Delayed fractional dosing clinical immunology paper published in JCI Insight

Working with Draper group colleagues and collaborators at the Vaccine Research Center (NIH, USA) and the Ragon Institute (USA), Carolyn has recently published analyses of the significance of delayed booster dosing for optimising RH5 responses (VAC063) in JCI Insight. This paper is one of the main outputs of her Sir Henry Wellcome Postdoctoral Fellowship research, which focused on interrogating the impact of vaccine platform and booster dosing regimens on the cellular drivers of humoral immunity.

Nielsen CM et al. 2023. Delayed boosting improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine. JCI Insight.

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 AS01-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 analysed 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 non-peripheral long-lived plasma cells.

The full open-access text can be found here: https://insight.jci.org/articles/view/163859.