Rational HIV immunogen design to target specific germline B cell receptors

By Joseph G. Jardine, J. Julien, Sergey Menis, T. Ota, Oleksandr Kalyuzhniy, A. McGuire, D. Sok, Po-Ssu Huang, Skye MacPherson, Meaghan Jones and 9 more. Science, 2013

697 citations recorded by the source corpus.

Building Better Vaccines In the past few years, several highly potent, broadly neutralizing antibodies (bNAbs) specific for the gp120 envelope protein of HIV-1 have been discovered. The goal of this work is to use this information to inform the design of vaccines that are able to induce such antibodies (see the Perspective by Crowe). However, because of extensive somatic hypermutation, the epitope bound by these antibodies often does not bind to the germline sequence. Jardine et al. (p. 711, published online 28 March; see the cover) used computational analysis and in vitro screening to design an immunogen that could bind to VRC01-class bNAbs and to their germline precursors. Georgiev et al. (p. 751) took advantage of the fact that only four sites on the HIV viral envelope protein seem to bind bNAbs, and sera that contain particular bNAbs show characteristic patterns of neutralization. An algorithm was developed that could successfully delineate the neutralization specificity of antibodies present in polyclonal sera from HIV-infected patients. Structural knowledge of broadly neutralizing antibodies against HIV-1 guides the design of an immunogen to elicit them. Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1–infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and germline precursors, and elucidated germline binding crystallographically. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.

Subfields: Molecular Biology, Radiology, Nuclear Medicine and Imaging, Virology

View Paper: https://www.semanticscholar.org/paper/39779eceaa9e1b1dea083bf8be074d0fdbd00ffb

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Citations in the corpus

Antibody Recognition of the Pandemic H1N1 Influenza Virus Hemagglutinin Receptor Binding Site (2013, background): “In addition, the structural information can be used to design immunogens that elicit RBS-targeted antibodies, along similar lines as the germ line-targeting engineered outer domain of HIV-1 gp120 (46).”
Self-assembling protein nanoparticles in the design of vaccines (2015, positive): “Jardine et al. engineered LS to display an optimized sub-component (termed, eOD-GT6) of the wild-type gp120 antigen from the Env trimer [99].”
OptMAVEn – A New Framework for the de novo Design of Antibody Variable Region Models Targeting Specific Antigen Epitopes (2014, background): “[29], superhumanization [30], framework shuffling [31] and guided selection [32] have produced antibodies more homologous to human sequences, often but not always leading to reductions in immunogenicity to clinically acceptable levels [33].”
Glycan-Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies (2018, positive): “eOD-GT6 (Jardine et al., 2013), a VRC01-class immunogen with lower affinity to VRC01-class precursors than eOD-GT8, which failed to isolate VRC01-class naive B cells from human PBMCs (Jardine et al.”
Molecular Evolution of Broadly Neutralizing Llama Antibodies to the CD4-Binding Site of HIV-1 (2014, background): “However, whether or not HCAb can more easily be elicited than IgG does not alter one similarity between neutralizing antibodies derived from HIV-positive patients and J3, namely that their unmutated ancestors do not bind HIV Env [46,47,48], except when modified to do exactly that [49,50,51] or in on”
Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens (2017, positive): “, 2016), and possess a binding modality that is opportune for germline-targeting immunogen design (Jardine et al., 2013; McGuire et al., 2013; Zhou et al., 2010).”
Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles (2016, positive): “A 60-meric LS nanoparticle presenting an engineered gp120 core lacking variable loops (V1V2 and V3) and inner domain has been used to target the germline precursors of VRC01 (refs 37,38), a CD4-binding site (CD4bs)-directed bNAb 51 .”
Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8 (2016, background): “These antibodies provide potential templates to guide HIV-1 vaccine strategies [3,4], and details of their generation and maturation have generated intense interest.”