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

Abstract

Background: 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).

Methods: 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).

Findings: 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.

Interpretation: 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.

Funding: Office of National Higher Education Science Research and Innovation Policy Council (Programme Management Unit Competitiveness), Thailand, and BioNet-Asia.