A reduced-dose recombinant pertussis vaccine booster in Thai adolescents: a phase 2/3, observer-blinded, randomised controlled, non-inferiority trial.

Abstract

A resurgence of pertussis has increased the demand for low-cost vaccines. The aim of this study was to test the immunogenicity of a booster acellular monovalent pertussis vaccine containing reduced-dose (2 μg) recombinant pertussis toxin (PT) and 5 μg filamentous haemagglutinin (FHA; ap_gen) against a version of ap_gen containing tetanus and reduced-dose diphtheria toxoids (Tdap_gen) and a licensed vaccine containing chemically detoxified PT and FHA combined with tetanus toxoid and reduced-dose diphtheria toxoid (Tdap_chem). This phase 2/3, observer-blinded, randomised, controlled, non-inferiority trial was done in adolescents aged 9-17 years at two clinical research centres in Bangkok and Pathum Thani, Thailand. Eligible participants were screened and randomly assigned (1:1:1) to receive one booster dose of ap_gen, Tdap_gen, or Tdap_chem vaccine. Participants were followed up until day 336 post-immunisation. The primary endpoint was non-inferior seroconversion rates in Tdap_gen and Tdap_chem vaccine groups, with seroconversion rate defined as the proportion of participants with at least a four-fold increase on day 28 post-immunisation relative to baseline of anti-PT and anti-FHA IgG. The non-inferiority for seroconversion rates of anti-PT and anti-FHA IgG was defined as the lower bound of the two-sided 95% CI of the seroconversion rate for Tdap_gen compared with Tdap_chem exceeding -10%. Immunogenicity was analysed in the per-protocol population. All safety data were collected, and the prevalence of adverse events was analysed in the intention-to-treat population. This trial was registered on the Thai Clinical Trial Registry (TCTR20181031001). Between June 18, and Aug 3, 2019, 450 adolescents (mean age 12·1 years, SD 2·5) were enrolled and randomly assigned (150 participants in each group). Day 28 anti-PT IgG seroconversion rates were 141 (94%) of 150 participants who received Tdap_gen (95% CI 88·8-97·0) and 105 (71%) of 149 participants who received Tdap_chem (62·7-77·2; p<0·0001). Day 28 anti-FHA IgG seroconversion rates were 144 (96%) of 150 participants who received Tdap_gen (91·4-98·3) and 124 (83%) of 149 participants who received Tdap_chem (76·4-88·4; p<0·0001). The difference in seroconversion rates was 23·5% (95% CI 15·3-31·8) for anti-PT IgG and 12·8% (6·0-19·6) for anti-FHA IgG, when comparing the Tdap_gen versus the Tdap_chem vaccine group. No vaccine-related serious adverse events were reported. Recombinant Tdap_gen vaccine showed non-inferior immunogenicity compared with Tdap_chem at day 28 in terms of seroconversion rate of anti-PT IgG and anti-FHA IgG relative to baseline. The reduced-dose approach for Tdap_gen vaccines thus presents as a potentially cost-saving booster strategy to protect adolescents against pertussis. Office of National Higher Education Science Research and Innovation Policy Council (Programme Management Unit Competitiveness), Thailand, and BioNet-Asia.