CoChat
Sign Up
PreprintCited by 8HIV Research and TreatmentMonoclonal and Polyclonal Antibodies Researchvaccines and immunoinformatics approaches

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Deep Mining of the Human Antibody Repertoire Identifies Frequent and Genetically Diverse CDRH3 Topologies Targetable by Vaccination

Open access
Habib, Rumi, Solieva, Shahlo O., Lin, Zi Jie, Ghosh, Sukanya, Bayruns, Kelly, Singh, Maya, Agostino, Colby J., Tursi, Nicholas J., Sowers, Kirsten J., Huang, Jinwei, Roark, Ryan S., Purwar, Mansi, Park, Younghoon, Ayyanathan, Kasirajan, Li, Hui, Carey, John W., Kim, Amber, Park, Joyce, McCanna, Madison E., Skelly, Ashwin N., Chokkalingam, Neethu, Kriete, Sinja, Shupin, Nicholas, Huynh, Alana, Walker, Susanne, Sadeesh, Roopak, Laenger, Niklas, Du, Jianqiu, Cui, Jiayan, Patel, Ami, Escolano, Amelia, Kwong, Peter D., Shapiro, Lawrence, Bowman, Gregory R., Hahn, Beatrice H., Shaw, George M., Weiner, David B., Pallesen, Jesper, Kulp, Daniel W.·2024·Proceedings of the National Academy of Sciences
DOI 10.1101/2024.10.04.616739

Preprint — published as 10.1073/pnas.2532810123

Open this paper in CoChat — free accountOpen PDF

Abstract

Germline targeting vaccination strategies against highly variable pathogens such as HIV aim to elicit broadly neutralizing antibodies (bnAbs) with particular immunogenetic or structural features. The V2 apex of the HIV Env protein is a promising target for a class of bnAbs that contain conserved structural motifs in the heavy chain complementarity determining region 3 (CDRH3). Here, we show that these structural motifs are targetable by vaccination by characterizing V2 apex ‘axe-like’ CDRH3s in the human repertoire and developing new immunogens capable of engaging them. We determined the frequency and diversity of axe-like CDHR3s in healthy human donors using a series of structural informatics approaches, finding these precursors in nearly 90% of donors. Axe-targeting immunogens based on the HIV Env Q23.17 bound axe-like precursors in cryo-EM structures, induced V2 apex-specific antibody responses in humanized mice, and induced axe-like heterologous neutralizing antibodies in rhesus macaques infected with a germline-targeted simian-human immunodeficiency virus. These results illustrate a new structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies. Significance Statement: Many broadly neutralizing antibodies (bnAbs) utilize modes of epitope recognition dominated by the antibody complementarity determining region 3 (CDRH3). The CDRH3 is the most diverse part of the antibody, posing a challenge for germline targeting vaccine designs that aim to elicit antibodies with particular immunogenetic features. Vaccine design strategies that accommodate CDRH3 variability are therefore needed. Many HIV Env V2 apex bnAbs share “axe-like” CDRH3 microfolds that arise from diverse immunogenetic origins. Here we determined the frequency in humans of B cells with such CDRH3 topologies and designed immunogens to engage their precursors. This work opens a path toward vaccines that engage specific structural classes of B cells, thereby advancing the rational design of immunogens for HIV and other pathogens.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2024.10.04.616739

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

  • Highly accurate protein structure prediction with AlphaFold

    Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764

  • Structure validation by Cα geometry: ϕ,ψ and Cβ deviation

    Lovell, S. C., Davis, I. W., Arendall, W. B., de Bakker, P. I. W., Word, J. M., Prisant, M. G., Richardson, J. S., & Richardson, D. C. (2003) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.10286 · Cited by 4,595 · cited 1×

    “The ‘turn-beta-turn’ pattern consists of at least two consecutive ‘turn’ residues defined using canonical turn metrics and types (48, 49), followed by two or more residues with ‘beta’ backbone geometry at least 20Å away from the start of the CDRH3 and capped by at least two more consecutive ‘turn’…”

