Whole‐cell pertussis vaccine in early infancy for the prevention of allergy

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the efficacy and safety of whole‐cell pertussis (wP) vaccinations in comparison to acellular pertussis (aP) vaccinations in early infancy for the prevention of atopic diseases in children.

Background

See Appendix 1 for a glossary defining some of the scientific terms used throughout this protocol.

Description of the condition

Allergic (atopic) diseases are the most common non‐communicable diseases of childhood (Prescott 2013). The atopic march is proposed to occur in a predictable way, commencing in early childhood with the development of eczema (atopic dermatitis), followed by immunoglobulin E (IgE)‐mediated food allergy and, later, asthma and hay fever (allergic rhinitis/allergic rhino‐conjunctivitis) (Hill 2018). The main mechanistic features of the atopic march are epidermal barrier disruption, pathologically skewed T helper (Th)₂ immune responses and chronic‐type inflammation. This model has been challenged by cohort studies describing different disease trajectories (Illi 2004; Punekar 2009), and more recently by the characterisation of diverse atopic dermatitis phenotypes, according to age of onset, presence of sensitisation to food and aero‐allergens, family history of atopic diseases and further development of asthma or other atopic comorbidities (Amat 2015; Roduit 2017).

Data from the Global Burden of Disease Study estimate that at least 6% of children aged between five and nine years have asthma; 3% of children aged between one and four years have hives (urticaria), and 8% within the same age range have atopic dermatitis (Global Burden of Disease 2018). For urticaria, the estimated prevalence is at least 2.5 times higher in countries with high socioeconomic indices than in less economically developed countries (Global Burden of Disease 2018).

While the prevalence of asthma has levelled off in countries with the most affluent economies, the epidemiology of IgE‐mediated food allergy reflects a different trend. Morbidity data have been used as a proxy of food‐specific IgE‐mediated hypersensitivity reactions, with an increasing number of paediatric hospital admissions coded as food‐related anaphylaxis in the UK (Turner 2015), New Zealand (Speakman 2018), and Australia (Mullins 2015). In Australia, the prevalence of challenge‐confirmed IgE‐mediated food allergy in the first year of life is extraordinarily high (10%) (HealthNuts Study 2011), and the rate of fatal food‐related anaphylaxis increased by almost 10% per year between 1997 and 2013 (Mullins 2016). By contrast, the prevalence of asthma has continued to increase in low‐ to middle‐income countries, along with urbanisation and the adoption of a Western lifestyle (Bousquet 2005; Holgate 2015). Despite some reports suggesting an increase in the prevalence of food allergies in upper‐ to middle‐income countries such as South Africa (Basera 2015) and China (Hu 2010), the data are scarce and the sensitisation trajectories are yet to be described.

Description of the intervention

Whole‐cell whooping cough (pertussis) containing vaccines (wP) are suspensions of killed Bordetella pertussis bacteria. These vaccines were introduced in the 1940s and further implemented by the World Health Organization (WHO) in 1974, as the standard of care for the primary prevention of pertussis through the Extended Program of Immunization (EPI) (Keja 1988). To date, 64% of countries worldwide have wP‐based national immunisation schedules (WHO 2015a). The cellular vaccine is safe (WHO 2015b), and is mainly available as a '5‐in‐1' (pentavalent) formulation with diphtheria (D) and tetanus (T) toxoids, Haemophilus influenzae type b and hepatitis B antigens. This formulation is available in 73 of the lowest‐income economies via the support of Gavi, the Vaccine Alliance (Gavi 2020), as well as in self‐financed lower‐middle income countries non‐eligible for Gavi's funding programmes (UNICEF 2017). The inception of Gavi's support for wP‐based '5‐in‐1' formulations commenced in 2001 and by the end of 2018, at least 467 million children living in eligible countries had been vaccinated (Gavi 2020). This not only contributes to drastically decreasing the global burden of disease and pertussis‐related deaths (Chow 2016), but also represents additional long‐term economic and social benefits.

Fever, irritability and local injection site reactions (such as pain, redness and swelling) are expected adverse events that arise following immunisation with wP‐based formulations. Although these events are self‐limiting, the development of a less reactogenic subunit (acellular) pertussis‐containing vaccine (DTaP) in the 1970s (Sato 1984), instigated a changeover from DTwP to DTaP‐based schedules in high‐income countries between the 1980s and early 2000s.

