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- Nonhuman Primate Models
- COVID-19/Coronavirus
A Single-Dose Intranasal Live-Attenuated Codon Deoptimized Vaccine Provides Broad Protection Against SARS-CoV-2 and Its Variants
Liu et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39187479
Researchers developed an intranasal, single-dose, live-attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) vaccine (CDO-7N-1) using codon deoptimization. This vaccine demonstrates broad protection against SARS-CoV-2 variants, with highly attenuated replication and minimal lung pathology across multiple in vivo passages. The vaccine induced robust mucosal and systemic neutralizing antibodies, as well as T-cell responses, in male and female hamsters, female K18-hACE2 mice, and male HFH4-hACE2 mice. In male and female cynomolgus macaques, CDO-7N-1 effectively prevented infection, reduced severe disease, and limited transmission of SARS-CoV-2 variants. This innovative approach offers potential advantages over traditional spike-protein vaccines by providing durable protection and targeting emerging variants to curb virus transmission. Supported by ORIP (K01OD026529).
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.
The Impact of SIV-Induced Immunodeficiency on Clinical Manifestation, Immune Response, and Viral Dynamics in SARS-CoV-2 Coinfection
Melton et al., bioRxiv. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680717/
The effects of immunodeficiency caused by chronic HIV infection on COVID-19 have not been directly addressed in a controlled setting. Investigators conducted a pilot study in which two pigtail macaques (PTMs) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and compared with SIV-naive PTMs infected with SARS-CoV-2. Despite the marked decrease in CD4+ T cells in the SIV-positive animals prior to exposure to SARS-CoV-2, investigators found that disease progression, viral persistence, and evolution of SARS-CoV-2 were comparable to the control group. These findings suggest that SIV-induced immunodeficiency alters the immune response to SARS-CoV-2 infection, leading to impaired cellular and humoral immunity. However, this impairment does not significantly alter the course of infection. Supported by ORIP (P51OD011104, U42OD013117, S10OD026800, S10OD030347) and NIAID.
Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates
Maity et al., Molecular & Cellular Proteomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981268/
In this study, researchers examined the proteins expressed in cerebrospinal fluid (CSF) in nonhuman primates (NHPs) to better understand how COVID-19 infection can result in brain pathology, a common outcome. The study found that even in NHPs with minimal or mild COVID‑19, CSF proteins were significantly dysregulated compared with uninfected NHPs. Furthermore, the most affected proteins were enriched in the same brain regions that show lesions after COVID-19 infection, including the cerebral cortex, basal ganglia, and brain stem. Collectively, these regions have wide-ranging control over such crucial functions as cognition, motor control, and breathing, showing how even mild COVID-19 infection can result in significant neurological impairment. Supported by ORIP (P51OD011104, S10OD032453), NIGMS, NCI, and NICHD.
Infant Rhesus Macaques Immunized Against SARS-CoV-2 Are Protected Against Heterologous Virus Challenge 1 Year Later
Milligan et al., Science Translational Medicine. 2023.
https://doi.org/10.1126/scitranslmed.add6383
The Moderna and Pfizer–BioNTech mRNA vaccines received emergency use authorization for infants 6 months and older in June 2022, but questions remain regarding the durability of vaccine efficacy against emerging variants in this age group. Using a two-dose vaccine regimen consisting of stabilized prefusion Washington-strain spike protein encoded by mRNA and encapsulated in lipid nanoparticles, the investigators immunized 2-month-old rhesus macaques of both sexes. They found that the immune responses persisted and protected from severe disease after heterologous challenge with the Delta variant 1 year later. The decay kinetics of vaccine-induced neutralizing antibody responses in the infant monkeys are comparable to those observed in adult humans and nonhuman primates. Supported by ORIP (P51OD011107), NIAID, and NCI.
SARS-CoV-2 Infects Neurons and Induces Neuroinflammation in a Non-Human Primate Model of COVID-19
Beckman et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111573
SARS-CoV-2 causes brain fog and other neurological complications in some patients. It has been unclear whether SARS-CoV-2 infects the brain directly or whether central nervous system sequelae result from systemic inflammatory responses triggered in the periphery. Using a rhesus macaque model, researchers detected SARS-CoV-2 in the olfactory cortex and interconnected regions 7 days after infection, demonstrating that the virus enters the brain through the olfactory nerve. Neuroinflammation and neuronal damage were more severe in elderly monkeys with type 2 diabetes. The researchers found that in aged monkeys, SARS-CoV-2 traveled farther along nerve pathways to regions associated with Alzheimer's disease. Supported by ORIP (P51OD011107) and NIA.
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.
Durable Protection Against the SARS-CoV-2 Omicron Variant Is Induced by an Adjuvanted Subunit Vaccine
Arunachalam et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abq4130
Additional SARS-CoV-2 vaccines are needed, owing to waning immunity to the original vaccines and the emergence of variants of concern. A recent study in male rhesus macaques demonstrated durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, an oil-in-water emulsion containing α‑tocopherol. Two immunizations with the vaccine resulted in durable immunity, without cross-reactivity. Further boosting with a version of the vaccine containing the Beta variant or the ancestral RBD elicited cross-reactive immune responses that conferred protection against Omicron challenge. Supported by ORIP (P51OD011104), NCI, 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.
CAR/CXCR5–T Cell Immunotherapy Is Safe and Potentially Efficacious in Promoting Sustained Remission of SIV Infection
Pampusch et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1009831
HIV and simian immunodeficiency virus (SIV) replication are concentrated within the B cell follicles of secondary lymphoid tissues. In this study, the researchers developed immunotherapeutic chimeric antigen receptor (CAR) T cells that home to follicles and clear SIV-infected cells in a rhesus macaque model. The CAR T cells localized to the follicle, replicated, and interacted directly with infected cells. Most of the treated animals maintained lower viral loads in the blood and follicles, compared to control animals. These findings demonstrate the safety and potential efficacy of this immunotherapy approach for long-term remission of HIV without requiring the lifelong use of antiretroviral therapy. Supported by ORIP (P51OD011106), NIAID, and NHLBI.