Selected Grantee Publications
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- Rodent Models
- niaid
- COVID-19/Coronavirus
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
Pathogenesis and Virulence of Coronavirus Disease: Comparative Pathology of Animal Models for COVID-19
Kirk et al., Virulence. 2024.
https://pubmed.ncbi.nlm.nih.gov/38362881
Researchers have used animal models that can replicate clinical and pathologic features of severe human coronavirus infections to develop novel vaccines and therapeutics in humans. The purpose of this review is to describe important animal models for COVID-19, with an emphasis on comparative pathology. The highlighted species included mice, ferrets, hamsters, and nonhuman primates. Knowledge gained from studying these animal models can help inform appropriate model selection for disease modeling, as well as for vaccine and therapeutic developments. Supported by ORIP (T32OD010993) and NIAID.
Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population
Cruz Cisneros et al., Vaccines. 2024.
https://pubmed.ncbi.nlm.nih.gov/38276675/
The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. Although host genetic factors are known to affect vaccine efficacy for such respiratory pathogens as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. Investigators used the diversity outbred mouse model to study the effects of genetic variation on vaccine efficiency. Data indicate that variations in vaccine response in mice are heritable, similar to that in human populations. Supported by ORIP (U42OD010924), NIAID, and NIGMS.
Fc-Mediated Pan-Sarbecovirus Protection After Alphavirus Vector Vaccination
Adams et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37000623/
Group 2B β-coronaviruses (i.e., sarbecoviruses) have resulted in regional and global epidemics. Here, the authors evaluate the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. They reported that vaccination does not prevent virus replication, but it protects against lethal heterologous disease outcomes in SARS-CoV-2 and clade 2 bat sarbecovirus challenge models. Full-length spike vaccines elicited the broadest pan-sarbecovirus protection. Additionally, antibody-mediated cross-protection was lost in absence of FcR function, supporting a model for non-neutralizing, protective antibodies. Taken together, these findings highlight the value of universal sarbecovirus vaccine designs that couple FcR-mediated cross-protection with potent cross-neutralizing antibody responses. Supported by ORIP (K01OD026529), NIAID, and NCI.
Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients Is Associated with Microbial Translocation and Bacteremia
Bernard-Raichon et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33395-6
The investigators demonstrated that SARS-CoV-2 infection induced gut microbiome dysbiosis in male mice. Samples collected from human COVID-19 patients of both sexes also revealed substantial gut microbiome dysbiosis. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicated that bacteria might translocate from the gut into the systemic circulation of COVID-19 patients. These results were consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Supported by ORIP (S10OD021747), NCI, NHLBI, NIAID, and NIDDK.
Distinct Sensitivities to SARS-CoV-2 Variants in Vaccinated Humans and Mice
Walls et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111299
Emergence of SARS-CoV-2 variants necessitates real-time evaluation of their impact on serum neutralizing activity, as a proxy for vaccine efficacy, to inform public health policies and guide vaccine development. The investigators report that vaccinated female BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses toward the SARS-CoV-2 Beta and Gamma variants of concern, compared with humans of both sexes and male nonhuman primates (i.e., rhesus and pigtail macaques). This finding was consistent across several vaccine modalities, doses, antigens, and assays, suggesting caution should be exercised when interpreting serum neutralizing data obtained from mice. Supported by ORIP (P51OD010425, U42OD011123) and NIAID.
Mosaic RBD Nanoparticles Protect Against Challenge by Diverse Sarbecoviruses in Animal Models
Cohen et al., Science. 2022.
https://www.doi.org/10.1126/science.abq0839
Two animal coronaviruses from the SARS-like betacoronavirus (sarbecovirus) lineage—SARS-CoV and SARS-CoV-2—have caused epidemics or pandemics in humans during the past 20 years. New SARS-CoV-2 variants have prolonged the COVID-19 pandemic, and the discovery of diverse sarbecoviruses in bats raises the possibility of another coronavirus pandemic. Vaccines and therapeutics are needed to protect against both SARS-CoV-2 variants and zoonotic sarbecoviruses with the potential to infect humans. The authors designed mosaic-8 nanoparticles (SARS-CoV-2 and seven animal sarbecoviruses) that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded rather than variable, immunodominant, and exposed. Their results of immune responses elicited by mosaic-8 RBD nanoparticles in mice and macaques suggest that mosaic nanoparticles could protect against both SARS-CoV-2 variants and zoonotic sarbecoviruses with the potential to infect humans. Supported by ORIP (P40OD012217, U42OD021458, S10OD028685) and NIAID.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.