In:
Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6623 ( 2022-12-02)
Abstract:
Vaccines that induce antibodies with predefined genetic features and binding specificities have promise to combat viruses with high antigenic diversity such as HIV, influenza, hepatitis C virus, and betacoronaviruses. Although these pathogens have eluded the development of vaccines that induce broad immunity covering their antigenic diversity, broadly neutralizing antibodies (bnAbs) have been discovered. Such bnAbs bind to relatively conserved epitopes on membrane glycoproteins of each pathogen, with features of each antibody allowing binding to a particular epitope. If vaccines could be developed to consistently induce similar bnAbs, preferably in conjunction with broad T cell immunity, protection against these pathogens might be achieved. RATIONALE bnAbs acquire affinity-enhancing mutations when a bnAb-precursor B cell mutates and matures from the original naïve B cell (or “germline”) state. Germline-targeting vaccine design aims to induce bnAbs by stimulating rare bnAb-precursor B cells that have antibody genes and other properties needed to develop into bnAbs for a specific epitope. This “priming” step must generate a pool of bnAb-precursor–derived germinal center and/or memory B cells that are susceptible to reactivation by a boost immunogen closer in structure to the native viral glycoprotein. Sequential boosting with immunogens of increasing similarity to the native glycoprotein then aims to guide somatic hypermutation and affinity maturation to produce bnAbs that target the desired epitope. RESULTS We conducted a first-in-human test of the germline-targeting strategy by evaluating the safety and immune responses of a germline-targeting priming vaccine candidate, eOD-GT8 60mer nanoparticle adjuvanted with AS01 B , in the IAVI G001 phase 1 clinical trial. Each participant received two administrations of placebo, low-dose vaccine, or high-dose vaccine 8 weeks apart. The eOD-GT8 immunogen was designed to activate B cell precursors for HIV VRC01-class bnAbs defined by their usage of heavy chain variable gene alleles VH1-2*02 or *04 and any light chain complementarity determining region 3 with a length of five amino acids. We collected immune cells from the blood and lymph nodes of participants and carried out epitope-specific B cell sorting, B cell receptor (BCR) sequencing, and bioinformatic and statistical analyses. We also produced monoclonal antibodies and measured their binding affinities for the vaccine antigen. The vaccine had a favorable safety profile and induced VRC01-class responses in 97% (35 of 36) of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G memory B cells in blood. bnAb-precursors shared multiple properties with bnAbs and made substantial gains in somatic hypermutation and affinity with the boost. CONCLUSION The results establish clinical proof of concept for the germline-targeting vaccine design priming strategy, support development of boosting regimens to generate VRC01-class bnAb responses against HIV, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens. Test of germline-targeting vaccine priming in healthy humans. Immune cells were isolated from recipients of eOD-GT8 60mer vaccine or placebo, and antibody sequences from vaccine-binding B cells were analyzed to measure the VRC01-class bnAb-precursor response rate among participants and the frequency of VRC01-class bnAb-precursor B cells among memory B cells (MBCs) in each participant. Somatic hypermutation (SHM) and binding affinity were measured. CREDIT: Christopher Cottrell. Created with Biorender.com
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.add6502
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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