SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species

Abstract

SummaryThere are no known cures or vaccines for COVID-19, the defining pandemic of this era. Animal models are essential to fast track new interventions and nonhuman primate (NHP) models of other infectious diseases have proven extremely valuable. Here we compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). During the first 3 days, macaques developed clinical signatures of viral infection and systemic inflammation, coupled with early evidence of viral replication and mild-to-moderate interstitial and alveolar pneumonitis, as well as extra-pulmonary pathologies. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days. Longitudinal studies showed that while both young and old macaques developed early signs of COVID-19, both groups recovered within a two-week period. Recovery was characterized by low-levels of viral persistence in the lung, suggesting mechanisms by which individuals with compromised immune systems may be susceptible to prolonged and progressive COVID-19. The lung compartment contained a complex early inflammatory milieu with an influx of innate and adaptive immune cells, particularly interstitial macrophages, neutrophils and plasmacytoid dendritic cells, and a prominent Type I-interferon response. While macaques developed moderate disease, baboons exhibited prolonged shedding of virus and extensive pathology following infection; and marmosets demonstrated a milder form of infection. These results showcase in critical detail, the robust early cellular immune responses to SARS-CoV-2 infection, which are not sterilizing and likely impact development of antibody responses. Thus, various NHP genera recapitulate heterogeneous progression of COVID-19. Rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.

Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates

“…Differently than was observed in humans and previous reported data in RM, we did not detect an increase in the number of neutrophils as these responses may have come up earlier than week after infection as shown by others 18 . Common to both species was the observation that animals with higher levels of myeloid and lymphoid cell infiltration in the lung had worse disease outcomes.…”

“…Following exposure, AGM and RM have high levels of virus replication in the respiratory tract for up to two weeks, and both species develop pulmonary pathology characteristic of COVID-19, that varies from very mild to severe 17 . Other groups have described the very early immune events in SARS-CoV-2 infected rhesus macaques, with perturbation of monocytes populations, increased macrophages in lungs, and cellular activation in blood all happening a few days following the infection 18 .…”

SARS-CoV-2 infection induces germinal center responses with robust stimulation of CD4 T follicular helper cells in rhesus macaques

“…While several recent studies have reported on T cell dynamics in peripheral blood of patients (17)(18)(19)(20)(21), early immune responses, particularly in lymphoid and respiratory tissues, are challenging to study in humans. Rhesus macaques have emerged as a robust model for SARS-CoV-2 (22)(23)(24)(25)(26)(27). Because healthy rhesus macaques infected with SARS-CoV-2 resist immediate re-challenge with the virus (24,27), we hypothesized that understanding the CD4 Tfh and germinal center (GC) response following exposure to SARS-CoV-2 will provide a framework for understanding immune mechanisms of protection thereby providing evidence-based data on which to select an effective vaccine.…”

High Affinity Nanobodies Block SARS-CoV-2 Spike Receptor Binding Domain Interaction with Human Angiotensin Converting Enzyme

“…[25,26] Subsequently, testing for in vivo safety and efficacy in an established large animal model of SARS-Cov-2 infection such as rhesus macaque or baboon will be conducted to further support an investigational new drug application. [27] While other nanobodies have been produced in large scale current Good Manufacturing Practice facilities by fermentation, there is no guarantee that NIH-CoVnb-112 constructs can be produced in sufficient quantities at reasonable cost. Exploration of the manufacturing parameters will be critical for product development.…”