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1.
Nat Immunol ; 23(3): 349-351, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1747202
2.
Cell Host Microbe ; 27(6): 879-882.e2, 2020 06 10.
Article in English | MEDLINE | ID: covidwho-1719463

ABSTRACT

The inflammatory response to SARS-coronavirus-2 (SARS-CoV-2) infection is thought to underpin COVID-19 pathogenesis. We conducted daily transcriptomic profiling of three COVID-19 cases and found that the early immune response in COVID-19 patients is highly dynamic. Patient throat swabs were tested daily for SARS-CoV-2, with the virus persisting for 3 to 4 weeks in all three patients. Cytokine analyses of whole blood revealed increased cytokine expression in the single most severe case. However, most inflammatory gene expression peaked after respiratory function nadir, except expression in the IL1 pathway. Parallel analyses of CD4 and CD8 expression suggested that the pro-inflammatory response may be intertwined with T cell activation that could exacerbate disease or prolong the infection. Collectively, these findings hint at the possibility that IL1 and related pro-inflammatory pathways may be prognostic and serve as therapeutic targets for COVID-19. This work may also guide future studies to illuminate COVID-19 pathogenesis and develop host-directed therapies.


Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/immunology , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Adult , Aged , Biological Variation, Individual , COVID-19 , Cluster Analysis , Coronavirus Infections/blood , Coronavirus Infections/pathology , Cytokines/blood , Gene Expression Regulation , Humans , Male , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Transcriptome , Up-Regulation
3.
NPJ Vaccines ; 7(1): 31, 2022 Mar 02.
Article in English | MEDLINE | ID: covidwho-1721525

ABSTRACT

COVID-19 vaccines are effective and important to control the ongoing pandemic, but vaccine reactogenicity may contribute to poor uptake. Analgesics or antipyretic medications are often used to alleviate vaccine side effects, but their effect on immunogenicity remains uncertain. Few studies have assessed the effect of analgesics/antipyretics on vaccine immunogenicity and reactogenicity. Some studies revealed changes in certain immune response parameters post-vaccination when analgesics/antipyretics were used either prophylactically or therapeutically. Still, there is no evidence that these changes impact vaccine efficacy. Specific data on the impact of analgesic/antipyretic medications on immunogenicity of COVID-19 vaccines are limited. However, available data from clinical trials of licensed vaccines, along with recommendations from public health bodies around the world, should provide reassurance to both healthcare professionals and vaccine recipients that short-term use of analgesics/antipyretics at non-prescription doses is unlikely to affect vaccine-induced immunity.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313670

ABSTRACT

RNA vaccines against Covid-19 have demonstrated ~95% efficacy in Phase III clinical trials. Although complete vaccination consisted of two-doses, the onset of protection for both licensed RNA vaccines was observed as early as 12 days after a single dose. The adaptive immune response that coincides with this onset of protection could represent the necessary elements of immunity against Covid-19. Herein, we tracked the early adaptive immune responses after Covid-19 RNA vaccination, in a cohort of 20 healthcare workers. Our findings suggest that early T cell and binding antibody responses, rather than either receptor-blocking or virus neutralizing activity, induced early protection against Covid-19.Funding: This study was partially funded through a generousdonation from The Hourglass to support Covid-19 research in ViREMiCS. SK receives salary support from the Transition Award, RdA receives funding from the Open Research Fund Young Investigator Award, JGL and EEO receive salary support from the Clinician Scientist Award, and AB receives salary support from the Singapore Translational Research Award, all administered by the National Medical Research Council of Singapore.Conflict of Interest: Duke-NUS Medical School is in partnership with Arcturus Therapeutics to develop a self-replicating RNA vaccine against Covid-19, with EEO as the principal investigator. No monetary or personal benefits are derived from this partnership.Ethical Approval: This study was approved by the SingHealth Centralized Institutional Review Board (CIRB/F2021/2014). Healthcare workers (HCWs) from the Singapore Health Services institutions whowere eligible for Covid-19 vaccination were invited to participate in this study, and written informed consent was obtained.

