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 1

Antigen-specific B cell and Ig postvaccination kinetics in DFx and monthly dosing regimens.

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Antigen-specific B cell and Ig postvaccination kinetics in DFx and month...
PBMC from prevaccination (Pre-vacc.) and post–final vaccination time points were analyzed by flow cytometry. (A and B) Frequencies of PfRH5-specific mBCs were defined as in Supplemental Figure 1A and compared between heterologous viral vector (ChAd63-MVA; ChAd63-PfRH5 prime, MVA-PfRH5 boost; refs. 10, 11) and protein/AS01B vaccinees (1), or monthly and DFx regimen protein/AS01B vaccinees. (C) Spearman’s correlation analysis was performed between PfRH5-specific mBCs and anti-PfRH5 serum IgG (4 weeks after final vaccination); protein/AS01B vaccinees only. Each triangle represents 1 vaccinee; purple triangles indicate DFx vaccinees. (D–G)Anti-full-length (FL) RH5.1 serum Ig was assayed by standardized ELISA to report IgG1, IgG2, IgG3, and IgG4. (H) Fold change in serum anti–PfRH5.1 FL Ig between 2 weeks (Monthly: Day 70; DFx: Day 196) and 6 months after final vaccination (Monthly: Day 240; DFx: Day 366). Full kinetics for IgA, IgA1, IgA2, and IgM, as well as a group-stratified version of H, are shown in Supplemental Figure 2. The relationship between anti-RH5.1 IgG and antiparasite functionality is shown in Supplemental Figure 3. Sample sizes for all assays were based on sample availability. (A) ChAd63-MVA/protein/AS01B: Pre-vacc. n = 15/18; 1-week n = 10/0; 2-week n =0/25; 4-week n =15/29; 12-week n = 13/25. (B) Monthly/DFx: Pre-vacc. n = 15/3; 2-week n = 16/9; 4-week n = 19/10; 12-week n = 17/8. (D–G) Monthly-low: n =12, except Day 696 (n = 9). Monthly-medium: n = 12, except Day 240 (n = 11) and Day 696 (n = 10). DFx: n = 12, except Day 366 (n = 11) and Day 822 (n=7). Monthly-high: n = 11, except Day 70 (n = 9), Day 240 (n = 10), and Day 696 (n = 4). (H) Monthly/DFx: n = 31/11 except IgG4 (n = 18/9). (A, B, and H) Comparisons were performed between regimens with Mann-Whitney U tests. Central box lines indicate medians, and whiskers denote 5th and 95th percentiles; samples outside the 5th–95th percentile range are shown as triangles. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.