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1.
J Infect Dis ; 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38261786

RESUMO

Non-human primate models are essential for the development of vaccines and antivirals against infectious diseases. Rhesus macaques are a widely utilized infection model for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We compared cellular tropism and virus replication in rhesus macaques inoculated with SARS-CoV-2 via the intranasal route, or via exposure to aerosols. Intranasal inoculation results in replication in the upper respiratory tract and limited lower respiratory tract involvement, whereas exposure to aerosols results in infection throughout the respiratory tract. In comparison to multi-route inoculation, the intranasal and aerosol inoculation routes result in reduced SARS-CoV-2 replication in the respiratory tract.

2.
Emerg Microbes Infect ; 12(2): 2276338, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37883246

RESUMO

There is tremendous heterogeneity in the severity of COVID-19 disease in the human population, and the mechanisms governing the development of severe disease remain incompletely understood. The emergence of SARS-CoV-2 variants of concern (VOC) Delta (B.1.617.2) and Omicron (B.1.1.529) further compounded this heterogeneity. Virus replication and host cell damage in the distal lung is often associated with severe clinical disease, making this an important site to consider when evaluating pathogenicity of SARS-CoV-2 VOCs. Using distal human lung organoids (hLOs) derived from multiple human donors, we compared the fitness and pathogenicity of SARS-CoV-2 VOC Delta and Omicron, along with an ancestral clade B variant D614G, and evaluated donor-dependent differences in susceptibility to infection. We observed substantial attenuation of Omicron in hLOs and demonstrated enhanced susceptibility to Omicron and D614G replication in hLOs from one donor. Transcriptomic analysis revealed that increased susceptibility to SARS-CoV-2 infection in these hLOs was associated with reduced tonic interferon signaling activity at baseline. We show that hLOs can be used to model heterogeneity of SARS-CoV-2 pathogenesis in humans, and propose that variability in tonic interferon signaling set point may impact susceptibility to SARS-CoV-2 VOCs and subsequent COVID-19 disease progression.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Organoides , Interferons/genética
3.
Sci Adv ; 8(46): eade1860, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36399566

RESUMO

Since the emergence of SARS-CoV-2, five different variants of concern (VOCs) have been identified: Alpha, Beta, Gamma, Delta, and Omicron. Because of confounding factors in the human population, such as preexisting immunity, comparing severity of disease caused by different VOCs is challenging. Here, we investigate disease progression in the rhesus macaque model upon inoculation with the Delta, Omicron BA.1, and Omicron BA.2 VOCs. Disease severity in rhesus macaques inoculated with Omicron BA.1 or BA.2 was lower than those inoculated with Delta and resulted in significantly lower viral loads in nasal swabs, bronchial cytology brush samples, and lung tissue in rhesus macaques. Cytokines and chemokines were up-regulated in nasosorption samples of Delta animals compared to Omicron BA.1 and BA.2 animals. Overall, these data suggest that, in rhesus macaques, Omicron replicates to lower levels than the Delta VOC, resulting in reduced clinical disease.

4.
bioRxiv ; 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35971544

RESUMO

Since the emergence of SARS-CoV-2, five different variants of concern (VOCs) have been identified: Alpha, Beta, Gamma, Delta, and Omicron. Due to confounding factors in the human population, such as pre-existing immunity, comparing severity of disease caused by different VOCs is challenging. Here, we investigate disease progression in the rhesus macaque model upon inoculation with the Delta, Omicron BA.1, and Omicron BA.2 VOCs. Disease severity in rhesus macaques inoculated with Omicron BA.1 or BA.2 was lower than those inoculated with Delta and resulted in significantly lower viral loads in nasal swabs, bronchial cytology brush samples, and lung tissue in rhesus macaques. Cytokines and chemokines were upregulated in nasosorption samples of Delta animals compared to Omicron BA.1 and BA.2 animals. Overall, these data suggests that in rhesus macaques, Omicron replicates to lower levels than the Delta VOC, resulting in reduced clinical disease.

5.
Life Sci Alliance ; 5(4)2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35039442

RESUMO

Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, we used the rhesus macaque model of SARS-CoV-2 infection. Eight older and eight younger macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at predefined time points in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication were limited. Transcriptional signatures of inflammation-associated genes in bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both cohorts. However, age-specific divergence of immune responses emerged during the post-acute phase. Older animals exhibited sustained local inflammatory innate responses, whereas local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, and persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling suggests that age may delay or impair antiviral cellular immune responses and delay efficient return to immune homeostasis.


