Immunization of Macaques With Soluble HIV Type 1 and Influenza Virus Envelope Glycoproteins Results in a Similarly Rapid Contraction of Peripheral B-Cell Responses After Boosting

Sundling, Christopher; Martinez, Paola; Soldemo, Martina; Spångberg, Mats; Bengtsson, Karin; Stertman, Linda; Forsell, Mattias N.E.; Hedestam, Gunilla B. Karlsson

doi:10.1093/infdis/jis696

Cited by 26 publications

(33 citation statements)

References 15 publications

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“…In the analysis of these previous studies, the short-lived kinetics of the response to Env was also examined. Here, we did not examine the durability of the B cell response; however, in similar Env immunogenicity studies, gp120-directed antibody responses did wane over time (59) and would be expected to do so as well here.…”

Section: Discussionmentioning

confidence: 97%

Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

Chakrabarti

Feng

Sharma

et al. 2013

J Virol

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e Host cell-mediated proteolytic cleavage of the human immunodeficiency virus type 1 (HIV-1) gp160 precursor glycoprotein into gp120 and gp41 subunits is required to generate fusion-competent envelope glycoprotein (Env) spikes. The gp120-directed broadly neutralizing monoclonal antibodies (bNabs) isolated from HIV-infected individuals efficiently recognize fully cleaved JRFL Env spikes; however, nonneutralizing gp120-directed monoclonal antibodies isolated from infected or vaccinated subjects recognize only uncleaved JRFL spikes. Therefore, as an immunogen, cleaved spikes that selectively present desired neutralizing epitopes to B cells may elicit cross-reactive neutralizing antibodies. Accordingly, we inoculated nonhuman primates (NHPs) with plasmid DNA encoding transmembrane-anchored, cleaved JRFL Env or by electroporation (EP). Priming with DNA expressing soluble, uncleaved gp140 trimers was included as a comparative experimental group of NHPs. DNA inoculation was followed by boosts with soluble JRFL gp140 trimers, and control NHPs were inoculated with soluble JRFL protein trimers without DNA priming. In the TZM-bl assay, elicitation of neutralizing antibodies against HIV-1 tier 1 isolates was robust following the protein boost. Neutralization of tier 2 isolates was detected, but only in animals primed with plasmid DNA and boosted with trimeric protein. Using the more sensitive A3R5 assay, consistent neutralization of both clade B and C tier 2 isolates was detected from all regimens assessed in the current study, exceeding levels achieved by our previous vaccine regimens in primates. Together, these data suggest a potential advantage of B cell priming followed by a rest interval and protein boosting to present JRFL Env spikes to the immune system to better generate HIV-1 cross-clade neutralizing antibodies.

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Section: Discussionmentioning

confidence: 97%

Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

Chakrabarti

Feng

Sharma

et al. 2013

J Virol

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“…Although low anti-MVA IgG titers were induced after a single immunization, the boost greatly enhanced the humoral response, which was the main rationale for selecting postboost time points for CyTOF evaluation. The peak of the serum Ab response occurred before D 28 PB; therefore, it is reasonable to assume that the contraction of the peripheral memory B cell response had commenced before this time point, as described in other reports of prime-boost vaccination of cynomolgus macaques (70). The expansion and contraction of cells in the peripheral CD20 + B compartment from a single SPADE DEC, DEC9, correlated with the total anti-MVA serum IgG response (R = 0.85, p = 0.00007) (Fig.…”

Section: Serum Ab Response and Correlation With Spade Decsmentioning

confidence: 67%

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Pejoski¹,

Tchitchek²,

Pozo³

et al. 2016

The Journal of Immunology

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Broadening our understanding of the abundance and phenotype of B cell subsets that are induced or perturbed by exogenous Ags will improve the vaccine evaluation process. Mass cytometry (CyTOF) is being used to increase the number of markers that can be investigated in single cells, and therefore characterize cell phenotype at an unprecedented level. We designed a panel of CyTOF Abs to compare the B cell response in cynomolgus macaques at baseline, and 8 and 28 d after the second homologous immunization with modified vaccinia virus Ankara. The spanning-tree progression analysis of density-normalized events (SPADE) algorithm was used to identify clusters of CD20+ B cells. Our data revealed the phenotypic complexity and diversity of circulating B cells at steady-state and significant vaccine-induced changes in the proportions of some B cell clusters. All SPADE clusters, including those altered quantitatively by vaccination, were characterized phenotypically and compared using double hierarchical clustering. Vaccine-altered clusters composed of previously described subsets including CD27hiCD21lo activated memory and CD27+CD21+ resting memory B cells, and subphenotypes with novel patterns of marker coexpression. The expansion, followed by the contraction, of a single memory B cell SPADE cluster was positively correlated with serum anti-vaccine Ab titers. Similar results were generated by a different algorithm, automatic classification of cellular expression by nonlinear stochastic embedding. In conclusion, we present an in-depth characterization of B cell subphenotypes and proportions, before and after vaccination, using a two-step clustering analysis of CyTOF data, which is suitable for longitudinal studies and B cell subsets and biomarkers discovery.

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“…The green line represents data for the persistence of anti-HPV antibody titers modeled by a modified power law in a study by David et al (60). The data in A and B were plotted from tables in the study by Yates et al (26) or digitized from the original publications (23,30,60) using the commercially available software DigitizeIt (www. digitizeit.de).…”

Section: Strategies To Elicit Continuous Protection Against Hiv By Vamentioning

confidence: 99%

“…22). The point is moot whether this problem is unique to HIV gp120 or extends to responses against other viral vaccines, as suggested for the influenza virus hemagglutinin (23); it must be solved for an effective HIV vaccine. The importance of this issue is immediately apparent in HIV vaccine trials involving Env.…”

mentioning

confidence: 99%

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

Proc. Natl. Acad. Sci. U.S.A.

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The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibodymediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 + T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Envbased AIDS vaccines regardless of the mechanism of antibody-mediated protection.

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Immunization of Macaques With Soluble HIV Type 1 and Influenza Virus Envelope Glycoproteins Results in a Similarly Rapid Contraction of Peripheral B-Cell Responses After Boosting

Cited by 26 publications

References 15 publications

Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

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