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Structures of Respiratory Syncytial Virus G Bound to Broadly Reactive Antibodies Provide Insights into Vaccine Design

Juarez et al., Scientific Reports. 2025.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11906780

Respiratory syncytial virus (RSV) is one of the leading causes of severe lower respiratory infection in both infants and older adults. RSV viral entry and modulation of the host immunity is mediated by attachment glycoprotein RSV G binding to the chemokine receptor CX3CR1. Antibodies isolated from RSV-exposed individuals have shown great promise in host protection. Researchers using an ORIP-funded electron microscope, in conjunction with X-ray crystallography, have solved the structure of these antibodies bound to the RSV G protein and identified a novel dual antibody binding region. The presence of dual antibody binding sites indicates the potential to elicit antibody responses that resist virus escape. These findings will help develop next-generation RSV prophylactics and provide insight for new concepts in vaccine design. Supported by ORIP (S10OD027012, S10OD025097), NIAID, NHGRI, and NIGMS.

Vaccination Induces Broadly Neutralizing Antibody Precursors to HIV gp41

Schiffner et al., Nature Immunology. 2024.

https://pubmed.ncbi.nlm.nih.gov/38816615

Primary immunogens that induce rare broadly neutralizing antibody (bnAb) precursor B cells are needed to develop vaccines against viruses of high antigenic diversity. 10E8-class bnAbs must possess a long, heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. Researchers developed germline-targeting epitope scaffolds with an affinity for 10E8-class precursors that exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens. Protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. This study showed that germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features. Supported by ORIP (P51OD011132, U42OD011023), NIAID, and NIGMS.

Broad Receptor Tropism and Immunogenicity of a Clade 3 Sarbecovirus

Lee et al., Cell Host and Microbe. 2023.

https://www.sciencedirect.com/science/article/pii/S1931312823004225

Investigators showed that the S glycoprotein of the clade 3 sarbecovirus PRD-0038 in the African Rhinolophus bat has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. They generated a cryogenic electron microscopy structure of the RBD bound to ACE2, explaining receptor tropism and highlighting differences between SARS-CoV-1 and SARS-CoV-2. PRD‑0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses, compared with SARS-CoV-2. These findings underline a potential molecular pathway for zoonotic spillover of a clade 3 sarbecovirus, as well as the need to develop pan-sarbecovirus vaccines and countermeasures. Supported by ORIP (S10OD032290, S10OD026959, S10OD021644), NIAID, NCI, and NIGMS.