A phase I, randomized, controlled, dose-ranging study of investigational acellular pertussis (aP) and reduced tetanus-diphtheria-acellular pertussis (TdaP) booster vaccines in adults

Geert Leroux-Roels, Maria Lattanzi, Claudia Dovali Solis, Mario Contorni, Marco Costantini, Luca Moraschini, Monia Bardelli, Sylvie Bertholet, Erica Borgogni, Francesca Buricchi, Rocco Cantisani, Elisa Faenzi, Oretta Finco, Rosanna Leuzzi, Mariagrazia Pizza, Domenico Rosa, Francesca Schiavetti, Anja Seubert, Fabiana Spensieri, Gianfranco Volpini, Luisanna Zedda, Giuseppe Del Giudice, Ilaria Galgani, Geert Leroux-Roels, Maria Lattanzi, Claudia Dovali Solis, Mario Contorni, Marco Costantini, Luca Moraschini, Monia Bardelli, Sylvie Bertholet, Erica Borgogni, Francesca Buricchi, Rocco Cantisani, Elisa Faenzi, Oretta Finco, Rosanna Leuzzi, Mariagrazia Pizza, Domenico Rosa, Francesca Schiavetti, Anja Seubert, Fabiana Spensieri, Gianfranco Volpini, Luisanna Zedda, Giuseppe Del Giudice, Ilaria Galgani

Abstract

Despite high vaccination coverage worldwide, pertussis has re-emerged in many countries. This randomized, controlled, observer-blind phase I study and extension study in Belgium (March 2012-June 2015) assessed safety and immunogenicity of investigational acellular pertussis vaccines containing genetically detoxified pertussis toxin (PT) (NCT01529645; NCT02382913). 420 healthy adults (average age: 26.8 ± 5.5 years, 60% female) were randomized to 1 of 10 vaccine groups: 3 investigational aP vaccines (containing pertussis antigens PT, filamentous hemagglutinin [FHA] and pertactin [PRN] at different dosages), 6 investigational TdaP (additionally containing tetanus toxoid [TT] and diphtheria toxoid [DT]), and 1 TdaP comparator containing chemically inactivated PT. Antibody responses were evaluated on days 1, 8, 30, 180, 365, and approximately 3 years post-booster vaccination. Cell-mediated immune responses and PT neutralization were evaluated in a subset of participants in pre-selected groups. Local and systemic adverse events (AEs), and unsolicited AEs were collected through day 7 and 30, respectively; serious AEs and AEs leading to study withdrawal were collected through day 365 post-vaccination. Antibody responses against pertussis antigens peaked at day 30 post-vaccination and then declined but remained above baseline level at approximately 3 years post-vaccination. Responses to FHA and PRN were correlated to antigen dose. Antibody responses specific to PT, toxin neutralization activity and persistence induced by investigational formulations were similar or significantly higher than the licensed vaccine, despite lower PT doses. Of 15 serious AEs, none were considered vaccination-related; 1 led to study withdrawal (premature labor, day 364; aP4 group). This study confirmed the potential benefits of genetically detoxified PT antigen. All investigational study formulations were well tolerated.

Keywords: adults; genetically detoxified PT; immunogenicity; persistence; pertussis; safety.

Figures

Figure 1.
Figure 1.
Flowchart main study and extension study. Footnote: FU, follow-up; N, number of participants in each group; SAE, serious adverse event.
Figure 2.
Figure 2.
Geometric mean concentrations and 95% confidence intervals against pertussis antigens PT, FHA and PRN in investigational aP and TdaP booster groups and licensed comparator group from day 1 through year 3 post-vaccination. Footnote: aP, acellular pertussis; CI, confidence interval; FHA, filamentous hemagglutinin; GMC, geometric mean concentration; IU/mL, International Units per milliliter; PRN, pertactin; PT, pertussis toxin; TdaP, tetanus diphtheria acellular pertussis.
Figure 3.
Figure 3.
Geometric mean concentrations and 95% confidence intervals against tetanus and diphtheria antigens in investigational TdaP booster groups and licensed comparator group from day 1 up through day 365 post-vaccination. Footnote: CI, confidence interval; DT, diphtheria toxoid; GMC, geometric mean concentration; IU/mL, International Units per milliliter; n, maximum number of participants with available results, TT, tetanus toxoid; TdaP, tetanus diphtheria acellular pertussis.
Figure 4.
Figure 4.
Geometric mean anti-pertussis neutralizing titers and 95% confidence intervals from day 1 through year 3 post-vaccination. Footnote: PT, pertussis toxin.
Figure 5.
Figure 5.
Median percentages of Memory B Cells (ELISpot) against pertussis antigens PT, FHA and PRN in high and low dose aP dose TdaP groups and licensed comparator from day 1 through day 365 post-vaccination. Footnote: aP, acellular pertussis; ELISpot, enzyme-linked immunospot assay; FHA, filamentous hemagglutinin; IgG, immunoglobulin G; IgM, immunoglobulin M; n, number of participants with available results; PRN, pertactin; PT, pertussis toxin; TdaP, tetanus diphtheria acellular pertussis.
Figure 6.
Figure 6.
Median percentages of antigen-specific CD4+ T cells in high and low aP dose groups and licensed comparator at baseline and days 8 and 30 post-vaccination. Footnote: CTK, cytokine; DT, diphtheria toxoid; FHA, filamentous hemagglutinin; n, maximum number of participants with available results; PRN, pertactin; PT, pertussis toxin; TdaP, tetanus, diphtheria, acellular pertussis; TT, tetanus toxoid.
Figure 7.
Figure 7.
Focus on Patient Section.

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