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1.
NPJ Vaccines ; 6(1): 153, 2021 Dec 16.
Article in English | MEDLINE | ID: covidwho-1585845

ABSTRACT

Recent approval of mRNA vaccines for emergency use against COVID-19 is likely to promote rapid development of mRNA-based vaccines targeting a wide range of infectious diseases. Compared to conventional approaches, this vaccine modality promises comparable potency while substantially accelerating the pace of development and deployment of vaccine doses. Already demonstrated successfully for single antigen vaccines such as for COVID-19, this technology could be optimized for complex multi-antigen vaccines. Herein, utilizing multiple influenza antigens, we demonstrated the suitability of the mRNA therapeutic (MRT) platform for such applications. Seasonal influenza vaccines have three or four hemagglutinin (HA) antigens of different viral subtypes. In addition, influenza neuraminidase (NA), a tetrameric membrane protein, is identified as an antigen that has been linked to protective immunity against severe viral disease. We detail the efforts in optimizing formulations of influenza candidates that use unmodified mRNA encoding full-length HA or full-length NA encapsulated in lipid nanoparticles (LNPs). HA and NA mRNA-LNP formulations, either as monovalent or as multivalent vaccines, induced strong functional antibody and cellular responses in non-human primates and such antigen-specific antibody responses were associated with protective efficacy against viral challenge in mice.

2.
J Infect Dis ; 224(4): 736, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1467349
3.
J Infect Dis ; 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1467346
4.
BMC Infect Dis ; 21(1): 737, 2021 Aug 03.
Article in English | MEDLINE | ID: covidwho-1435227

ABSTRACT

BACKGROUND: The serum surfactant protein D (SP-D) level is suggested to be a useful biomarker for acute lung injuries and acute respiratory distress syndrome. Whether the serum SP-D level could identify the severity of coronavirus disease 2019 (COVID-19) in the early stage has not been elucidated. METHODS: We performed an observational study on 39 laboratory-confirmed COVID-19 patients from The Fourth People's Hospital of Yiyang, Hunan, China. Receiver operating characteristic (ROC) curve analysis, correlation analysis, and multivariate logistic regression model analysis were performed. RESULTS: In the acute phase, the serum levels of SP-D were elevated significantly in severe COVID-19 patients than in mild cases (mean value ± standard deviation (SD), 449.7 ± 125.8 vs 245.9 ± 90.0 ng/mL, P<0.001), while the serum levels of SP-D in the recovery period were decreased dramatically than that in the acute phase (mean value ± SD, 129.5 ± 51.7 vs 292.9 ± 130.7 ng/ml, P<0.001), and so were for the stratified patients. The chest CT imaging scores were considerably higher in the severe group compared with those in the mild group (median value, 10.0 vs 9.0, P = 0.011), while markedly lower in the recovery period than those in the acute phase (median value, 2.0 vs 9.0, P<0.001), and so were for the stratified patients. ROC curve analysis revealed that areas under the curve of lymphocyte counts (LYM), C-reaction protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), and SP-D for severe COVID-19 were 0.719, 0.833, 0.817, 0.837, and 0.922, respectively. Correlation analysis showed that the SP-D levels were negatively correlated with LYM (r = - 0.320, P = 0.047), while positively correlated with CRP (r = 0.658, P<0.001), IL-6 (r = 0.471, P = 0.002), the duration of nucleic acid of throat swab turning negative (r = 0.668, P<0.001), chest CT imaging score on admission (r = 0.695, P<0.001) and length of stay (r = 0.420, P = 0.008). Multivariate logistic regression model analysis showed that age (P = 0.041, OR = 1.093) and SP-D (P = 0.008, OR = 1.018) were risk factors for severe COVID-19. CONCLUSIONS: Elevated serum SP-D level was a potential biomarker for the severity of COVID-19; this may be useful in identifying patients whose condition worsens at an early stage.


Subject(s)
COVID-19 , Pulmonary Surfactant-Associated Protein D , Humans , Prognosis , ROC Curve , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
6.
Sci Transl Med ; 13(607)2021 08 18.
Article in English | MEDLINE | ID: covidwho-1329034

ABSTRACT

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike protein trimers (preS dTM) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHPs). Binding and functional neutralization assays and systems serology revealed that the vaccinated NHP developed AS03-dependent multifunctional humoral responses that targeted distinct domains of the spike protein and bound to a variety of Fc receptors mediating immune cell effector functions in vitro. The neutralizing 50% inhibitory concentration titers for pseudovirus and live SARS-CoV-2 were higher than titers for a panel of human convalescent serum samples. NHPs were challenged intranasally and intratracheally with a high dose (3 × 106 plaque forming units) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days after challenge, vaccinated NHPs showed rapid control of viral replication in both the upper and lower airways. Vaccinated NHPs also had increased spike protein-specific immunoglobulin G (IgG) antibody responses in the lung as early as 2 days after challenge. Moreover, passive transfer of vaccine-induced IgG to hamsters mediated protection from subsequent SARS-CoV-2 challenge. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine were sufficient to mediate protection against SARS-CoV-2 in NHPs and that rapid anamnestic antibody responses in the lung may be a key mechanism for protection.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Cricetinae , Immunization, Passive , Lung , Primates , SARS-CoV-2 , Vaccination
7.
J Microbiol Immunol Infect ; 54(1): 85-88, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1272559

ABSTRACT

As the world witnessed the rapid spread of SARS-CoV-2, the World Health Organization has called for governing bodies worldwide to intensify case findings, contact tracing, monitoring, and quarantine or isolation of contacts with COVID-19. Drive-through (DT) screening is a form of case detection which has recently gain preference globally. Proper implementation of this system can help remediate the outbreak.


