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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (4)

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    Single Prime hAd5 Spike (S) + Nucleocapsid (N PROTEIN) Dual Antigen Vaccination of Healthy Volunteers Induces a Ten-Fold Increase in Mean S- and N- T-Cell Responses Equivalent to T-Cell Responses from Patients Previously Infected with SARS-CoV-2

    Authors: Pete Sieling; Thomas King; Raymond Wong; Andy Nguyen; Kamil Wnuk; Elizabeth R Gabitzsch; Adrian Rice; Helty Adisetiyo; Melanie Hermreck; Mohit Verma; Lise Zakin; Annie Shin; Brett Morimoto; Wendy Higashide; Kyle Dinkins; Joseph Balint; Victor Peykov; Justin Taft; Roosheel Patel; Sofija Buta; Marta Martin-Fernandez; Dusan Bogunovic; Patricia Spilman; Lennie Sender; Sandeep Reddy; Philip Robinson; Shahrooz Rabizadeh; Kayvan Niazi; Patrick Soon-Shiong

    doi:10.1101/2021.04.05.21254940 Date: 2021-04-07 Source: medRxiv

    In response to the need for a safe, efficacious vaccine that provides broad immune protection against SARS-CoV-2 infection MESHD, we have developed a dual-antigen COVID-19 MESHD vaccine. The vaccine delivers both the viral spike (S) protein PROTEIN modified to increase cell-surface expression (S-Fusion) and the viral nucleocapsid (N) protein PROTEIN with an Enhanced T-cell Stimulation Domain (N-ETSD) to enhance MHC class I and II presentation and T-cell responses. The vaccine antigens are delivered using a human adenovirus serotype 5 (hAd5) platform with E1, E2b, and E3 regions deleted that has been shown in previous cancer MESHD vaccine studies to be effective in the presence of pre-existing hAd5 immunity. Here, we demonstrate the hAd5 S-Fusion + N-ETSD (hAd5 S + N) vaccine antigens when expressed by dendritic cells (DCs) of previously SARS-CoV-2-infected MESHD patients elicit Th1 HGNC dominant activation of autologous patient T cells, indicating the vaccine antigens have the potential for generating immune responses in patients previously infected MESHD or vaccinated. We further demonstrate that participants in our open-label Phase 1b study of the dual-antigen hAd5 S + N vaccine generate Th1 HGNC dominant S- and N- specific T cells after a single prime subcutaneous injection and that the magnitude of these responses were comparable to those seen for T cells from previously infected patients. We further present our in silico prediction of T-cell epitope HLA binding for both the first-wave SARS-CoV-2 A strain and the K417N, E484K, and N501Y S as well as the T201I N variants that suggests T-cell responses to the hAd5 S + N vaccine will retain efficacy against these variants. These findings that the dual-antigen hAd5 S + N vaccine elicits SARS-CoV-2-relevant T-cell responses and that such cell-mediated protection is likely to be sustained against emerging variants supports the testing of this vaccine as a universal booster that would enhance and broaden existing immune protection conferred by currently approved S-based vaccines.

    Induction of Th1 HGNC/Th2-Balanced Protection Against SARS-CoV-2 Through Mucosal Delivery of An Adenovirus Vaccine Expressing an Engineered Spike Protein PROTEIN

    Authors: Nai-Hsiang Chung; Ying-Chin Chen; Shiu-Ju Yang; Yu-Ching Lin; Horng-Yunn Dou; Ching-Len Liao; Yen-Hung Chow