5.
Med (N Y) ; 3(2): 104-118.e4, 2022 Feb 11.
Article in English | MEDLINE | ID: covidwho-1628746

ABSTRACT

Background: Protection offered by coronavirus disease 2019 (COVID-19) vaccines wanes over time, requiring an evaluation of different boosting strategies to revert such a trend and enhance the quantity and quality of Spike-specific humoral and cellular immune responses. These immunological parameters in homologous or heterologous vaccination boosts have thus far been studied for mRNA and ChAdOx1 nCoV-19 vaccines, but knowledge on individuals who received a single dose of Ad26.COV2.S is lacking. Methods: We studied Spike-specific humoral and cellular immunity in Ad26.COV2.S-vaccinated individuals (n = 55) who were either primed with Ad26.COV2.S only (n = 13) or were boosted with a homologous (Ad26.COV2.S, n = 28) or heterologous (BNT162b2, n = 14) second dose. We compared our findings with the results found in individuals vaccinated with a single (n = 16) or double (n = 44) dose of BNT162b2. Findings: We observed that a strategy of heterologous vaccination enhanced the quantity and breadth of both Spike-specific humoral and cellular immunity in Ad26.COV2.S-vaccinated individuals. In contrast, the impact of the homologous boost was quantitatively minimal in Ad26.COV2.S-vaccinated individuals, and Spike-specific antibodies and T cells were narrowly focused to the S1 region. Conclusions: Despite the small sample size of the study and the lack of well-defined correlates of protection against COVID-19, the immunological features detected support the utilization of a heterologous vaccine boost in individuals who received Ad26.COV2.S vaccination. Funding: This study is partially supported by the Singapore Ministry of Health's National Medical Research Council under its COVID-19 Research Fund (COVID19RF3-0060, COVID19RF-001, and COVID19RF-008), The Medical College St. Bartholomew's Hospital Trustees - Pump Priming Fund for SMD COVID-19 Research.

6.
Clin Infect Dis ; 74(1): 144-148, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1621566

ABSTRACT

We are learning that the host response to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a "one size fits all" approach to immunomodulation in patients with coronavirus disease 2019 (COVID-19). We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anticytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.


Subject(s)
COVID-19 , Immunomodulation , Precision Medicine , COVID-19/immunology , COVID-19/therapy , Cytokines , Humans , Immunity , Lung , SARS-CoV-2
7.
Mikrochim Acta ; 189(1): 14, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1556195

ABSTRACT

In the ongoing COVID-19 pandemic, simple, rapid, point-of-care tests not requiring trained personnel for primary care testing are essential. Saliva-based antigen rapid tests (ARTs) can fulfil this need, but these tests require overnight-fasted samples; without which independent studies have demonstrated sensitivities of only 11.7 to 23.1%. Herein, we report an Amplified Parallel ART (AP-ART) with sensitivity above 90%, even with non-fasted samples. The virus was captured multimodally, using both anti-spike protein antibodies and Angiotensin Converting Enzyme 2 (ACE2) protein. It also featured two parallel flow channels. The first contained spike protein binding gold nanoparticles which produced a visible red line upon encountering the virus. The second contained signal amplifying nanoparticles that complex with the former and amplify the signal without any linker. Compared to existing dual gold amplification techniques, a limit of detection of one order of magnitude lower was achieved (0.0064 ng·mL-1). AP-ART performance in detecting SARS-CoV-2 in saliva of COVID-19 patients was investigated using a case-control study (139 participants enrolled and 162 saliva samples tested). Unlike commercially available ARTs, the sensitivity of AP-ART was maintained even when non-fasting saliva was used. Compared to the gold standard reverse transcription-polymerase chain reaction testing on nasopharyngeal samples, non-fasting saliva tested on AP-ART showed a sensitivity of 97.0% (95% CI: 84.7-99.8); without amplification, the sensitivity was 72.7% (95% CI: 83.7-94.8). Thus, AP-ART has the potential to be developed for point-of-care testing, which may be particularly important in resource-limited settings, and for early diagnosis to initiate newly approved therapies to reduce COVID-19 severity.