Flagged first, then by citations

Research works printed but not linked: 79

  1. 10.1146/annurev-immunol-080219-023629 · DOI
  2. 10.1038/nature01470 · DOI · Paper page
  3. 10.1038/nature01188 · DOI
  4. 10.1128/JVI.75.13.5721-5729.2001 · DOI
  5. 10.2174/1570162X15666171124122044 · DOI
  6. 10.1128/JVI.00198-11 · DOI
  7. 10.1128/JVI.01482-09 · DOI
  8. 10.1016/j.immuni.2018.04.029 · DOI
  9. 10.1371/journal.ppat.1005369 · DOI
  10. 10.1097/QAD.0000000000000106 · DOI
  11. 10.1038/nm.4187 · DOI
  12. 10.1038/nbt.2197 · DOI
  13. 10.1038/nature17677 · DOI
  14. 10.1056/NEJMoa2031738 · DOI · Paper page
  15. B. Julg et al., Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge. Science Translational Medicine 9, eaal1321 (2017). · DOI
  16. 10.1038/nm.1974 · DOI
  17. 10.1016/j.chom.2012.09.008 · DOI
  18. 2022, Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies, Nature Reviews Immunology, 23, 142
  19. 2025, The germline targeting vaccine concept: overview and updates from HIV pre-clinical and clinical trials, Current HIV Research, 23, e1570162X
  20. 10.1111/imr.12483 · DOI
  21. 10.1016/j.immuni.2017.11.002 · DOI
  22. 10.1038/nature13165 · DOI · Paper page
  23. 10.1126/science.abd2638 · DOI
  24. 10.1101/2025.05.03.652068 · DOI
  25. 10.1016/j.immuni.2022.09.001 · DOI
  26. 10.1016/j.immuni.2017.03.017 · DOI
  27. 10.1038/nsmb.3144 · DOI
  28. 10.1038/nature10696 · DOI · Paper page
  29. 10.1073/pnas.1004600107 · DOI
  30. 10.1073/pnas.1217537110 · DOI
  31. 2020, Structure of super-potent antibody CAP256-VRC26.25 in complex with HIV-1 envelope reveals a combined mode of trimer-apex recognition, Cell Reports, 31, 107488, 10.1016/j.celrep.2020.03.052 · DOI
  32. 2025, Structural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies, The Journal of Experimental Medicine, 222, e20250638, 10.1084/jem.20250638 · DOI
  33. 10.1101/2025.09.19.677470 · DOI
  34. 10.1101/2025.10.22.684023 · DOI
  35. 10.1128/JVI.05045-11 · DOI
  36. 10.1126/science.1178746 · DOI
  37. 2017, Elicitation of neutralizing antibodies targeting the V2 apex of the HIV envelope trimer in a wild-type animal model, Cell Reports, 21, 222, 10.1016/j.celrep.2017.09.024 · DOI
  38. 10.1016/j.immuni.2012.11.011 · DOI
  39. 2022, Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer, Nature Communications, 13, 695, 10.1038/s41467-022-28363-z · DOI
  40. 10.1002/PRO.4205 · DOI · Paper page
  41. 10.1038/S41586-024-07487-W · DOI · Paper page
  42. 2008, Large-scale analysis of human heavy chain V(D)J recombination patterns, Immunome Research, 4, 3, 10.1186/1745-7580-4-3 · DOI
  43. 10.3390/molecules28103991 · DOI
  44. 2023, Fast, accurate antibody structure prediction from deep learning on massive set of natural antibodies, Nature Communications, 14, 2389, 10.1038/s41467-023-38063-x · DOI
  45. 10.1002/pro.4865 · DOI · Paper page
  46. 2016, Extension of the classical classification of β-turns, Scientific Reports, 6, 33191, 10.1038/srep33191 · DOI
  47. 10.1093/nar/gkt1043 · DOI · Paper page
  48. 2023, Accelerating cryptic pocket discovery using AlphaFold, Journal of Chemical Theory and Computation, 19, 4355, 10.1021/acs.jctc.2c01189 · DOI
  49. E. Waltari et al., 5′ rapid amplification of cDNA ends and Illumina MiSeq reveals B cell receptor features in healthy adults, adults with chronic HIV-1 infection, cord blood, and humanized mice. Frontiers in Immunology 9, 628 (2018). · DOI
  50. 10.1128/JVI.73.7.5255-5264.1999 · DOI
  51. 10.1016/j.immuni.2016.08.016 · DOI
  52. 2017, Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding, Nature Communications, 8, 1655, 10.1038/s41467-017-01549-6 · DOI
  53. 2017, Improving the immunogenicity of native-like HIV-1 envelope trimers by hyperstabilization, Cell Reports, 20, 1805, 10.1016/j.celrep.2017.07.077 · DOI
  54. 10.1371/journal.ppat.1008665 · DOI
  55. 2020, Automated design by structure-based stabilization and consensus repair to achieve prefusion-closed envelope trimers in a wide variety of HIV strains, Cell Reports, 33, 108432, 10.1016/j.celrep.2020.108432 · DOI
  56. 2018, A universal approach to optimize the folding and stability of prefusion-closed HIV-1 envelope trimers, Cell Reports, 23, 584, 10.1016/j.celrep.2018.03.061 · DOI
  57. 10.1016/j.immuni.2020.08.001 · DOI
  58. 10.1126/science.aat9120 · DOI
  59. 10.1016/j.coi.2019.03.003 · DOI
  60. 10.1080/14760584.2019.1578216 · DOI
  61. 2025, Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-like antibodies, PLoS Pathog, 21, e1013039, 10.1371/journal.ppat.1013039 · DOI
  62. 10.1016/j.immuni.2022.09.003 · DOI
  63. 2020, In vivo assembly of nanoparticles achieved through synergy of structure-based protein engineering and synthetic DNA generates enhanced adaptive immunity, Advanced Science, 7, 1902802, 10.1002/advs.201902802 · DOI
  64. 10.1101/2023.11.20.563479 · DOI
  65. 10.1016/j.cell.2019.04.012 · DOI · Paper page
  66. 2022, mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice, Cell Reports, 38, 110514, 10.1016/j.celrep.2022.110514 · DOI
  67. 2021, New SHIVs and improved design strategy for modeling HIV-1 transmission, immunopathogenesis, prevention and cure, Journal of Virology, 95, e00071
  68. 10.1073/pnas.1606636113 · DOI
  69. 10.1128/mbio.03370-22 · DOI
  70. 10.1128/JVI.00202-07 · DOI
  71. 10.1371/journal.ppat.1002721 · DOI
  72. 2024, Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques, Cell Reports, 44, 115848
  73. 10.1016/j.cell.2024.10.003 · DOI
  74. 10.1016/j.immuni.2018.07.009 · DOI
  75. 2021, Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM, Nature Communications, 12, 4817, 10.1038/s41467-021-25087-4 · DOI
  76. 10.1038/s41590-024-01833-w · DOI
  77. 10.1126/science.1207227 · DOI
  78. 10.1016/j.coviro.2019.02.004 · DOI
  79. 10.1101/2025.06.12.659380 · DOI

