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Rogers, Thomas F.

Publications and source records attributed to Rogers, Thomas F..

Directed evolution of a stem-helix–targeting antibody enables MERS-CoV cross-neutralization through enhanced binding affinity

Broadly neutralizing antibodies (bnAbs) targeting conserved regions of the betacoronavirus spike are important for pan-betacoronavirus protection and pandemic preparedness. Here, we report the isolation of a human monoclonal antibody, CC65.1, from a SARS-CoV-2 convalescent donor that targets the conserved S2 stem helix region. CC65.1 neutralizes various sarbecoviruses, including SARS-CoV-2, and binds to the MERS-CoV spike but lacks MERS-CoV-neutralizing activity due to insufficient binding affinity. We utilized directed evolution to enhance the binding affinity of CC65.1 for the MERS-CoV S2 stem helix, yielding engineered antibody variants with newly acquired MERS-CoV-neutralizing activity. High-resolution structural analysis reveals key paratope mutations that enhance binding and stabilize epitope engagement. Our findings demonstrate the potential of in vitro affinity maturation to expand the neutralization breadth of stem-helix-targeting antibodies across divergent betacoronaviruses. This work supports the development of engineered bnAbs for broadly protective betacoronavirus countermeasures and provides a strategy for achieving cross-lineage neutralization.

Zhou, Panpan↗

Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.

60 APPLIED LIFE SCIENCES↗

A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a CoV disease 2019 (COVID-19) convalescent donor that exhibits broad reactivity with human β-CoVs. Here, we showed that CC40.8 targets the conserved S2 stem helix region of the CoV spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem peptide at 1.6-Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted that CC40.8-like bnAbs are relatively rare in human COVID-19 infection, and therefore, their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan–β-CoV vaccines.

60 APPLIED LIFE SCIENCES↗

Structural basis of a shared antibody response to SARS-CoV-2

Molecular understanding of neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could accelerate vaccine design and drug discovery. We analyzed 294 anti–SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53–neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme 2 (ACE2)–binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate the design of antigens that elicit this type of neutralizing response.

59 BASIC BIOLOGICAL SCIENCES↗

General Public Space Travel and Tourism: Executive Summary - Volume 1

Travel and tourism is one of the world's largest businesses. Its gross revenues exceed $400 billion per year in the U.S. alone, and it is our second largest employer. U.S. private sector business revenues in the space information area now approximate $10 billion per year, and are increasing rapidly. Not so in the human spaceflight area. After spending $100s of billions (1998 dollars) in public funds thereon, and continuing to spend over $5 billion per year, the government is still the only customer for human spaceflight goods and services. Serious and detailed consideration was first given to the possibility of space being opened up to trips by the general public three decades ago, and some initial attempts to do so were made a dozen years ago. But the difficulties were great and the Challenger disaster put an end to them. In recent years professional space tourism studies have been conducted in the United Kingdom, Germany and, especially, Japan. In the U.S., technological progress has been pronounced; we have had nearly a decade's experience in seeing our astronauts travel to-from low Earth orbit (LEO) safely, and we expect to commence assembly of a LEO space station housing a half-dozen people this year. Too, NASA and our space industry now have new and promising space transportation development programs underway, especially the X-33 and X-34 programs, and some related, further generation, basic technology development programs. And five private companies are also working on the design of new surface - LEO vehicles. The first professional space tourism market studies have been conducted in several countries in the past few years, especially in Japan and here. The U.S. study makes it clear that, conceptually, tens of millions of us would like to take a trip to space if we could do so with reasonable safety, comfort and reliability, and at an acceptable price. Initial businesses will address the desires of those willing to pay a greater price and accept a greater risk. A two-year cooperative Space Act agreement study has been conducted by our National Aeronautics and Space Administration and the Space Transportation Association. It was conducted by NASA and STA study leaders drawing upon the competence, experience and hard-nosed imagination of a national Steering Group and scores of attendees at a multi-day Workshop. The study has involved scores of professionals and business people from various areas: astronauts; space booster technology and operations professionals; a hotel architect and a hotel operator; an airline planner; insurance underwriters; space sickness experts; space theme park designers; space and travel and tourism association and business executives; a space-related financier; university tourism and space policy experts; present and former space-responsible government officials; space entrepreneurs; space writers; This study concludes that serious national attention should now be given to activities that would enable the expansion of today's terrestrial space tourism businesses, and the creation of in-space travel and tourism businesses. Indeed, it concludes that, in time, it should become a very important part of our Country's overall commercial and civil space business-program structure.

ONeil, Daniel↗