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Broadening vaccine strategies to induce HIV broadly neutralizing antibodies

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Science Translational Medicine  14 Aug 2019:
Vol. 11, Issue 505, eaay7699
DOI: 10.1126/scitranslmed.aay7699

Abstract

Vaccination with anti-idiotype antibodies can activate and target germline B cell precursors of HIV broadly neutralizing antibodies.

The induction of broadly neutralizing and protective antibodies is a key strategy for successful vaccination. However, for many important global diseases, such as HIV and influenza, highly effective vaccinations are lacking. One strategy for development of new vaccines has focused on identifying specific targets of vulnerability on pathogens, which are targeted by protective antibodies. For HIV infection, this approach has focused on identifying the targets of broadly neutralizing antibodies (bNAbs), which develop in a small subset of HIV-infected individuals and can mediate protection from diverse virus strains. Despite multiple targets of bNAb on HIV-1 envelope protein (Env) being identified, to date diverse vaccine approaches of specific structure-based Env immunogens have failed to induce protective bNAbs in humans.

Taking a new approach to this problem, Bancroft et al. investigated the ability of vaccination with anti-idiotype antibodies. They targeted germline B cells of one HIV-1 bNAb, b12, for which Env-immunogens have not been identified. To do this, the authors developed specific anti-idiotype antibodies to the inferred germline version bNAb b12. Generated germline anti-idiotype antibodies were successfully able to identify reactive B cells from a polyclonal human B cell repertoire in a HIV-uninfected donor. However, the B cell receptors of anti-idiotype– reactive B cells had only moderate similarity to the predicted germline precursor of b12. This underrepresentation could be due to autoreactivity of germline b12 precursor B cells, which resulted in deletion and anergy of these specific B cells in a mouse heavy chain knock-in model. Despite this, immunization with anti-idiotype antibodies overcame B cell anergy, resulting in activation of target B cells and entry of targeted B cells to the germinal center.

Together, this work shows that anti-idiotype antibodies can identify precursor B cells of a specific B cell receptor and can also be used as a vaccination approach to activate desired B cells clones in mice. Additional studies are required to confirm that this strategy will induce B cell precursors from an unmanipulated polyclonal pool and in humans, and that the approach will result in induction of bNAbs from targeted B cells. Further, additional approaches will be required to overcome other difficulties in targeting germline precursors of bNAbs, such as the multiple rounds of somatic hypermutation that are required for the development of specific bNAbs. However, data suggest that anti-idiotype approaches may be an additional useful approach to structure-based immunogens in the development of vaccines that induce bNAbs targeting HIV and other pathogens.

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