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1.
Vaccine ; 2022 Jul 06.
Article in English | MEDLINE | ID: covidwho-1915072

ABSTRACT

The emergence of SARS-CoV-2 in December 2019 resulted in the COVID-19 pandemic. Recurring disease outbreaks repeatedly overloaded the public health sector and severely affected the global economy. We developed a candidate COVID-19 vaccine based on a recombinant Newcastle disease virus (NDV) vaccine vector, encoding a pre-fusion stabilized full-length Spike protein obtained from the original SARS-CoV-2 Wuhan isolate. Vaccination of hamsters by intra-muscular injection or intra-nasal instillation induced high neutralizing antibody responses. Intranasal challenge infection with SARS-CoV-2 strain Lelystad demonstrated that both vaccination routes provided partial protection in the upper respiratory tract, and almost complete protection in the lower respiratory tract, as measured by suppressed viral loads and absence of histological lung lesions. Activity wheel measurements demonstrated that animals vaccinated by intranasal inoculation rapidly recovered to normal activity. NDV constructs encoding the spike of SARS-CoV-2 may be attractive candidates for development of intra-nasal COVID-19 booster vaccines.

2.
mBio ; 13(3): e0124922, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1891739

ABSTRACT

The ability of SARS-CoV-2 to evolve in response to selective pressures poses a challenge to vaccine and antiviral efficacy. The S1 subunit of the spike (S) protein contains the receptor-binding domain and is therefore under selective pressure to evade neutralizing antibodies elicited by vaccination or infection. In contrast, the S2 subunit of S is only transiently exposed after receptor binding, which makes it a less efficient target for antibodies. As a result, S2 has a lower mutational frequency than S1. We recently described monomeric and dimeric SARS-CoV-2 fusion-inhibitory lipopeptides that block viral infection by interfering with S2 conformational rearrangements during viral entry. Importantly, a dimeric lipopeptide was shown to block SARS-CoV-2 transmission between ferrets in vivo. Because the S2 subunit is relatively conserved in newly emerging SARS-CoV-2 variants of concern (VOCs), we hypothesize that fusion-inhibitory lipopeptides are cross-protective against infection with VOCs. Here, we directly compared the in vitro efficacies of two fusion-inhibitory lipopeptides against VOC, in comparison with a set of seven postvaccination sera (two doses) and a commercial monoclonal antibody preparation. For the beta, delta, and omicron VOCs, it has been reported that convalescent and postvaccination sera are less potent in virus neutralization assays. Both fusion-inhibitory lipopeptides were equally effective against all five VOCs compared to ancestral virus, whereas postvaccination sera and therapeutic monoclonal antibody lost potency to newer VOCs, in particular to omicron BA.1 and BA.2. The neutralizing activity of the lipopeptides is consistent, and they can be expected to neutralize future VOCs based on their mechanism of action. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, with waves resulting from new variants that evade immunity generated by vaccines and previous strains and escape available monoclonal antibody therapy. Fusion-inhibitory peptides may provide an intervention strategy that is not similarly affected by this viral evolution.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Ferrets , Humans , Lipopeptides/chemistry , Lipopeptides/pharmacology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus
3.
Viruses ; 14(6)2022 05 29.
Article in English | MEDLINE | ID: covidwho-1869826

ABSTRACT

Measles virus (MV) is a highly contagious respiratory virus responsible for outbreaks associated with significant morbidity and mortality among children and young adults. Although safe and effective measles vaccines are available, the COVID-19 pandemic has resulted in vaccination coverage gaps that may lead to the resurgence of measles when restrictions are lifted. This puts individuals who cannot be vaccinated, such as young infants and immunocompromised individuals, at risk. Therapeutic interventions are complicated by the long incubation time of measles, resulting in a narrow treatment window. At present, the only available WHO-advised option is treatment with intravenous immunoglobulins, although this is not approved as standard of care. Antivirals against measles may contribute to intervention strategies to limit the impact of future outbreaks. Here, we review previously described antivirals and antiviral assays, evaluate the antiviral efficacy of a number of compounds to inhibit MV dissemination in vitro, and discuss potential application in specific target populations. We conclude that broadly reactive antivirals could strengthen existing intervention strategies to limit the impact of measles outbreaks.


Subject(s)
COVID-19 , Measles , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Child , Humans , Measles Vaccine , Measles virus , Pandemics , Vaccination
4.
Thromb Res ; 210: 6-11, 2022 02.
Article in English | MEDLINE | ID: covidwho-1634248

ABSTRACT

BACKGROUND: Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection. OBJECTIVES: This study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis. MATERIAL AND METHODS: Histology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed. RESULTS: Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation. CONCLUSIONS: We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited.


Subject(s)
COVID-19 , Thrombosis , Venous Thrombosis , Animals , Blood Proteins , Ferrets , Humans , Lung , Mice , Rats , SARS-CoV-2
5.
Science ; 371(6536): 1379-1382, 2021 03 26.
Article in English | MEDLINE | ID: covidwho-1476374

ABSTRACT

Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.


