Pertussis Immunisation and Food Allergy
Condition: Food Allergy
MeSH terms: Whooping Cough; Hypersensitivity; Food Hypersensitivity
Study type: Observational

Summary: 
      Aim To assess the possible food allergy-preventive benefit of using whole cell pertussis(wP)
      vaccination compared with acelluar pertussis vaccine(aP) for whooping cough vaccination in
      childhood.

      Background Whooping cough, caused by the bacteria, Bordetella pertussis, represents a
      significant public health burden in Australia and around the world. Acellular pertussis
      vaccination (aP) replaced whole cell vaccination against pertussis (wP) in the late 1990s.
      This replacement coincides temporally in an observed rapid rise in the occurrence of severe
      food allergy responses. Previous research has suggested that acellular pertussis vaccination
      results in the development of immunity that may predispose children to allergic responses. A
      retrospective case-controlled trial design, targeting cases of previously diagnosed allergy,
      and comparing case vaccination history to that of the whole population, is a powerful means
      of assessing the association between immunisation and allergy.

      Participant Groups 1000 allergy cases, 10,000 controls

      Project Design This is a retrospective individually-matched case-control study of Australian
      children born during the period of transition from use of wP vaccines to aP vaccines (year of
      birth 1997-1999 inclusive) and who are registered on the Australian Children Immunisation
      Register. Cases will be drawn from allergy clinics associated with tertiary teaching
      hospitals around Australia.

      Methods Cases: will be retrospectively identified from patient lists from allergy clinics
      around Australia, born during the period of pertussis vaccine changeover, and be confirmed to
      have IgE-mediated food allergy on the basis of 1) a documented history of consistent clinical
      symptoms following ingestion of an implicated food, and 2) evidence of sensitisation to that
      food via laboratory testing.

      Controls: Controls will be sampled from a de-identified database of children born during the
      transition from wP to aP vaccination appearing on the ACIR. Cases and controls will be
      matched by date of birth (+/-7 days), jurisdiction and socioeconomic decile.

      Expected outcomes: Following the study, investigators will be able determine if there is an
      association between the type of vaccination received and development of IgE mediated food
      allergy. If whole cell vaccination is found to have a protective association against the
      development of allergy, this will have profound impact on health policy in Australia and
      around the world.
    

Detailed description: 
      BACKGROUND Atopic diseases have become the most important cause of chronic morbidity among
      children in wealthy countries. In particular, food allergy, including life-threatening
      food-related anaphylaxis, is growing at an alarming rate. For example, one Australian allergy
      clinic observed a 12-fold rise in consultations for food allergy in children between 1995 and
      2006. In the 15 years to 2009/10, hospitalisations for food-related anaphylaxis in young
      Australian children increased more than 8-fold. No effective broadly implementable strategies
      to curb this 'second wave' of atopic disease have been discovered.

      In Australia, an abrupt rise in food allergy coincided closely with the replacement of the
      antigenically complex whole-cell pertussis vaccine (wP) with the subunit acellular pertussis
      vaccine (aP) beginning in the late 1990s. Pertussis vaccine protects against Bordatella
      Pertussis, the causative agent of whooping cough.

      Investigators previously shown the marked differences in the immune stimulating profile of wP
      compared with aP. wP has been shown to induce strong Th1 type immunity while aP induces a Th2
      type response. Immune responses can be broadly grouped into cellular (Th1) and antibody
      mediated immunity (Th2). Natural protective immunity to pertussis relies on strong Th1 type
      responses to clear the pathogen. This is closely mimicked by the immunity induced by whole
      cell vaccine (wP). In contrast, the acellular vaccine relies on the development of antibody
      mediated protection. While antibody mediated responses are protective in the short term, the
      strong induction of Th2 responses may be deleterious to other aspects of the immune response.

      The developing infant immune system has been shown to have a Th2 bias, which may be further
      skewed by the delivery of a vaccine with a strong Th2 immune profile. Dysregulation of the
      Th1/Th2 balance which should exist in the immune system can lead to disease states.
      Predominance of a Th2 environment leads to the development of atopy and allergy. A number of
      studies, exemplified by those from our centre, detail the Th2 immune bias induced in some
      infants who received DTaP-only schedules, resulting in excessive IgE production against
      vaccine antigens. This is likely due to the combined effect of 1) carry-over of the
      Th2-biased in utero phenotype, 2) the presence of alum and pertussis toxin which have
      Th2-adjuvantising properties, and 3) the absence of the balancing Th1-stimulating ligands
      present in DTwP. These effects manifest most strongly in infancy and among children with
      evidence of an underlying Th2-skewed phenotype.

