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

BACKGROUND: Protection induced by acellular pertussis (aP) vaccines is partial and short-lived, especially in teenagers, calling for novel immunization strategies. METHODS: We conducted an investigator-driven proof-of-concept randomized controlled trial in aP-primed adolescents in Geneva to assess the immunogenicity and reactogenicity of a novel recombinant aP (r-aP) vaccine including recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) coadministered with tetanus-diphtheria toxoids (Td), compared to a licensed tetanus-diphtheria-aP vaccine containing chemically detoxified PT (cd/Tdap). The primary immunological endpoints were day 28/365 geometric mean concentrations (GMCs) of total and neutralizing anti-PT antibodies. Memory B cells were assessed. RESULTS: Sixty-two aP-primed adolescents were randomized and vaccinated with r-aP + Td or cd/Tdap. Reactogenicity, adverse events, and baseline GMCs were similar between the groups. Day 28 PT-neutralizing GMCs were low after cd/Tdap (73.91 [95% confidence interval {CI}, 49.88-109.52] IU/mL) and approximately 2-fold higher after r-aP + Td (127.68 [95% CI, 96.73-168.53] IU/mL; P = .0162). Anti-PT GMCs were also low after cd/Tdap (52.43 [95% CI, 36.41-75.50] IU/mL) and 2-fold higher after r-aP + Td (113.74 [95% CI, 88.31-146.50] IU/mL; P = .0006). Day 28 anti-FHA GMCs were similar in both groups. Day 365 anti-PT (but not PT-neutralizing) GMCs remained higher in r-aP + Td vaccinees. PT-specific memory B cells increased significantly after r-aP + Td but not cd/Tdap boosting. CONCLUSIONS: Boosting aP-primed adolescents with r-aP induced higher anti-PT and PT-neutralizing responses than cd/Tdap and increased PT-specific memory B cells. Despite this superior immunogenicity, r-aP may have to be given repeatedly, earlier, and/or with novel adjuvants to exert an optimal influence in aP-primed subjects. CLINICAL TRIALS REGISTRATION: NCT02946190.

Transplacental transfer of maternal antibodies following immunization with recombinant pertussis vaccines during pregnancy: Real-world evidence.

AIM/OBJECTIVE: This study investigates placental antibody transfer following recombinant pertussis vaccination in pregnancy in a real-world setting. METHODS: This postmarketing observational study recruited pregnant women vaccinated with monovalent recombinant acellular pertussis (aP) vaccine (aPgen; n = 199) or combined to tetanus-diphtheria (TdaPgen; n = 200), or Td-vaccine only (n = 54). Pregnancy, delivery, and neonatal outcomes were assessed. Cord blood was collected postdelivery and pertussis toxin (PT)-IgG, filamentous hemagglutinin (FHA)-IgG, and PT-neutralizing antibodies (PT-Nab) were assessed. RESULTS: No adverse pregnancy, delivery, or neonatal outcomes attributed to aPgen, TdaPgen, or Td vaccination were reported. High anti-PT antibody levels were detected in cord samples from women vaccinated with aPgen (geometric mean concentration [GMC] PT-IgG 206.1 IU/ml, 95% confidence intervals [CI]: 164.3-258.6; geometric mean titer [GMT] PT-Nab 105.3 IU/ml, 95% CI: 81.7-135.8) or TdaPgen (GMC PT-IgG 153.1 IU/ml, 95% CI: 129.1-181.5; GMT PT-Nab 81.5 IU/ml, 95% CI: 66.4-100.0). In the Td-only group, anti-PT antibodies were low (GMC PT-IgG 6.5 IU/ml, 95% CI: 4.9-8.8; GMT PT-Nab 3.8 IU/ml, 95% CI: 2.8-5.1). The same was found for FHA-IgG. Recombinant pertussis vaccination at <27 or 27-36 weeks gestation induced similar cord pertussis antibody levels. CONCLUSION: This first real-world study confirms that recombinant pertussis vaccination in the second or third trimester of pregnancy results in high levels of passive immunity in infants. Thai Clinical Trial Registry: TCTR20200528006.

Antibody persistence 2 and 3 years after booster vaccination of adolescents with recombinant acellular pertussis monovalent aPgen or combined TdaPgen vaccines.