Metadata

Authors
Habib, R., Solieva, S. O., Lin, Z. J., Ghosh, S., Bayruns, K., Singh, M., Agostino, C. J., Tursi, N. J., Sowers, K. J., Huang, J., Roark, R. S., Purwar, M., Park, Y., Ayyanathan, K., Li, H., Carey, J. W., Kim, A., Park, J., McCanna, M. E., Skelly, A. N., Chokkalingam, N., Kriete, S., Shupin, N., Huynh, A., Walker, S., Sadeesh, R., Laenger, N., Du, J., Cui, J., Patel, A., Escolano, A., Kwong, P. D., Shapiro, L., Bowman, G. R., Hahn, B. H., Shaw, G. M., Weiner, D. B., Pallesen, J., & Kulp, D. W.
Affiliations
  • The Wistar Institute (US)
  • University of Pennsylvania (US)
  • Aaron Diamond AIDS Research Center (US)
Corresponding author
  • Habib, Rumi
  • Solieva, Shahlo O.
  • Lin, Zi Jie
  • Ghosh, Sukanya
  • Hahn, Beatrice H.
  • Shaw, George M.
  • Weiner, David B.
  • Pallesen, Jesper
  • Kulp, Daniel W.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2024-10-05
Volume
123
Issue
18
Pages
e2532810123-e2532810123
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2024.10.04.616739
OpenAlex
W7158988392
Cited by
8
References
2
Citations by year
2026: 4 · 2025: 4
FWCI
13.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
National Institutes of Health (AI166916, AI165080, AI007632, GM132039)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
HIV broadly neutralizing antibodies, HIV Env, human antibody repertoire, immunoinformatics, humanized mice, rhesus monkeys

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review