Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: a randomised, double-blind, non-inferiority trial

Background In most high-income countries, infant vaccination with acellular pertussis (aP) vaccines is the standard of care for the prevention of pertussis disease. Based on immunological and epidemiological evidence, we hypothesised that substitution of the first aP dose in the vaccination schedule with whole-cell (wP) vaccine might protect against the development of IgE-mediated food allergy. Here we report the results of a randomised comparison of the reactogenicity, immunogenicity, and IgE-mediated immune responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. Methods OPTIMUM is a Bayesian, two-stage, double-blind, group sequential trial, enrolling healthy Australian-born infants. At approximately 6 weeks old, participants are randomly assigned (1:1) to a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB; Pentabio, PT Bio Farma, Indonesia) versus a hexavalent aP vaccine, which includes inactivated poliovirus vaccine (IPV) types 1, 2, and 3 in its formulation (DTaP-Hib-HepB-IPV; Infanrix Hexa, GlaxoSmithKline, Australia). All infants receive a hexavalent aP vaccine at 4 and 6 months old, as well as a tetravalent aP-based formulation at 18 months old (DTaP-IPV; Infanrix-IPV, GlaxoSmithKline, Australia) to ensure at least three doses of IPV as part of their childhood schedule while preserving blinding. In stage one, pertussis antigen-specific IgG responses were measured before and approximately one month after the 6-month aP vaccine doses. The immunogenicity of the mixed schedule (wP/aP/aP) was defined as being non-inferior to that of the aP-only schedule (aP/aP/aP) using a non-inferiority margin of 2/3 on the ratio of the geometric mean concentrations of pertussis toxin (PT) IgG approximately one month after the 6-month aP dose. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The trial is registered with ANZCTR (ACTRN12617000065392p). Results Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). Demographic and baseline characteristics were balanced across the study arms. Most infants were born to aP-vaccinated mothers. In the intent-to-treat analysis, PT-IgG responses of the mixed schedule were non-inferior to the aP-only schedule approximately one month after a 6-month aP dose [geometric mean ratio (GMR) = 0·98, 95% Bayesian credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99]. Severe solicited systemic adverse reactions were reported among 14 of 74 (19%) infants after a first dose of wP and among 8 of 72 (11%) infants after a first dose of aP; irritability after the first dose of pertussis-containing vaccine was the most frequent severe event (11 of 74 [15%] wP recipients versus 7 of 72 [10%] aP recipients). Within 6 months of enrolment, 7 serious adverse events were reported, with none deemed related to the study vaccines. Parental acceptance of the mixed schedule was high (97% would agree to have this schedule again). Interpretation The mixed wP/aP schedule was associated with more reactions than the aP-only schedule, but these were mostly non-severe. The mixed schedule was well accepted by parents and evoked non-inferior PT-IgG responses after completion of the three-dose primary series. Funding Telethon New Children’s Hospital Research Fund and National Health and Medicine Research Council. Research in context We searched PubMed on April 17, 2023, for paediatric studies of heterologous priming with whole-cell pertussis (wP) vaccine and acellular pertussis (aP) vaccine, with no language or date restrictions. We used the terms [“whole-cell pertussis vaccine” AND “acellular pertussis vaccine”], OR [“IgE” AND “tetanus toxoid”]. Of the 997 articles retrieved, we found no published randomised comparisons between heterologous versus exclusive primary routine vaccination with either wP or aP-based formulations. In two observational studies, laboratory-confirmed pertussis disease was less common among school-aged children and adolescents who received wP versus aP as a first dose. A heterologous wP/aP primary schedule (in which the first dose was wP) was associated with lower rates of pertussis disease than an aP-only primary schedule. In a case-control study, pertussis was less common among children who had received mixed wP/three-component (3c)-aP vaccine (including pertussis toxoid, filamentous haemagglutinin, and pertactin) versus those exclusively primed with 3c-aP vaccine formulations. No evidence of a difference was observed among those vaccinated with a heterologous wP/five-component (5c)-aP primary schedule versus those exclusively primed with a 5c-aP vaccine formulation (including the above-mentioned pertussis antigens as well as fimbriae type 2 and 3). In contrast, another case-control study found that compared to the 5c-aP-only priming strategy, a primary series including one or more doses of a wP vaccine formulation, with reported efficacy against laboratory-confirmed pertussis between 36% (95% CI 14% to 52%) and 48% (95% 37% to 58%), was associated with higher vaccine effectiveness against pertussis disease more than a decade after priming. In none of the case-control analyses was the nature of the heterologous schedules further described. Two clinical and immunological studies reported that wP-only schedules were associated with lower post-priming tetanus toxoid (TT)-IgE concentrations than homologous priming with aP-containing vaccines. An additional study reported lower TT-IgE concentrations after a first dose of wP versus aP. Added value of this study To our knowledge, this is the first trial to evaluate the immunogenicity, reactogenicity, and IgE-mediated immune responses to a mixed primary schedule consisting of a first dose of wP given at approximately 6 weeks old, followed by aP at 4, and 6 months old. Implications of all the available evidence This trial provides supporting evidence of the safety and immunogenicity of a mixed wP/aP vaccine schedule in a setting with high maternal pertussis vaccine coverage. The findings warrant further investigation of the comparative clinical effects of a mixed wP/aP versus the standard aP-only schedule. ### Competing Interest Statement Unrelated to the work presented in this paper, DEC declared part time employment in DBV Technologies, as well as DBV Technologies stock and stock options. DEC has also served on the scientific advisory board for AllerGenis. Unrelated to the work presented in this paper, MO is the non-remunerated Director of ASCIA, a not-for-profit company and the peak professional body for allergy/immunology specialists in Australia and New Zealand. Unrelated to the work presented in this paper, PCR has served on pertussis vaccine scientific advisory boards for GlaxoSmithKline and Sanofi on behalf of his institution. He participated in multicentre vaccine trials of pertussis vaccines sponsored by industry, also unrelated to the work presented in this paper. He has received no personal remuneration for these activities. All other authors report no potential conflicts. ### Clinical Trial ACTRN12617000065392p ### Clinical Protocols ### Funding Statement This trial is funded by the Telethon New Children's Hospital Research Fund (stage one) and Australia's National Health and Medicine Research Council (stage two). GPC was supported by a Stan Perron Post-PhD Career Launching Award, the Australian Department of Education and Training Endeavour Scholarship, as well as top-up scholarships from the Wesfarmers Centre of Vaccine and Infectious Diseases at the Telethon Kids Institute and the Forrest Research Foundation. KPP is supported by an NHMRC Investigator Grant and a Melbourne Children's Clinician-Scientist Fellowship. SM was supported by the Australian Government Research Training Program Scholarship, the Stan Perron Excellence Award, and top-up scholarships from the UWA Safety Net, Wesfarmers Centre of Vaccine and Infectious Diseases, and the Stan Perron Foundation. TS is supported by an MRFF Investigator Award (MRF1195153). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Child and Adolescent Health Service Ethics Committee of Western Australia, Australia gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from the study will be available at the completion of follow-up, analysis and reporting of OPTIMUM stage two; no end date. Deidentified, individual participant data and a data dictionary defining each field in the set, will be made available to researchers who provide a methodologically sound proposal to the corresponding author (TS), subject to a signed data access agreement and any necessary ethics approvals (see ANZCTR trial registration). The study protocol and statistical analysis plan are published, other study related documentation is available on request.