BACKGROUND: Recombinant pertussis vaccines inducing long-lasting immune responses could help to control the rise in pertussis. We here report on persisting antibody responses 2 and 3 years after booster vaccination with a new generation recombinant acellular pertussis vaccine. METHODS: Participants of a phase 2/3 randomised-controlled clinical trial with a monovalent pertussis vaccine containing genetically inactivated pertussis toxin (aPgen) or its tetanus and diphtheria toxoids combination (TdaPgen), or a chemically detoxified comparator vaccine (Tdapchem), (originally conducted between July and August 2015) were invited to participate in observational studies of persisting antibody responses 2 and 3 years after vaccination. Serum IgG against pertussis toxin (PT-IgG) and filamentous hemagglutinin (FHA-IgG) were assessed by ELISA, and PT-neutralising antibodies (PT-Nab) by Chinese Hamster Ovary cell assay. FINDINGS: Waning of antibodies stabilised in aPgen and TdaPgen vaccinees 2 and 3 years after vaccination. Three years post-vaccination PT-neutralising antibodies remained 4·6-fold (95% Confidence Interval (CI) 2·6-8·1) and 3·7-fold (95% CI 2·2-6·1) higher, PT-IgG antibodies 3·0-fold (95% CI 2·2-4·1) and 2·5-fold (95% CI 1·9-3·3) higher, and FHA-IgG antibodies 1·8-fold (95% CI 1·3-2·5) and 1·6-fold (95% CI 1·2-2·1) higher than baseline in aPgen and TdaPgen recipients, respectively. In the Tdapchem group, PT-neutralising and PT-IgG and FHA-IgG antibodies were back at baseline levels 2 years post-vaccination. Three years post-vaccination seroconversion rates for PT-neutralising antibodies were 65·0% (95% CI 44·1-85·9) and 55·0% (95% CI 33·2-76·8) in aPgen and TdaPgen recipients, respectively. INTERPRETATION: Considering the persistence of elevated antibody responses 3 years post-booster vaccination, genetically detoxified monovalent aPgen and TdaPgen vaccines can be expected to induce longer-lasting protection than chemically inactivated Tdap vaccines. FUNDING: BioNet-Asia.

A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial.

BACKGROUND: Increasing evidence shows that protection induced by acellular pertussis vaccines is short-lived, requiring repeated booster vaccination to control pertussis disease. We aimed to assess the safety and immunogenicity of a recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin and filamentous haemagglutinin, as either a monovalent vaccine (aP[PTgen/FHA]) or in combination with tetanus and reduced-dose diphtheria vaccines (TdaP[PTgen/FHA]), versus a licensed tetanus and reduced-dose diphtheria and acellular pertussis combination vaccine (Tdap). METHODS: We did this phase 2/3, randomised controlled non-inferiority trial at two sites in Bangkok, Thailand. Healthy adolescents (aged 12-17 years) were randomly assigned (1:1:1), via a computer-generated randomisation list with block sizes of three, to receive one dose (0·5 mL) of aP(PTgen/FHA), TdaP(PTgen/FHA), or Tdap (comparator). Clinical research staff responsible for participant randomisation, vaccine preparation and administration, and accountability were aware of group allocation. However, allocation was concealed from all other site study staff, data management personnel, statisticians, laboratory staff, and study participants. The primary outcome was non-inferior immunogenicity of TdaP(PTgen/FHA) to Tdap based on seroconversion rates (a four-fold increase or more) for pertussis toxin and filamentous haemagglutinin IgG antibodies 28 days after vaccination, with a predefined 10% margin of equivalence. We did analysis by per protocol. This study is registered with the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between July 6 and Aug 20, 2015, we allocated 450 participants to receive one dose of TdaP(PTgen/FHA) (n=150), aP(PTgen/FHA) (n=150), or comparator Tdap (n=150). 28 days after vaccination, seroconversion rates for anti-pertussis toxin IgG were 96·6% (95% CI 93·8-99·5; n=144) in the TdaP(PTgen/FHA) group and 55·0% (47·1-63·0; n=82) in the comparator Tdap group (difference 41·6%, 95% CI 33·1-50·1; p<0·0001). Seroconversion rates for anti-filamentous haemagglutinin were 82·6% (95% CI 76·5-88·6; n=123) in the TdaP(PTgen/FHA) group and 54·4% (46·4-62·4; n=81) in the comparator group (difference 28·2%, 95% CI 18·1-38·2 p<0·0001). 28 days after vaccination, seroconversion rates in the aP(PTgen/FHA) group were 96·0% (95% CI 92·8-99·1; n=142) for anti-pertussis toxin IgG and 93·2% (89·2-97·3; n=138) for anti-filamentous haemagglutinin IgG. These findings support the non-inferior immunogenicity of TdaP(PTgen/FHA) over comparator Tdap. Reactogenicity and incidence of adverse events were similar between groups. INTERPRETATION: The new TdaP(PTgen/FHA) vaccine is safe and induces higher pertussis responses 28 days after vaccination than does the available licensed Tdap booster vaccine. Results of our trial led to the licensure of new acellular pertussis vaccines containing genetically inactivated pertussis toxin in Thailand. The availability of recombinant monovalent pertussis vaccines that induce high antibody responses provides the medical community and consumers with the opportunity to vaccinate against pertussis when immunisation against diphtheria and tetanus is not required or not desired. Studies are underway to pave the way for licensure studies of this acellular pertussis vaccine in other countries. FUNDING: BioNet-Asia.

Antibody persistence after vaccination of adolescents with monovalent and combined acellular pertussis vaccines containing genetically inactivated pertussis toxin: a phase 2/3 randomised, controlled, non-inferiority trial.

BACKGROUND: The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. METHODS: We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12-17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64-88) participants in the aP(PTgen/FHA) group and 41 (81%, 70-92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1-16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71-93 and 64%, 51-77, respectively) and TdaP(PTgen/FHA) group (75%, 63-87 and 56%, 42-70, respectively) than in the Tdap group (4%, 0-9, p<0·0001, and 28%, 16-41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. INTERPRETATION: A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. FUNDING: BioNet-Asia.