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Background: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. Methods and findings: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. 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 primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). Conclusions Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registration: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371998&isReview=true. Just one registry (as above). Gladymar Pérez Chacón and colleagues report the safety and immunogenicity of a mixed whole-cell and acellular pertussis vaccine in Australian infants in stage 1 of the two-stage OPTIMUM trial. Author summary: Why was this study done?: Evidence-based strategies to lower the risk of food allergies developing in young children are limited. A previous observational study suggested that food allergies appear to be less common among Australian-born children vaccinated with a first dose of whole-cell whooping cough (wP) vaccine before 4 months old versus those receiving a first dose of acellular whooping cough (aP) vaccine at the same age. Why did the researchers do and find?: In the first stage of a 2-stage, double-blind, noninferiority trial, Australian-born infants were randomised to receive a first dose of wP versus aP at approximately 6 weeks old; in both study groups, aP vaccine is given at 4 and 6 months old. Stage (phase) one examined the immunogenicity, reactogenicity, and IgE-mediated immune responses of the mixed vaccine schedule (wP/aP/aP) versus the standard aP-only vaccination strategy (aP/aP/aP) in a cohort of 150 infants; stage two is ongoing and was designed to ascertain the development of food allergy by 12 months old (primary outcome) in a cohort of up to 3,000 infants. At 7 months old, the mixed schedule was noninferior to the standard aP-only strategy with respect to pertussis toxin IgG responses; at the same age, we observed no difference across the study groups in IgE responses to hen's egg and tetanus toxoid antigens. The mixed schedule was more reactogenic but well accepted by parents. What do these findings mean?: These findings support the acceptable immunogenicity and reactogenicity of the mixed schedule and are relevant for countries in which wP and aP vaccines are licensed and readily available. While the reported IgE responses are not conclusive, further studies of CD4+ T cell polarisation in response to pertussis antigens, along with primary outcome data will provide a comprehensive picture of the atopic immunophenotypic responses across the study groups. Additional evidence is required to understand the population-level acceptability of the mixed vaccination strategy. [ABSTRACT FROM AUTHOR]

Background: Asthma is among the commonest noncommunicable diseases of childhood and often occurs with other atopic comorbidities. A previous case-control study found evidence that compared to children who received acellular pertussis (aP) vaccines in early infancy, children who received one or more doses of whole-cell pertussis (wP) vaccine had lower risk of developing IgE-mediated food allergy. We hypothesized that wP vaccination in early infancy might protect against atopic asthma in childhood. Methods: Retrospective record-linkage cohort study of children between 5 and < 15 years old and born between January 1997, and December 1999, in the Australian states of Western Australia (WA) and New South Wales (NSW), receiving wP versus aP vaccine as the first pertussis vaccine dose. The main outcome and measures were first and recurrent hospitalizations for asthma; hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by means of Cox and Andersen and Gill models. Results: 274,405 children aged between 5 and < 15 years old (78.4% NSW-born) received a first dose of either wP (67.8%) or aP vaccine before 4 months old. During the follow-up period, there were 5,905 hospitalizations for asthma among 3,955 children. The incidence rate for first hospitalization was 1.5 (95% CI 1.4–1.5) per 1,000 child-years among children receiving wP vaccine as a first dose, and 1.5 (95% CI 1.4–1.6) among those vaccinated with aP vaccine as a first dose. The adjusted HRs for those who received wP vaccine versus aP vaccine as the first dose were 1.02 (95% CI 0.94–1.12) for first hospitalizations and 1.07 (95% CI 0.95–1.2) for recurrent hospitalizations for asthma. Conclusions: We found no convincing evidence of a clinically relevant association between receipt of wP versus aP vaccines in early infancy and hospital presentations for asthma in childhood. [ABSTRACT FROM AUTHOR]

Introduction: The burden of IgE-mediated food allergy in Australian born children is reported to be among the highest globally. This illness shares risk factors and frequently coexists with asthma, one of the most common noncommunicable diseases of childhood. Findings from a case-control study suggest that compared to immunisation with acellular pertussis vaccine, early priming of infants with whole-cell pertussis vaccine may be associated with a lower risk of subsequent IgE-mediated food allergy. If whole-cell vaccination is protective of food allergy and other atopic diseases, especially if protective against childhood asthma, the population-level effects could justify its preferential recommendation. However, the potential beneficial effects of whole-cell pertussis vaccination for the prevention of atopic diseases at a population-scale are yet to be investigated. Methods and analysis: Analyses of population-based record linkage data will be undertaken to compare the rates of admissions to hospital for asthma in children aged between 5 and 15 years old, who were born in Western Australia (WA) or New South Wales (NSW) between 1997 and 1999 (329,831) when pertussis immunisation in Australia transitioned from whole-cell to acellular only schedules. In the primary analysis we will estimate hazard ratios and 95% confidence intervals for the time-to-first-event (hospital admissions as above) using Cox proportional hazard models in recipients of a first dose of whole-cell versus acellular pertussis-containing vaccine before 112 days old (~4 months of age). Similarly, we will also fit time-to-recurrent events analyses using Andersen-Gill models, and robust variance estimates to account for potential within-child dependence. Hospitalisations for all-cause anaphylaxis, food anaphylaxis, venom, all-cause urticaria and atopic dermatitis will also be examined in children who received at least one dose of pertussis-containing vaccine by the time of the cohort entry, using analogous statistical methods. Presentations to the emergency departments will be assessed separately using the same statistical approach. [ABSTRACT FROM AUTHOR]