The tolerability profile of aP versus wP has been reviewed systematically elsewhere and favours aP formulations (Patterson 2018; Zhang 2014); however, priming with wP is safe, and may result in longer lasting protection against pertussis than priming with DTaP vaccines (CDC 2012; Liko 2013; Sheridan 2012; van der Lee 2018). A potential causal relationship between DTwP and rare neurological outcomes (i.e. encephalopathy) was not confirmed by re‐examination of the UK National Childhood Encephalopathy Study (Miller 1993), epidemiological (Ray 2006), and genomic analyses (Berkovic 2006; McIntosh 2010). Therefore, the WHO have advised that countries with EPI‐wP‐only schedules should continue with wP‐based primary courses (WHO 2015b).

How the intervention might work

During the neonatal and early infancy periods, a diversity of stimuli, including infections and vaccines, might determine future functional adaptations of the immune system (Olin 2018). In that regard, differential immune profiles elicited by Bordetella pertussis and pertussis‐containing vaccines have been described in human (de Graaf 2019), non‐human primate (Warfel 2014), and other animal models (Mills 1998).

Priming with aP‐containing vaccines induces Th₂‐dominated immune responses (Ausiello 1997; Rowe 2000), with transient enhanced production of diphtheria, tetanus toxoid and pertussis toxin IgE (Aalberse 2019; Hedenskog 1989; Holt 2016). Furthermore, Th₂‐skewed responses seen in aP vaccines appear to extend beyond DTP antigens, as evidenced by a transiently increased egg‐ and milk‐specific IgE at the age of four months (Holt 2016), as well as the induction of type 2 cytokines to the food antigen beta‐lactoglobulin at six months of age (Mascart 2007). In contrast, the infection with Bordetella pertussis and wP‐containing vaccines induce Th₁/Th₁₇ polarisation with minimal expression of type 2 immunity (Ausiello 1997; Higgs 2012; Mascart 2007; Warfel 2014). This effect is hypothesised to facilitate the transition from a Th₂‐biased immunophenotype seen in early infancy, to a more balanced Th₁/Th₁₇/Th₂ phenotype that could play a role in the development of oral tolerance and allergy protective immune responses (Estcourt 2020). Therefore, mixed wP/aP schedules using wP as the first infant pertussis vaccine might be sufficient to overcome the described immunophenotypic differences (Holt 2016).

Although the mechanistic studies of Ausiello 1997 and Mascart 2007 demonstrate a propensity of developing type 1 T‐cell differentiation following early priming with wP and possibly, an 'allergy protective immunophenotype', two European studies found no association between the type of pertussis vaccine and further development of atopic diseases (Nilsson 1998; Venter 2016).

Why it is important to do this review

Allergic diseases have a significant economic, healthcare and quality‐of‐life impact. The rise in the prevalence of IgE‐mediated food allergy in high‐income countries coincides with the changeover from wP‐ to aP‐only schedules (Estcourt 2020; Venter 2016). However, systematic reviews on the safety of pertussis‐containing vaccines have not addressed whether wP play a role in the protection against this and other allergy outcomes (Patterson 2018; Zhang 2014). Therefore, this review will provide a critical appraisal of the relevant evidence and provide directions for the future development of immunisation and allergy prevention guidelines.

Objectives

To assess the efficacy and safety of whole‐cell pertussis (wP) vaccinations in comparison to acellular pertussis (aP) vaccinations in early infancy for the prevention of atopic diseases in children.

Methods

Criteria for considering studies for this review

Types of studies

We will include the following study designs, irrespective of publication status, date of publication, publication type or language.

1. Randomised controlled trials (RCTs) and cluster RCTs.

2. Controlled clinical trials (CCTs) or trials in which it is not clearly stated that the intervention or comparison was allocated at random; however, it is not possible to exclude randomisation (Lefebvre 2019a). We will classify quasi‐randomised studies as CCTs.

3. For atopic outcomes, we will assess case‐control and cohort studies (hereafter referred as non‐randomised studies of interventions (NRSIs)) in which the individual vaccine status of the study participants is known.

On biological plausibility grounds, we will not include cross‐over trials since the differential T‐cell polarisation induced by the first dose of wP or aP is likely to have a long‐term effect that is still patent in adulthood, irrespective of subsequent booster doses of aP during or after adolescence (Bancroft 2016; da Silva Antunes 2018).

Types of participants

Children aged less than 18 years, who received their first dose of wP‐ or aP‐containing vaccines before the age of six months, irrespective of any subsequent pertussis vaccinations (wP, aP or none).

Types of interventions

The experimental intervention will be vaccination with any formulation that contains wP. The comparator will be vaccination with any formulation that contains aP. Placebo or no intervention will not be accepted as comparators, as they do not represent the standard of care for the primary prevention of pertussis.

