Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen

Jardine, Joseph G.; Ota, Takayuki; Sok, Devin; Pauthner, Matthias; Kulp, Daniel W.; Kalyuzhniy, Oleksandr; Skog, Patrick; Thinnes, Theresa C.; Bhullar, Deepika; Briney, Bryan; Menis, Sergey; Jones, Meaghan; Kubitz, Mike; Spencer, Skye; Adachi, Yumiko; Burton, Dennis R.; Schief, William R.; Nemazee, David

doi:10.1126/science.aac5894

Cited by 379 publications

(604 citation statements)

References 51 publications

(98 reference statements)

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“…101 Unmutated common ancestors, the putative na€ ıve B cell receptors of bnAb could be targeted with relevant priming Env immunogens to trigger affinity maturation, followed by boosting to develop breadth. A germline-targeting, gp120 outer domain immunogen (OD-GT8) on self-assembling nanoparticles, was able to activate VRC01-class precursors, select productive mutations, create a pool of memory phenotype B cells and induced antibodies that showed characteristics of the VRC01-class bnAb, in a germline reverted VRC01 Hchain knock-in mouse model (VRCO1 gH) 102 ; as well as isolate VRC01-class precursor na€ ıve B cells from HIV-uninfected donors. 103 Furthermore, administration of boosting immunogens (BG505 core-GT3 nanoparticle (NP) and BG505 SOSIP-GT3 trimer) drove the maturation of eOD-GT8 60-mer primed B cells toward VRC01-class bnAb and induced broad neutralization of near-native (N276A) viruses and weak neutralization of a fully native virus in VRC01 gH mice.…”

Section: Eliciting Broadly Neutralizing Antibodies Through Immunizationmentioning

confidence: 99%

Progress in HIV vaccine development

Hsu

O’Connell

2017

Human Vaccines & Immunotherapeutics

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Section: Eliciting Broadly Neutralizing Antibodies Through Immunizationmentioning

confidence: 99%

Progress in HIV vaccine development

Hsu

O’Connell

2017

Human Vaccines & Immunotherapeutics

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“…We next examined the relationship between plasma CXCL13 and GC activity after protein immunization in animal vaccination models (6,(29)(30)(31). We first immunized mice with 4-hydroxy-3-nitrophenyl acetyl haptenated ovalbumin in aluminum hydroxide adjuvant (alum + NP-OVA).…”

Section: Plasma Cxcl13 Is Correlated With Lymph Node Gcs In Mice Aftermentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

291

311

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Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

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“…This information can then be used to design or to select immunogens that maximize the elicitation frequency of target antibodies 59, 60, 61, 67…”

Section: Antibodyomics5mentioning

confidence: 99%

“…Additional multidonor classes have now been identified including CD4‐binding‐site antibodies from the VH1‐46 germline5, 39 and V1V2‐directed antibodies characterized by a protruding anionic loop formed by recombination 6, 11. More recently, mouse models incorporating knock‐in germline genes has demonstrated the priming of multidonor VRC01 class antibodies in response to germline‐targeting immunogens 58, 60, 67. We have also applied Antibodyomics5 to the quantification of multidonor class antibodies that neutralize both group 1 and group 2 influenza A viruses 16.…”

Section: Antibodyomics5mentioning

confidence: 99%

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

Kwong

Chuang

DeKosky

et al. 2017

Immunological Reviews

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SummaryNumerous antibodies have been identified from HIV‐1‐infected donors that neutralize diverse strains of HIV‐1. These antibodies may provide the basis for a B cell‐mediated HIV‐1 vaccine. However, it has been unclear how to elicit similar antibodies by vaccination. To address this issue, we have undertaken an informatics‐based approach to understand the genetic and immunologic processes controlling the development of HIV‐1‐neutralizing antibodies. As DNA sequencing comprises the fastest growing database of biological information, we focused on incorporating next‐generation sequencing of B‐cell transcripts to determine the origin, maturation pathway, and prevalence of broadly neutralizing antibody lineages (Antibodyomics1, 2, 4, and 6). We also incorporated large‐scale robotic analyses of serum neutralization to identify and quantify neutralizing antibodies in donor cohorts (Antibodyomics3). Statistical analyses furnish another layer of insight (Antibodyomics5), with physical characteristics of antibodies and their targets through molecular dynamics simulations (Antibodyomics7) and free energy perturbation analyses (Antibodyomics8) providing information‐rich output. Functional interrogation of individual antibodies (Antibodyomics9) and synthetic antibody libraries (Antibodyomics10) also yields multi‐dimensional data by which to understand and improve antibodies. Antibodyomics, described here, thus comprise resolution‐enhancing tools, which collectively embody an information‐driven discovery engine aimed toward the development of effective B cell‐based vaccines.

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Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen

Cited by 379 publications

References 51 publications

Progress in HIV vaccine development

Progress in HIV vaccine development

CXCL13 is a plasma biomarker of germinal center activity

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

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