Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope
Abstract VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunog...
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Nature Portfolio
2025-08-01
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| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-025-01235-5 |
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| author | Andrew Wilcox-King Yu-Hsin Wan Samuel C. Scharffenberger Crystal B. Chhan Amelia R. Davis Leah J. Homad Emilie Seydoux Kellie J. MacPhee Latha Kallur Siddaramaiah Mariane Melo Pia Dosenovic Darrell J. Irvine Ollivier Hyrien Leonidas Stamatatos Andrew T. McGuire |
| author_facet | Andrew Wilcox-King Yu-Hsin Wan Samuel C. Scharffenberger Crystal B. Chhan Amelia R. Davis Leah J. Homad Emilie Seydoux Kellie J. MacPhee Latha Kallur Siddaramaiah Mariane Melo Pia Dosenovic Darrell J. Irvine Ollivier Hyrien Leonidas Stamatatos Andrew T. McGuire |
| author_sort | Andrew Wilcox-King |
| collection | DOAJ |
| description | Abstract VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunogens capable of initiating VRC01-class B cell response. Among these, we developed an anti-idiotypic monoclonal antibody (ai-mAb)-derived VRC01 class targeting immunogen. Because it is distinct from Env, we speculated that the ai-mAb will selectively engage naive VRC01 class B cells while limiting B cell responses directed at off-target epitopes on Env during prime-boost regimens. Here, we evaluated the serum and B cell responses to ai-mAb prime/Env boost, and Env-prime/Env boost regimens in a murine adoptive transfer model where VRC01 precursor B cells are present at physiological levels. We found that the Env-Env regimen led to the greatest expansion of on-target VRC01 B cells, drove larger VRC01-class GC responses, and elicited higher titers of circulating antibodies despite also eliciting substantial off-target Env-specific responses. Single-cell sorting experiments revealed that the ai-mAb was driving off-track somatic mutations. IgG transfer experiments demonstrated that circulating off-target antibodies provide a positive feedback mechanism that potentiates on-target B cell responses. Collectively, the results suggest that non-Env immunogens are not ideal for priming VRC01-class B cells, where sequential boosting with Env will be required to drive maturation of neutralizing breadth. |
| format | Article |
| id | doaj-art-e8bf2c0106d04274a0289a668597c38c |
| institution | DOAJ |
| issn | 2059-0105 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj-art-e8bf2c0106d04274a0289a668597c38c2025-08-20T03:04:22ZengNature Portfolionpj Vaccines2059-01052025-08-0110111710.1038/s41541-025-01235-5Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelopeAndrew Wilcox-King0Yu-Hsin Wan1Samuel C. Scharffenberger2Crystal B. Chhan3Amelia R. Davis4Leah J. Homad5Emilie Seydoux6Kellie J. MacPhee7Latha Kallur Siddaramaiah8Mariane Melo9Pia Dosenovic10Darrell J. Irvine11Ollivier Hyrien12Leonidas Stamatatos13Andrew T. McGuire14Vaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterKoch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyDepartment of Microbiology, Tumor and Cell Biology, Division of Virology and Immunology, Karolinska InstitutetKoch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterVaccine and Infectious Disease Division, Fred Hutchinson Cancer CenterAbstract VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunogens capable of initiating VRC01-class B cell response. Among these, we developed an anti-idiotypic monoclonal antibody (ai-mAb)-derived VRC01 class targeting immunogen. Because it is distinct from Env, we speculated that the ai-mAb will selectively engage naive VRC01 class B cells while limiting B cell responses directed at off-target epitopes on Env during prime-boost regimens. Here, we evaluated the serum and B cell responses to ai-mAb prime/Env boost, and Env-prime/Env boost regimens in a murine adoptive transfer model where VRC01 precursor B cells are present at physiological levels. We found that the Env-Env regimen led to the greatest expansion of on-target VRC01 B cells, drove larger VRC01-class GC responses, and elicited higher titers of circulating antibodies despite also eliciting substantial off-target Env-specific responses. Single-cell sorting experiments revealed that the ai-mAb was driving off-track somatic mutations. IgG transfer experiments demonstrated that circulating off-target antibodies provide a positive feedback mechanism that potentiates on-target B cell responses. Collectively, the results suggest that non-Env immunogens are not ideal for priming VRC01-class B cells, where sequential boosting with Env will be required to drive maturation of neutralizing breadth.https://doi.org/10.1038/s41541-025-01235-5 |
| spellingShingle | Andrew Wilcox-King Yu-Hsin Wan Samuel C. Scharffenberger Crystal B. Chhan Amelia R. Davis Leah J. Homad Emilie Seydoux Kellie J. MacPhee Latha Kallur Siddaramaiah Mariane Melo Pia Dosenovic Darrell J. Irvine Ollivier Hyrien Leonidas Stamatatos Andrew T. McGuire Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope npj Vaccines |
| title | Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope |
| title_full | Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope |
| title_fullStr | Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope |
| title_full_unstemmed | Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope |
| title_short | Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope |
| title_sort | priming vrc01 precursor b cells with non envelope immunogens disfavors boosting with hiv 1 envelope |
| url | https://doi.org/10.1038/s41541-025-01235-5 |
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