Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies

Duan, Hongying; Chen, Xuejun; Boyington, Jeffrey C.; Cheng, Cheng; Zhang, Yi; Jafari, Alexander J.; Stephens, Tyler; Tsybovsky, Yaroslav; Kalyuzhniy, Oleksandr; Zhao, Peng; Menis, Sergey; Nason, Martha; Normandin, Erica; Mukhamedova, Maryam; DeKosky, Brandon J.; Wells, Lance; Schief, William R.; Tian, Ming; Alt, Frederick W.; Kwong, Peter D.; Mascola, John R.

doi:10.1016/j.immuni.2018.07.005

Cited by 123 publications

(128 citation statements)

References 63 publications

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“…While slow delivery immunization can alter the immunodominance of epitopes and enhance the response to immunization, immunogens should be also be optimized to minimize responses against non-neutralizing epitopes. These results are consistent with immunodominance findings in HIV-1 bnAb mouse models (Abbott et al, 2018; Duan et al, 2018). Osmotic pumps have been used in humans for drug delivery and are feasible for early human vaccine trials.…”

Section: Discussionsupporting

confidence: 91%

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

Cirelli

Carnathan

Nogal

et al. 2018

Preprint

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35The observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has 36 generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization 37 strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other 38 difficult pathogens, due to the significant immunological hurdles posed, including B cell 39 immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine 40 needle aspirates, we found that two independent methods of slow delivery immunization of rhesus 41 macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells 42 with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 43 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified 44 differential IgV gene usage between slow delivery immunized and conventional bolus immunized 45 animals. The most immunodominant IgV gene used by conventionally immunized animals was 46 associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated 47 targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted 48 in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb 49 development by altering GCs and modulating immunodominance of non-neutralizing epitopes. 50 51

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Section: Discussionsupporting

confidence: 91%

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

Cirelli

Carnathan

Nogal

et al. 2018

Preprint

Self Cite

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“…Recently, several self-assembling proteins such as ferritin, lumazine synthase, and encapsulin have been successfully used as scaffolds to present complex glycoprotein antigens derived from influenza hemagglutinin (Kanekiyo et al., 2013, Yassine et al., 2015), HIV envelope (Abbott et al., 2018, He et al., 2016, Jardine et al., 2015, McGuire et al., 2016, Sliepen et al., 2015), and Epstein-Barr virus (Kanekiyo et al., 2015). In all cases, immunogenicity of the antigen was increased by multivalent presentation, and in some cases, an epitope-focusing effect was observed in which potent neutralizing epitopes were preferentially targeted (Duan et al., 2018, Kanekiyo et al., 2015, Yassine et al., 2015). …”

Section: Introductionmentioning

confidence: 99%

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Marcandalli

Fiala

Ols

et al. 2019

Cell

373

405

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SummaryRespiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

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“…Moreover, VLPs/NPs are also supposed to enhance antigen uptake by antigen presenting cells (APCs) which subsequently support the adaptive arms of the immune system [87]. Finally, VLPs/NPs have also been proven, in some cases, to generate an epitope-focusing effect in which antigenic sites promoting the generation of potent neutralizing mAbs were preferentially targeted [88,89]. Over the last decades, several platforms for VLPs/NPs design have been generated, including the usage of viral core proteins, covalent links of individual folded proteins through site-specific ligations and de novo protein nanostructure formation via non-covalent intramolecular and intermolecular interactions.…”

Section: Virus-like Particles and Nanoparticles For Antigen Displaymentioning

confidence: 99%

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

Perotti

Perez

2019

Viruses

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Human cytomegalovirus (HCMV) infects more than 70% of the human population worldwide. HCMV is responsible for high morbidity and mortality in immunocompromised patients and remains the leading viral cause of congenital birth defects. Despite considerable efforts in vaccine and therapeutic development, HCMV infection still represents an unmet clinical need and a life-threatening disease in immunocompromised individuals and newborns. Immune repertoire interrogation of HCMV seropositive patients allowed the identification of several potential antigens for vaccine design. However, recent HCMV vaccine clinical trials did not lead to a satisfactory outcome in term of efficacy. Therefore, combining antigens with orthogonal technologies to further increase the induction of neutralizing antibodies could improve the likelihood of a vaccine to reach protective efficacy in humans. Indeed, presentation of multiple copies of an antigen in a repetitive array is known to drive a more robust humoral immune response than its soluble counterpart. Virus-like particles (VLPs) and nanoparticles (NPs) are powerful platforms for multivalent antigen presentation. Several self-assembling proteins have been successfully used as scaffolds to present complex glycoprotein antigens on their surface. In this review, we describe some key aspects of the immune response to HCMV and discuss the scaffolds that were successfully used to increase vaccine efficacy against viruses with unmet medical need.

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Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies

Cited by 123 publications

References 63 publications

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

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