Assuntos
Envelhecimento/imunologia , COVID-19/imunologia , COVID-19/veterinária , SARS-CoV-2/imunologia , Doença Aguda , Animais , Formação de Anticorpos/imunologia , Líquido da Lavagem Broncoalveolar , COVID-19/complicações , COVID-19/genética , Citocinas/sangue , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Imunidade Celular/genética , Imunomodulação , Inflamação/complicações , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Tecido Linfoide/patologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Modelos Biológicos , Análise de Célula Única , Linfócitos T/imunologia , Transcrição Gênica
6.
Antiviral Res ; 198: 105246, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35032523

RESUMO

The utility of remdesivir treatment in COVID-19 patients is currently limited by the necessity to administer this antiviral intravenously, which has generally limited its use to hospitalized patients. Here, we tested a novel, subcutaneous formulation of remdesivir in the rhesus macaque model of SARS-CoV-2 infection that was previously used to establish the efficacy of remdesivir against this virus in vivo. Compared to vehicle-treated animals, macaques treated with subcutaneous remdesivir from 12 h through 6 days post inoculation showed reduced signs of respiratory disease, a reduction of virus replication in the lower respiratory tract, and an absence of interstitial pneumonia. Thus, early subcutaneous administration of remdesivir can protect from lower respiratory tract disease caused by SARS-CoV-2.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Doenças Pulmonares Intersticiais/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/uso terapêutico , Administração Cutânea , Alanina/administração & dosagem , Alanina/farmacocinética , Alanina/uso terapêutico , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Modelos Animais de Doenças , Feminino , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
7.
J Infect Dis ; 225(7): 1118-1123, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34940844

RESUMO

B-cell-depleting therapies may lead to prolonged disease and viral shedding in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and this viral persistence raises concern for viral evolution. We report sequencing of early and late samples from a 335-day infection in an immunocompromised patient. The virus accumulated a unique deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts.


Assuntos
COVID-19 , SARS-CoV-2 , Linfócitos B , Humanos , Hospedeiro Imunocomprometido , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Eliminação de Partículas Virais
8.
Sci Adv ; 7(43): eabj3627, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34678071

RESUMO

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors. Here, we compared variants of concern (VOC) B.1.1.7 and B.1.351 to a recent B.1 SARS-CoV-2 isolate containing the D614G spike substitution in the rhesus macaque model. B.1.1.7 behaved similarly to D614G with respect to clinical disease and replication in the respiratory tract. Inoculation with B.1.351 resulted in lower clinical scores, lower lung virus titers, and less severe lung lesions. In bronchoalveolar lavages, cytokines and chemokines were up-regulated on day 4 in animals inoculated with D614G and B.1.1.7 but not with B.1.351. In nasal samples, cytokines and chemokines were up-regulated only in the B.1.1.7-inoculated animals. Together, our study suggests that circulation under diverse evolutionary pressures favors transmissibility and immune evasion rather than increased pathogenicity.

9.
medRxiv ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34642697

RESUMO

BACKGROUND: B-cell depleting therapies may lead to protracted disease and prolonged viral shedding in individuals infected with SARS-CoV-2. Viral persistence in the setting of immunosuppression raises concern for viral evolution. METHODS: Amplification of sub-genomic transcripts for the E gene (sgE) was done on nasopharyngeal samples over the course of 355 days in a patient infected with SARS-CoV-2 who had previously undergone CAR T cell therapy and had persistently positive SARS-CoV-2 nasopharyngeal swabs. Whole genome sequencing was performed on samples from the patient's original presentation and 10 months later. RESULTS: Over the course of almost a year, the virus accumulated a unique in-frame deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Also, minority variants that were identified in the early samples-reflecting the heterogeneity of the initial infection-were found to be fixed late in the infection. Remdesivir and high-titer convalescent plasma treatment were given, and the infection was eventually cleared after 335 days of infection. CONCLUSIONS: The unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts, and the implication of these mutations in the emergence of viral variants. SUMMARY: We report an immunocompromised patient with persistent symptomatic SARS-CoV-2 infection for 335 days. During this time, the virus accumulated a unique in-frame deletion in the spike, and a complete deletion of ORF7b and ORF8 which is the first report of its kind in an immunocompromised patient.

10.
Nat Microbiol ; 6(10): 1245-1258, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34465900

RESUMO

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.


