scholarly journals The SARS-CoV-2 B.1.1.529 Omicron virus causes attenuated infection and disease in mice and hamsters

2021 ◽  
Author(s):  
Michael Diamond ◽  
Peter Halfmann ◽  
Tadashi Maemura ◽  
Kiyoko Iwatsuki-Horimoto ◽  
Shun Iida ◽  
...  
Keyword(s):  
Viral Evolution ◽  
Lung Infection ◽  
Spike Protein ◽  
Rodent Models ◽  
Respiratory Tract Disease ◽  
Wild Type ◽  
Antigenic Sites ◽  
Binding Data ◽  
Recent Emergence ◽  
Tract Disease

Abstract Despite the development and deployment of antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. The recent emergence of B.1.1.529, the Omicron variant1,2, which has more than 30 mutations in the spike protein, has raised concerns for escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in pre-clinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of multiple B.1.1.529 Omicron isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2) expressing mice and hamsters. Despite modeling and binding data suggesting that B.1.1.529 spike can bind more avidly to murine ACE2, we observed attenuation of infection in 129, C57BL/6, and BALB/c mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. Although K18-hACE2 transgenic mice sustained infection in the lungs, these animals did not lose weight. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from multiple independent laboratories of the SAVE/NIAID network with several different B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

scholarly journals Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erik Laurini ◽  
Domenico Marson ◽  
Suzana Aulic ◽  
Alice Fermeglia ◽  
Sabrina Pricl
Keyword(s):  
Monoclonal Antibodies ◽  
In Silico ◽  
Structural Information ◽  
Viral Evolution ◽  
Protein A ◽  
Immune Surveillance ◽  
Protein S ◽  
Spike Protein ◽  
Wild Type ◽  
Experimental Findings

AbstractThe purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

scholarly journals Recombinant Human Metapneumovirus Lacking the Small Hydrophobic SH and/or Attachment G Glycoprotein: Deletion of G Yields a Promising Vaccine Candidate

2004 ◽  
Vol 78 (23) ◽  
pp. 12877-12887 ◽  
Author(s):  
Stéphane Biacchesi ◽  
Mario H. Skiadopoulos ◽  
Lijuan Yang ◽  
Elaine W. Lamirande ◽  
Kim C. Tran ◽  
...  
Keyword(s):  
Cell Culture ◽  
Respiratory Tract ◽  
Human Metapneumovirus ◽  
Reverse Genetic System ◽  
Deletion Mutants ◽  
Upper Respiratory Tract ◽  
Respiratory Tract Disease ◽  
Wild Type ◽  
Tract Disease

ABSTRACT Human metapneumovirus (HMPV) has recently been identified as a significant cause of serious respiratory tract disease in humans. In particular, the emerging information on the contribution of HMPV to pediatric respiratory tract disease suggests that it will be important to develop a vaccine against this virus for use in conjunction with those being developed for human respiratory syncytial virus and the human parainfluenza viruses. A recently described reverse genetic system (S. Biacchesi, M. H. Skiadopoulos, K. C. Tran, B. R. Murphy, P. L. Collins, and U. J. Buchholz, Virology 321:247-259, 2004) was used to generate recombinant HMPVs (rHMPVs) that lack the G gene, the SH gene, or both. The ΔSH, ΔG, and ΔSH/G deletion mutants were readily recovered and were found to replicate efficiently during multicycle growth in cell culture. Thus, the SH and G proteins are not essential for growth in cell culture. Apart from the absence of the deleted protein(s), the virions produced by the gene deletion mutants were similar by protein yield and gel electrophoresis protein profile to wild-type HMPV. When administered intranasally to hamsters, the ΔG and ΔSH/G mutants replicated in both the upper and lower respiratory tracts, showing that HMPV containing F as the sole viral surface protein is competent for replication in vivo. However, both viruses were at least 40-fold and 600-fold restricted in replication in the lower and upper respiratory tract, respectively, compared to wild-type rHMPV. They also induced high titers of HMPV-neutralizing serum antibodies and conferred complete protection against replication of wild-type HMPV challenge virus in the lungs. Surprisingly, G is dispensable for protection, and the ΔG and ΔSH/G viruses represent promising vaccine candidates. In contrast, ΔSH replicated somewhat more efficiently in hamster lungs compared to wild-type rHMPV (20-fold increase on day 5 postinfection). This indicates that SH is completely dispensable in vivo and that its deletion does not confer an attenuating effect, at least in this rodent model.

scholarly journals An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies

2021 ◽  
Author(s):  
Laura A VanBlargan ◽  
John M Errico ◽  
Peter Halfmann ◽  
Seth J Zost ◽  
James E. Crowe ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Clinical Development ◽  
Spike Protein ◽  
Clinical Use ◽  
Receptor Binding Domain ◽  
Antigenic Sites ◽  
Recent Emergence ◽  
Therapeutic Monoclonal Antibodies ◽  
The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic resulting in millions of deaths worldwide. Despite the development and deployment of highly effective antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. Indeed, the recent emergence of the highly-transmissible B.1.1.529 Omicron variant is especially concerning because of the number of mutations, deletions, and insertions in the spike protein. Here, using a panel of anti-receptor binding domain (RBD) monoclonal antibodies (mAbs) corresponding to those with emergency use authorization (EUA) or in advanced clinical development by Vir Biotechnology (S309, the parent mAbs of VIR-7381), AstraZeneca (COV2-2196 and COV2-2130, the parent mAbs of AZD8895 and AZD1061), Regeneron (REGN10933 and REGN10987), Lilly (LY-CoV555 and LY-CoV016), and Celltrion (CT-P59), we report the impact on neutralization of a prevailing, infectious B.1.1.529 Omicron isolate compared to a historical WA1/2020 D614G strain. Several highly neutralizing mAbs (LY-CoV555, LY-CoV016, REGN10933, REGN10987, and CT-P59) completely lost inhibitory activity against B.1.1.529 virus in both Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells, whereas others were reduced (~12-fold decrease, COV2-2196 and COV2-2130 combination) or minimally affected (S309). Our results suggest that several, but not all, of the antibody products in clinical use will lose efficacy against the B.1.1.529 Omicron variant and related strains.

