechanistically, we observe disseminated viral antigen staining throughout the lung and pulmonary vasculature in KO mice, as well as increased heart infection, indicating that IFITM3 constrains dissemination of SARS-CoV-2. Global transcriptomic analysis of infected lungs shows upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS-CoV-2 infection and overall demonstrate that IFITM3 is protective in SARS-CoV-2 infections in vivo. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3P4184A9H | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2799: Low neutralizing activity of AZD7442 against current SARS-CoV-2 Omicron variants in patients with B-cell malignancies | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Individuals who are immunocompromised, including patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL), often mount ineffective antibody responses after SARS-CoV-2 vaccination1, 2, 3 and remain at a high risk of severe COVID-19.4 Several monoclonal antibodies against the SARS-CoV-2 spike protein have been developed for prophylaxis or treatment against infection.5 AZD7442 is a combination of 2 such antibodies (tixagevimab and cilgavimab) with a half-life of ∼90 days.6 It received emergency use authorization (EUA) for use as preexposure prophylaxis in patients who are immunocompromised based on the PROVENT trial, which showed a reduced risk of symptomatic infection among patients deemed at risk of inadequate vaccine response or increased viral exposure.7 However, only 7.2% of the participants had cancer, and 3.2% received immunosuppressive therapy. Importantly, PROVENT was conducted before the emergence of the B.1.1.529 (Omicron) variant. Using purified antibodies and/or pseudoviruses, some studies showed that many antibody formulations developed against the original SARS-CoV-2, including AZD7442, lost significant in vitro activity against Omicron variants.8 Additionally, sera from patients who received AZD7442 blocked the binding between the wild-type spike receptor binding domain (RBD) and plates coated with its receptor ACE2 but had minimal efficacy at blocking the binding between Omicron BA.1 RBD and ACE2.9 Reduced efficacy against Omicron variants was observed in patients treated with half-dose AZD7442,10 and ∼10% of AZD7442-treated kidney transplant recipients developed COVID-19 afterwards, with 35.9% of them requiring hospitalization.11 Although these reports raise concerns that AZD7442 has limited efficacy against Omicron variants, the neutralizing activity of full dose AZD7442 against live, contemporary Omicron variants after administration to patients who are immunocompromised remains unknown. We measured the antibody binding and neutralizing activities of plasma from AZD7442-treated patients with NHL/CLL for several live SARS-CoV-2 variants, including Omicron BA.2.75, BA.5, BQ.1.1, and XBB, which are currently in circulation. | ||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||
| DOI: | 10.21430/M3MYWPKNIW | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||
| Publications: |
|
||||||||||||||||||
| Resources: |
|
||||||||||||||||||
| Assays: |
|
||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2800: Continued evasion of neutralizing antibody response by Omicron XBB.1.16 | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the efficacy of vaccination efforts against coronavirus disease 2019 (COVID-19). The Omicron XBB lineage of SARS-CoV-2 has presented dramatic evasion of neutralizing antibodies stimulated by mRNA vaccination and COVID-19 convalescence. XBB.1.16, characterized by two mutations relative to the dominating variant XBB.1.5, i.e., E180V and K478R, has been on the rise globally. In this study, we compare the immune escape of XBB.1.16 with XBB.1.5, alongside ancestral variants D614G, BA.2, and BA.4/5. We demonstrate that XBB.1.16 is strongly immune evasive, with extent comparable to XBB.1.5 in bivalent-vaccinated healthcare worker sera, 3-dose-vaccinated healthcare worker sera, and BA.4/5-wave convalescent sera. Interestingly, the XBB.1.16 spike is less fusogenic than that of XBB.1.5, and this phenotype requires both E180V and K478R mutations to manifest. Overall, our findings emphasize the importance of the continued surveillance of variants and the need for updated mRNA vaccine formulations. | |||||||||||||||||||||
| Program/Contract: |
|
|||||||||||||||||||||
| DOI: | 10.21430/M3T7L3EPTY | |||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||
| Study PI, contact: |
|
|||||||||||||||||||||
| Publications: |
|
|||||||||||||||||||||
| Resources: |
|
|||||||||||||||||||||
| Assays: |
|
|||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2801: Relative contribution of COVID-19 vaccination and SARS-CoV-2 infection to population-level seroprevalence of SARS-CoV-2 spike antibodies in a large integrated health system | |||||||||||||||||||
