Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates

Yi-Nan Zhang, Jennifer Paynter, Aleksandar Antanasijevic, Joel D. Allen, Mor Eldad, Yi-Zong Lee, Jeffrey Copps, Maddy L. Newby, Linling He, Deborah Chavez, Pat Frost, Anna Goodroe, John Dutton, Robert Lanford, Christopher Chen, Ian A. Wilson, Max Crispin, Andrew B. Ward and Jiang Zhu ()
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Yi-Nan Zhang: The Scripps Research Institute
Jennifer Paynter: The Scripps Research Institute
Aleksandar Antanasijevic: The Scripps Research Institute
Joel D. Allen: University of Southampton
Mor Eldad: The Scripps Research Institute
Yi-Zong Lee: The Scripps Research Institute
Jeffrey Copps: The Scripps Research Institute
Maddy L. Newby: University of Southampton
Linling He: The Scripps Research Institute
Deborah Chavez: Texas Biomedical Research Institute
Pat Frost: Texas Biomedical Research Institute
Anna Goodroe: Texas Biomedical Research Institute
John Dutton: Texas Biomedical Research Institute
Robert Lanford: Texas Biomedical Research Institute
Christopher Chen: Texas Biomedical Research Institute
Ian A. Wilson: The Scripps Research Institute
Max Crispin: University of Southampton
Andrew B. Ward: The Scripps Research Institute
Jiang Zhu: The Scripps Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-29

Abstract: Abstract Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development.

Date: 2023
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DOI: 10.1038/s41467-023-37742-z

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