RESUMO
Tick-borne encephalitis (TBE) is a neurotropic flaviviral disease. TBE was previously thought to be absent from the United Kingdom. We report the second probable case of United Kingdom-acquired TBE and demonstrate deer TBE-serocomplex seropositivity in the surrounding area, providing further evidence of the presence of TBE in England.
Assuntos
Cervos , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Ixodes , Animais , Encefalite Transmitida por Carrapatos/epidemiologia , Encefalite Transmitida por Carrapatos/veterinária , Humanos , Reino Unido/epidemiologiaRESUMO
There is an urgent requirement for safe and effective vaccines to prevent COVID-19. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferrets and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen 7 days after infection in ferrets. This increased lung pathology was observed at day 7 but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.
RESUMO
Vaccines against SARS-CoV-2 are urgently required, but early development of vaccines against SARS-CoV-1 resulted in enhanced disease after vaccination. Careful assessment of this phenomena is warranted for vaccine development against SARS CoV-2. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent high dose challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titre were boosted by a second dose. Data from these challenge models on the absence of enhanced disease and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19.
Assuntos
Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , ChAdOx1 nCoV-19 , Furões , Macaca mulattaRESUMO
A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.
Assuntos
COVID-19/imunologia , COVID-19/virologia , Pulmão/patologia , Pulmão/virologia , Animais , Modelos Animais de Doenças , Feminino , Imunidade Celular/fisiologia , Interferon gama/metabolismo , Macaca fascicularis , Macaca mulatta , Masculino , Pandemias , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidadeRESUMO
There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.
Assuntos
COVID-19/imunologia , Modelos Animais de Doenças , Furões/imunologia , SARS-CoV-2/imunologia , Animais , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , Relação Dose-Resposta a Droga , Feminino , Pulmão/imunologia , Pulmão/patologia , RNA Viral/isolamento & purificação , SARS-CoV-2/genética , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/imunologiaRESUMO
BACKGROUND: The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. METHODS: SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E). FINDINGS: We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals. INTERPRETATION: The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19. FUNDING: This work was funded by Ena Respiratory, Melbourne, Australia.
Assuntos
Lipopeptídeos/administração & dosagem , Sistema Respiratório/virologia , SARS-CoV-2/patogenicidade , Receptor 2 Toll-Like/agonistas , Receptor 6 Toll-Like/agonistas , Eliminação de Partículas Virais , Administração Intranasal , Animais , COVID-19/patologia , Modelos Animais de Doenças , Feminino , Furões , Imunidade Inata , Lipopeptídeos/química , Lipopeptídeos/farmacologia , Cavidade Nasal/patologia , Cavidade Nasal/virologia , Faringe/patologia , Faringe/virologia , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sistema Respiratório/patologia , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Carga Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Type I interferon receptor knockout mice (strain A129) were assessed as a disease model of hantavirus infection. A range of infection routes (intramuscular, intraperitoneal and intranasal) were assessed using minimally passaged Seoul virus (strain Humber). Dissemination of virus to the spleen, kidney and lung was observed at 5 days after intramuscular and intraperitoneal challenge, which was resolved by day 14. In contrast, intranasal challenge of A129 mice demonstrated virus tropism to the lung, which was maintained to day 14 post-challenge. These data support the use of the A129 mouse model for future infection studies and the in vivo evaluation of interventions.