Development of a coronavirus disease 2019 nonhuman primate model using airborne exposure

Johnston, Sara C.; Ricks, Keersten M.; Jay, A. Nelson; Raymond, Jo Lynne; Rossi, Franco; Zeng, Xiankun; Scruggs, Jennifer L.; Dyer, David; Frick, Ondraya; Koehler, Jeffrey W.; Kuehnert, Paul A.; Clements, Tamara L.; Shoemaker, Charles J.; Coyne, S. R.; Delp, Korey L.; Moore, Joshua L.; Berrier, Kerry; Esham, Heather L.; Shamblin, Joshua D.; Sifford, Willie; Fiallos, Jimmy; Klosterman, Leslie; Stevens, Stephen; White, Lauren E.; Bowling, Philip A; García, Teresa Martín; Jensen, Christopher E.; Ghering, Jeanean; Nyakiti, David; Bellanca, Stephanie; Kearney, Brian; Giles, Wendy; Alli, Nazira A; Paz, Fabián Mendéz; Akers, Kristen; Danner, Denise K.; Barth, James F.; Johnson, Joshua A.; Durant, Matthew; Kim, Ruth; Hooper, Jay W.; Smith, Jeffrey M.; Kugelman, Jeffrey R.; Beitzel, Brett; Gibson, Kathleen M.; Pitt, M. Louise M.; Minogue, Timothy D.; Nalca, Aysegul

doi:10.1371/journal.pone.0246366

Cited by 57 publications

(95 citation statements)

References 33 publications

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“…To date, only a few studies have examined disease presentation following inhalation of aerosolized SARS-CoV-2, despite the potential relevance of this route of exposure [22][23][24][25][26]. Furthermore, these studies only examined disease presentation following exposure to a single dose of SARS-CoV-2.…”

Section: Plos Pathogensmentioning

confidence: 99%

“…Such particles are potentially hazardous as they would remain airborne for extended periods of time, and multiple studies have demonstrated that SARS-CoV-2 present in aerosol particles in this size range can remain infectious for long durations under some conditions [16][17][18][19][20][21]. Finally, it has been shown that nonhuman primates exposed to aerosols with aerodynamic diameters less than 5 μm containing SARS-CoV-2 develop disease similar to COVID-19 in humans [22][23][24][25][26]. Taken together, these studies suggest that transmission of SARS-CoV-2 by aerosols generated from the respiratory tract may be possible.…”

Section: Introductionmentioning

confidence: 99%

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Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19

et al. 2021

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While evidence exists supporting the potential for aerosol transmission of SARS-CoV-2, the infectious dose by inhalation remains unknown. In the present study, the probability of infection following inhalation of SARS-CoV-2 was dose-dependent in a nonhuman primate model of inhalational COVID-19. The median infectious dose, assessed by seroconversion, was 52 TCID50 (95% CI: 23–363 TCID50), and was significantly lower than the median dose for fever (256 TCID50, 95% CI: 102–603 TCID50), resulting in a group of animals that developed an immune response post-exposure but did not develop fever or other clinical signs of infection. In a subset of these animals, virus was detected in nasopharyngeal and/or oropharyngeal swabs, suggesting that infected animals without signs of disease are able to shed virus and may be infectious, which is consistent with reports of asymptomatic spread in human cases of COVID-19. These results suggest that differences in exposure dose may be a factor influencing disease presentation in humans, and reinforce the importance of public health measures that limit exposure dose, such as social distancing, masking, and increased ventilation. The dose-response data provided by this study are important to inform disease transmission and hazard modeling, and, ultimately, mitigation strategies. Additionally, these data will be useful to inform dose selection in future studies examining the efficacy of therapeutics and vaccines against inhalational COVID-19, and as a baseline in healthy, young adult animals for assessment of the importance of other factors, such as age, comorbidities, and viral variant, on the infectious dose and disease presentation.

