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

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.

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

“…The increased expansion of activated memory T cells and the appearance of memory-like NK cell populations in gdPT-stimulated cultures suggests that the immunogenicity effect associated with native PTx is maintained, supporting the overall superiority of the gdPT antigen compared to PTd. The results from this assay are consistent with clinical observations of a relatively lower potency elicited with chemically detoxified PTx antigen and provides additional insight into how gdPT can induce a more robust immune response 15 , 22 , 23 .…”

“…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.…”

Pediatric Vaccine Hesitancy and the Utilization of Antibody Measurements: A Novel Strategy with Implications for COVID 19

“…It may be stressed to the parent that their child is or is not protected against preventable disease with reference to personal laboratory results. 3 , 4 …”

“…2 This pattern of disease outbreaks and low immunization rates also applies to other preventable diseases. 3,4 In another study, infants not vaccinated against hepatitis B at birth had lower vaccination rates later in life to childhood vaccines. 5 This study emphasizes early discussion and resolution of parental concerns.…”