The first dose of the wP‐ or aP‐containing vaccines must have been administered before participants reached six months of age, irrespective of any subsequent pertussis vaccinations (wP, aP or none). Booster dose studies will be considered eligible if they meet the following criteria:

1. the comparison is between recipients of one or more doses of wP versus aP;

2. participants received a first dose before the age of six months;

3. information on the type of first dose of pertussis‐containing vaccine is available.

We will accept co‐administered vaccines in either the experimental and control group. Matching between groups will not be required for randomised studies, as the nature of randomisation is to minimise confounding; for NRSIs, we will adjust accordingly.

Types of outcome measures

Primary and secondary outcomes are dichotomous. Allergy outcomes were selected on the basis of related systematic reviews of interventions for the prevention of atopic diseases (Gunaratne 2015; Lodge 2015; Osborn 2006; Osborn 2007; Osborn 2013; Osborn 2018; Schindler 2016; Yepes‐Nuñez 2018). We will only include studies with at least six months of follow‐up.

Study eligibility will not be restricted based on the outcomes listed below.

Primary outcomes

1. Diagnosis of IgE‐mediated food allergy.

2. Serious adverse events following immunisation with wP or aP (safety). Serious adverse events are defined as any adverse event that resulted in death, was life‐threatening, required hospitalisation or prolongation of existing hospitalisation, or resulted in persistent or significant disability or incapacity (ICH 1997). Pragmatically, we will also accept adverse events characterised as 'serious', irrespective of whether the report refers to the ICH 1997 definition.

Secondary outcomes

1. Diagnosis of anaphylaxis.

2. Diagnosis of asthma.

3. Diagnosis of encephalopathy (safety).

4. Diagnosis of allergic rhinitis or allergic rhino‐conjunctivitis.

5. Diagnosis of eczema or atopic dermatitis.

6. Diagnosis of urticaria.

Primary and secondary allergic outcomes may be diagnosed at any point after enrolment by:

1. a positive history measured via:

   1. parental report (whether using validated questionnaires or not);

   2. clinician diagnosis;

   3. parental report and clinician diagnosis;

2. evidence of IgE‐mediated sensitisation via:

   1. a positive skin prick test;

   2. total or specific elevated IgE measured by ImmunoCAP, or other methods;

3. one or both (where applicable) of:

   1. evidence of a formal positive oral food challenge to the implicated food;

   2. confirmed expiratory airflow limitation (i.e. spirometrically confirmed asthma).

If eligible studies report atopic outcomes using more than one method, we will use the following hierarchy of diagnoses: clinician‐diagnosed allergic disease with evidence of IgE‐mediated sensitisation; clinician diagnosis without confirmed IgE‐mediated sensitisation. However, clinician diagnosis without confirmed IgE‐mediated sensitisation will be used over parental report using validated questionnaires or not. Where applicable, we will use formal food‐challenge confirmed IgE‐mediated food allergy or evidence of variable expiratory airflow limitation over clinician diagnosed allergic disease with evidence of IgE‐mediated sensitisation.

As pertussis vaccine efficacy has been investigated by a Cochrane Review conducted by Zhang 2014, and solicited systemic and local adverse events following immunisation with aP and wP have been reviewed by Patterson 2018, we decided not to include them as outcomes in this review.

Search methods for identification of studies

We will follow the recommendations provided in Chapter 4 (Lefebvre 2019b)/Technical Supplement (Lefebvre 2019a) and Chapter 25 (Reeves 2019) of the Cochrane Handbook of Systematic Reviews of Interventions for the identification and selection of eligible studies.

Electronic searches

We will search the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid). We will restrict our searches from 1970 to present, as aP were developed in Japan in the late 1970s, and used for the first time in Japan for mass‐immunisation in 1981 (Sato 1984). We modified the CENTRAL search strategy of Zhang 2014 by using free‐text words for subject specific aspects and by incorporating the study population into the search fields (Appendix 2). This strategy will be adapted for the searches of other electronic databases.

Searching other resources

We will search the US National Library of Medicine's trial registry (ClinicalTrials.gov; clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) portal (apps.who.int/trialsearch/) to access unpublished and ongoing studies. We will check the reference list and citations of eligible studies, grey literature (Open Grey, www.opengrey.eu/), regulatory bodies' websites (i.e. US Food and Drug Administration and the European Medicines Agency), related systematic reviews and pertinent medical pharmaceutical companies trial registries. Where required, we will attempt to contact authors of the original reports for clarification or to request missing data.