| Status: | New | ||||||||||||||||||
| Description: | Background: Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions. Methods: Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates. Results: We enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0-88.9) in May 2021 to 93.5% (CI 89.5-97.5) in April 2022. By April 2022, 68.5% (CI 61.9-74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7-17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5-14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1-7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status. Conclusions: By April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence. | ||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||
| DOI: | 10.21430/M3F42RO93C | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||
| Publications: |
|
||||||||||||||||||
| Resources: |
|
||||||||||||||||||
| Assays: |
|
||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2802: Association of Cytomegalovirus Serostatus With Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Responsiveness in Nursing Home Residents and Healthcare Workers | ||||||||||
| Status: | New | |||||||||
| Description: | Background Latent cytomegalovirus (CMV) infection is immunomodulatory and could affect mRNA vaccine responsiveness. We sought to determine the association of CMV serostatus and prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with antibody (Ab) titers after primary and booster BNT162b2 mRNA vaccinations in healthcare workers (HCWs) and nursing home (NH) residents. Methods: Nursing home residents (N = 143) and HCWs (N = 107) were vaccinated and serological responses monitored by serum neutralization activity against Wuhan and Omicron (BA.1) strain spike proteins, and by bead-multiplex immunoglobulin G immunoassay to Wuhan spike protein and its receptor-binding domain (RBD). Cytomegalovirus serology and levels of inflammatory biomarkers were also measured. Results: Severe acute respiratory syndrome coronavirus 2-naive CMV seropositive (CMV+) HCWs had significantly reduced Wuhan-neutralizing Ab (P = .013), anti-spike (P = .017), and anti-RBD (P = .011) responses 2 weeks after primary vaccination series compared with responses among CMV seronegative (CMV−) HCWs, adjusting for age, sex, and race. Among NH residents without prior SARS-CoV-2 infection, Wuhan-neutralizing Ab titers were similar 2 weeks after primary series but were reduced 6 months later (P = .012) between CMV+ and CMV− subjects. Wuhan-neutralizing Ab titers from CMV+ NH residents who had prior SARS-CoV-2 infection consistently trended lower than titers from SARS-CoV-2 experienced CMV− donors. These impaired Ab responses in CMV+ versus CMV− individuals were not observed after booster vaccination or with prior SARS-CoV-2 infection. Conclusions: Latent CMV infection adversely affects vaccine-induced responsiveness to SARS-CoV-2 spike protein, a neoantigen not previously encountered, in both HCWs and NH residents. Multiple antigenic challenges may be required for optimal mRNA vaccine immunogenicity in CMV+ adults. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3LNVQE4HE | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2803: Understanding Concerns about COVID-19 and Vaccination: Perspectives from Kidney Transplant Recipients | ||||||||||
| Status: | New | |||||||||
| Description: | The COVID-19 pandemic poses a significant risk for immunosuppressed groups such as transplant patients. The purpose of this study was to improve our understanding of the impact of the COVID-19 pandemic on kidney transplant recipients, including their views on COVID-19 vaccination. Semi-structured interviews were conducted from December 2021 to August 2022 with 38 kidney transplant recipients who had an appointment with their transplant care team within the previous 6 months. We used qualitative thematic analysis to characterize the perspectives of interviewees. Regardless of COVID-19 vaccination status, most interviewees reported utilizing public health measures such as masking, hand washing, and avoiding crowds to protect themselves against COVID-19. Vaccinated interviewees (n = 31) noted that they chose to receive a COVID-19 vaccine because of their increased risk due to their immunocompromised state. For unvaccinated interviewees (n = 7), reasons for not receiving a COVID-19 vaccine included concerns about the safety and efficacy of the vaccine. Both vaccinated and unvaccinated interviewees expressed concerns about the lack of adequate testing of the vaccine in transplant patients and questioned if the vaccine might have unknown side effects for transplant recipients. Regardless of the vaccination status, most interviewees noted having trust in their healthcare team. Interviewees also described interpersonal tensions that arose during the pandemic, many of which surrounded vaccination and other preventive measures that were important to participants to protect their health. Together, these data demonstrate differing concerns and experiences related to the COVID-19 pandemic for vaccinated and unvaccinated transplant recipients. These findings highlight the unique needs of transplant recipients and reveal opportunities to support this vulnerable patient population in efforts to protect their health as the COVID-19 pandemic evolves. