Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development

Wiehe, Kevin; Bradley, Todd; Meyerhoff, Robert; Hart, Connor; Williams, Wilton B.; Easterhoff, David; Faison, William J.; Kepler, Thomas B.; Saunders, Kevin O.; Alam, S. Munir; Bonsignori, Mattia; Haynes, Barton F.

doi:10.1016/j.chom.2018.04.018

Cited by 110 publications

(215 citation statements)

References 71 publications

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“…In addition, bnAbs have been reported to develop more readily in the setting of autoimmune disease such as systemic lupus erythematosus, but even in that setting, bnAbs do not develop immediately, but only after years of stimulation 68 . While tolerance was interrupted in the setting of CTLA-4 and PD-1 antibody administration to macaques, bnAbs were not induced, indicating the need for specifically designed sequential Envs to overcome additional limitations on induction of bnAbs, including the development of Envs to select for improbable mutations that are common in bnAb B cell lineages 69,70 .…”

Section: Discussionmentioning

confidence: 99%

“…Overall, several vaccine traits will need to be optimized simultaneously to induce full development of broadly neutralizing antibodies. Optimizations required include: comparing Env structure (including multimerization and/or presentation on viral membranes), sequential Env designs to "guide" desired but usually disfavored and rare bnAb B cell lineages with improbable mutations, comparing modes of immunization (protein, DNA, and mRNA), and altering adjuvant formulations 67,69,70,73 . Here, we have shown that one additional factor that is plausible to consider is the addition of immune modulators to enhance titers of neutralizing antibody responses in HIV-1 Env vaccination.…”

Section: Discussionmentioning

confidence: 99%

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Immune checkpoint modulation enhances HIV-1 antibody induction

et al. 2020

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Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immune checkpoint modulation enhances HIV-1 antibody induction

et al. 2020

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“…In the context of a protein subunit vaccine, the ability to drive SHM remains a much larger hurdle. Another issue is that key mutations for development of breadth are not found at traditional AID hotspots and these have been coined improbable mutations that represent hurdles in bnAb development [40,41]*. Potential prime boost strategies can however "shepherd" SHM toward bnAbs, and proof-of-concept was demonstrated a number of years ago [42,43].…”

Section: Somatic Hypermutationmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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Please cite this article as: Ward AB, Wilson IA, Innovations in structure-based antigen design and immune monitoring for next generation vaccines, J o u r n a l P r e -p r o o f Highligthts Immunofocusing as a strategy for structure-based vaccine design. Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. Structure-based vaccine design translated into the clinic. AbstractThe recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, hepatitis C and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate result of ever increasingly breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development.

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“…While RV305 was necessary to mature C1C2-specific antibody responses, additional boosting with ALVAC/AIDSVAX B/E would not increase ADCC breadth and potency. Likely rationally designed sequential [18] boosting immunogens to select for critical mutations [19] that directionally affinity mature highly functional ALVAC/AIDSVAX B/E-induced C1C2-specific antibodies are needed.…”

Section: Discussionmentioning

confidence: 99%

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

Easterhoff

Pollara

Luo

et al. 2019

Preprint

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Significance 26Over one million people become infected with HIV-1 each year making the development 27 of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human 28 HIV-1 vaccine-regimen is the only HIV-1 clinical trial to date to demonstrate vaccine- 29 efficacy. An area of focus has been on identifying ways by which to improve upon 30 RV144 vaccine-efficacy. The RV305 HIV-1 vaccine-regimen was a follow-up boost of 31 RV144 vaccine-recipients that occurred 6-8 years after the conclusion of RV144. Our 32 2 studies focused on the effect of delayed boosting in humans on the vaccine-induced 33 antibody repertoire. It was found that boosting with a HIV-1 Env vaccine increased 34 antibody-mediated effector function potency and breadth. 35Abstract 36 Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One 37 strategy is to induce non-neutralizing antibodies that kill virus-infected cells as these 38 antibody specificities have been implicated in slowing HIV-1 disease progression and in 39 protection. HIV-1 Env constant region 1 and 2 (C1C2) antibodies frequently contain 40 potent antibody dependent cellular cytotoxicity (ADCC) making them a vaccine target. 41Here we explore the effect of delayed and repetitive boosting of RV144 vaccinee 42 recipients with ALVAC/AIDSVAX B/E on the C1C2-specific antibody repertoire. It was 43 found that boosting increased clonal lineage specific ADCC breadth and potency. A 44 ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-45 specific antibody showed that it bound a highly conserved Env gp120 epitope. Thus, 46 rationally designed boosting strategies to affinity mature these type of IgG C1C2-47 specific antibody responses may be one method by which to make an improved HIV 48 vaccine with higher efficacy than seen in the RV144 trial. 49 INTRODUCTION 50CD4-inducible (CD4i) epitopes within HIV-1 envelope (Env) constant regions 1 and 51 2 (C1C2) are targets for antibodies that mediate antibody dependent cellular cytotoxicity 52 (ADCC) [1]. C1C2-specific antibody epitopes have been termed Cluster A [1] and defined 53 by two Env-targeted monoclonal antibodies (mAbs), A32 [2] and C11 [1]. Structural 54 analyses of antigen complexes formed by A32, A32-like [3-5] and C11-like antibodies [6] 55 3 indicate that these antibodies bind distinct Env epitopes. The A32 epitope involves a 56 discontinuous sequence within layers 1 and 2 of the inner domain [4, 5] while the C11 57 epitope maps to the inner domain eight-stranded β sandwich [6]. Importantly, both 58 antibodies are non-neutralizing for tier 2 HIV strains, but are capable of broad and potent 59 ADCC [1, 2]. 60 The secondary analysis of HIV-1 infection risk in RV114 (NCT00223080) 61 indicated that ADCC in the presence of low anti-Env IgA responses correlated with 62 decreased HIV-1 acquisition [7]. While antibodies representative of the Env variable 63 region 2 (V2) response inversely correlated with HIV-1 acquisition [7], we previously 64 demo...

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Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development

Cited by 110 publications

References 71 publications

Immune checkpoint modulation enhances HIV-1 antibody induction

Immune checkpoint modulation enhances HIV-1 antibody induction

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

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