Data collection and analysis

Selection of studies

Two review authors (of GPC, MJE, JR) will independently screen the titles and abstracts of search results against our prespecified criteria (Criteria for considering studies for this review). Any disagreements will be resolved through discussion with a third review author and we will obtain the full‐text of potentially eligible studies. Two review authors (of GPC, MJE, JR) will independently appraise the full‐text reports against the eligibility criteria. Any disagreements will be resolved through discussion with a third review author (of CBJ, PR, PH or TS). We will document the selection process to allow us to complete a PRISMA flow diagram. We will list included studies in the 'Characteristics of included studies' table. We will list studies excluded at the full‐text stage in the 'Characteristics of excluded studies' table. If we require clarification from study authors or are unable to obtain full texts, we will list the studies in the 'Characteristics of studies awaiting classification' table. We will list ongoing studies in the 'Characteristics of ongoing studies' table.

We will collate multiple references of studies under the same identifier, so that the study, rather than the reference, is the unit of interest.

Data extraction and management

Randomised controlled trials

Two review authors (of GPC, MJE, JR) will independently extract data from the eligible studies using a customised data collection form, observing the recommendations provided in Chapter 5 of the Cochrane Handbook of Systematic Reviews of Interventions (Li 2019). We will resolve discrepancies through discussion or through the arbitration of a third review author (of CBJ, PR, PH or TS). We will extract the following information.

1. Initials of data extractors, date of data extraction and citation.

2. Study characteristics: study design, recruitment and sampling procedures, start and end dates of the trial, length of follow‐up.

3. Participants/population (P): study setting, country and World Bank income level of country, ethnicity, eligibility criteria, unit of analysis, number of participants in each study group, withdrawals and loss to follow‐up, mean age, age range, sex, comorbidities.

4. Intervention (I) and comparator (C): type of pertussis‐containing vaccine administered (generic name), manufacturer, route of delivery, dose, schedule.

5. Vaccines co‐administered: generic name, manufacturer, route of delivery, dose, schedule.

6. Vaccination with Bacille‐Calmette‐Guérin (BCG or vaccine against tuberculosis): manufacturer and dose timing.

7. Antipyretic/analgesic use.

8. Outcomes (O): primary and secondary outcomes and their definition, evidence of assessment and whether they were collected systematically, time points reported and method of aggregation.

9. Judgement of directness of each one of the PICO elements using Schünemann 2013 checklist.

10. Risk of bias (as per Assessment of reporting biases).

11. Source of funding.

12. Authors' conflicts of interest.

13. Miscellaneous: correspondence required, comments from the reviewers or study authors.

If a cluster RCT is identified as eligible, we will also extract the number of clusters allocated to the intervention or comparator, the mean cluster size and the intracluster correlation coefficient (ICC) where reported.

Non‐randomised studies of interventions

For NRSI, we will extract the information as for RCTs, as well as potential confounding factors (and any attempt to adjust for these).

Assessment of risk of bias in included studies

Randomised controlled trials

Two review authors (of GPC, MJE, JR) will independently assess the risk of bias using Cochrane's 'Risk of bias' tool. The version we use (1 or 2) will depend on software availability at the time of data extraction. Regardless of what tool we use, we will follow the guidance set out in the Cochrane Handbook of Systematic Reviews of Interventions to evaluate the appropriate domains. For risk of bias 1 these are sequence generation; allocation concealment; blinding of participants, personnel and outcome assessment; incomplete outcome data and selective reporting, as well as other sources of bias (Higgins 2011). In this case, each domain will be assessed as having low, unclear or high risk of bias. However, if risk of bias 2 is deemed feasible, we will evaluate studies within the following domains: bias arising from the randomisation process, bias arising from identification or recruitment of individual participants within clusters (for cluster RCTs), bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported result (Sterne 2019). In this case, the overall risk of bias will be categorised as either: low risk of bias (if all the domains are judged at low risk of bias), high risk of bias (if at least one domain is judged at high risk of bias), or some concern (if at least one domain is judged as having some concerns, and no domain is judged at high risk of bias) (Sterne 2019). We will resolve disagreements by discussion, and, where required, through the arbitration of a third review author (of CBJ, PR, PH or TS).