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3I2GO9MBK | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY2804: Endemic Human Coronavirus Antibody Levels Are Unchanged after Convalescent or Control Plasma Transfusion for Early Outpatient COVID-19 Treatment | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The impact of preexisting antibodies to the four endemic human coronaviruses (ehCoV) (229E, OC43, NL63, and HKU1) on severe (hospitalization) coronavirus disease 2019 (COVID-19) outcomes has been described in small cohorts. Many studies have measured ehCoV 229E, OC43, NL63, and HKU1 antibody levels weeks after recovery rather than in the first weeks of illness, which is more relevant to early hospitalizations. Antibody levels to the spike protein of the four coronaviruses (229E, OC43, NL63, and HKU1), as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were measured both before and immediately after convalescent or control plasma transfusion in 51 participants who were hospitalized and 250 who were not hospitalized, as well as in 71 convalescent and 50 control plasma donors as a subset from a completed randomized controlled trial. In COVID-19 convalescent plasma donors, the ehCoV spike antibodies were 1.2 to 2 times greater than the control donor unit levels, while donor COVID-19 convalescent plasma (CCP) SARS-CoV-2 spike antibodies were more than 600 times the control plasma units. Plasma transfusion, whether COVID-19 convalescent or control, did not alter the post-transfusion antibody levels for the endemic human coronaviruses (229E, OC43, NL63, and HKU1) in those hospitalized and not hospitalized, despite the 1.2- to 2-fold elevation in donor COVID-19 convalescent plasma. There was no influence of prior antibody levels to 229E, OC43, NL63, and HKU1 or post-transfusion antibody levels on subsequent hospitalization. These data, from a well-controlled prospective randomized clinical trial, add evidence that antibodies to ehCoV do not significantly impact COVID-19 outcomes, despite the apparent back-boosting of some ehCoV after SARS-CoV-2 infection. IMPORTANCE The relevance of preexisting immunity to the four endemic human coronaviruses in the first week of COVID-19 illness on the outcome of COVID-19 progression stems from the high prevalence of the ehCoV and SARS-CoV-2 coronaviruses. The question has been raised of whether therapeutic convalescent plasma or control plasma containing ehCoV antibodies might alter the outcome of COVID-19 progression to hospitalization. Here, we observed that plasma transfusion did not significantly change the preexisting ehCoV antibody levels. In over 50 hospitalized participants and 250 nonhospitalized participants, ehCoV antibody levels were comparable, without statistical differences. Antibody levels were stable over the more than 12 months of the intervention trial, with individual heterogeneity similar in hospitalized and nonhospitalized participants. The ehCoV antibodies in plasma transfusion did not alter the recipient preexisting antibody levels nor hasten the COVID-19 progression to hospitalization in this clinical trial data. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3H0UAEZ7S | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2805: Anti-PF4 antibodies associated with disease severity in COVID-19 | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The pathogenic mechanisms that trigger the most severe complications of COVID-19 are still largely unknown. Widespread formation of microscopic thrombi has been detected in the lungs and other organs, suggesting that coagulation abnormalities are involved in the pathogenic process. This study shows that virtually all patients with severe COVID-19 develop anomalous antibodies that target an endogenous protein, platelet factor 4 (PF4), and that are the hallmark of two life-threatening disorders characterized by thrombosis and thrombocytopenia: heparin-induced thrombocytopenia and vaccine-induced thrombosis with thrombocytopenia. Anti-PF4 antibodies are the hallmark of two life-threatening disorders: heparin-induced thrombocytopenia and vaccine-induced thrombosis with thrombocytopenia. Higher antibody levels were found in patients with the most severe disease and the most conspicuous platelet reductions. These findings suggest that anti-PF4 antibodies may play a role in the severe multiorgan disease manifestations of COVID-19. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M34YF8KMQ2 | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2807: Minding the margins: Evaluating the impact of COVID-19 among Latinx and Black communities with optimal qualitative serological assessment tools | ||||||||||||||||||||||
