Safety and immunogenicity of a combined Tetanus, Diphtheria, recombinant acellular Pertussis vaccine (TdaP) in healthy Thai adults

Abstract

Background: An acellular Pertussis (aP) vaccine containing recombinant genetically detoxified Pertussis Toxin (PTgen), Filamentous Hemagglutinin (FHA) and Pertactin (PRN) has been developed by BioNet-Asia (BioNet). We present here the results of the first clinical study of this recombinant aP vaccine formulated alone or in combination with tetanus and diphtheria toxoids (TdaP). Methods: A phase I/II, observer-blind, randomized controlled trial was conducted at Mahidol University in Bangkok, Thailand in healthy adult volunteers aged 18–35 y. The eligible volunteers were randomized to receive one dose of either BioNet's aP or Tetanus toxoid-reduced Diphtheria toxoid-acellular Pertussis (TdaP) vaccine, or the Tdap Adacel® vaccine in a 1:1:1 ratio. Safety follow-up was performed for one month. Immunogenicity was assessed at baseline, at 7 and 28 d after vaccination. Anti-PT, anti-FHA, anti-PRN, anti-tetanus and anti-diphtheria IgG antibodies were assessed by ELISA. Anti-PT neutralizing antibodies were assessed also by CHO cell assay. Results: A total of 60 subjects (20 per each vaccine group) were enrolled and included in the safety analysis. Safety laboratory parameters, incidence of local and systemic post-immunization reactions during 7 d after vaccination and incidence of adverse events during one month after vaccination were similar in the 3 vaccine groups. One month after vaccination, seroresponse rates of anti-PT, anti-FHA and anti-PRN IgG antibodies exceeded 78% in all vaccine groups. The anti-PT IgG, anti-FHA IgG, and anti-PT neutralizing antibody geometric mean titers (GMTs) were significantly higher following immunization with BioNet's aP and BioNet's TdaP than Adacel® (P< 0.05). The anti-PRN IgG, anti-tetanus and anti-diphtheria GMTs at one month after immunization were comparable in all vaccine groups. All subjects had seroprotective titers of anti-tetanus and anti-diphtheria antibodies at baseline. Conclusion: In this first clinical study, PTgen-based BioNet's aP and TdaP vaccines showed a similar tolerability and safety profile to Adacel® and elicited significantly higher immune responses to PT and FHA.

Genetically detoxified pertussis toxin displays near identical structure to its wild-type and exhibits robust immunogenicity

“…It should be noted that gdPT-containing vaccines are progressing or have progressed through clinical evaluation to licensure in combination with other pertussis antigens 15,22,23,38,39 . While these clinical studies have all demonstrated improved quality of the humoral response, relative to the chemically detoxified antigen, few have addressed the importance of the cellular response in detail.…”

“…Significant progress has been made to better understand the immunological properties of gdPT 17,20,21 . Furthermore, two recent clinical trials that included gdPT in an aP vaccine revealed significant improvements in the antibody titers and duration of the responses 22,23 . Nevertheless, the impact of the double mutation on the overall structure, as well as the molecular basis for the lack of toxicity, is not completely understood.…”

Boosting Teenagers With Acellular Pertussis Vaccines Containing Recombinant or Chemically Inactivated Pertussis Toxin: A Randomized Clinical Trial

“…A Phase I/II randomized controlled trial (RCT) including wP-primed Thai adults indicated similar safety but significantly higher PT seroresponses to the BNA rPT-containing recombinant aP vaccine (r-aP) than to the cdPT-containing Tdap (cd/Tdap) comparator [27]. This was subsequently confirmed in 450 wP-primed Thai adolescents [28].…”

“…The primary immunological endpoint was the PT-neutralizing GMCs. Secondary endpoints Anti-PT and anti-FHA IgG antibody concentrations were measured by standardized enzyme linked immunosorbent assays (ELISA) at the Center for Vaccinology (Geneva) using plates coated with BNA's purified rPT or FHA as described [27]. Responses to BNA rPT strongly correlate (R 2 =0.9837, not shown) to those assessed with native PT (nPT), as recommended for use in PT-specific assays [28,29,31,32].…”

“…The limit of detection was defined at 1 IU/ml. Anti-TT and anti-DT IgG concentrations were determined in the same laboratory using SERION ELISA classic (Virion/Serion, Germany) [27] with a 0.05 IU/ml cut-off. Seropositivity was defined as >0.1 IU/ml.…”