Non‐randomised studies of interventions

Two review authors (of GPC, MJE, JR) will independently assess the risk of bias using the ROBINS‐I tool (Sterne 2016). The outcomes that will be assessed for risk of bias are: diagnosis of IgE‐mediated food allergy, diagnosis of anaphylaxis and diagnosis of asthma. We will judge the bias arising from pre‐intervention (bias due to confounding and selection of participants into the study); at‐intervention (bias in classification of interventions) and post‐intervention domains (bias due to deviations from intended interventions, due to missing data, in measurement of the outcome and in selection of the reported result), answering 'signalling questions' with further risk of bias judgement, guided by the tool algorithms. We will resolve disagreements through discussion, and where required, through the arbitration of a third review author (of CBJ, PR, PH or TS). Judgements will be documented in free‐text boxes and incorporated into the 'Risk of bias' table.

We will consider the following confounders: year of birth, birth order, prematurity, breastfeeding, family history of allergic diseases, socioeconomic status and vaccination with BCG. We will also consider whether the study involves unmatched co‐administration of vaccines between groups.

We will classify the overall risk of bias judgement for a specific outcome within each NRSI as: low risk of bias (if we judge all the domains at low risk of bias); moderate risk of bias (if we judge all the domains at low or moderate risk of bias, and the study provided good‐quality evidence for an RCT, but it is not comparable to a well‐conducted RCT); serious risk of bias (if we judge at least one domain at serious risk of bias, but no domain as having a critical risk of bias); critical risk of bias (if we judge at least one domain at critical risk of bias) or no information (if data are insufficient and judgement cannot be completed) (Sterne 2016). We will only include NRSIs deemed at low or moderate risk of bias in our meta‐analyses.

Measures of treatment effect

We will summarise and report the proportion of participants who experience primary and secondary outcomes at least once (rather than as a count of outcomes per participants). We will quantify the effect of wP versus aP as a ratio of the risk (using risk ratios (RRs) and 95% confidence intervals (CIs)) or ratio of the odds for case‐control studies (odds ratio (ORs) and 95% CIs), for each outcome.

Unit of analysis issues

If a study has multiple comparison groups, we will omit the groups that do not meet our inclusion criteria, but list them in the 'Characteristics of included studies' table. Where appropriate, we will consider the following strategies:

1. where more than one relevant group is reported, we will combine them to create a single pair‐wise comparison or;

2. we will include the intervention group separately in the analysis and split the control group.

If a cluster RCT is eligible for this review, but failed to use the clusters as the unit of analysis, we will use the ICC to correct the analyses; if unavailable, we will use external estimates from similar studies (Higgins 2019).

Dealing with missing data

We will deal with missing data as advised in Chapter 10 of the Cochrane Handbook of Systematic Reviews (Deeks 2019); hence, where possible, we will perform intention‐to‐treat analyses for primary and secondary outcomes (randomised studies). Irrespective of the study design, we will try to contact the trial investigators or sponsors to obtain missing outcome data. Where these data remain unavailable, we will rate the relevant domains of the Cochrane tools for assessing risk of bias accordingly (Higgins 2011; Higgins 2019; Sterne 2016).

Assessment of heterogeneity

We will analyse the data in RCTs and NRSI separately. We will examine the clinical and methodological diversity between studies and use this information to decide whether studies are similar enough to be pooled meaningfully. Where meta‐analyses are carried out, we will assess the presence of statistical heterogeneity of intervention effects across studies by inspecting the point estimates and CIs of forest plots. We will assess the results of the Chi² test for each meta‐analysis (with significance at the 0.1 level) and quantify heterogeneity using the I² statistic. We will use the thresholds recommended in Chapter 10 of the Cochrane Handbook of Systematic Reviews of Interventions (Deeks 2019), with considerable heterogeneity defined as an I² greater than 75%. If we detect heterogeneity over this threshold, we will not present a pooled estimate.

We will investigate potential causes of any detected heterogeneity as described in the Subgroup analysis and investigation of heterogeneity and Sensitivity analysis sections.

Assessment of reporting biases

Where 10 or more studies are meta‐analysed (see Data synthesis), we will use contour‐enhanced funnel plots to distinguish non‐reporting biases from other sources of asymmetry (Page 2019; Peters 2008). These plots will be derived using R (R 2019).

Data synthesis

Where studies are clinically and methodologically homogeneous, we will carry out stratified meta‐analyses using random‐effects, inverse variance methods with RRs and 95% CIs for dichotomous outcomes. RCTs and cluster RCTs will be pooled separately to NRSIs. We will only include studies deemed at low or moderate risk of bias in our analyses of NRSIs. For NRSIs, unadjusted and adjusted RRs (ORs for case‐control studies) and 95% CIs will be obtained separately. Where there are too few studies to be able to carry out meta‐analyses within the prespecified outcomes, we will consider grouping studies within a broader outcome domain (i.e. allergy outcomes) (McKenzie 2019a; McKenzie 2019b; Thomas 2019). We will carry out meta‐analyses in Review Manager 5 (Review Manager 2014). However, if meta‐analyses are not appropriate, we will undertake a synthesis without meta‐analysis following the SWiM Reporting Guideline (Campbell 2020), presenting individual study results in forest plots and suppressing the summary estimate (Reeves 2019).

