Crystal structure of B055 scaffold boost immunogen in complex with a mature 10E8 Fab
Structural highlights
8v2e is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds 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. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
Vaccination induces broadly neutralizing antibody precursors to HIV gp41.,Schiffner T, Phung I, Ray R, Irimia A, Tian M, Swanson O, Lee JH, Lee CD, Marina-Zarate E, Cho SY, Huang J, Ozorowski G, Skog PD, Serra AM, Rantalainen K, Allen JD, Baboo S, Rodriguez OL, Himansu S, Zhou J, Hurtado J, Flynn CT, McKenney K, Havenar-Daughton C, Saha S, Shields K, Schulze S, Smith ML, Liang CH, Toy L, Pecetta S, Lin YC, Willis JR, Sesterhenn F, Kulp DW, Hu X, Cottrell CA, Zhou X, Ruiz J, Wang X, Nair U, Kirsch KH, Cheng HL, Davis J, Kalyuzhniy O, Liguori A, Diedrich JK, Ngo JT, Lewis V, Phelps N, Tingle RD, Spencer S, Georgeson E, Adachi Y, Kubitz M, Eskandarzadeh S, Elsliger MA, Amara RR, Landais E, Briney B, Burton DR, Carnathan DG, Silvestri G, Watson CT, Yates JR 3rd, Paulson JC, Crispin M, Grigoryan G, Ward AB, Sok D, Alt FW, Wilson IA, Batista FD, Crotty S, Schief WR Nat Immunol. 2024 Jun;25(6):1073-1082. doi: 10.1038/s41590-024-01833-w. Epub 2024 , May 30. PMID:38816615[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Schiffner T, Phung I, Ray R, Irimia A, Tian M, Swanson O, Lee JH, Lee CD, Marina-Zárate E, Cho SY, Huang J, Ozorowski G, Skog PD, Serra AM, Rantalainen K, Allen JD, Baboo S, Rodriguez OL, Himansu S, Zhou J, Hurtado J, Flynn CT, McKenney K, Havenar-Daughton C, Saha S, Shields K, Schulze S, Smith ML, Liang CH, Toy L, Pecetta S, Lin YC, Willis JR, Sesterhenn F, Kulp DW, Hu X, Cottrell CA, Zhou X, Ruiz J, Wang X, Nair U, Kirsch KH, Cheng HL, Davis J, Kalyuzhniy O, Liguori A, Diedrich JK, Ngo JT, Lewis V, Phelps N, Tingle RD, Spencer S, Georgeson E, Adachi Y, Kubitz M, Eskandarzadeh S, Elsliger MA, Amara RR, Landais E, Briney B, Burton DR, Carnathan DG, Silvestri G, Watson CT, Yates JR 3rd, Paulson JC, Crispin M, Grigoryan G, Ward AB, Sok D, Alt FW, Wilson IA, Batista FD, Crotty S, Schief WR. Vaccination induces broadly neutralizing antibody precursors to HIV gp41. Nat Immunol. 2024 Jun;25(6):1073-1082. PMID:38816615 doi:10.1038/s41590-024-01833-w