Subject(s)
Antigens/analysis , COVID-19/diagnosis , Point-of-Care Testing , Saliva/virology , COVID-19/virology , Case-Control Studies , Gold/chemistry , Immunoassay/instrumentation , Immunoassay/methods , Metal Nanoparticles/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Sensitivity and Specificity
8.
JCI Insight ; 6(7)2021 04 08.
Article in English | MEDLINE | ID: covidwho-1472322

ABSTRACT

Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis.


Subject(s)
Antiviral Agents/pharmacology , Host-Pathogen Interactions/physiology , Virus Diseases/metabolism , Virus Diseases/virology , Host-Pathogen Interactions/drug effects , Humans , Hypoxia , Hypoxia-Inducible Factor 1/metabolism , Virus Diseases/drug therapy , Virus Diseases/immunology
9.
J Clin Invest ; 131(17)2021 09 01.
Article in English | MEDLINE | ID: covidwho-1463086

ABSTRACT

Defining the correlates of protection necessary to manage the COVID-19 pandemic requires the analysis of both antibody and T cell parameters, but the complexity of traditional tests limits virus-specific T cell measurements. We tested the sensitivity and performance of a simple and rapid SARS-CoV-2 spike protein-specific T cell test based on the stimulation of whole blood with peptides covering the SARS-CoV-2 spike protein, followed by cytokine (IFN-γ, IL-2) measurement in different cohorts including BNT162b2-vaccinated individuals (n = 112), convalescent asymptomatic and symptomatic COVID-19 patients (n = 130), and SARS-CoV-1-convalescent individuals (n = 12). The sensitivity of this rapid test is comparable to that of traditional methods of T cell analysis (ELISPOT, activation-induced marker). Using this test, we observed a similar mean magnitude of T cell responses between the vaccinees and SARS-CoV-2 convalescents 3 months after vaccination or virus priming. However, a wide heterogeneity of the magnitude of spike-specific T cell responses characterized the individual responses, irrespective of the time of analysis. The magnitude of these spike-specific T cell responses cannot be predicted from the neutralizing antibody levels. Hence, both humoral and cellular spike-specific immunity should be tested after vaccination to define the correlates of protection necessary to evaluate current vaccine strategies.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 , Immunity, Cellular/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes , Adult , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
10.
Mol Ther ; 29(6): 1970-1983, 2021 06 02.
Article in English | MEDLINE | ID: covidwho-1386766

ABSTRACT

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/administration & dosage , Alphavirus/genetics , Alphavirus/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/biosynthesis , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Female , Gene Expression , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Mice , Mice, Transgenic , Replicon/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/virology , Transgenes , Treatment Outcome , Vaccination/methods , Vaccines, Synthetic/biosynthesis , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
11.
Lancet Infect Dis ; 20(9): 996-998, 2020 09.
Article in English | MEDLINE | ID: covidwho-1386891
12.
Nature ; 584(7821): 457-462, 2020 08.
Article in English | MEDLINE | ID: covidwho-1373437

ABSTRACT

Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections1. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to 'common cold' human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , T-Lymphocytes/immunology , Betacoronavirus/chemistry , COVID-19 , Case-Control Studies , Coronavirus Infections/virology , Coronavirus Nucleocapsid Proteins , Cross Reactions/immunology , Humans , Immunodominant Epitopes/immunology , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/immunology , Pandemics , Phosphoproteins , Pneumonia, Viral/virology , SARS-CoV-2
13.
Viruses ; 13(8)2021 07 30.
Article in English | MEDLINE | ID: covidwho-1335233

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus in humans, has expanded globally over the past year. COVID-19 remains an important subject of intensive research owing to its huge impact on economic and public health globally. Based on historical archives, the first coronavirus-related disease recorded was possibly animal-related, a case of feline infectious peritonitis described as early as 1912. Despite over a century of documented coronaviruses in animals, the global animal industry still suffers from outbreaks. Knowledge and experience handling animal coronaviruses provide a valuable tool to complement our understanding of the ongoing COVID-19 pandemic. In this review, we present an overview of coronaviruses, clinical signs, COVID-19 in animals, genome organization and recombination, immunopathogenesis, transmission, viral shedding, diagnosis, treatment, and prevention. By drawing parallels between COVID-19 in animals and humans, we provide perspectives on the pathophysiological mechanisms by which coronaviruses cause diseases in both animals and humans, providing a critical basis for the development of effective vaccines and therapeutics against these deadly viruses.