Subgroup analysis and investigation of heterogeneity

Where possible, we will perform the following subgroup analyses.

1. Grouped by age at first dose of pertussis‐containing vaccine: less than three months versus three months or greater. Priming with wP or aP in the first months of life may induce differential and long‐lasting T‐cell phenotypes that dictate the immune responses to future doses (Bancroft 2016; da Silva Antunes 2018). In addition, the reactogenicity of wP‐only 'accelerated schedules' or primary courses of wP given at two, three and four months of age, appears to be reduced for pyrexia and injection site reactions, when compared to wP‐only 'long schedules', or doses given at 3, 4.5 to 5 and 8.5 to 11 months of age (Bergman 2014; Miller 1993; Ramsay 1992). Similarly, minor differences in cumulative local and systemic adverse reactions following immunisation have been described for wP compared to accelerated aP‐only doses (Miller 1997). Hence, we estimate that if wP has an allergy protective benefit, this might be stronger in children primed before the age of three months, and the number of serious adverse events following immunisation might be lower compared to recipients of a first dose of wP after three months of age.

2. Grouped by BCG‐vaccinated versus not BCG vaccinated. The Th₁‐polarising properties of BCG, may prevent atopic dermatitis (Steenhuis 2008; Thøstesen 2018) and other allergic diseases in childhood. This in turn could reduce the benefits of priming with wP. Evidence from a meta‐analysis does not support an allergy protective benefit from BCG vaccination; however, it is worth noting that most of the studies included in that synthesis were NRSIs (Linehan 2014).

We will perform subgroup analyses to investigate other factors that may be influencing the risk of developing atopic diseases.

1. Family history of asthma, atopic dermatitis, food allergy, allergic rhinitis/rhino‐conjunctivitis, or a combination of these in first‐degree relatives (only if reported in the eligible studies, or where applicable, if pre‐specified and stratified at randomisation).

2. World Bank income group.

Sensitivity analysis

Where feasible, we will conduct the following sensitivity analyses.

1. Removing studies judged at high risk of bias from any meta‐analyses pooling RCTs.

2. Restricting the analysis to studies in which 'asthma' or 'current asthma' had been diagnosed after the age of five years. Birth cohort studies conducted in Europe have described childhood wheezing phenotypes that tend to self‐resolve before the age of eight years and more persistent patterns that extend beyond preschool age (Savenije 2011). Of interest, persistent patterns that extend beyond preschool age are more likely to be associated with underlying atopy (Savenije 2011). Thus, this sensitivity analysis will explore if wP may have a protective benefit against the development of persistent atopic airway disease.

3. Removing studies funded by pharmaceutical companies/industry.

Summary of findings and assessment of the certainty of the evidence

Two review authors (of GPC, MJE, JR) will independently assess the certainty of the body of evidence as high, moderate, low or very low, using the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness and publication bias) and standard Cochrane methods (Guyatt 2008; Schünemann 2019). The comparison of interest will be the first dose of wP versus aP before the age of six months; and the outcomes we will assess are: diagnosis of IgE‐mediated food allergy, serious adverse events following immunisation with wP or aP, diagnosis of anaphylaxis, diagnosis of asthma and diagnosis of encephalopathy. We will generate the 'Summary of findings' table using GRADEpro GDT software (GRADEpro GDT). Where justified, we will downgrade or upgrade the level of evidence and document all judgements clearly in the footnote. We will resolve discrepancies by discussion or through the arbitration of a third review author (of CBJ, PR, PH or TS). Where synthesis without meta‐analysis is appropriate, we will use narrative outcomes to prepare the 'Summary of findings' tables using the GRADE approach (Guyatt 2008; Santesso 2016; Schünemann 2019), and GRADEpro GDT software (GRADEpro GDT).

