Pertussis Immunisation and Food Allergy
Pertussis Immunisation and Food Allergy
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.
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.
Eligibility Criteria

 1. All cases and controls must be registered on ACIR as having had a first dose of any
 pertussis containing vaccine before age 16 weeks and during the period of time in which the
 transition between aP and wP vaccine occurred; birth dates within 1st Janurary 1997 and
 31st December 1999 depending on the jurisdiction.

 Case Inclusion Criteria- Cases will be considered 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 either positive skin-prick test or elevated
 specific IgE to the implicated food, with onset after the first pertussis-containing
 vaccine but before age 15 years.

 IgE-mediated food allergy is defined as BOTH:

 1. The clinical notes or clinical letter arising from the allergy consult must explicitly
 document the presence of one or more of the following features. Onset of at least one
 these features must be within 1 hour of ingestion of suspected food where this can
 reasonably inferred from statements such as "immediate", "within x mins" where x is
 <60:

 -  urticaria

 -  angioedema

 -  emesis

 -  vocal hoarseness

 -  persistent cough

 -  wheeze

 -  stridor

 -  collapse

 -  hypotension

 AND

 2. Documented evidence of allergic sensitisation to the implicated food through EITHER:

 -  specific IgE positive (serum specific IgE >0.35KU/l) to suspected food ), OR

 -  positive skin prick test (wheal diameter >3mm) against suspected food (SPT)
 Evidence of sensitisation must be at the time of consultation or the 6 months
 after the clinical encounter for the case to meet definition.

 Exclusion Criteria- none