Functional Antibodies and Innate Immune Responses to WRSS1, a Live Oral Shigella sonnei Vaccine Candidate, in Bangladeshi Adults and Children

Protim Sarker, Akhirunnesa Mily, Anjuman Ara, Farjana Haque, Nicole Maier, Thomas F Wierzba, Richard I Walker, Malabi M Venkatesan, Rubhana Raqib, Protim Sarker, Akhirunnesa Mily, Anjuman Ara, Farjana Haque, Nicole Maier, Thomas F Wierzba, Richard I Walker, Malabi M Venkatesan, Rubhana Raqib

Abstract

Background: We demonstrated in a randomized placebo-controlled trial that WRSS1, a live oral Shigella sonnei vaccine candidate, is safe in Bangladeshi adults and children, and elicits antigen-specific antibodies. Here, we describe functional antibody and innate immune responses to WRSS1.

Methods: Adults (18-39 years) and children (5-9 years) received 3 doses of 3 × 105 or 3 × 106 colony forming units (CFU) of WRSS1 or placebo, 4 weeks apart; children additionally received 3 × 104 CFU. Blood and stool were collected at baseline and 7 days after each dose. Functional antibodies were measured using serum bactericidal antibody (SBA) assay. Cytokine/chemokine concentrations were measured in lymphocyte cultures. Host defense peptides LL-37, HBD-1, and HD-5 were analyzed in plasma and stool.

Results: Children showed increased SBA titers over baseline after the third dose of 3 × 106 CFU (P = .048). Significant increases of Th-17 and proinflammatory cytokines (TNF-α, G-CSF, MIP-1β), and reduction of anti-inflammatory and Th2 cytokines (IL-10, IL-13, GM-CSF) were observed in children. Plasma HBD-1 and LL-37 decreased in children after vaccination but were increased/unchanged in adults.

Conclusions: Functional antibodies and Th1/Th17 cytokine responses in children may serve as important indicators of immunogenicity and protective potential of WRSS1. Clinical Trials Registration: NCT01813071.

Keywords: anti-inflammatory cytokines; host defense peptides; mucosal immune responses; proinflammatory cytokines; protective immunity; serum bactericidal antibody assay.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Schematic diagram of dosing and follow-up status of adult and child participants receiving different concentration of WRSS1 vaccine or placebo. Abbreviation: CFU, colony-forming unit.
Figure 2.
Figure 2.
Serum bactericidal antibody (SBA) titers before and after administration of WRSS1vaccine or placebo in Bangladeshi adults (A) and children (B). Data are presented as median and interquartile range. Statistical significance between pre- and postvaccination days within group was determined using Wilcoxon Signed rank test. Kruskal-Wallis test was applied to compare vaccine groups with placebo at each time point.
Figure 3.
Figure 3.
Interleukin 7 (IL-7) concentration in lymphocyte culture of Bangladeshi adult participants before and after administration of WRSS1 vaccine or placebo. Data are presented as median and interquartile range. Statistical significance between pre- and postvaccination days within group was determined using Wilcoxon Signed rank test. Kruskal-Wallis test was applied to compare vaccine groups with placebo at each time point.
Figure 4.
Figure 4.
Plasma levels of LL-37 in adults (A), LL-37 in children (B), human β defensin-1 (HBD-1) in adults (C), and HBD-1 in children (D) before and after administration of WRSS1 vaccine or placebo. Data are presented as median and interquartile range. Statistical significance between pre- and postvaccination days within group was determined using Wilcoxon Signed rank test. Kruskal-Wallis test was applied to compare vaccine groups with placebo at each time point.

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