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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. 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. 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. 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.

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. 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). 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 registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Background Long COVID is an infection-associated chronic condition with uncertain evolution, leading to ambiguity in case definitions and various hypotheses about its pathophysiology. Despite this diversity, causal models may offer a unified understanding of post-acute COVID-19 mechanisms. This study aimed to examine whether dynamic Bayesian networks could facilitate inferences on long COVID. Methods Using a causal engineering approach, we developed directed acyclic graphs and qualitatively parametrised them as Bayesian networks to depict the hypothesised mechanisms of long COVID in a theory-agnostic manner. Based on the literature and expert knowledge, we created a general modelling framework summarising biological pathways from mild or severe COVID-19 to the development of respiratory symptoms and fatigue over four key periods ( t 1 to t 4 ). We used qualitative parametrisation for design and validation, and tested the framework against four scenarios: A) mild COVID-19 at t 1 (start of acute infection); B) severe acute COVID-19 at t 1 ; C) symptoms reported at t 1 (acute COVID-19 disease); and D) symptoms reported at t 1 and t 3 (e.g., 3-to-6 months post-acute infection), indicating long COVID. Results Here we show that, in scenario A, the probability of progressing to severe disease and developing persistent organ dysfunction 1-to-2 years post-acute COVID-19 was lower than in scenario C. Those reporting symptoms at t 1 and t 3 have the highest probability of developing persistent organ dysfunction beyond the acute infection period. Conclusions Our findings lay the foundations for a better understanding of the progression of long COVID syndromes. Illustrative simulations support the use of causal models to help address both diagnostic and prognostic questions in long COVID research. Plain Language Summary Long COVID can affect some people after having COVID-19. It usually starts within three months of infection and can last for at least two months. People with long COVID may struggle with work, daily tasks, and social activities. Researchers find it hard to study because its causes aren’t directly visible. This study uses diagrams to show expert ideas about what might cause long COVID and how symptoms relate to those causes. By looking at four examples, it shows how explanations can change when new information appears. The approach helps researchers think in terms of “cause and effect”, which can improve understanding and communication about long COVID. It could also guide clinical trials, public health studies, and experiments. Pérez Chacón et al. develop a causal modelling framework to guide diagnosis and prognosis of long COVID. The framework based on modelling scenarios involving expert knowledge, qualitative parameters, and statistical simulations can predict progression to severe and persistent organ dysfunction associated with long COVID beyond the acute infection.

Objective The purpose of this double-blind, randomised, controlled trial is to compare allergic outcomes in children following vaccination with acellular pertussis (aP) antigen (standard of care in Australia) given at 2 months of age versus whole cell pertussis (wP) in the infant vaccine schedule. Participants Up to 3000 Australian infants 6 to <12 weeks of age born ≥32 weeks gestation. Interventions The intervention is a wP containing vaccine as the first scheduled pertussis vaccine dose instead of an aP containing vaccine. Outcomes The primary outcome is a binary indicator of history of IgE-mediated food allergy at the age of 12 months confirmed, where necessary, with an oral food challenge before 18 months of age. Secondary outcomes include (1) history of parent-reported clinician-diagnosed new onset of atopic dermatitis by 6 or 12 months of age with a positive skin prick test to any allergen before 12 months of age, (2) geometric mean concentration in pertussis toxin-specific IgG before and 21 to 35 days after a booster dose of aP at 18 months of age, and (3) sensitisation to at least one allergen by 12 months of age. Results Operating characteristics of trial decision rules were evaluated by trial simulation. The selected rules for success and futility approximately maintain type I error of 0.05 and achieved power 0.85 for a reduction in the primary outcome from 10% in the control group to 7% in the intervention group. Discussion A detailed, prospective statistical analysis plan (SAP) is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptive elements, decision thresholds, statistical methods, and the simulations used to evaluate the operating characteristics of the trial. Application of this SAP will minimise bias and supports transparent and reproducible research. Trial registration Australia & New Zealand Clinical Trials Registry, ACTRN12617000065392 . Registered on 12 January 2017 Study protocol https://doi.org/10.1136/bmjopen-2020-042838

IntroductionCombination vaccines containing whole-cell pertussis antigens were phased out from the Australian national immunisation programme between 1997 and 1999 and replaced by the less reactogenic acellular pertussis (aP) antigens. In a large case–control study of Australian children born during the transition period, those with allergist diagnosed IgE-mediated food allergy were less likely to have received whole-cell vaccine in early infancy than matched population controls (OR: 0.77 (95% CI, 0.62 to 0.95)). We hypothesise that a single dose of whole-cell vaccine in early infancy is protective against IgE-mediated food allergy.Methods and analysisThis adaptive double-blind randomised controlled trial is investigating whether a mixed whole-cell/aP vaccine schedule prevents allergic disease in the first year of life. The primary outcome is IgE-mediated food allergy by 12 months of age. Secondary outcomes include new onset of atopic dermatitis by 6 or 12 months of age; sensitisation to at least one allergen by 12 months of age; seroconversion in anti-pertussis toxin IgG titres after vaccination with aP booster at 18 months of age; and solicited systemic and local adverse events following immunisation with pertussis-containing vaccines. Analyses will be performed using a Bayesian group sequential design.Ethics and disseminationThis study has been approved by the Child and Adolescent Health Service Human Research Ethics Committee, Perth, Western Australia (RGS 00019). The investigators will ensure that this trial is conducted in accordance with the principles of the Declaration of Helsinki and with the International Conference on Harmonisation Guidelines for Good Clinical Practice. Individual consent will be requested. Parents will be reimbursed reasonable travel and parking costs to attend the study visits. The dissemination of these research findings will follow the National Health and Medical Research Council of Australia Open Access Policy.Trial registration numberACTRN12617000065392p.

IntroductionAtopic diseases, including food allergy, have become a predominant cause of chronic illness among children in developed countries. In Australia, a rise in hospitalisations among infants coded as anaphylaxis to foods coincided with the replacement of whole-cell pertussis (wP) vaccine with subunit acellular pertussis (aP) vaccine on the national immunisation schedule in the late 1990s. Atopy is characterised by a tendency to mount T helper type 2 (Th2) responses to otherwise innocuous environmental antigens. Compared with infants who receive aP as their first pertussis vaccine, those who receive wP appear less likely to mount Th2 immune responses to either vaccine or extraneous antigens. We therefore speculate that removal of wP from the vaccine schedule contributed to the observed rise in IgE-mediated food allergy among Australian infants.Methods and analysisThis is a retrospective individually matched case–control study among a cohort of Australian children born from 1997 to 1999, the period of transition from wP to aP vaccines; we include in the cohort children listed on Australia’s comprehensive population-based immunisation register as having received a first dose of either pertussis vaccine by 16 weeks old. 500 cohort children diagnosed as having IgE-mediated food allergy at specialist allergy clinics will be included as cases. Controls matched to each case by date and jurisdiction of birth and regional socioeconomic index will be sampled from the immunisation register. Conditional logistic regression will be used to estimate OR (±95% CI) of receipt of wP (vs aP) as the first vaccine dose among cases compared with controls.Ethics and disseminationThe study is approved by all relevant human research ethics committees: Western Australia Child and Adolescent Health Services (2015052EP), Women’s and Children’s Hospital (HREC/15/WCHN/162), Royal Children’s Hospital (35230A) and Sydney Children’s Hospital Network (HREC/15/SCHN/405). Outcomes will be disseminated through publication and scientific presentation.Trial registration number NCT02490007.