Subject(s)
Animal Diseases/virology , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Coronavirus/physiology , Animal Diseases/epidemiology , Animals , COVID-19/epidemiology , COVID-19/virology , Coronavirus/genetics , Coronavirus Infections/epidemiology , Humans , Public Health , SARS-CoV-2/genetics , SARS-CoV-2/physiology
14.
Antiviral Res ; 193: 105138, 2021 09.
Article in English | MEDLINE | ID: covidwho-1300619

ABSTRACT

The global spread of SARS-CoV-2 has made millions ill with COVID-19 and even more from the economic fallout of this pandemic. Our quest to test new therapeutics and vaccines require small animal models that replicate disease phenotypes seen in COVID-19 cases. Rodent models of SARS-CoV-2 infection thus far have shown mild to moderate pulmonary disease; mortality, if any, has been associated with prominent signs of central nervous system (CNS) infection and dysfunction. Here we describe the isolation of SARS-CoV-2 variants with propensity for either pulmonary or CNS infection. Using a wild-type SARS-CoV-2 isolated from a COVID-19 patient, we first found that infection was lethal in transgenic mice expressing the human angiotensin I-converting enzyme 2 (hACE2). Fortuitously, full genome sequencing of SARS-CoV-2 from the brain and lung of these animals showed genetic differences. Likewise, SARS-CoV-2 isolates from brains and lungs of these also showed differences in plaque morphology. Inoculation of these brain and lung SARS-CoV-2 isolates into new batch of hACE2 mice intra-nasally resulted in lethal CNS and pulmonary infection, respectively. Collectively, our study suggests that genetic variants of SARS-CoV-2 could be used to replicate specific features of COVID-19 for the testing of potential vaccines or therapeutics.


Subject(s)
COVID-19/pathology , Disease Models, Animal , Lung/pathology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Animals , Brain/pathology , Brain/virology , COVID-19/metabolism , COVID-19/mortality , COVID-19/virology , Female , Humans , Lung/virology , Mice , Mice, Transgenic , Peptidyl-Dipeptidase A/metabolism
15.
Science ; 372(6546): 1041-1042, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1276878
16.
Med (N Y) ; 2(6): 682-688.e4, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1174423

ABSTRACT

BACKGROUND: RNA vaccines against coronavirus disease 2019 (COVID-19) have demonstrated ∼95% efficacy in phase III clinical trials. Although complete vaccination consisted of 2 doses, the onset of protection for both licensed RNA vaccines was observed as early as 12 days after a single dose. The adaptive immune response that coincides with this onset of protection could represent the necessary elements of immunity against COVID-19. METHODS: Serological and T cell analysis was performed in a cohort of 20 healthcare workers after receiving the first dose of the Pfizer/BioNTech BNT162b2 vaccine. The primary endpoint was the adaptive immune responses detectable at days 7 and 10 after dosing. FINDINGS: Spike-specific T cells and binding antibodies were detectable 10 days after the first dose of the vaccine, in contrast to receptor-blocking and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) neutralizing antibodies, which were mostly undetectable at this early time point. CONCLUSIONS: Our findings suggest that early T cell and binding antibody responses, rather than either receptor-blocking or virus neutralizing activity, induced early protection against COVID-19. FUNDING: The study was funded by a generous donation from The Hour Glass to support COVID-19 research.


