DNA vaccine protection against SARS-CoV-2 in rhesus macaques

Ganatra

et al. 2020

Preprint

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.

Section: Mainmentioning

confidence: 99%

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

Ganatra

et al. 2020

Preprint

“…SARS-CoV-2 fuses with and enters host cells following engagement of its surface spike (S) protein with human angiotensin-converting enzyme 2 (hACE2) 18,19 , which is expressed on multiple tissues, notably including the lung alveolar epithelium and vascular endothelium, and also in the liver, colon, esophagus, small intestine, duodenum, kidney, brain, and tongue [20][21][22] . A number of investigators are currently setting up animal models susceptible to SARS-CoV-2 infection such as mice, ferrets, hamsters, rats, and monkeys [23][24][25][26][27] , but earlier studies have indicated that, due to species differences, these models cannot recapitulate key aspects of the human anti-viral, immune, and pathological responses to coronaviruses 28 .…”

Section: Introductionmentioning

confidence: 99%

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

Brumeanu

Vir

Shashikumar

et al. 2020

Preprint

The current SARS-CoV-2 pandemic is accompanied by high morbidity and mortality rates, and there is a compelling need for effective vaccines and therapeutic agents to lessen the severity of COVID-19 disease. Appropriate animal models are essential for testing of vaccines and therapeutics and for mechanistic studies of infection and the host response. The Spike (S) protein of SARS-COV-2 has a high affinity for the human ACE2 receptor, which is expressed on multiple cell types including alveolar epithelial and vascular endothelial cells. Wild-type mice are not susceptible to developing coronavirus-mediated diseases. Accordingly, several human (h)ACE2 transgenic mouse models have been developed for coronavirus research. However, these mice have failed to closely mimic important aspects of the human immunopathological responses to SARS-CoV-2. We report herein that DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL-2R. gammac KO.NOD) mice infused with human hematopoietic stem cells from cord blood reconstitute a fully functional human immune system, as well as engraft human epithelial and endothelial cells, sustain SARS-CoV-2 infection, and develop severe COVID-19-like symptoms. In pilot experiments, infected mice developed parenchymal and epithelial lung infiltrations with granzyme B+ and perforin+ CD8+ T cells and alveolar CD61+ microthrombi, mimicking human immunopathological responses to SARS-CoV-2. We propose the DRAGA mouse as a novel pre-clinical tool for studying COVID-19 immunopathology and human immune responses to SARS-CoV-2, including events leading to the cytokine storm and coagulopathies, as well as for testing of candidate vaccines and therapeutics.

“…This has important implications for COVID-19 vaccine development as virus-specific T cells are thought to play an important role in SARS-CoV-2 infection [18][19][20][21][22] . While no correlate of protection has been defined for COVID-19, recent publications suggest that neutralising antibody titres may be correlated with protection in animal challenge models 23,24 . A single dose of ChAdOx1 nCoV-19 induces antibody responses, but we demonstrate here that antibody responses are significantly enhanced after homologous boost in one mouse strain and to a greater extent in pigs.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19

Graham

McLean

Spencer

et al. 2020

Preprint

Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replicationdeficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.