Subject(s)
COVID-19/diagnosis , COVID-19/prevention & control , Mass Screening/organization & administration , COVID-19/transmission , Contact Tracing , Disease Outbreaks/prevention & control , Epidemiological Monitoring , Humans , Mass Screening/methods , Medical Records Systems, Computerized , Public Health Surveillance , Quarantine , Research Report , SARS-CoV-2/isolation & purification , World Health Organization
8.
J Infect Dis ; 223(1): 179-180, 2021 01 04.
Article in English | MEDLINE | ID: covidwho-1258776
9.
J Infect Dis ; 223(8): 1499-1500, 2021 Apr 23.
Article in English | MEDLINE | ID: covidwho-1244883
10.
NPJ Vaccines ; 6(1): 61, 2021 Apr 19.
Article in English | MEDLINE | ID: covidwho-1193587

ABSTRACT

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

11.
Preprint in English | bioRxiv | ID: ppbiorxiv-433390

ABSTRACT

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FC receptors mediating effector functions in vitro. Pseudovirus and live virus neutralizing IC50 titers were on average greater than 1000 and significantly higher than a panel of human convalescent sera. NHP were challenged intranasally and intratracheally with a high dose (3x106 PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike-specific IgG antibody responses in the lung as early as 2 days post challenge. Moreover, vaccine-induced IgG mediated protection from SARS-CoV-2 challenge following passive transfer to hamsters. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials.

12.
Mediterr J Hematol Infect Dis ; 13(1): e2021015, 2021.
Article in English | MEDLINE | ID: covidwho-1045343

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) is highly contagious and deadly and is associated with coagulopathy. Pentraxin-3(PTX3) participates in innate resistance to infections and plays a role in thrombogenesis. Purpose: The present study aimed to investigate the role of PTX3 in coagulopathy in patients with COVID-19. Methods: A retrospective study, including thirty-nine COVID-19 patients, enrolled in Hunan, China, were performed. The patients were classified into the D-dimer_L (D-dimer <1mg/L) and D-dimer_H (D-dimer≥1mg/L) groups basing on the plasma D-dimer levels on admission. Serum PTX3 levels were detected by enzyme-linked immunosorbent assays and compared between those two groups, then receiver operating characteristic (ROC) curve analysis, correlation analysis, and linear regression models were performed to analyze the association between PTX3 and D-dimer. Results: Our results showed that serum PTX3 levels (median values, 10.21 vs. 3.36, P<0.001), computerized chest tomography (C.T.) scores (median values, 10.0 vs. 9.0, P<0.05), and length of stay (LOS) (mean values, 16.0 vs. 10.7, P=0.001) in the D-dimer_H group were significantly higher than that in D-dimer_L group. ROC curve analysis revealed that the AUC of white blood corpuscle counts, C-reaction protein, erythrocyte sedimentation rate, and PTX3 for COVID-19 were 0.685, 0.863, 0.846, and 0.985, respectively. Correlation analysis showed that there was a positive relationship between PTX3 and D-dimer (r=0.721, P<0.001), chest CT imaging score (r=0.418, P=0.008), and LOS (r=0.486, P=0.002). Multiple linear regression analysis showed that the coefficient of determination was 0.657 (P < 0.001). Conclusion: Serum level of PTX3 was positively correlated with disease severity and coagulopathy. Detection of serum PTX3 level could help identify severer patients on admission and may be a potential therapeutic target for coagulopathy in patients with COVID-19.

13.
Preprint in English | bioRxiv | ID: ppbiorxiv-337535

ABSTRACT

An effective vaccine to address the global pandemic of coronavirus disease 2019 (COVID-19) is an urgent public health priority1. Novel synthetic mRNA and vector-based vaccine technologies offer an expeditious development path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on Spike (S) glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus causing COVID-19. Several mRNA constructs expressing various structural conformations of S-protein, including wild type (WT), a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), were tested in a preclinical animal model for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques. The selected 2P/GSAS vaccine formulation, now designated MRT5500, elicited potent nAbs as measured in two types of neutralization assays. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate species, a result that helps to address a hypothetical concern regarding potential vaccine-associated enhanced respiratory diseases associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for clinical development against COVID-19.

14.
Preprint | SSRN | ID: ppcovidwho-504

ABSTRACT

Background: 2019 novel coronavirus infection is high epidemical in China from January 2020. It is very important to detect it rapidly because of its high infect

15.
J Infect Dis ; 222(6): 894-898, 2020 08 17.
Article in English | MEDLINE | ID: covidwho-613973

ABSTRACT

In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.


Subject(s)
Amine Oxidase (Copper-Containing)/blood , Betacoronavirus , Cell Adhesion Molecules/blood , Chemokine CX3CL1/blood , Coronavirus Infections/blood , Intercellular Adhesion Molecule-1/blood , Pneumonia, Viral/blood , Vascular Cell Adhesion Molecule-1/blood , Amine Oxidase (Copper-Containing)/metabolism , Blood Coagulation Disorders/virology , COVID-19 , Cell Adhesion Molecules/metabolism , Chemokine CX3CL1/metabolism , China , Enzyme-Linked Immunosorbent Assay , Female , Humans , Intercellular Adhesion Molecule-1/metabolism , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2 , Vascular Cell Adhesion Molecule-1/metabolism
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