History

Protocol first published: Issue 7, 2020

Appendices

Appendix 1. Glossary

Acellular pertussis (whooping cough) vaccine	A whooping cough vaccine prepared from the purified antigenic components of the bacterium Bordetella pertussis. This type of vaccine is usually available in combination with diphtheria and tetanus toxoids.
Allergen	Antigen that can cause an allergic reaction.
Allergic rhinitis or allergic rhino‐conjunctivitis (hay fever)	Allergic reaction to aero‐allergens (e.g. house dust mite, pollens, etc.) that causes itchy nose, nasal congestion, sneezing, itchy/watery eyes, or a combination.
Anaphylaxis	A serious allergic reaction that is rapid in onset and may cause death.
Antibody	See immunoglobulin.
Antigen	Any substance that is recognised by the immune system. Antigens normally trigger a reaction by the immune system.
Asthma	A long‐term condition of the lungs where inflammation causes narrowing and swelling of the airways and increased production of mucous. It commonly manifests as persistent cough, wheezing and difficulty breathing.
Atopic dermatitis (atopic eczema)	A long‐term non‐infectious skin disease that often starts before the age of 12 months, and commonly causes dry, hot, itchy and red skin.
Atopic march	Proposed theory of the disease progression of some allergic illnesses. The theory suggests disease starts in early infancy with eczema, followed by IgE‐mediated food allergy, hay fever and asthma.
Bacillus Calmette‐Guérin (BCG) vaccine	Suspension of a live but weakened strain of the bacterium Mycobacterium bovis, used as a vaccine against tuberculosis.
Beta‐lactoglobulin	The major whey protein of cow's milk. Beta‐lactoglobulin is absent in human's milk.
Case‐control study	A study that compares people with a specific disease or outcome of interest (cases) to people from the same population without that disease or outcome (controls), and which seeks to find associations between the outcome and prior exposure to particular risk factors. This design is particularly useful where the outcome is rare and past exposure can be reliably measured.
Challenge‐confirmed IgE‐mediated food allergy	Diagnosis of Ig‐E mediated food allergy confirmed with a medically supervised oral food challenge.
Chronic‐type inflammation (chronic allergic inflammation)	Long‐term inflammatory response caused by repetitive exposure to a particular allergen. Its main features are the presence of many immune cells at the affected site, as well as changes in the function and external characteristic of the cells within the affected tissue.
Cluster randomised trial	A trial in which clusters of individuals (e.g. clinics, families, geographical areas), rather than individuals themselves, are randomised to different groups.
Cohort study	An observational study in which a defined group of people (the cohort) is followed over time. The outcomes of people in subsets of this cohort are compared, to examine people who were exposed or not exposed (or exposed at different levels) to a particular intervention or other factor of interest. A prospective cohort study assembles participants and follows them into the future. A retrospective (or historical) cohort study identifies participants from past records and follows them from the time of those records to the present.
Comorbidity	The presence of ≥ 1 diseases or conditions other than those of primary interest.
Cytokines	Proteins secreted by a variety of cells, including the immune cells. Cytokines are important regulators of the intensity and duration of the immune response. They can act on the same cell that secreted them, on nearby cells, and more rarely, on distant cells.
Encephalopathy	General term used to describe a disease that alters the functioning of the brain.
Epidermal barrier	See epidermis.
Epidermal barrier disruption	Damage of the external layer of the skin. In people with atopic dermatitis, this may lead to ongoing exposure to allergens (e.g. peanut) and further allergic (IgE‐mediated) sensitisation.
Epidermis	The external (non‐vascular) layer of the skin.
Genomic analysis	Analysis of genomic content using next or third‐generation sequencing technologies.
Immune response	The body's reaction of cells and fluid to a substance that is recognised by the immune system as foreign.
Immunoglobulin	A protein produced by some immune cells that helps the body fight disease. In some cases (e.g. atopic diseases), immunoglobulins may be directly involved in the disease mechanism.
Immunoglobulin E (IgE)	The class of antibody involved in allergic reactions (allergic immune responses).
Immunoglobulin‐E (IgE)‐mediated hypersensitivity reaction	Immune response to a specific allergen (e.g. peanut) that is mediated by immunoglobulin E.
Immunoglobulin‐E (IgE)‐mediated sensitisation	Development of Ig‐E against a specific allergen (e.g. house dust mite).
Immunophenotype	Phenotypic features (types of antigens or markers) of the immune cells.
Lung (pulmonary) function tests	A group of tests that measure how well the lungs work.
Morbidity	Illness or harm.
Non‐communicable diseases	Diseases that are usually long in duration and are not contagious.
Oral food challenge	Medically supervised procedure where small and increasing amounts of a food are fed to a patient, to confirm if the food being tested causes an allergic reaction.
Pathologically skewed Th2 immune responses	Abnormally biased (polarised) Th2 immune response (see T‐cell polarisation and type 2 immune response for further explanation).
Pentavalent vaccine (pentavalent formulation)	In the text, this term alludes a '5‐in‐1' vaccine that provides protection against diphtheria, tetanus, whooping cough (pertussis), hepatitis B and Haemophilus influenzae type b disease. The '5‐in‐1' combination vaccine that this text refers to contains wP.
Phenotype	Observable characteristics of an organism.
Priming	A key process for the generation of vaccine‐specific immune cells.
Randomised controlled trial	An experiment in which ≥ 2 interventions, possibly including a control intervention or no intervention, are compared by being randomly allocated to participants.
Reactogenicity	Local (e.g. injection site redness) and systemic (e.g. fever, diarrhoea) expected reactions that occur following vaccination and are usually mild and self‐limiting.
Spirometrically confirmed asthma	Diagnosis of asthma confirmed by lung function testing.
T‐cell polarisation	Biased or skewed immune response for a T‐cell type(s). This occurs due to the release of cytokines triggered by antigen presenting cells.
Th1 cells	Subset of CD4+ T cells that enhances the immune response against intracellular (within the cell) pathogens (micro‐organisms that can cause disease).
Th17 cells	Subset of CD4+ T cells that enhances the immune response against some fungi and bacteria.
Th2 cells	Subset of CD4+ T cells that enhances the production of IgE and the immune response to helminths (worms) and allergens.
Toxoid	A toxin that has been altered or inactivated and cannot cause disease. Toxoids are used in some combination vaccines (e.g. diphtheria and tetanus toxoids) as they can elicit immune responses.
Type 1 immune response	Immune response to intracellular (within the cell) pathogens (micro‐organisms that can cause disease).
Type 2 cytokines	Cytokines involved in type 2 immune responses (e.g. interleukin‐4, interleukin‐5 and interleukin‐13).
Urticaria	A type of vascular reaction of the skin, characterised by a red or pink itchy rash and the presence of blotches (wheals). Some common conditions that may present with urticaria are infection, stress and allergy.
Variable expiratory airflow limitation	More variation in how much air is blown out (exhaled) than would be expected in a healthy person.
Whole‐cell (whooping cough) pertussis vaccine	A whooping cough vaccine prepared from inactivated Bordetella pertussis. This type of vaccine is mainly available as a pentavalent formulation with diphtheria and tetanus toxoids, Haemophilus influenzae type b and hepatitis B antigens.

