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Clinical Trial
. 2024 Oct 16;230(4):e971-e984.
doi: 10.1093/infdis/jiae273.

Safety and Immunogenicity of a 4-Component Generalized Modules for Membrane Antigens Shigella Vaccine in Healthy European Adults: Randomized, Phase 1/2 Study

Isabel Leroux-Roels  1 , Cathy Maes  1 , Francesca Mancini  2 , Bart Jacobs  1 , Eleanna Sarakinou  2 , Azhar Alhatemi  1 , Jasper Joye  1 , Silvia Grappi  3 , Giulia Luna Cilio  4 , Alimamy Serry-Bangura  4 , Claudia G Vitali  5 , Pietro Ferruzzi  2 , Elisa Marchetti  2 , Francesca Necchi  2 , Rino Rappuoli  6 , Iris De Ryck  4 , Jochen Auerbach  2 , Anna M Colucci  2 , Omar Rossi  2 , Valentino Conti  2 , Francesco Berlanda Scorza  2 , Ashwani Kumar Arora  2 , Francesca Micoli  2 , Audino Podda  2 , Usman N Nakakana  2 ; Shigella Project Team
Collaborators, Affiliations
Clinical Trial

Safety and Immunogenicity of a 4-Component Generalized Modules for Membrane Antigens Shigella Vaccine in Healthy European Adults: Randomized, Phase 1/2 Study

Isabel Leroux-Roels et al. J Infect Dis. .

Erratum in

Abstract

Background: We report data from stage 1 of an ongoing 2-staged, phase 1/2 randomized clinical trial with a 4-component generalized modules for membrane antigens-based vaccine against Shigella sonnei and Shigella flexneri 1b, 2a, and 3a (altSonflex1-2-3; GSK).

Methods: Europeans aged 18-50 years (N = 102) were randomized (2:1) to receive 2 injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at prespecified time points.

Results: The most common solicited administration-site event (until 7 days after each injection) and unsolicited adverse event (until 28 days after each injection) were pain (altSonflex1-2-3, 97.1%; placebo, 58.8%) and headache (32.4%; 23.5%), respectively. All serotype-specific functional IgG antibodies peaked 14-28 days after injection 1 and remained substantially higher than prevaccination at 3 or 6 months postvaccination; the second injection did not boost but restored the initial immune response. The highest seroresponse rates (≥4-fold increase in titers over baseline) were obtained against S. flexneri 2a (enzyme-linked immunosorbent assay [ELISA] after injection 1, 91.0%; after injection 2 [day 113; day 197], 100%; 97.0% and serum bactericidal activity [SBA] after injection 1, 94.4%; after injection 2, 85.7%; 88.9%) followed by S. sonnei (ELISA after injection 1, 77.6%; after injection 2, 84.6%; 78.8% and SBA after injection 1, 83.3%; after injection 2, 71.4%; 88.9%). Immune responses against S. flexneri 1b and S. flexneri 3a, as measured by both ELISA and SBA, were numerically lower compared to those against S. sonnei and S. flexneri 2a.

Conclusions: No safety signals or concerns were identified. altSonflex1-2-3 induced functional serotype-specific immune responses, allowing further clinical development in the target population. Clinical Trials Registration . NCT05073003.

Keywords: Shigella vaccine; O-antigen; altSonflex1-2-3; immunogenicity; safety.

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Conflict of interest statement

Potential conflicts of interest. U. N. N., F. Ma., E. S., J. J., G. L. C., A. S. B., C. G. V., P. F., E. M., F. N., R. R., I. D. R., J. A., A. M. C., F. B. S., O. R., V. C., F. Mi., A. K. A., and A. P. are or were employees of GSK when the study was designed, initiated, and/or conducted. U. N. N., J. J., G. L. C., A. S. B., C. G. V., F. N., I. D. R., J. A., F. B. S., O. R., V. C., F. Mi., A. K. A., and A. P. hold shares in GSK as part of their remuneration. A. K. A. reports GSK scientific writer support for this study. F. Mi. reports a patent issued on the 4-component Shigella GMMA formulation. I. L. R. reports funding to her institution for the conduct of GSK Vaccines Institute for Global Health (GVGH) studies; being a data safety monitoring board member of a phase 3 (non-Shigella) vaccine trial for Janssen Vaccines; and funding to her institution for the conduct of various vaccine trials (none were Shigella vaccine studies) from GSK, Janssen, Curevac, Osivax, Vaccitech, Icosavax, OSE Immunotherapeutics, Icon Genetics, Virometix, and MSD. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Percentage of participants with (A) solicited AEs and (B) unsolicited AEs. Abbreviations: AE, adverse event; altSonflex, participants randomized to receive altSonflex1-2-3 vaccine at 3- or 6-month interval (n = 68, pooled data); CI, confidence interval; placebo, participants randomized to receive placebo (n = 34).
Figure 2.
Figure 2.
Reverse cumulative distribution curves of (A and B) anti-Shigella sonnei LPS serum IgG as measured by ELISA: (A) altSonflex3M group up to 1 month after injection 2; (B) altSonflex6M group up to 1 month after injection 2; and (C and D) bactericidal antibody activity as measured by SBA in a subset of participants: (C) altSonflex3M group up to 1 month after injection 2; (D) altSonflex6M group up to 1 month after injection 2. Left vertical line shows 1:800 titers in TAU assay, which correspond to 124 EU/mL in the ELISA. Right vertical line shows 1:1600 titers in TAU assay, which correspond to 315 EU/mL in ELISA; see Supplementary Material 6 for further details. Abbreviations: altSonflex3M, participants randomized to receive altSonflex1-2-3 vaccine at 3-month interval; altSonflex6M, participants randomized to receive altSonflex1-2-3 vaccine at 6-month interval; ELISA, enzyme-linked immunosorbent assay; EU, ELISA unit; IC50, half maximum inhibitory concentration; IgG, immunoglobulin G; LPS, lipopolysaccharide; n, number of participants with available data at a given time point; SBA, serum bactericidal assay; TAU, Tel Aviv University.
Figure 3.
Figure 3.
Reverse cumulative distribution curves of (A and B) anti-Shigella flexneri 2a O-antigen serum IgG as measured by ELISA: (A) altSonflex3M group up to 1 month after injection 2; (B) altSonflex6M group up to 1 month after injection 2; and (C and D) bactericidal antibody activity as measured by SBA in a subset of participants: (C) altSonflex3M group up to 1 month after injection 2; (D) altSonflex6M group up to 1 month after injection 2. Abbreviations: altSonflex3M, participants randomized to receive altSonflex1-2-3 vaccine at 3-month interval; altSonflex6M, participants randomized to receive altSonflex1-2-3 vaccine at 6-month interval; ELISA, enzyme-linked immunosorbent assay; EU, ELISA unit; IgG, immunoglobulin G; n, number of participants with available data at a given time point; SBA, serum bactericidal assay.
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