scholarly journals Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization

2021 ◽  
Author(s):  
David Ho ◽  
Pengfei Wang ◽  
Lihong Liu ◽  
Sho Iketani ◽  
Yang Luo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Viral Evolution ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Effective Interventions ◽  
Recent Emergence ◽  
New Challenges ◽  
The Uk

Abstract The Covid-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Two monoclonal antibody (mAb) therapeutics have received emergency use authorization, and more are in the pipeline. Furthermore, multiple vaccine constructs have shown promise, including two with ~95% protective efficacy against Covid-19. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. Considerable viral evolution has occurred since, including variants with a D614G mutation that have become dominant. Viruses with this mutation alone do not appear to be antigenically distinct, however. Recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a number of mAbs to the receptor-binding domain (RBD). It is modestly more resistant to convalescent plasma (~3 fold) and vaccinee sera (~2 fold). Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple potent mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

scholarly journals Construction and Characterization of a Recombinant Human Respiratory Syncytial Virus Encoding Enhanced Green Fluorescence Protein for Antiviral Drug Screening Assay

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Min Xu ◽  
Yue-Ying Jiao ◽  
Yuan-Hui Fu ◽  
Nan Jiang ◽  
Yuan-Bo Zheng ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Drug Screening ◽  
Green Fluorescence Protein ◽  
Respiratory Tract Disease ◽  
Green Fluorescence ◽  
Enhanced Green Fluorescence Protein ◽  
Fluorescence Protein ◽  
Syncytial Virus ◽  
Tract Disease

Human respiratory syncytial virus (RSV) is the single most important cause of lower respiratory tract disease in infants and young children and a major viral agent responsible for respiratory tract disease in immunosuppressed individuals and the elderly, but no vaccines and antiviral drugs are available. Herein the recombinant RSV (rRSV) encoding enhanced green fluorescence protein (EGFP, rRSV-EGFP) was constructed and the potential for screening anti-RSV drugs was investigated. The recombinant plasmid of pBRATm-rRSV-EGFP, containing T7 transcription cassette composed of T7 promoter, RSV antigenomic cDNA with EGFP gene, HDV ribozyme (δ), and T7 terminator in the order of 5′ to 3′, was constructed and cotransfected into BHK/T7-9 cells together with helper plasmids encoding N, P, L, and M2-1 gene, respectively. The rescued rRSV-EGFP was confirmed by increasing expression of EGFP over blind passages and by RT-PCR. rRSV-EGFP was comparable to the other two recombinant RSVs encoding red fluorescent protein (RFP, rRSV-RFP) or luciferase (Luc, rRSV-Luc) in the growth kinetic, and there was a difference in sensitivity between them for screening anti-RSV agents based on infection of HEp-2 cells. The EGFP-encoding rRSV has been constructed and rescued successfully and has the potential for high-throughput anti-RSV drug screening in vitro.

Clinical Characteristics of the Afebrile Pneumonia Associated With Chlamydia trachomatis Infection in Infants Less Than 6 Months of Age

PEDIATRICS ◽  
1979 ◽  
Vol 63 (2) ◽  
pp. 192-197
Author(s):  
Margaret A. Tipple ◽  
Marc O. Beem ◽  
Evelyn M. Saxon
Keyword(s):  
Chlamydia Trachomatis ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Clinical Characteristics ◽  
Respiratory Tract Disease ◽  
Chlamydia Trachomatis Infection ◽  
Lower Respiratory Tract Disease ◽  
Tract Disease ◽  
Blood Eosinophils ◽  
Respiratory Tract Colonization

Respiratory tract colonization with Chlamydia trachomatis commonly occurs in natally acquired chlamydial infection and is sometimes associated with a chronic, afebrile pneumonia that has relatively distinctive clinical characteristics. To further define the frequency and clinical characteristics of lower respiratory tract disease associated with C trachomatis, we grouped 56 infants aged less than 6 months with afebrile pneumonia according to nasopharyngeal shedding of Chlamydia and viruses and compared their illnesses. Forty-one (73%) were positive for C trachomatis (23 had C trachomatis only, while 18 had C trachomatis plus a virus [cytomegalovirus, respiratory synctial virus, adenovirus, rhinovirus, or enterovirus]), and 15 were C trachomatis negative (nine had a virus only, and six had neither C trachomatis nor virus). The 41 infants with C trachomatis alone or C trachomatis plus a virus were similar clinically and differed significantly from other infants in several ways: (1) onset of symptoms before 8 weeks of age; (2) gradually worsening symptoms; (3) presentation for care at 4 to 11 weeks of age; (4) presence of conjunctivitis and ear abnormalities; (5) chest roentgenograms showing bilateral, symmetrical, interstitial infiltrates and hyperexpansion; (6) peripheral blood eosinophils ≥300/cu mm; and (7) elevated values for serum immunoglobulins M, G, and A.

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