Immune checkpoint modulation enhances HIV-1 antibody induction

Bradley, Todd; Kuraoka, Masayuki; Yeh, Chen-Hao; Tian, Ming; Chen, Huan; Cain, Derek W.; Chen, Xuejun; Cheng, Cheng; Ellebedy, Ali H.; Parks, Robert; Barr, Maggie; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy; Bouton-Verville, Hilary; Santra, Sampa; Wiehe, Kevin; Lewis, Mark G.; Ogbe, Ane; Borrow, Persephone; Montefiori, David C.; Bonsignori, Mattia; Moody, M. Anthony; Verkoczy, Laurent; Saunders, Kevin O.; Ahmed, Rafi; Mascola, John R.; Kelsoe, Garnett; Alt, Frederick W.; Haynes, Barton F.

doi:10.1038/s41467-020-14670-w

Cited by 28 publications

(31 citation statements)

References 97 publications

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“…Alternative animal models, such as rabbits, transgenic/humanized mouse models, or non-human primates are more suitable animal models to specifically interrogate the induction of bnAbs and whether or not the addition of CTLA-4 blockade can improve neutralizing antibody responses [79][80][81][82][83]. A recent report in rhesus macaques and bnAb immunoglobulin knock-in (KI) mice that express diverse precursors of the CD4 binding site of HIV-1 bnAbs supports our hypothesis by demonstrating that co-administering antibodies targeting both CTLA-4 and PD-1 along with HIV Env vaccines augmented the HIV-1 Env antibody responses, increased germinal center B and Tfh cells, and plasma neutralizing antibodies [84].…”

Section: Discussionsupporting

confidence: 77%

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

et al. 2020

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Studies have shown that blockade of CTLA-4 promoted the expansion of germinal center B-cells in viral infection or immunization with model antigens. Few studies have evaluated the immunological consequences of CTLA-4 blockade during immunization against relevant vaccine candidates. Here, we investigated the effects of CTLA-4 blockade on HIV virus-like particles (VLPs) vaccination in a C57BL/6J mouse model. We found that CTLA-4 blockade during HIV VLP immunization resulted in increased CD4+ T-cell activation, promoted the expansion of HIV envelope (Env)-specific follicular helper T cell (Tfh) cells, and significantly increased HIV Gag- and Env-specific IgG with higher avidity and antibody-dependent cellular cytotoxicity (ADCC) capabilities. Furthermore, after only a single immunization, CTLA-4 blockade accelerated T-cell dependent IgG class switching and the induction of significantly high serum levels of the B-cell survival factor, A proliferation-inducing ligand (APRIL). Although no significant increase in neutralizing antibodies was observed, increased levels of class-switched Env- and Gag-specific IgG are indicative of increased polyclonal B-cell activation, which demonstrated the ability to mediate and enhance ADCC in this study. Altogether, our findings show that CTLA-4 blockade can increase the levels of HIV antigen-specific B-cell and antigen-specific Tfh cell activity and impact humoral immune responses when combined with a clinically relevant HIV VLP-based vaccine.

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Section: Discussionsupporting

confidence: 77%

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

et al. 2020

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“…Much recent effort is being placed on the delivery to, and persistence of antigen in, germinal centers to further promote somatic hypermutation. Continuous delivery of antigen [44,45]**,**, multivalent antigen presentation [46,47]*,* adjuvants, and other technologies, including immune checkpoint modultation to promote germinal center activity, [48] may help overcome the limitations of protein subunits as immunogens. Many of these concepts must now be tested empirically.…”

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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“…Further research is needed to understand whether polyreactive broadly neutralizing B cells against influenza viruses are counter-selected or become anergic. Notably, breaking B cell tolerance or blocking immune checkpoints allows for the selection of high-affinity B cell clones and broadly neutralizing B cells ( Kaur et al., 2015 ; Schroeder et al., 2017 ; Bradley et al., 2020 ), suggesting that the precursors of B cells against conserved epitopes are limited by clonal deletion or anergy. Mice with a genetically targeted introduction of a polyreactive HIV-binding BCR counter-select these polyreactive B cells ( Verkoczy et al., 2010 ), indicating B cell tolerance limits polyreactive pathogen-binding antibody responses.…”

Section: Discussionmentioning

confidence: 99%

Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses

et al. 2020

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Summary Polyreactivity is the ability of a single antibody to bind to multiple molecularly distinct antigens and is a common feature of antibodies induced upon pathogen exposure. However, little is known about the role of polyreactivity during anti-influenza virus antibody responses. By analyzing more than 500 monoclonal antibodies (mAbs) derived from B cells induced by numerous influenza virus vaccines and infections, we found mAbs targeting conserved neutralizing influenza virus hemagglutinin epitopes were polyreactive. Polyreactive mAbs were preferentially induced by novel viral exposures due to their broad viral binding breadth. Polyreactivity augmented mAb viral binding strength by increasing antibody flexibility, allowing for adaption to imperfectly conserved epitopes. Lastly, we found affinity-matured polyreactive B cells were typically derived from germline polyreactive B cells that were preferentially selected to participate in B cell responses over time. Together, our data reveal that polyreactivity is a beneficial feature of antibodies targeting conserved epitopes.

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Immune checkpoint modulation enhances HIV-1 antibody induction

Cited by 28 publications

References 97 publications

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

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

Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses

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