Biology subjects

Reidy, J. X.

Publications and source records attributed to Reidy, J. X..

5 recordsLinked to original sources

bioRxiv2022

Potently neutralizing human monoclonal antibodies against the zoonotic pararubulavirus Sosuga virus

Sosuga virus (SOSV) is a recently discovered paramyxovirus with a single known human case of disease. There has been little laboratory research on SOSV pathogenesis or immunity, and no approved therapeutics or vaccines are available. Here, we report the discovery of human monoclonal antibodies (mAbs) from the circulating memory B cells of the only known human case and survivor of SOSV infection. We isolated six mAbs recognizing the functional attachment protein (HN) and 18 mAbs against the fusion (F) protein. The anti-HN mAbs all target the globular head of the HN protein and can be organized into 4 competition-binding groups that exhibit epitope diversity. The anti-F mAbs can be divided into pre- or post-fusion conformation-specific categories and further into 8 competition-binding groups. Generally, pre-fusion conformation-specific anti-F mAbs showed higher potency in neutralization assays than did mAbs only recognizing the post-fusion conformation of F protein. Most of the anti-HN mAbs were more potently neutralizing than the anti-F mAbs, with mAbs in one of the HN competition-binding groups possessing ultra-potent (<1 ng/mL) half maximal inhibitory (IC50) virus neutralization values. These findings provide insight into the molecular basis for human antibody recognition of paramyxovirus surface proteins and the mechanisms of SOSV neutralization.

immunology↗

bioRxiv2022

Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies

Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While sporadic in North and South America, many infections occur in Europe and Asia, with mortality ranging from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity across hantavirus species. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.

immunology↗

bioRxiv2022

Systematic analysis of human antibody response to ebolavirus glycoprotein reveals high prevalence of neutralizing public clonotypes

Understanding the human antibody response to emerging viral pathogens is key to epidemic preparedness. As the size of the B cell response to a pathogenic virus protective antigen is undefined, we performed deep paired heavy and light chain sequencing in EBOV-GP specific memory B cells, allowing analysis of the ebolavirus-specific antibody repertoire both genetically and functionally. This approach facilitated investigation of the molecular and genetic basis for evolution of cross-reactive antibodies by elucidating germline-encoded properties of antibodies to EBOV and identification of the overlap between antibodies in the memory B-cell and serum repertoire. We identified 73 public clonotypes to EBOV, 20% of which encoded antibodies with neutralization activity and capacity to protect in vivo. This comprehensive analysis of the public and private antibody repertoire provides insight into the molecular basis of the humoral immune response to EBOV-GP, which informs vaccine design of new vaccines and improved therapeutics.

immunology↗

bioRxiv2020

Potently neutralizing human antibodies that block SARS-CoV-2 receptor binding and protect animals

The COVID-19 pandemic is a major threat to global health for which there are only limited medical countermeasures, and we lack a thorough understanding of mechanisms of humoral immunity1,2. From a panel of monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein isolated from the B cells of infected subjects, we identified several mAbs that exhibited potent neutralizing activity with IC50 values as low as 0.9 or 15 ng/mL in pseudovirus or wild-type (wt) SARS-CoV-2 neutralization tests, respectively. The most potent mAbs fully block the receptor-binding domain of S (SRBD) from interacting with human ACE2. Competition-binding, structural, and functional studies allowed clustering of the mAbs into defined classes recognizing distinct epitopes within major antigenic sites on the SRBD. Electron microscopy studies revealed that these mAbs recognize distinct conformational states of trimeric S protein. Potent neutralizing mAbs recognizing unique sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two murine models of SARS-CoV-2 infection, passive transfer of either COV2-2916 or COV2-2130 alone or a combination of both mAbs protected mice from severe weight loss and reduced viral burden and inflammation in the lung. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic cocktails.

immunology↗

bioRxiv2020

Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein

Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes based on their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of new antibody discovery methodologies.

immunology↗