Subject(s)
COVID-19/transmission , Lipopeptides/administration & dosage , Membrane Fusion/drug effects , SARS-CoV-2/drug effects , Viral Fusion Protein Inhibitors/administration & dosage , Virus Internalization/drug effects , Administration, Intranasal , Animals , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Drug Design , Ferrets , Lipopeptides/chemistry , Lipopeptides/pharmacokinetics , Lipopeptides/pharmacology , Mice , Pre-Exposure Prophylaxis , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Tissue Distribution , Vero Cells , Viral Fusion Protein Inhibitors/chemistry , Viral Fusion Protein Inhibitors/pharmacokinetics , Viral Fusion Protein Inhibitors/pharmacology
6.
Curr Opin Virol ; 50: 8-16, 2021 10.
Article in English | MEDLINE | ID: covidwho-1284020

ABSTRACT

SARS-CoV-2 emerged in China as a zoonotic virus in December 2019. The virus proved to be human-to-human transmissible and its global spread resulted in the ongoing COVID-19 pandemic, associated with high morbidity and mortality. Vaccines were developed at an unprecedented speed and proved to be efficacious in preventing disease, but it remains to be determined if vaccines are able to interrupt transmission. Moreover, virus variants of concern continue to emerge that appear more transmissible and/or less sensitive to virus-specific immune responses. Here, we briefly review the role of animal models in assessing prophylactic and therapeutic options to interrupt SARS-CoV-2 transmission.


Subject(s)
COVID-19/transmission , Disease Models, Animal , SARS-CoV-2 , Animals , COVID-19/prevention & control , Cricetinae , Humans
7.
Sci Immunol ; 6(59)2021 05 25.
Article in English | MEDLINE | ID: covidwho-1243688

ABSTRACT

The emergence of SARS-CoV-2 variants harboring mutations in the spike (S) protein has raised concern about potential immune escape. Here, we studied humoral and cellular immune responses to wild type SARS-CoV-2 and the B.1.1.7 and B.1.351 variants of concern in a cohort of 121 BNT162b2 mRNA-vaccinated health care workers (HCW). Twenty-three HCW recovered from mild COVID-19 disease and exhibited a recall response with high levels of SARS-CoV-2-specific functional antibodies and virus-specific T cells after a single vaccination. Specific immune responses were also detected in seronegative HCW after one vaccination, but a second dose was required to reach high levels of functional antibodies and cellular immune responses in all individuals. Vaccination-induced antibodies cross-neutralized the variants B.1.1.7 and B.1.351, but the neutralizing capacity and Fc-mediated functionality against B.1.351 was consistently 2- to 4-fold lower than to the homologous virus. In addition, peripheral blood mononuclear cells were stimulated with peptide pools spanning the mutated S regions of B.1.1.7 and B.1.351 to detect cross-reactivity of SARS-CoV-2-specific T cells with variants. Importantly, we observed no differences in CD4+ T-cell activation in response to variant antigens, indicating that the B.1.1.7 and B.1.351 S proteins do not escape T-cell-mediated immunity elicited by the wild type S protein. In conclusion, this study shows that some variants can partially escape humoral immunity induced by SARS-CoV-2 infection or BNT162b2 vaccination, but S-specific CD4+ T-cell activation is not affected by the mutations in the B.1.1.7 and B.1.351 variants.


Subject(s)
Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19 Vaccines/immunology , Cell Line , Cross Reactions/immunology , Humans , Immunologic Memory/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination
8.
Science ; 371(6536): 1379-1382, 2021 03 26.
Article in English | MEDLINE | ID: covidwho-1088184

ABSTRACT

Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.


Subject(s)
COVID-19/transmission , Lipopeptides/administration & dosage , Membrane Fusion/drug effects , SARS-CoV-2/drug effects , Viral Fusion Protein Inhibitors/administration & dosage , Virus Internalization/drug effects , Administration, Intranasal , Animals , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Drug Design , Ferrets , Lipopeptides/chemistry , Lipopeptides/pharmacokinetics , Lipopeptides/pharmacology , Mice , Pre-Exposure Prophylaxis , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Tissue Distribution , Vero Cells , Viral Fusion Protein Inhibitors/chemistry , Viral Fusion Protein Inhibitors/pharmacokinetics , Viral Fusion Protein Inhibitors/pharmacology
10.
Sci Immunol ; 5(48)2020 06 26.
Article in English | MEDLINE | ID: covidwho-617063

ABSTRACT

SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients the infection results in moderate to severe acute respiratory distress syndrome (ARDS), requiring invasive mechanical ventilation. High serum levels of IL-6, IL-10 and an immune hyperresponsiveness referred to as a 'cytokine storm' have been associated with poor clinical outcome. Despite the large numbers of COVID-19 cases and deaths, information on the phenotype and kinetics of SARS-CoV-2-specific T cells is limited. Here, we studied 10 COVID-19 patients who required admission to an intensive care unit and detected SARS-CoV-2-specific CD4+ and CD8+ T cells in 10 out of 10 and 8 out of 10 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T cells in 2 out of 10 healthy controls not previously exposed to SARS-CoV-2, which is indicative of cross-reactivity due to past infection with 'common cold' coronaviruses. The strongest T-cell responses were directed to the spike (S) surface glycoprotein, and SARS-CoV-2-specific T cells predominantly produced effector and Th1 cytokines, although Th2 and Th17 cytokines were also detected. Furthermore, we studied T-cell kinetics and showed that SARS-CoV-2-specific T cells are present relatively early and increase over time. Collectively, these data shed light on the potential variations in T-cell responses as a function of disease severity, an issue that is key to understanding the potential role of immunopathology in the disease, and also inform vaccine design and evaluation.


Subject(s)
Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Phenotype , Pneumonia, Viral/immunology , Respiratory Distress Syndrome/immunology , Aged , COVID-19 , Cells, Cultured , Coronavirus Infections/blood , Coronavirus Infections/virology , Cytokines/metabolism , Female , Humans , Immunologic Memory , Kinetics , Longitudinal Studies , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , Viral Load/immunology
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