Subject(s)
COVID-19 Vaccines , COVID-19 , Antibodies, Viral , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Humans , Immunoglobulin G , RNA , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes , Vaccines, Synthetic
17.
EBioMedicine ; 65: 103262, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1124859

ABSTRACT

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic has cost lives and economic hardships globally. Various studies have found a number of different factors, such as hyperinflammation and exhausted/suppressed T cell responses to the etiological SARS coronavirus-2 (SARS-CoV-2), being associated with severe COVID-19. However, sieving the causative from associative factors of respiratory dysfunction has remained rudimentary. METHODS: We postulated that the host responses causative of respiratory dysfunction would track most closely with disease progression and resolution and thus be differentiated from other factors that are statistically associated with but not causative of severe COVID-19. To track the temporal dynamics of the host responses involved, we examined the changes in gene expression in whole blood of 6 severe and 4 non-severe COVID-19 patients across 15 different timepoints spanning the nadir of respiratory function. FINDINGS: We found that neutrophil activation but not type I interferon signaling transcripts tracked most closely with disease progression and resolution. Moreover, transcripts encoding for protein phosphorylation, particularly the serine-threonine kinases, many of which have known T cell proliferation and activation functions, were increased after and may thus contribute to the upswing of respiratory function. Notably, these associative genes were targeted by dexamethasone, but not methylprednisolone, which is consistent with efficacy outcomes in clinical trials. INTERPRETATION: Our findings suggest neutrophil activation as a critical factor of respiratory dysfunction in COVID-19. Drugs that target this pathway could be potentially repurposed for the treatment of severe COVID-19. FUNDING: This study was sponsored in part by a generous gift from The Hour Glass. EEO and JGL are funded by the National Medical Research Council of Singapore, through the Clinician Scientist Awards awarded by the National Research Foundation of Singapore.


Subject(s)
COVID-19/pathology , Lymphocyte Activation/immunology , Neutrophil Activation/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adult , Aged , Disease Progression , Drug Repositioning , Female , Gene Expression/genetics , Gene Expression Profiling , Humans , Male , Middle Aged , Neutrophils/immunology , Prospective Studies , T-Lymphocytes/immunology
18.
FEBS J ; 288(17): 5055-5070, 2021 09.
Article in English | MEDLINE | ID: covidwho-894751

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a large-scale pandemic that is afflicting millions of individuals in over 200 countries. The clinical spectrum caused by SARS-CoV-2 infections can range from asymptomatic infection to mild undifferentiated febrile illness to severe respiratory disease with multiple complications. Elderly patients (aged 60 and above) with comorbidities such as cardiovascular diseases and diabetes mellitus appear to be at highest risk of a severe disease outcome. To protect against pulmonary immunopathology caused by SARS-CoV-2 infection, the host primarily depends on two distinct defense strategies: resistance and disease tolerance. Resistance is the ability of the host to suppress and eliminate incoming viruses. By contrast, disease tolerance refers to host responses that promote host health regardless of their impact on viral replication. Disruption of either resistance or disease tolerance mechanisms or both could underpin predisposition to elevated risk of severe disease during viral infection. Aging can disrupt host resistance and disease tolerance by compromising immune functions, weakening of the unfolded protein response, progressive mitochondrial dysfunction, and altering metabolic processes. A comprehensive understanding of the molecular mechanisms underlying declining host defense in elderly individuals could thus pave the way to provide new opportunities and approaches for the treatment of severe COVID-19.


Subject(s)
Aging/genetics , COVID-19/genetics , Disease Resistance/genetics , SARS-CoV-2/pathogenicity , Aged , COVID-19/pathology , COVID-19/virology , Host-Pathogen Interactions/genetics , Humans , Immune Tolerance/genetics , Pandemics , SARS-CoV-2/genetics , Virus Replication/genetics
19.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-753

ABSTRACT

Background: Coronavirus disease 2019 is a respiratory illness caused by the newly emerged SARS-coronavirus-2 (SARS-CoV-2). Starting with an epidemic of viral pn

20.
N Engl J Med ; 383(5): 452-459, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-692294

ABSTRACT

BACKGROUND: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America. METHODS: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion. RESULTS: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group. CONCLUSIONS: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Yellow Fever Vaccine , Yellow Fever/drug therapy , Yellow fever virus/immunology , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Humans , Kaplan-Meier Estimate , Viremia/drug therapy , Yellow Fever/virology , Yellow fever virus/drug effects
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