| Status: | New | |||||||||||||||||||||
| Description: | COVID-19 disproportionately affected minorities, while research barriers to engage underserved communities persist. Serological studies reveal infection and vaccination histories within these communities, however lack of consensus on downstream evaluation methods impede meta-analyses and dampen the broader public health impact. To reveal the impact of COVID-19 and vaccine uptake among diverse communities and to develop rigorous serological downstream evaluation methods, we engaged racial and ethnic minorities in Massachusetts in a cross-sectional study (April-July 2022), screened blood and saliva for SARS-CoV-2 and human endemic coronavirus (hCoV) antibodies by bead-based multiplex assay and point-of-care (POC) test and developed across-plate normalization and classification boundary methods for optimal qualitative serological assessments. Among 290 participants, 91.4% reported receiving at least one dose of a COVID-19 vaccine, while 41.7% reported past SARS-CoV-2 infections, which was confirmed by POC- and multiplex-based saliva and blood IgG seroprevalences. We found significant differences in antigen-specific IgA and IgG antibody outcomes and indication of cross-reactivity with hCoV OC43. Finally, 26.5% of participants reported lingering COVID-19 symptoms, mostly middle-aged Latinas. Hence, prolonged COVID-19 symptoms were common among our underserved population and require public health attention, despite high COVID-19 vaccine uptake. Saliva served as a less-invasive sample-type for IgG-based serosurveys and hCoV cross-reactivity needed to be evaluated for reliable SARS-CoV-2 serosurvey results. The use of the developed rigorous downstream qualitative serological assessment methods will help standardize serosurvey outcomes and meta-analyses for future serosurveys beyond SARS-CoV-2. | |||||||||||||||||||||
| Program/Contract: |
|
|||||||||||||||||||||
| DOI: | 10.21430/M3UXCHOCPN | |||||||||||||||||||||
| Subjects: | 0 | |||||||||||||||||||||
| Study PI, contact: |
|
|||||||||||||||||||||
| Publications: |
|
|||||||||||||||||||||
| Resources: |
|
|||||||||||||||||||||
| Assays: |
|
|||||||||||||||||||||
| Clinical Assessments: | None | |||||||||||||||||||||
| SDY2808: Hybrid Immunity Shifts the Fc-Effector Quality of SARS-CoV-2 mRNA Vaccine-Induced Immunity | ||||||||||
| Status: | New | |||||||||
| Description: | Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures—either hybrid immunity or two doses of vaccine alone—represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M3KPXQBM7D | |||||||||
| Subjects: | 0 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2809: Nasally delivered interferon lambda protects mice against SARS-CoV-2 infection | |||||||
| Status: | New | ||||||
| Description: | Here, we show that IFN-l protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M3FGEA29GM | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2810: Sialylated IgG-induced RE1-Silencing Transcription Factor (REST) protects against lung inflammation and severe influenza disease | |||||||
| Status: | New | ||||||
| Description: | The investigators, first, profiled Fc glycans on anti-hemagglutinin (HA) IgGs from people with mild or severe influenza virus infections. Then, using a murine challenge model, they show that enrichment for sialylated, but not asialylated IgG, is broadly protective against heterologous influenza viruses. | ||||||
| Program/Contract: |
|
||||||
| DOI: | 10.21430/M38BQ3HJWL | ||||||
| Subjects: | 0 | ||||||
| Study PI, contact: |
|
||||||
| Publications: |
|
||||||
| Resources: |
|
||||||
| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY2811: Modeling in higher dimensions to improve diagnostic testing accuracy: Theory and examples for multiplex saliva-based SARS-CoV-2 antibody assays | |||||||||||||
| Status: | New | ||||||||||||
