A5019567842- SARS-CoV-2 and COVID-19 Research
- Respiratory viral infections research
- Virus-based gene therapy research
- Animal Virus Infections Studies
- COVID-19 Clinical Research Studies
- SARS-CoV-2 detection and testing
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- vaccines and immunoinformatics approaches
- Pneumonia and Respiratory Infections
- Immunodeficiency and Autoimmune Disorders
- Monoclonal and Polyclonal Antibodies Research
- HIV Research and Treatment
- RNA Research and Splicing
- Microtubule and mitosis dynamics
- interferon and immune responses
- CRISPR and Genetic Engineering
- Cytomegalovirus and herpesvirus research
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Neonatal Respiratory Health Research
- RNA Interference and Gene Delivery
- Cellular transport and secretion
- Viral Infections and Vectors
- Influenza Virus Research Studies
AstraZeneca (United States)
2021-2025
Penn State Milton S. Hershey Medical Center
2020
University of Rochester
2014
Commonwealth Medical College
2012
Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform development improved therapeutics. We determined structures two human monoclonal antibodies–AZD8895 and AZD1061–which form investigational antibody cocktail AZD7442, in complex with receptor-binding domain (RBD) to define genetic structural neutralization. AZD8895 forms an 'aromatic cage' at heavy/light chain interface using germ line-encoded residues...
Despite the success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there remains a need for more prevention and treatment options individuals remaining at risk disease 2019 (COVID-19). Monoclonal antibodies (mAbs) against viral spike protein have potential to both prevent treat COVID-19 reduce death. Here, we describe AZD7442, combination two mAbs, AZD8895 (tixagevimab) AZD1061 (cilgavimab), that simultaneously bind distinct, nonoverlapping epitopes on receptor...
The SARS-CoV-2 pandemic has led to an urgent need understand the molecular basis for immune recognition of spike (S) glycoprotein antigenic sites. To define genetic and structural neutralization, we determined structures two human monoclonal antibodies COV2-2196 COV2-2130 1 , which form investigational antibody cocktail AZD7442, in complex with receptor binding domain (RBD) SARS-CoV-2. forms “aromatic cage” at heavy/light chain interface using germline-encoded residues complementarity...
Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from infections were subtyped, sequenced analyzed for binding site substitutions; subsequently, recombinant RSVs engineered microneutralization susceptibility testing. Here we show frequency caused...
ABSTRACT Influenza A and B viruses cocirculate in humans together cause disease seasonal epidemics. These two types of influenza are evolutionarily divergent, exchange genetic segments inside coinfected cells occurs frequently within but never between viruses. Possible mechanisms inhibiting the intertypic reassortment could be due to incompatible protein functions segment homologs, a lack processing heterotypic by virus RNA-dependent RNA polymerase, an inhibitory effect viral proteins on...
Nirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower tract infection infants for duration a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct neutralization. Here we use preclinical models explore whether fragment crystallizable (Fc)-mediated effector functions contribute...
Therapeutic anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (MAbs) provide immunosuppressed and vulnerable populations with prophylactic treatment interventions against disease 2019 (COVID-19). AZD7442 (tixagevimab-cilgavimab) is a combination of extended-half-life neutralizing MAbs that bind to distinct epitopes on the receptor binding domain (RBD) SARS-CoV-2 spike protein. The Omicron variant concern carries mutations at >35 positions in protein has...
Robust, quantitative serology assays are required to accurately measure antibody levels following vaccination and natural infection. We present validation of a quantitative, multiplex, SARS-CoV-2, electrochemiluminescent (ECL) assay; show correlation with two established SARS-CoV-2 immunoassays; calibration results for reference standards.Precision, dilutional linearity, ruggedness, analytical sensitivity specificity were evaluated. Clinical assessed using serum from prepandemic polymerase...
Abstract Background Nirsevimab is an extended half-life monoclonal antibody (mAb) that binds to the prefusion conformation of respiratory syncytial virus (RSV) fusion (F) protein, and approved for prevention RSV-associated lower tract infection in neonates infants. Rapid antigen testing routinely used clinical diagnosis RSV, primarily relies on direct interaction with RSV F protein patient nasal samples. While expected mAb levels samples are low (< 1 μg/mL), some mAbs targeting such...
