Selected Grantee Publications
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- 77 results found
- Cardiovascular
- COVID-19/Coronavirus
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.
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.
Spike and Nsp6 Are Key Determinants of SARS-CoV-2 Omicron BA.1 Attenuation
Chen et al., Nature. 2023.
https://pubmed.ncbi.nlm.nih.gov/36630998/
The ability of the SARS-CoV-2 virus to mutate and create variants of concern demands new vaccines to control the COVID-19 pandemic. The SARS-CoV-2 Omicron variant was shown to be more immune evasive and less virulent than current major variants. The spike (S) protein in this variant carries many mutations that drive these phenotypes. Researchers generated a chimeric recombinant SARS-CoV-2 virus encoding the S gene of Omicron (BA.1 lineage) in an ancestral SARS-CoV-2 isolate and compared it with the naturally circulating Omicron variant. The Omicron S-bearing virus escaped vaccine-induced humoral immunity, owing to mutations in the receptor-binding motif. The recombinant virus replicated efficiently in distal lung cell lines and in K18-hACE2 mice. Moreover, mutations induced in non-structural protein 6 (nsp6) in addition to the S protein were sufficient to restate the attenuated phenotype of Omicron. These findings indicate that the pathogenicity of Omicron is determined by mutations both inside and outside of the S gene. Supported by ORIP (S10OD026983, S10OD030269).
A Deep Learning Platform to Assess Drug Proarrhythmia Risk
Serrano et al., Cell Stem Cell. 2023.
https://www.sciencedirect.com/science/article/pii/S1934590922004866?via%3Dihub=
Investigators trained a convolutional neural network (CNN) classifier to learn and ultimately identify features of in vitro action potential recordings of human induced pluripotent stem cell (iPSC)–derived cardiomyocytes (hiPSC-CMs) that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia. The risk profiles of the test drugs were similar across hiPSC-CMs derived from different healthy donors. In addition, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high‑risk drugs in the hiPSC-CMs. These data indicate that deep learning can identify in vitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia. Supported by ORIP (S10OD030264) and NHLBI.
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.
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.
Wastewater Sequencing Reveals Early Cryptic SARS-CoV-2 Variant Transmission
Karthikeyan et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-05049-6
The investigators explored the use of SARS-CoV-2 RNA concentration in wastewater as a practical approach to estimate community prevalence of COVID-19, detect emerging variants, and track regional infection dynamics. Two obstacles must be overcome to leverage wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. The investigators developed and deployed improved virus concentration protocols and deconvolution software to fully resolve multiple virus strains from wastewater. Results indicate that emerging variants of concern were detected up to 14 days earlier in wastewater samples, and multiple instances of virus spread that were not captured by clinical genomic surveillance were identified by wastewater-based genomic surveillance. The study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission. The work suggests a critical, urgently needed methodology for early detection of emerging variants and early public health interventions. Supported by ORIP (S10OD026929), and NIAID.
Evolution of the Nitric Oxide Synthase Family in Vertebrates and Novel Insights in Gill Development
Annona et al., Proceedings of the Royal Society B. 2022.
https://www.doi.org/10.1098/rspb.2022.0667
Nitric oxide (NO) plays essential roles in biological systems, including cardiovascular homeostasis, neurotransmission, and immunity. Knowledge of NO synthases (NOS) is substantial, but the origin of nos gene orthologues in fishes, with respect to tetrapods, remains largely unknown. The recent identification of nos3 in the spotted gar, considered lost in this lineage, prompted the authors to explore nos gene evolution. Here, they report that nos2 experienced several lineage-specific gene duplications and losses. Additionally, nos3 was found to be lost independently in two teleost lineages, Elopomorpha and Clupeocephala. Further, the expression of at least one nos paralogue in gills of developing shark, bichir, sturgeon, and gar, but not in gills of lamprey, suggests nos expression in the gill might have arisen in the last common ancestor of gnathostomes. These results provide a framework for further research on the role of nos genes. Supported by ORIP (P40OD019794, R01OD011116).
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.