| Description: | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the importance and challenges of correctly interpreting antibody test results. Identification of positive and negative samples requires a classification strategy with low error rates, which is hard to achieve when the corresponding measurement values overlap. Additional uncertainty arises when classification schemes fail to account for complicated structure in data. We address these problems through a mathematical framework that combines high dimensional data modeling and optimal decision theory. Specifically, we show that appropriately increasing the dimension of data better separates positive and negative populations and reveals nuanced structure that can be described in terms of mathematical models. We combine these models with optimal decision theory to yield a classification scheme that better separates positive and negative samples relative to traditional methods such as confidence intervals (CIs) and receiver operating characteristics. We validate the usefulness of this approach in the context of a multiplex salivary SARS-CoV-2 immunoglobulin G assay dataset. This example illustrates how our analysis: (i) improves the assay accuracy, (e.g. lowers classification errors by up to 42% compared to CI methods); (ii) reduces the number of indeterminate samples when an inconclusive class is permissible, (e.g. by 40% compared to the original analysis of the example multiplex dataset) and (iii) decreases the number of antigens needed to classify samples. Our work showcases the power of mathematical modeling in diagnostic classification and highlights a method that can be adopted broadly in public health and clinical settings. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M33WC6JLYP | ||||||||||||
| Subjects: | 0 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: |
|
||||||||||||
| Resources: |
|
||||||||||||
| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
Updated Studies
| SDY1364: Roles for Treg Expansion and HMGB1 Signaling through the TLR1-2-6 Axis in Determining the Magnitude of the Antigen-Specific Immune Response to MVA85A | |||||||||
| Status: | Updated | ||||||||
| Description: | A better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-_ (IFN-g) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2R_ two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans. | ||||||||
| Program/Contract: |
|
||||||||
| DOI: | 10.21430/M3NJTLGRT4 | ||||||||
| Subjects: | 24 | ||||||||
| Study PI, contact: |
|
||||||||
| Publications: |
|
||||||||
| Resources: |
|
||||||||
| Assays: |
|
||||||||
| Clinical Assessments: | None | ||||||||
| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | ||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | |||||||||||||||||||||||||||
| Program/Contract: |
|
|||||||||||||||||||||||||||
| DOI: | 10.21430/M3H1YHLR5Z | |||||||||||||||||||||||||||
| Subjects: | 1218 | |||||||||||||||||||||||||||
| Study PI, contact: |
|
|||||||||||||||||||||||||||
| Publications: |
|
|||||||||||||||||||||||||||
| Resources: | ||||||||||||||||||||||||||||
| Assays: |
|
|||||||||||||||||||||||||||
| Clinical Assessments: |
|
|||||||||||||||||||||||||||
| SDY2282: JAX CCHI-Modulation of Lung Responses to Viral Infection- ALI SARS-CoV-2 | ||||||||||
| Status: | Updated | |||||||||
| Description: | Epithelial barriers lie at the interface between host and environment, where they sense invading pathogen. Dendritic cells (DCs) present pathogen-derived antigens to T and B cells to induce immune responses. However, the impact of the human lung tissue environment on DC and other cells, such as the newly identified innate lymphoid cell (ILC) family, as well as bacteria-reactive MAIT cells, is not completely understood. An understudied environmental factor is the lung microbiome. The JAX CCHI seeks to address these critical questions using a multi-disciplinary experimental approach that will integrate immunology with epithelial cell biology along with genomic, cellular, functional and microbiome parameters identified in human lung tissues. Our overarching hypothesis is that the quality and magnitude of mucosal T cell responses to respiratory viral infections are determined by the cross- talk between microbiota, epithelial cells and leukocytes. To address this hypothesis, we structured the JAX CCHI around two integrated research projects focused on basic immunological mechanisms of lung antiviral immunity; a technology development project that will create sophisticated cellular models leveraging 3D bioprinting, gene editing tools and microbiome-immune assays to support project objectives; a sample core for storage and distribution of human tissues; and a microbiome core for specialized microbiome profiling, cultivation, and computational analysis. Our Center will bring together clinicians with experts in lung immunology, the microbiome, bioengineering, genomics and computational biology to achieve our goals and maximize the potential of this research. The goals of this CCHI are to: 1) Understand how the networks of epithelial cells and immune cells in the human lung regulate innate and adaptive immunity to respiratory