Assuntos
Líquido da Lavagem Broncoalveolar/microbiologia , COVID-19/terapia , Respiração Artificial , SARS-CoV-2/patogenicidade , Imunidade Adaptativa , Adulto , Idoso , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Carga Bacteriana , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/imunologia , COVID-19/microbiologia , COVID-19/mortalidade , Estado Terminal , Feminino , Hospitalização , Humanos , Imunidade Inata , Masculino , Microbiota , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Estudos Prospectivos , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , Carga Viral
11.
bioRxiv ; 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34382034

RESUMO

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors that affect observed pathogenicity and transmissibility data in the human population. Here, we studied the pathogenicity of variants of concern (VOC) B.1.1.7 and B.1.351 in rhesus macaques and compared it to a recent clade B.1 SARS-CoV-2 isolate containing the D614G substitution in the spike protein. The B.1.1.7 VOC behaved similarly to the D614G with respect to clinical disease, virus shedding and virus replication in the respiratory tract. Inoculation with the B.1.351 isolate resulted in lower clinical scores in rhesus macaques that correlated with lower virus titers in the lungs, less severe histologic lung lesions and less viral antigen detected in the lungs. We observed differences in the local innate immune response to infection. In bronchoalveolar lavages, cytokines and chemokines were upregulated on day 4 in animals inoculated with D614G and B.1.1.7 but not in those inoculated with B.1.351. In nasal samples, we did not detect upregulation of cytokines and chemokines in D614G or B.1.351-inoculated animals. However, cytokines and chemokines were upregulated in the noses of B.1.1.7-inoculated animals. Taken together, our comparative pathogenicity study suggests that ongoing circulation under diverse evolutionary pressure favors transmissibility and immune evasion rather than an increase in intrinsic pathogenicity.

12.
Res Sq ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33791687

RESUMO

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

13.
medRxiv ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33655261

RESUMO

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

15.
Sci Transl Med ; 13(578)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33431511

RESUMO

Detailed knowledge about the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is important for uncovering the viral and host factors that contribute to coronavirus disease 2019 (COVID-19) pathogenesis. Old-World nonhuman primates recapitulate mild to moderate cases of COVID-19, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with infectious SARS-CoV-2 or irradiated, inactivated virus to study the dynamics of virus replication throughout the respiratory tract. Genomic RNA from the animals inoculated with the irradiated virus was found to be highly stable, whereas subgenomic RNA, an indicator of viral replication, was found to degrade quickly. We combined this information with single-cell RNA sequencing of cells isolated from the lung and lung-draining mediastinal lymph nodes and developed new analysis methods for unbiased targeting of important cells in the host response to SARS-CoV-2 infection. Through detection of reads to the viral genome, we were able to determine that replication of the virus in the lungs appeared to occur mainly in pneumocytes, whereas macrophages drove the inflammatory response. Monocyte-derived macrophages recruited to the lungs, rather than tissue-resident alveolar macrophages, were most likely to be responsible for phagocytosis of infected cells and cellular debris early in infection, with their roles switching during clearance of infection. Together, our dataset provides a detailed view of the dynamics of virus replication and host responses over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.


Assuntos
COVID-19/epidemiologia , COVID-19/virologia , Pulmão/virologia , SARS-CoV-2/fisiologia , Análise de Sequência de RNA , Análise de Célula Única , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , Animais , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/genética , Chlorocebus aethiops , DNA Viral/genética , Feminino , Genoma Viral/genética , Inflamação/patologia , Pulmão/patologia , Linfonodos/patologia , Macrófagos/patologia , Macrófagos/virologia , Masculino , Mediastino/patologia , Transcrição Gênica , Carga Viral , Replicação Viral
16.
bioRxiv ; 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32839775

RESUMO

Detailed knowledge about the dynamics of SARS-CoV-2 infection is important for unraveling the viral and host factors that contribute to COVID-19 pathogenesis. Old-World nonhuman primates recapitulate mild-moderate COVID-19 cases, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with SARS-CoV-2 or inactivated virus to study the dynamics of virus replication throughout the respiratory tract. RNA sequencing of single cells from the lungs and mediastinal lymph nodes allowed a high-resolution analysis of virus replication and host responses over time. Viral replication was mainly localized to the lower respiratory tract, with evidence of replication in the pneumocytes. Macrophages were found to play a role in initiating a pro-inflammatory state in the lungs, while also interacting with infected pneumocytes. Our dataset provides a detailed view of changes in host and virus replication dynamics over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.

17.
Nature ; 586(7830): 578-582, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32731258

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic3. Vaccines are an essential countermeasure and are urgently needed to control the pandemic4. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime-boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Macaca mulatta , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Adenoviridae/genética , Animais , Líquido da Lavagem Broncoalveolar , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Citocinas/imunologia , Feminino , Imunidade Celular , Imunidade Humoral , Imunoglobulina G/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Masculino , Camundongos , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th1/imunologia , Vacinação , Carga Viral , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
18.
bioRxiv ; 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32511299

RESUMO

An outbreak of a novel coronavirus, now named SARS-CoV-2, causing respiratory disease and a ~2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented rapid global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs of all animals. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.

19.
bioRxiv ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32511319

RESUMO

Background: Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. Methods: To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy. Results: In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue. Conclusions: Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

20.
bioRxiv ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32511340

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.

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