Strategies for a multi-stage neutralizing antibody-based HIV vaccine

Andrabi, Raiees; Bhiman, Jinal N.; Burton, Dennis R.

doi:10.1016/j.coi.2018.04.025

Cited by 101 publications

(103 citation statements)

References 61 publications

(105 reference statements)

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“…With large-scale research and translational efforts ongoing to develop a vaccine that induces a broadly neutralizing Ab (bnAb) response to HIV-1, a new standard in vaccine development is emerging that draws upon fundamental B cell research (Andrabi et al, 2018;Bonsignori et al, 2017). These efforts involve studying the response of long term non-progressors and other individuals who show protection from the virus, with isolation of HIV-1-specific peripheral blood B cells and identification of rare bnAbs.…”

Section: Broadly Neutralizing Antibody-induction Requirementsmentioning

confidence: 99%

B Cell Responses: Cell Interaction Dynamics and Decisions

Cyster

Allen

2019

Cell

639

634

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B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short-and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.

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Section: Broadly Neutralizing Antibody-induction Requirementsmentioning

confidence: 99%

B Cell Responses: Cell Interaction Dynamics and Decisions

Cyster

Allen

2019

Cell

639

634

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“…Trimers coupled per IO-NP B41 SOSIP.v4. 1 13 Table 2. Design of C-terminal TCHE tags on B41 SOSIP.v4.1 trimers.…”

Section: Appendixmentioning

confidence: 99%

“…A vaccine to prevent human immunodeficiency virus type 1 (HIV-1) infection will most likely need to induce potent and broad neutralizing antibodies (NAbs) that recognize the gp120 plus gp41 envelope glycoprotein trimer on the virion surface (1)(2)(3)(4)(5). The fragile virion-associated trimer can be appropriately mimicked for vaccine development by soluble recombinant SOSIP trimers that are stabilized by engineered sequence changes and produced in amounts sufficient for animal and human studies (3,4,6,7).…”

Section: Introductionmentioning

confidence: 99%

Neutralizing Antibody Induction by HIV-1 Envelope Glycoprotein SOSIP Trimers on Iron Oxide Nanoparticles May Be Impaired by Mannose Binding Lectin

Ringe

Portillo

Dosenovic

et al. 2020

J Virol

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We covalently attached human immunodeficiency virus type 1 (HIV-1) Env SOSIP trimers to iron oxide nanoparticles (IO-NPs) to create a particulate immunogen for neutralizing antibody (NAb) induction. The attached trimers, ∼20 per particle, retained native-like antigenicity, judged by reactivity with NAbs and non-NAbs. Bivalent (BG505 and B41) trimer IO-NPs were made, as were IO-NPs displaying B41 trimers carrying a PADRE T-cell helper epitope (TCHE). We immunized mice with B41 soluble or IO-NP trimers after PADRE peptide priming. After two immunizations, IO-NP presentation and the TCHE tag independently and substantially increased anti-trimer antibody responses, but titer differences waned after two further doses. Notable and unexpected findings were that autologous NAbs to the N289 glycan hole epitope were consistently induced in mice given soluble but not IO-NP trimers. Various recombinant mannose binding lectins (MBLs) and MBLs in sera of both murine and human origin bound to soluble and IO-NP trimers. MBL binding occluded the autologous NAb epitope on the B41 IO-NP trimers, which may contribute to its poor immunogenicity. The exposure of a subset of broadly active NAb epitopes was also impaired by MBL binding, which could have substantial implications for the utility of trimer-bearing nanoparticles in general and perhaps also for soluble Env proteins. IMPORTANCE Recombinant trimeric SOSIP proteins are vaccine components intended to induce neutralizing antibodies (NAbs) that prevent cells from infection by human immunodeficiency virus type 1 (HIV-1). A way to increase the strength of antibody responses to these proteins is to present them on the surface of nanoparticles (NPs). We chemically attached about 20 SOSIP trimers to NPs made of iron oxide (IO). The resulting IO-NP trimers had appropriate properties when we studied them in the laboratory but, unexpectedly, were less able to induce NAbs than nonattached trimers when used to immunize mice. We found that mannose binding lectins, proteins naturally present in the serum of mice and other animals, bound strongly to the soluble and IO-NP trimers, blocking access to antibody epitopes in a way that may impede the development of NAb responses. These findings should influence how trimer-bearing NPs of various designs are made and used.

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“…Given their protective efficacy in passive transfer studies the elicitation of broadly neutralizing antibodies (bnAbs) is one of the primary objectives of current HIV research (1)(2)(3)(4)(5)(6). Stabilized envelope glycoprotein (Env) SOSIP trimers contain all bnAb epitopes aside from the membrane proximal external region (MPER), and have provided a platform for elicitation of such bnAb responses (7)(8)(9). These stabilized SOSIP immunogens yield neutralization titers against immunogen-matched neutralization resistant (Tier-2) viruses in many animals (10)(11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

HIV Envelope Trimer-Elicited Autologous Neutralizing Antibodies Bind a Region Overlapping the N332 Glycan Supersite

Nogal

McCoy²,

Gils

et al. 2019

Preprint

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To date, immunization studies of rabbits with the BG505 SOSIP.664 HIV envelope glycoprotein trimers have revealed the 241/289 glycan hole as the dominant neutralizing antibody epitope. Here, we isolated monoclonal antibodies from a rabbit that did not exhibit glycan hole-dependent autologous serum neutralization. The antibodies did not compete with a previously isolated glycan hole-specific antibody but did compete with N332 glycan supersite broadly neutralizing antibodies. A high resolution cryoEM structure of one of the antibodies in complex with the BG505 SOSIP.664 trimer demonstrated that, while the epitope recognized overlapped with the N332 glycan supersite by contacting the GDIR motif at the base of V3, the primary contacts were located in the variable V1 loop. These data suggest that strain-specific responses to V1 may interfere with broadly neutralizing responses to the N332 glycan supersite and vaccine immunogens may require engineering to minimize these off-target responses or steer them toward a more desirable pathway.

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Strategies for a multi-stage neutralizing antibody-based HIV vaccine

Cited by 101 publications

References 61 publications

B Cell Responses: Cell Interaction Dynamics and Decisions

B Cell Responses: Cell Interaction Dynamics and Decisions

Neutralizing Antibody Induction by HIV-1 Envelope Glycoprotein SOSIP Trimers on Iron Oxide Nanoparticles May Be Impaired by Mannose Binding Lectin

HIV Envelope Trimer-Elicited Autologous Neutralizing Antibodies Bind a Region Overlapping the N332 Glycan Supersite

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