    doi:10.21203/rs.3.rs-134494/v1 Date: 2020-12-23 Source: ResearchSquare

    We developed a series of recombinant human type 5 adenoviruses that express the full-length or membrane-truncated spike protein (S PROTEIN) of SARS-CoV-2 (AdCoV2-S or AdCoV2-SdTM, respectively). We tested the immunoprotective efficacy against SARS-CoV-2 via intranasal (i.n.) or subcutaneous (s.c.) immunization in a rodent model following two-dose immunizations. Mucosal delivery of adenovirus (Ad) vaccines could induce anti-SARS-CoV-2 IgG and IgA in the serum and in the mucosal, respectively as indicated by vaginal wash (vw). Serum anti-SARS-CoV-2 IgG but not IgA was induced in the vw by s.c. injection of AdCoV2-S. Intranasal administration of AdCoV2-S was able to induce higher anti-SARS-CoV-2 antibody levels than s.c. injection. Immunization with AdCoV2-SdTM induced a lower antibody response than AdCoV2-S. In addition, the degree of neutralization of clinically isolated SARS-CoV-2 in the serum correlated with the above anti-SARS-CoV-2 responses; the most potent neutralizing activity was observed in the AdCoV2-S i.n. group, and less viral neutralizing activity was observed in response to AdCoV2-S s.c. and AdCoV2dTM i.n. Novelty, S-specific IgG1 which represented Th2-mediated humoral response was dominantly induced in Ad i.n.-immunized serum in contrast to more IgG2a which represented Th1 HGNC-mediated cellular response found in Ad s.c.-immunized serum. The activation of S-specific IFN-ɣ and IL-4 HGNC in Th1 HGNC and Th2 cells, respectively, was observed in the AdCoV2s i.n. and s.c. groups, indicating the Th1 HGNC/Th2-balenced immunity was activated. During the protection study, two doses of i.n. AdCoV2-S or i.n. AdCoV2-SdTM significantly prevented body weight loss MESHD and reduced pulmonary viral loads in hamsters. A significant reduction in inflammation MESHD in the lungs was observed in AdCoV-S-immunized hamsters following a SARS-CoV-2 challenge. It correlated to Th1 HGNC cytokine but no inflammatory cytokines secretions found in i.n. AdCoV-immunized respiratory tract. These results indicate that intranasal delivery of AdCoV2-S vaccines is safe and potent at preventing SARS-CoV-2 infections MESHD SARS-CoV-2 infections MESHD.

    Th1 HGNC Dominant Nucleocapsid and Spike Antigen-Specific CD4+ and CD8+ Memory T Cell Recall Induced by hAd5 S-Fusion + N-ETSD Infection of Autologous Dendritic Cells from Patients Previously Infected with SARS-CoV-2

    Authors: Peter Sieling; Lise Zakin; Annie Shin; Brett Morimoto; Helty Adisetiyo; Hermes Garban; Philip Liu; Adrian Rice; Justin Taft; Roosheel Patel; Sofija Buta; Marta Martin-Fernandez; Dusan Bogunovic; Elizabeth Gabitzsch; Jeffrey T. Safrit; Lennie Sender; Patricia Spilman; Shahrooz Rabizadeh; Kayvan Niazi; Patrick Soon-Shiong

    doi:10.1101/2020.11.04.20225417 Date: 2020-11-06 Source: medRxiv

    To address the need for a safe, efficacious vaccine against SARS-CoV-2 infection MESHD with the critical properties of enabling both blocking viral entry into cells and clearing virus from cells already infected, we have developed a bivalent, human adenovirus serotype 5 (hAd5) SARS-CoV-2 S MESHD-Fusion + N-ETSD vaccine that is currently in clinical testing. This vaccine uses the next-generation hAd5 [E1-, E2b-, E3-] platform previously used successfully in cancer MESHD patients with pre-existing adenovirus immunity, engineered to express both SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN modified to improve the generation of neutralizing antibodies to block entry of the virus, and nucleocapsid (N) protein PROTEIN with an Enhanced T cell Stimulation Domain (ETSD) to activate CD4+ and CD8+ T cells to clear the virus and block replication by killing infected cells. The targeting of N to endosomes and lysosomes to enhance CD4+ and CD8+ T-cell responses distinguishes our vaccine. In our previously reported pre-clinical studies we showed that in mice, the hAd5 S-Fusion + N-ETSD vaccine elicits both humoral and T-cell responses that are robust and T helper cell 1 (Th1) dominant. Here we report that the hAd5 S-Fusion + N-ETSD vaccine is recognized by anti-sera and T cells from previously SARS-CoV-2 infected MESHD patients, and that the presence of N is vital for T-cell recall. The findings presented herein: i. demonstrate specific recognition of hAd5 S-Fusion + N-ETSD infected MESHD cells by plasma antibodies from previously SARS-CoV-2 infected MESHD patients, but not antibodies from virus-naive subjects; ii. show enhanced binding of plasma SARS-CoV-2 antibodies from previously infected MESHD patients to monocyte-derived dendritic cells (MoDCs) expressing the hAd5 S-Fusion + N-ETSD vaccine as compared to hAd5 S-Fusion alone; iii. reveal N-ETSD localizes to vesicles associated with MHC class II antigen presentation, including endosomes, lysosomes, and autophagosomes in MoDCs; iv. demonstrate endosome/lysosome-targeted N-ETSD elicits higher interferon-gamma T-cell responses than cytoplasm-localized N; and v. N-ETSD alone or in the hAd5 S-Fusion + N-ETSD construct induces both CD4+ and CD8+ T cell memory recall MESHD. This recognition of hAd5 S-Fusion + N-ETSD vaccine antigens by T cells from previously SARS-CoV-2 infected MESHD patients, together with the ability of this vaccine candidate to elicit de novo immune responses in naive mice suggests that it re-capitulates the natural immune response to SARS-CoV-2 to activate both B and T cells towards viral neutralization and recognition of infected cells, critical for prevention of COVID-19 MESHD disease. Intriguingly, our hAd5 S-Fusion + N-ETSD T-cell biased vaccine has the potential to not only provide protection for uninfected individuals, but also to be utilized as a therapeutic for already infected MESHD patients to induce rapid clearance of the virus by activating T cells to kill the virus-infected cells, thereby reducing viral replication and lateral transmission.