viruses; 2) Define how inflammation driven by the microbiome dictates the steady state of tissue, i.e., immune set-point; 3) Determine if and how this immune set-point is altered in two pulmonary diseases, childhood asthma and adult lung cancer, which have a major impact on public health; and 4) Develop innovative technologies to model human lung-immune dynamics and elucidate molecular mechanisms, cell types and pathways key to lung antiviral responses. Impact: Through studies focused on the sensors, inducers and modulators of antiviral immunity in the human lung, our CCHI will contribute insights that could help improve outcomes for infectious and other immune diseases that originate in or secondarily impact the lung. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M32KGRDM51 | |||||||||
| Subjects: | 8 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2464: Metabolomics in urine and serum of 4Gy exposed NHP (2 year followup) | |||||||||||||||||||
| Status: | Updated | ||||||||||||||||||
| Description: | Nonhuman primates exposed to total body irradiation of 4 Gy gamma were followed for two years after exposure. Urine and serum were collected at various time points up until 2 years after exposure, and appropriately age matched controls were identified for the later time points. Metabolomic analysis was conducted through untargeted metabolomics and metabolic fingerprinting, based on published radiation biomarkers. The radiation signal persisted for at least 2 years after exposure with high sensitivity and specificity. | ||||||||||||||||||
| Program/Contract: |
|
||||||||||||||||||
| DOI: | 10.21430/M3RAB4X3PW | ||||||||||||||||||
| Subjects: | 0 | ||||||||||||||||||
| Study PI, contact: |
|
||||||||||||||||||
| Publications: | None | ||||||||||||||||||
| Resources: |
|
||||||||||||||||||
| Assays: | None | ||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||
| SDY2471: U19 CCHI_Project 1. The Role of CD4 Memory Phenotype, Memory, and Effector T Cells in | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | The purpose of this study is provide a better understanding of the adaptive immune response to the licensed flu vaccines. We hope the information learned from this study will help identify and describe important factors | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M30UY9XYSX | ||||||||||||
| Subjects: | 12 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: | None | ||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2497: Effects of Aging on Primary and Secondary Vaccine Responses in a 15-Year Longitudinal Cohort | |||||||||||||
| Status: | Updated | ||||||||||||
| Description: | Investigators will carry out an in-depth study of human B cell and T cell immune responses to vaccines that the person hasn't previously encountered, as well as to seasonal influenza vaccination, and determine which aspects of immune function are most affected by aging in each case. The research subjects are a well-characterized longitudinal cohort of young and elderly individuals whose influenza vaccine responses have been studied each year for up to 9 years, and who will be vaccinated for Hepatitis A in this new study. Improved understanding of human immune system function obtained by studying individual B cells and T cells and their fates following vaccination will help in the design and testing of new vaccines against emergent diseases. | ||||||||||||
| Program/Contract: |
|
||||||||||||
| DOI: | 10.21430/M3Y7FDJGD6 | ||||||||||||
| Subjects: | 57 | ||||||||||||
| Study PI, contact: |
|
||||||||||||
| Publications: | None | ||||||||||||
| Resources: |
|
||||||||||||
| Assays: |
|
||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY2608: mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations | ||||||||||
| Status: | Updated | |||||||||
| Description: | In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. | |||||||||
| Program/Contract: |
|
|||||||||
| DOI: | 10.21430/M393Q1VZXO | |||||||||
| Subjects: | 133 | |||||||||
| Study PI, contact: |
|
|||||||||
| Publications: |
|
|||||||||
| Resources: |
|
|||||||||
| Assays: |
|
|||||||||
| Clinical Assessments: | None | |||||||||
| SDY2656: SeroNet Reference Study v2.2 | ||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Updated | |||||||||||||||||||||||||||||||||||||||||||||
