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Clinical Trial
. 2025 Mar 17;231(3):e511-e520.
doi: 10.1093/infdis/jiae466.

Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study

Isabel Leroux-Roels  1 , Azhar Alhatemi  1 , Magalie Caubet  2 , Fien De Boever  1 , Bertrand de Wergifosse  2 , Mohamed El Idrissi  2 , Guilherme S Ferreira  3 , Bart Jacobs  1 , Axel Lambert  4 , Sandra Morel  2 , Charlotte Servais  2 , Juan Pablo Yarzabal  4
Affiliations
Clinical Trial

Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study

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

Abstract

Background: This study investigated the safety, reactogenicity, and immunogenicity in healthy subjects of a Clostridioides difficile vaccine candidate with/without adjuvant, targeting toxins A and B.

Methods: In this first-in-human, phase 1, observer-blind study, subjects aged 18-45 years were randomized to receive F2 antigen (n = 10) or placebo (n = 10), and subjects aged 50-70 years to receive F2 antigen plus AS01 adjuvant (n = 45), F2 antigen (n = 45), or placebo (n = 30) in 2 doses 1 month apart. A subcohort (n = 40) received a third dose 15 months later. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days after each dose. Immunogenicity was assessed at baseline and after each dose.

Results: Solicited AEs were transient and most frequent in subjects receiving F2 antigen plus AS01. No serious AEs were considered related to study vaccine. Immunogenicity was substantially higher in subjects receiving F2 antigen plus AS01 than subjects receiving F2 antigen alone. A third dose increased the immune response in subjects with baseline neutralization titers below the assay lower limit of quantitation.

Conclusions: The GSK C. difficile vaccine candidate was immunogenic, especially when given with AS01, and was well tolerated with an acceptable safety profile.

Clinical trial registration: NCT04026009.

Keywords: Clostridioides difficile; adjuvant; immunogenicity; safety; vaccine candidate.

Plain language summary

Bacterial infection with Clostridioides difficile can be severe or life threatening. A vaccine candidate to prevent C. difficile infection is being developed, containing a protein (F2 antigen) that stimulates the immune system to neutralize 2 C. difficile toxins. This is the first study investigating this vaccine candidate in people. Healthy people aged 18–45 years were given 2 doses of placebo or F2 antigen. People aged 50–70 years were given 2 doses of placebo, F2 antigen, or F2 antigen with an additional component (adjuvant) that helps stimulate the immune response. Some also received a third dose of F2 antigen or F2 antigen with adjuvant. The vaccine candidate was well tolerated with an acceptable safety profile. Injection site pain, tiredness, and headache were the most common side effects. The effects were mostly mild to moderate and transient, and were more frequently reported in the adjuvanted group, as expected. No serious safety events were considered related to the vaccine candidate. The vaccine candidate induced neutralization activity against both toxins, especially when given with adjuvant. In people with no measurable neutralization activity at the study start, a third dose increased the response. These findings offer potentially valuable insights for C. difficile vaccine development.

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Conflict of interest statement

Potential conflicts of interest. M. C., B. d. W., G. S. F., A. L., S. M., C. S., and J. P. Y. are employees of GSK. M. E. I. was an employee of GSK at the time of the study. B. d. W., M. E. I., S. M., C. S., G. S. F., and J. P. Y. hold financial equities in GSK. B. d. W. also holds shares in Haleon. G. S. F. was an employee of Janssen Biologics, 3D-PharmXchange Consultancy, and Access to Medicine Foundation over the past 36 months. I. L.-R. reports funding from GSK to her institution for the conduct of this study; and funding to her institution for the conduct of various vaccine trials (non-C. difficile vaccine studies) from Janssen, MSD, Moderna, Curevac, Osivax, Vaccitech, Icosavax, OSE Immunotherapeutics, Icon Genetics, and Virometix. 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

Figure 1.
Figure 1.
Study design. aVisit 1 (day 1) was to be scheduled as soon as the results from hematology and biochemistry analysis were available. bA subcohort of subjects who successfully completed all visits up to visit 7, received 2 doses on an active arm (ie, the subjects who received placebo were not to be considered for dose 3), did not meet any contraindication for subsequent vaccination, and still met the eligibility criteria received an additional dose, that is, dose 3. Abbreviations: AS01, liposome-based vaccine adjuvant system containing 2 immunostimulants: 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21; D, day; iSRC, internal safety review committee; PBMC, peripheral blood mononuclear cell; V, visit.
Figure 2.
Figure 2.
Subject disposition. Abbreviations: AE, adverse event; AS01, liposome-based vaccine adjuvant system containing 2 immunostimulants: 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21; ICF, informed consent form; n, number of subjects meeting criteria of status.
Figure 3.
Figure 3.
A, Geometric mean titer of anti-TcdA neutralization activity for subjects aged 50–70 years who received F2 antigen with or without AS01, and subjects aged 18–45 years who received F2 antigen (per-protocol set). B, Geometric mean titer of anti-TcdB neutralization activity for subjects aged 50–70 years who received F2 antigen with or without AS01, and subjects aged 18–45 years who received F2 antigen (per-protocol set). Abbreviations: AS01, liposome-based vaccine adjuvant system containing 2 immunostimulants: 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21; CI, confidence interval; dil, dilution; GMT, geometric mean titer; LLOQ, lower limit of quantitation; n, number of subjects with available results; TcdA, C. difficile toxin A; TcdB, C. difficile toxin B; V, visit.
Figure 4.
Figure 4.
A, Geometric mean titer of anti-TcdA neutralization activity for subjects aged 50–70 years who received 3 doses of F2 antigen with or without AS01, (subcohort exposed set), by baseline neutralization titer. B, Geometric mean titer of anti-TcdB neutralization activity for subjects aged 50–70 years who received 3 doses of F2 antigen with or without AS01, (subcohort exposed set), by baseline neutralization titer. Abbreviations: AS01, liposome-based vaccine adjuvant system containing 2 immunostimulants: 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21; CI, confidence interval; dil, dilution; GMT, geometric mean titer; LLOQ, lower limit of quantitation; n, number of subjects with available results; TcdA, C. difficile toxin A; TcdB, C. difficile toxin B; V, visit.
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