    Preclinical study of DNA vaccines targeting SARS-CoV-2

    Authors: Hiroki Hayashi; Jiao Sun; Yuka Yanagida; Takako Otera; Ritsuko Kubota-Kotetsu; Tatsuo Shioda; Chikako Ono; Yoshiharu Matsuura; Hisashi Arase; Shota Yoshida; Ryo Nakamaru; Ryoko Ide; Akiko Tenma; Sotaro Kawabata; Takako Ehara; Makoto Sakaguchi; Hideki Tomioka; Munehisa Shimamura; Sachiko Okamoto; Yasunori Amaishi; Hideto Chono; Junichi Mineno; Takao Komatsuno; Yoshimi Saito; Hiromi Rakugi; Ryuichi Morishita; Hironori Nakagami; Jacob Moran-Gilad; Yakir Berchenko; Itay Bar-Or; Ariel Kushmaro; Timothy Spector; Claire J Steves

    doi:10.1101/2020.10.21.347799 Date: 2020-10-21 Source: bioRxiv

    To fight against the worldwide COVID-19 MESHD COVID-19 MESHD pandemic, the development of an effective and safe vaccine against SARS-CoV-2 is required. As potential pandemic vaccines, DNA or RNA vaccines, viral vector vaccines and protein-based vaccines have been rapidly developed to prevent pandemic spread worldwide. In this study, we designed plasmid DNA vaccine targeting the SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD glycoprotein (S PROTEIN protein) as pandemic vaccine, and the humoral, cellular, and functional immune responses were characterized to support proceeding to initial human clinical trials. After intramuscular injection of DNA vaccine encoding S protein PROTEIN with alum adjuvant (three times at 2-week intervals), the humoral immunoreaction, as assessed by anti- S protein PROTEIN or anti-receptor-binding domain (RBD) antibody titers, and the cellular immunoreaction, as assessed by antigen-induced IFN-g HGNC expression, were up-regulated. In IgG subclass analysis, IgG2b was induced as the main subclass. Based on these analyses, DNA vaccine with alum adjuvant preferentially induced Th1 HGNC-type T cell polarization. We confirmed the neutralizing action of DNA vaccine-induced antibodies via two different methods, a binding assay of RBD recombinant protein with angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC), a receptor of SARS-CoV-2, and pseudovirus assay. Further B cell epitope mapping analysis using a peptide array showed that most vaccine-induced antibodies recognized the S2 and RBD subunits, but not the S1 subunit. In conclusion, DNA vaccine targeting the spike glycoprotein PROTEIN of SARS-CoV-2 might be an effective and safe approach to combat the COVID-19 pandemic MESHD.

    sMAdCAM:IL-6 (sMIL Index): A novel signature associated with COVID-19 MESHD disease progression and development of anti-SARS-CoV-2 antibodies

    Authors: Dhanashree Jagtap; Vikrant M Bhor; Shilpa Bhowmick; Nandini Kasarpalkar; Pooja Sagvekar; Bhalchandra Kulkarni; Manish Pathak; Nirjhar Chatterjee; Pranam Dolas; Harsha Palav; Snehal Kaginkar; Sharad Bhagat; Itti Munshi; Swapneil Parikh; Sachee Agrawal; Chandrakant Pawar; Mala Kaneria; Smita Mahale; Jayanthi Shastri; Vainav Patel

