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Delayed boosting improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine
Carolyn M. Nielsen, … , Galit Alter, Simon J. Draper
Carolyn M. Nielsen, … , Galit Alter, Simon J. Draper
Published January 24, 2023
Citation Information: JCI Insight. 2023;8(2):e163859. https://doi.org/10.1172/jci.insight.163859.
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Research Article Immunology Vaccines

Delayed boosting improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine

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Abstract

Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) — using AS01B-adjuvanted RH5.1 malaria antigen — substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells.

Authors

Carolyn M. Nielsen, Jordan R. Barrett, Christine Davis, Jonathan K. Fallon, Cyndi Goh, Ashlin R. Michell, Catherine Griffin, Andrew Kwok, Carolin Loos, Samuel Darko, Farida Laboune, Mehmet Tekman, Ababacar Diouf, Kazutoyo Miura, Joseph R. Francica, Amy Ransier, Carole A. Long, Sarah E. Silk, Ruth O. Payne, Angela M. Minassian, Douglas A. Lauffenburger, Robert A. Seder, Daniel C. Douek, Galit Alter, Simon J. Draper

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Figure 3

Systems serology computational analyses to define Ig feature sets that distinguish DFx from monthly dosing regimen.

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Systems serology computational analyses to define Ig feature sets that d...
Partial least squares discriminant analysis (PLS-DA) was performed with univariate read-outs from the systems serology analyses to compare DFx and monthly dosing regimens. (A and B) Significant features were chosen via the LASSO feature selection algorithm and those chosen in at least 80% of 100 repetitions were used to build PLS-DA classifiers. Correlation networks were built to reveal additional serology features significantly associated with the selected features. (C) Serology features significantly (P < 0.05, after a Benjamini-Hochberg correction) correlated via Spearman’s correlation (rS > |0.7|) were selected as cocorrelates. The gradient color of edges represents correlation value between the features, represented as nodes. Nodes are colored according to selected status, with gray nodes as selected features and white nodes as cocorrelate features. (D–I) This approach was also used to directly compare DFx vaccinees with monthly-high and DFx/monthly-high vaccinees with monthly-low/monthly-medium regimens. Line style (solid versus hash) of features in B, E, and H relates to group with significant increase in that feature with 95% CI. Models had cross-validation accuracies of 0.85 (A), 0.74 (D), and 0.83 (G), with comparisons to null models generated by random feature selection (P = 0.01, P = 0.09, and P = 0.01, respectively) or permuted labels (P < 0.01, P = 0.04, and P < 0.01, respectively) being significant for all but comparison to a null model built with randomly selected features in DFx versus monthly-high vaccinees. This is likely due to the limited number of samples and the high correlations between selected features and nonselected features (F). LV, latent variable; ADCD, antibody-dependent complement deposition; ADCP, antibody-dependent cellular (monocyte THP-1) phagocytosis; ADNP, antibody-dependent neutrophil phagocytosis; ADNKA, antibody-dependent NK cell activation. Monthly-low, n = 12; monthly-medium, n = 11; DFx, n = 12; monthly-high, n = 9.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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