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Section: Plos Pathogensmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19

et al. 2021

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“…During the entire study, including the acute infection phase, only mild clinical symptoms were noticed. This sharply contrasts with findings of others that described SARS-CoV-2-induced clinical disease, with clear signs of fever directly following infection, respiratory symptoms, and changes in hematology and clinical chemistry parameters [46, 48]. Unbiased measurement of the body temperature and activity of each animal was performed continuously by using telemetry.…”

Section: Discussionmentioning

confidence: 83%

“…The study specifically focused on the post-acute phase of the SARS-CoV-2 infection in rhesus and cynomolgus macaques, defined as the 3-4 weeks period following the disappearance of detectable virus from the nose and throat swab samples. The majority of published COVID-19 NHP studies concentrate on the first two weeks of infection when evidence was found for acute viral interstitial pneumonia and virus was cleared from the nose and throat samples and lung lavages [29, 33, 35, 46, 60]. As the PET-CTs performed in this study on days 8 and 10 pi revealed an increase in 18 F-FDG-uptake in the lungs and various tracheobronchial lymph nodes, it was decided to extend the observation period with weekly PET-CTs for all macaques for several weeks (rhesus macaques 35 or 36 days pi, for cynomolgus macaques 38 or 42 days pi, depending on the PET-CT findings).…”

Section: Discussionmentioning

confidence: 99%

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The post-acute phase of SARS-CoV-2 infection in two macaques species is associated with signs of ongoing virus replication and pathology in pulmonary and extrapulmonary tissues

Böszörményi

Stammes

Fagrouch

et al. 2020

Preprint

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SARS-CoV-2 is a coronavirus that sparked the current COVID-19 pandemic. To stop the shattering effect of COVID-19, effective and safe vaccines, and antiviral therapies are urgently needed. To facilitate the preclinical evaluation of intervention approaches, relevant animal models need to be developed and validated. Rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are widely used in biomedical research and serve as models for SARS-CoV-2 infection. However, differences in study design make it difficult to compare and understand potential species-related differences. Here, we directly compared the course of SARS-CoV-2 infection in the two genetically closely-related macaque species. After inoculation with a low passage SARS-CoV-2 isolate, clinical, virological, and immunological characteristics were monitored. Both species showed slightly elevated body temperatures in the first days after exposure while a decrease in physical activity was only observed in the rhesus macaques and not in cynomolgus macaques. The virus was quantified in tracheal, nasal, and anal swabs, and in blood samples by qRT-PCR, and showed high similarity between the two species. Immunoglobulins were detected by various enzyme-linked immunosorbent assays (ELISAs) and showed seroconversion in all animals by day 10 post-infection. The cytokine responses were highly comparable between species and computed tomography (CT) imaging revealed pulmonary lesions in all animals. Consequently, we concluded that both rhesus and cynomolgus macaques represent valid models for evaluation of COVID-19 vaccine and antiviral candidates in a preclinical setting.

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Characteristics of animal models for COVID‐19

Qin

2022

Anim Models and Exp Med

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease 2019 (COVID‐19), the most consequential pandemic of this century, threatening human health and public safety. SARS‐CoV‐2 has been continuously evolving through mutation of its genome and variants of concern have emerged. The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID‐19, a core requirement for the prevention and control of SARS‐CoV‐2 pandemic. The animal model construction techniques developed during the SARS‐CoV and MERS‐CoV pandemics were rapidly deployed and applied in the establishment of COVID‐19 animal models. To date, a large number of animal models for COVID‐19, including mice, hamsters, minks and nonhuman primates, have been established. Infectious diseases produce unique manifestations according to the characteristics of the pathogen and modes of infection. Here we classified animal model resources around the infection route of SARS‐CoV‐2, and summarized the characteristics of the animal models constructed via transnasal, localized, and simulated transmission routes of infection.

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Development of a coronavirus disease 2019 nonhuman primate model using airborne exposure

Cited by 57 publications

References 33 publications

Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19

Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19

The post-acute phase of SARS-CoV-2 infection in two macaques species is associated with signs of ongoing virus replication and pathology in pulmonary and extrapulmonary tissues

Characteristics of animal models for COVID‐19

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