    doi:10.1101/2020.10.13.20182949 Date: 2020-10-16 Source: medRxiv

    IMPORTANCE: Recent studies positing the gut as a sanctuary site for viral persistence in SARS-CoV-2 infection MESHD highlight the importance of assimilating profiles of systemic as well as gut inflammatory mediators to understand the pathology of COVID-19 MESHD. Also, the role of these markers in governing virus specific immunity following infection remains largely unexplored. OBJECTIVE: To evaluate the role of systemic and gut inflammatory markers in disease progression and development of anti-viral humoral immunity following SARS-CoV-2 infection MESHD. DESIGN, SETTING AND PARTICIPANTS: This cohort study (n=58) of SARS-CoV-2 infected MESHD individuals included a group of in-patients (n=36) at various stages of disease progression together with convalescent individuals (n=22) recruited between April and June 2020 (peak of the epidemic) from a tertiary care hospital in Mumbai, India. Follow-up of 11 in-patients at day 7 post diagnosis was carried out, resulting in a total of 47 in-patient samples. EXPOSURES: Diagnosis of SARS-CoV-2 infections MESHD was confirmed by reverse transcriptase-polymerase chain reaction-based testing of nasopharyngeal/oropharyngeal samples. MAIN OUTCOMES AND MEASURES: Primary outcomes were the measurement of inflammatory markers including Th1 HGNC/Th2/Th17 cytokines and levels of soluble mucosal addressin cell adhesion molecule (sMAdCAM) in plasma. Anti-viral humoral response was measured by rapid antibody test (IgG, IgM) and chemiluminescent immunoassay (CLIA) (IgG). Also antibodies binding to SARS-CoV-2 proteins were measured by surface plasmon resonance ( SPR HGNC). Secondary outcomes were correlation of the inflammatory signature with clinical information, including age, sex, disease duration and co-morbidities. RESULTS: Twenty eight of 36 (78%) in-patients and 19 of 22 (86%) convalescents were males. Out of 47 in-patient samples, 22 (46%), 11 (23%) and 14 (30%) were IgG-/IgM-, IgG+/IgM+ and IgG+/IgM- respectively. Of 22 convalescent samples, 3 (14%), 1 (4%) and 17 (77%) were respectively IgG-/IgM-, IgG+/IgM+ and IgG+/IgM-. Two out of 22 (9%) convalescents showed high IL-6 HGNC levels (>100pg/ml) and 4 (18%) had high TNF HGNC levels (>30pg/ml). However, the convalescents (n =22) had significantly lower levels of IL-6 HGNC [Median=27.48 (IQR=23.54-39.92)] compared to followed up in-patients (n = 11) at day 0 [Median=111(IQR=68-129.7), p =0.0002] and higher levels of sMAdCAM [Median=1940 (1711-2174) pg/ml] compared to these individuals at day 0 [Median=1701 (IQR=1532-1836) pg/ml; p=0.032] and day 7 [Median=1534 (IQR=1236-1654) pg/ml; p=0.0007]. Further, IL-6 HGNC and sMAdCAM levels among in-patients inversely correlated with one another (r =-0.374, p = 0.009, CI = 95%). When expressed as a novel integrated marker, sMIL (sMAdCAM/ IL-6 HGNC ratio) index, these levels were incrementally and significantly higher across various disease states with convalescents exhibiting the highest values [Median= 64.74 (IQR=47.33-85.58)]. Also, the sMIL index was significantly higher in convalescents (with class-switched responses) compared to IgG+/IgM+ individuals at early stages of infection [Median=28.65 (IQR=13.63-96.26), p = 0.034]. Real-time measurement by SPR HGNC of plasma antibody binding to viral nucleocapsid (NC), receptor binding domain (RBD) and spike (S) revealed waxing and waning of plasma antibody responses to all 3 targets. Importantly, sMAdCAM levels as well as sMIL index (fold change) correlated with peak association rates of RBD-binding (r = 0.462, p = 0.03, CI = 95%) and fold change in binding to S (r = 0.68, p = 0.050, CI = 95%) respectively. CONCLUSION AND RELEVANCE: Our results highlight key systemic and gut-associated immune parameters that need to be monitored and investigated further to optimally guide therapeutic and prophylactic interventions for COVID-19 MESHD.

    Could Unconventional Immunomodulatory Agents Help Alleviate COVID-19 MESHD Symptoms and Severity?

    Authors: Stephen Mamber; Steven Krakowka; Jeffrey Osborn; Lloyd Saberski; Ryan Rhodes; Albert Dahlberg; Kara Fitzgerald; Neal Wright; Sarah Beseme; John McMichael

    id:202004.0014/v2 Date: 2020-04-27 Source: Preprints.org

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS coronavirus 2 or SARS-CoV-2) is the cause of the respiratory infection MESHD known as COVID-19 MESHD. From an immunopathological standpoint, coronaviruses such as SARS-CoV-2 induce an increase in a variety of T-helper 1 ( Th1 HGNC) and inflammatory cytokines and chemokines including interleukins IL-1 HGNC, IL-6 HGNC, CCL2 HGNC protein and CXCL10 HGNC protein. In the absence of proven antiviral agents or an effective vaccine, substances with immunomodulatory activity may be able to inhibit inflammatory and Th1 HGNC cytokines and/or yield an anti-inflammatory and/or Th2 immune response to counteract COVID-19 MESHD symptoms and severity. This report briefly describes four unconventional but commercially accessible immunomodulatory agents that could be employed in clinical trials to evaluate their effectiveness at alleviating disease symptoms and severity: Low-dose oral interferon-alpha, microdose DNA, low-dose thimerosal and phytocannabinoids.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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