Appendix 2. CENTRAL search strategy

1. MeSH descriptor: [Pertussis Vaccine] explode all trees

2. (pertussis vaccin*):ti,ab,kw

3. (Whooping cough vaccin*):ti,ab,kw

4. MeSH descriptor: [Diphtheria‐Tetanus‐Pertussis Vaccine] explode all trees

5. (whole‐cell OR "whole cell" OR wP OR DTwP OR DTPw OR DTP OR DTwcP OR DTPwc) NEAR/5 vaccine

6. MeSH descriptor: [Whooping Cough] explode all trees

7. (whoop*):ti,ab,kw

8. MeSH descriptor: [Bordetella pertussis] explode all trees

9. (pertuss*):ti,ab,kw

10. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

11. #10 with Publication Year from 1970 to present, in Trials

12. child* OR preschool* OR school* OR young OR infant* OR toddler* OR pediatric* OR paediatric*

13. #11 AND #12

Contributions of authors

GPC conceived, drafted the protocol and is the guarantor.

TS provided statistical expertise.

All authors read, provided feedback and approved the final version of the protocol.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Australian Department of Education and Training Endeavour Scholarship; Wesfarmers Centre of Vaccine and Infectious Diseases top‐up scholarship, Telethon Kids Institute; and Forrest Research Foundation supplementary scholarship, Australia

  Funding for GPC PhD

• National Health and Medical Research Council, Australia

  CBJ is supported by an Early Career Fellowship (GNT1142897)

• National Health and Medical Research Council, Australia

  TS is supported by Career Development Fellowship (GNT1111657)

Declarations of interest

GPC: has received travel support from Seqirus to attend a conference (June 2018). Seqirus solely manufacture influenza vaccines and, therefore, are not associated with pertussis vaccines. GPC did not benefit personally from the grant.

MJE: no conflict of interest.

JR: no conflict of interest.

CBJ: no conflict of interest.

PR: his institution (University of Western Australia) received a grant from GlaxoSmithKline. PR did not benefit financially. The research funding was controlled by the University of Western Australia. He served on advisory panels for GlaxoSmithKline (2019) and Sanofi (2019) with no remuneration.

PH: no conflict of interest.

TS: no conflict of interest.

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