      Studies have demonstrated that the inclusion of even a single wP dose in a pertussis priming
      schedule is associated with a reduction in Th2-polarised T cell memory and the magnitude of
      the IgE response compared with a aP-only schedule. Based on these findings it is hypothesised
      that the inclusion of a single wP dose in the pertussis priming schedule might preserve the
      Th1/Th2 balance of the developing infant immune system.

      Thus, this study will test the hypothesise that removal of wP from the infant vaccine
      schedule has contributed to the observed rise in IgE-mediated food allergy.

      AIM To assess the possible food allergy-preventive benefit of using wP compared with aP for
      pertussis vaccination in childhood.

      OBJECTIVES AND OUTCOME MEASURES

      Primary objective To determine if Australian children born between 1997 to 1999 (inclusive)
      who received wP as their first pertussis vaccine dose in infancy were less likely to
      subsequently develop IgE-mediated food allergy compared with contemporaneous children who
      received aP as their first pertussis vaccine dose in infancy.

      Secondary objectives To determine if Australian children born in the years 1997 to 1999
      (inclusive) who received at least one dose of a wP pertussis vaccine at any age were less
      likely to subsequently develop IgE-mediated food allergy compared with contemporaneous
      children who received only aP pertussis vaccines.

      To determine if Australian children born in the years 1997 to 1999 (inclusive) who received
      wP pertussis vaccines exclusively were less likely to subsequently develop IgE-mediated food
      allergy compared with contemporaneous children who received only aP pertussis vaccines.

      STUDY DESIGN This is a retrospective individually-matched case-control study of Australian
      children born during the period of transition from use of wP containing pertussis vaccines to
      aP containing pertussis vaccines (year of birth 1997-1999 inclusive) and who are registered
      on ACIR and received their first dose of pertussis vaccine before age 16 weeks. Cases will be
      drawn from allergy clinics associated with tertiary teaching hospitals around Australia. 1000
      cases, identified as having IgE mediated food allergy from reviewing case histories, and
      appearing on ACIR will be enrolled. Controls will be drawn from a de-identified database of
      the Australian Childhood Immunisation Register held by the National Centre for Immunisation
      Research and Surveillance of Vaccine Preventable Diseases. Each case will be individually
      matched to 10 controls.

      Project coordination and epidemiological analysis will be conducted from the Wesfarmers
      Centre of Vaccines and Infectious Diseases at the Telethon Kids Institute Western Australia.

      STATISTICS AND ANALYSIS Sample size and power considerations Sample size: A study with 1000
      matched sets of cases and controls, with 10 matched controls for each case, will have at
      least 80% power to detect a 17% lower risk (odds ratio 0.83) of food allergy among children
      who received wP as their first dose of pertussis vaccine compared with those who received aP
      as their first dose. This assumes that: (i) 50% of controls receive a first pertussis vaccine
      dose of wP; (ii) the correlation coefficient for exposure (first dose of wP) between matched
      cases and controls is 0.5; and (iii) a significance level of 5% (α=0.05). Investigators
      believe that a small effect size will not influence policy or research direction. If only 500
      cases meet the case criteria the study will still have at least 80% power to detect a 23%
      lower risk (odds ratio 0.77) of food allergy.

      Description of Statistical Methods The cohort characteristics will be summarised by case or
      control status using means and standard deviations for symmetric distributions and medians
      and inter-quartile ranges for asymmetric distributions. Conditional logistic regression will
      be used to estimate odds ratios and the corresponding 95% confidence intervals for the
      associations between (exposure) pertussis vaccine type (wP or aP) and the risk of
      IgE-mediated food allergy. Because controls will be sampled from the register cohort
      irrespective of past or future case status, the odds ratio will be interpreted as an unbiased
      estimator of the relative risk of food allergy among children receiving wP compared with aP
      vaccines.
    

Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        All participants appear on the Australian Childhood Immunisation Register (ACIR) and have
        received their first pertussis vaccination before the age of 16 weeks. They will have been
        born during the period of change over from whole cell pertussis vaccine to acellular
        pertussis vaccine (1997-1999). Allergy case participants have all attended allergy clinics
        associated with tertiary teaching hospitals. They have confirmed IgE-mediated food allergy
        as defined by the case description and as ascertained by their medical records.
      
Keywords: Acellular pertussis vaccine; whole cell pertussis vaccine; IgE-mediated food allergy