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

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 2

Fc-mediated functionality of peak postvaccination antigen-specific Ig in DFx and monthly dosing regimens.

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Fc-mediated functionality of peak postvaccination antigen-specific Ig in...
Plasma from prevaccination (Pre-vacc.) and 2 weeks following the final vaccination was assessed for the capacity of anti–PfRH5 Ig to induce Fc-mediated innate immune activation following incubation with PfRH5-coupled beads. (A–D) The Fc-mediated functionality was compared between dosing regimen with respect to antibody-dependent complement deposition (ADCD), antibody-dependent neutrophil phagocytosis (ADNP), NK cell activation, and antibody-dependent cellular (monocyte) phagocytosis (ADCP). (A) Beads were incubated with plasma, and guinea pig complement and C3 complement deposition was detected by staining with an anti-C3 fluorescent antibody and reported with the median anti-C3 fluorescence intensity (MFI) of each sample. (B) The functional capacity of pre-/postvaccination plasma to induce antibody-dependent monocyte phagocytosis was compared based on the capacity of anti-PfRH5–bound beads to induce phagocytosis by the THP-1 (monocyte) cell line in the presence of plasma. Phagocytic score of each sample = (% bead+ cells) × (MFI)/(10× MFI of first bead+ peak). (C) Neutrophils were isolated from fresh blood and then incubated with plasma and beads; they were then stained to define neutrophils as SSChiCD66b+CD14–CD3– cells. Induction of phagocytosis was compared by calculating phagocytic scores as (% bead+ cells) × (geometric median fluorescence intensity [MFI] of bead-positive cells)/(10 × gMFI of the first bead+ peak). (D) NK cells were purified from buffy coats then incubated with plasma and antigen-coated ELISA plates; they were then stained to define NK cells as CD56+CD3– cells. Activation was measured as the percentage of NK cells expressing MIP1β, CD107a, or IFN-γ as detected by fluorescent antibodies. Plasma was available from all vaccinees for inclusion in these analyses in technical duplicates. Prevaccination/postvaccination: Monthly-low n = 12/12; monthly-medium n = 11/11; DFx n = 11/11; monthly-high n = 9/9. Comparisons between groups were performed by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. Central box lines indicate medians and whiskers denote 5th and 95th percentiles. *P < 0.05, **P < 0.01, ****P < 0.0001.