Angela Huttner1, Christoph Hatz2, Germie van den Dobbelsteen3, Darren Abbanat4, Alena Hornacek5, Rahel Frölich5, Anita M Dreyer5, Patricia Martin5, Todd Davies4, Kellen Fae3, Ingrid van den Nieuwenhof3, Stefan Thoelen3, Serge de Vallière6, Anette Kuhn7, Enos Bernasconi8, Volker Viereck9, Tilemachos Kavvadias10, Kerstin Kling11, Gloria Ryu12, Tanja Hülder13, Sabine Gröger14, David Scheiner15, Cristina Alaimo5, Stephan Harbarth16, Jan Poolman3, Veronica Gambillara Fonck5. 1. Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. Electronic address: angela.huttner@hcuge.ch. 2. Epidemiology, Biostatistics and Prevention Institute, Zurich University, Zurich, Switzerland; Swiss Tropical and Public Health Institute, Basel University, Basel, Switzerland. 3. Bacterial Vaccines Discovery & Early Development, Janssen Vaccines and Prevention, Leiden, Netherlands. 4. Janssen Research and Development, Raritan, NJ, USA. 5. LimmaTech Biologics, Schlieren, Switzerland. 6. Policlinique Médicale Universitaire and Service of Infectious Diseases, University Hospital Lausanne, Lausanne, Switzerland. 7. Universitätsklinik für Frauenheilkunde, University Hospital Bern, Bern, Switzerland. 8. Ospedale Regionale di Lugano, Lugano, Switzerland. 9. Blasen-und Beckenbodenzentrum, Kantonsspital Frauenfeld, Frauenfeld, Switzerland. 10. Frauenklinik, University Hospital Basel, Basel, Switzerland. 11. Swiss Tropical and Public Health Institute, Basel University, Basel, Switzerland. 12. Frauenklinik, Kantonsspital Aarau, Aarau, Switzerland. 13. Frauenklinik, Kantonsspital St Gallen, St Gallen, Switzerland. 14. Neue Frauenklinik, Luzerner Kantonsspital, Lucerne, Switzerland. 15. Department of Gynecology, University Hospital Zurich, Zurich, Switzerland. 16. Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Abstract
BACKGROUND: Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V). METHODS: In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794. FINDINGS:Between Jan 20, 2014, and Aug 27, 2014, 93 women receivedtarget-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002). INTERPRETATION: This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings. FUNDING: GlycoVaxyn, Janssen Vaccines.
RCT Entities:
BACKGROUND:Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V). METHODS: In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794. FINDINGS: Between Jan 20, 2014, and Aug 27, 2014, 93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002). INTERPRETATION: This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings. FUNDING: GlycoVaxyn, Janssen Vaccines.
Authors: Darren Abbanat; Todd A Davies; Karen Amsler; Wenping He; Kellen Fae; Sarah Janssen; Jan T Poolman; Germie P J M van den Dobbelsteen Journal: Clin Vaccine Immunol Date: 2017-12-05
Authors: Bernadette Jones-Freeman; Michelle Chonwerawong; Vanessa R Marcelino; Aniruddh V Deshpande; Samuel C Forster; Malcolm R Starkey Journal: Mucosal Immunol Date: 2021-02-04 Impact factor: 7.313
Authors: Marko Anderluh; Francesco Berti; Anna Bzducha-Wróbel; Fabrizio Chiodo; Cinzia Colombo; Federica Compostella; Katarzyna Durlik; Xhenti Ferhati; Rikard Holmdahl; Dragana Jovanovic; Wieslaw Kaca; Luigi Lay; Milena Marinovic-Cincovic; Marco Marradi; Musa Ozil; Laura Polito; Josè Juan Reina; Celso A Reis; Robert Sackstein; Alba Silipo; Urban Švajger; Ondřej Vaněk; Fumiichiro Yamamoto; Barbara Richichi; Sandra J van Vliet Journal: FEBS J Date: 2021-06-01 Impact factor: 5.622