| Description: | The National Cancer Institute’s Serological Sciences Network (SeroNet) is the nation’s largest coordinated effort to study the immune response to COVID-19 and increase the nation’s antibody testing capacity. SeroNet is a collaboration across 26 biomedical research institutions to enhance understanding of the immune response to the novel coronavirus, SARS-CoV-2. The COVID-19 Serology Laboratory coordinates much of the SeroNet research and is leading COVID-19 serology standardization efforts for the network. The SeroNet Coordinating Center, headquartered at and managed by the Vaccine, Immunity, and Cancer Directorate at the Frederick National Laboratory, provides program logistical support. SeroNet launched in October 2020, less than a year into the COVID-19 pandemic. It aims to answer critical questions regarding serology and the pandemic. SeroNet is a major component of the National Cancer Institute’s response to COVID-19. In April 2020, the National Cancer Institute received an emergency appropriation of $306 million from Congress to develop, validate, and implement serological testing and associated technologies. More than half of the funding is devoted to SeroNet. Data and studies generated by SeroNet are available on the ImmPort system, which provides a sustainable, publicly accessible archive of data generated by investigators at the National Institute of Allergy and Infectious Diseases. In early 2021, the Frederick National Laboratory supported the development and production of the Human SARS-CoV-2 Serology Standard for calibration in COVID-19 studies conducted around the U.S. and world. Lab scientists have worked with the National Cancer Institute, U.S. Food and Drug Administration, Centers for Disease Control and Prevention, other government agencies, and universities to develop sample evaluation panels to evaluate the performance (sensitivity and specificity) of antibody tests developed by external organizations before they are made available to the public. | |||||||||||||||||||||||||||||||||||||||||||||
| Program/Contract: |
|
|||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.21430/M3AUTZYP4Q | |||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | 909 | |||||||||||||||||||||||||||||||||||||||||||||
| Study PI, contact: |
|
|||||||||||||||||||||||||||||||||||||||||||||
| Publications: | None | |||||||||||||||||||||||||||||||||||||||||||||
| Resources: |
|
|||||||||||||||||||||||||||||||||||||||||||||
| Assays: |
|
|||||||||||||||||||||||||||||||||||||||||||||
| Clinical Assessments: |
|
|||||||||||||||||||||||||||||||||||||||||||||
| SDY2735: Immunology of Severe Febrile Illness in Children | |||||||||
| Status: | Updated | ||||||||
| Description: | A comparative approach to severe febrile illnesses in children may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by decreased signaling by, and lower gene expression of, interferon receptors. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children. | ||||||||
| Program/Contract: |
|
||||||||
| DOI: | 10.21430/M3GTQGMQZ4 | ||||||||
| Subjects: | 152 | ||||||||
| Study PI, contact: |
|
||||||||
| Publications: | None | ||||||||
| Resources: |
|
||||||||
| Assays: |
|
||||||||
| Clinical Assessments: | None | ||||||||
| SDY2753: Bystander monocytic cells drive infection-independent NLRP3 inflammasome response to SARS-CoV-2 | |||||||||||||||
| Status: | Updated | ||||||||||||||
| Description: | The pathogenesis of COVID-19 is associated with a hyperinflammatory immune response. Monocytes and macrophages play a central role in this hyperinflammatory response to SARS-CoV-2. NLRP3 inflammasome activation has been observed in monocytes of patients with COVID-19, but the mechanism and consequences of inflammasome activation require further investigation. In this study, we inoculated a macrophage-like THP-1 cell line, primary differentiated human nasal epithelial cell (hNEC) cultures, and primary monocytes with SARS-CoV-2. We found that the activation of the NLRP3 inflammasome in macrophages does not rely on viral replication, receptor-mediated entry, or actin-dependent entry. SARS-CoV-2 productively infected hNEC cultures without triggering the production of inflammasome cytokines IL-18 and IL-1β. Importantly, these cytokines did not inhibit viral replication in hNEC cultures. SARS-CoV-2 inoculation of primary monocytes led to inflammasome activation and induced a macrophage phenotype in these cells. Monocytic cells from bronchoalveolar lavage (BAL) fluid, but not from peripheral blood, of patients with COVID-19, showed evidence of inflammasome activation, expressed the proinflammatory marker CD11b, and displayed oxidative burst. These findings highlight the central role of activated macrophages, as a result of direct viral sensing, in COVID-19 and support the inhibition of IL-1β and IL-18 as potential therapeutic strategies to reduce immunopathology without increasing viral replication. | ||||||||||||||
| Program/Contract: |
|
||||||||||||||
| DOI: | 10.21430/M37BXVEH52 | ||||||||||||||
| Subjects: | 0 | ||||||||||||||
| Study PI, contact: |
|
||||||||||||||
| Publications: |
|
||||||||||||||
| Resources: |
|
||||||||||||||
| Assays: |
|
||||||||||||||
| Clinical Assessments: | None | ||||||||||||||