Most previously authorized clinical antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lost neutralizing activity to recent variants due rapid viral evolution. To mitigate such escape, we preemptively enhance AZD3152, an antibody for prophylaxis in immunocompromised individuals. Using deep mutational scanning (DMS) on the SARS-CoV-2 antigen, identify AZD3152 vulnerabilities at antigen positions F456 and D420. Through two iterations of computational design...
The ability of the retroviral Gag protein Rous sarcoma virus (RSV) to transiently traffic through nucleus is well-established and has been implicated in genomic RNA (gRNA) packaging Although other proteins (human immunodeficiency type 1, HIV-1; feline virus, FIV; Mason-Pfizer monkey MPMV; mouse mammary tumor MMTV; murine leukemia MLV; prototype foamy PFV) have also observed nucleus, little known about what, if any, role nuclear trafficking plays those viruses. In case HIV-1, interacts...
Retroviruses cause severe diseases in animals and humans, including cancer acquired immunodeficiency syndromes. To propagate infection, retroviruses assemble new virus particles that contain viral proteins unspliced vRNA to use as gRNA. Despite the critical requirement for gRNA packaging, molecular mechanisms governing identification selection of by Gag protein remain poorly understood. In this report, we demonstrate Rous sarcoma (RSV) colocalizes with nucleus interchromatin space. Using...
Abstract Objectives The evolution of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard measuring virus‐neutralising (nAb) titres in serum. However, authentic virus‐based pose inherent practical challenges nAb SARS‐CoV‐2 variants (e.g. storing infectious viruses and testing at biosafety level‐3 facilities)....
Abstract Despite the success of SARS-CoV-2 vaccines, there remains a need for more prevention and treatment options individuals remaining at risk COVID-19. Monoclonal antibodies (mAbs) against viral spike protein have potential to both prevent treat COVID-19, reduce severe disease death. Here, we describe AZD7442, combination two mAbs, AZD8895 (tixagevimab) AZD1061 (cilgavimab), that simultaneously bind distinct non-overlapping epitopes on receptor binding domain potently neutralize...
Cytoskeleton-associated protein 4 (CKAP4; also known as p63, CLIMP-63, or ERGIC-63) is a 63 kDa, reversibly palmitoylated and phosphorylated, type II transmembrane (TM) protein, originally identified resident of the endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC). When localized to ER, major function CKAP4 anchor rough ER microtubules, organizing overall structure with respect microtubule network. There steadily accumulating evidence for diverse roles outside including data...
We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants identified from breakthrough infections in the PROVENT preexposure prophylaxis trial.Variants participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility variant-specific pseudotyped virus-like particles.At completion 6...
AZD7442, a combination of two long-acting monoclonal antibodies (tixagevimab [AZD8895] and cilgavimab [AZD1061]), has been authorized for the prevention treatment coronavirus disease 2019 (COVID-19). The rapid emergence severe acute respiratory syndrome 2 (SARS-CoV-2) variants requires methods capable quickly characterizing resistance to AZD7442. To support AZD7442 monitoring, biolayer interferometry (BLI) assay was developed screen binding tixagevimab SARS-CoV-2 spike proteins reduce number...
Abstract Background Nirsevimab is an extended half-life monoclonal antibody that binds the prefusion conformation of RSV fusion (F) protein and has been approved for prevention respiratory syncytial virus (RSV) lower tract disease in neonates infants EU, Great Britain, Canada. Global surveillance studies found nirsevimab binding site was highly conserved across variants between 1956–2021. While B F substitutions I206M Q209R have dominated since 2017/2018 season, both remain fully susceptible...
Abstract Background Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection (LRTI) and hospitalization in infants. In two global pivotal placebo-controlled studies, nirsevimab, a monoclonal antibody to RSV prefusion (F) protein with extended half-life, reduced medically attended (MA) LRTI versus placebo throughout season (MELODY (Primary Cohort)/Study 3 (Proposed Dose) Pool, 79.5% efficacy). Here we summarize resistance analyses all RT-PCR-confirmed isolates...
Abstract Background AZD7442 is a combination of extended–half-life SARS-CoV-2–neutralizing monoclonal antibodies (tixagevimab/cilgavimab) that bind to distinct epitopes on the SARS-CoV-2 spike protein. In PROVENT study, single 300 mg intramuscular dose demonstrated 77% efficacy for prevention COVID-19 vs placebo at primary analysis, with 83% through 6-months follow-up, and was well-tolerated. We report conservation binding sites neutralizing activity against pseudotyped virus-like particles...