Statement on the Booster for 4-6 year-olds for Protection against Pertussis - An Advisory Committee Statement (ACS) - National Advisory Committee on Immunization (NACI)

An Advisory Committee Statement (ACS) - National Advisory Committee on Immunization (NACI) Footnote *

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as the Agency) with ongoing and timely medical, scientific, and public health advice relating to immunization. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Agency's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

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Related Topics

Summary of Information Contained in This NACI Statement

The following summary provides key information for immunization providers. Please refer to the remainder of the Statement for details.

1. What

Children in Canada receive a booster dose of diphtheria (d or D), tetanus (T), acellular pertussis (ap or aP) and inactivated polio vaccine (IPV) - at 4-6 years of age through vaccines that contain combinations of these antigens. There are products with a lower concentration of pertussis antigen (ap) and others with a higher concentration of pertussis antigen (aP). Fewer adverse events (local immunization site reactions) are reported with Tdap-IPV. DTaP-IPV elicits a greater immune response to pertussis, however, the clinical significance of this is not known. Either DTaP-IPV or Tdap-IPV vaccines may be used for the 4- to 6-year-old booster in children. NACI does not preferentially recommend one vaccine over the other.

2. Who

Children 4-6 years of age who are scheduled to receive booster vaccines.

3. How

One dose of combined diphtheria, tetanus, acellular pertussis and inactivated polio vaccine product should be administered intramuscularly.

4. Why

Pertussis continues to occur in a cyclic pattern every 2-5 years, therefore ongoing protection is needed.

I. Introduction

The purpose of this statement is to review the literature relevant to the 4- to 6-year-old preschool booster immunization and provide updated recommendations as required. Current recommendations for the 4- to 6-year-old preschool booster include additional doses of diphtheria, tetanus, acellular pertussis and polio containing vaccine (DTaP-IPV or Tdap-IPV). These four components are usually given as a single injection. In Canada, there are products approved for use that contain either a lower concentration of pertussis and diphtheria [Tdap-IPV (Adacel®-Polio, Boostrix®-Polio)] or higher concentration of pertussis and diphtheria [DTaP-IPV (Quadracel®, Infanrix™-IPV)]. According to the Canadian Immunization Guide (CIG), products with either higher or lower concentration of can be used between 4 and 6 years old.

In January 2012, there was an impending shortage of Quadracel® which prompted a review of other currently available vaccines that could serve as alternatives to Quadracel®.

The question NACI investigated and answers in this statement is:

  • Should there be a preferential recommendation for either low or high concentration pertussis product for children at 4-6 years of age?

II. Methods

NACI reviewed the key questions and literature review proposed by the Tetanus, Diphtheria, Pertussis and Polio Working Group including such considerations as the burden of illness of the disease to be prevented and the target population(s), safety, immunogenicity, efficacy, effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall immunization strategy. The knowledge synthesis was performed by two medical specialists and a research coordinator and supervised by the Tetanus, Diphtheria, Pertussis and Polio Working Group.

In conjunction with Library Services at Public Health Ontario (PHO), a literature search was designed to address the questions tasked to the NACI Tetanus, Diphtheria, Pertussis and Polio Working Group. Results of the literature search were assessed for inclusion by a single reviewer and studies included were limited to immunization of pre-school/early school-age children who had been primed with acellular pertussis products. Nineteen studies were relevant.

Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy (Tables 5 and 6) were prepared, and proposed recommendations for vaccine use developed. The Working Group chair and PHAC medical specialist presented the evidence and draft statement to NACI on February 7th, 2012. Following further review of the evidence and statement by NACI, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.

For further information, NACI methodology has been summarized in  Evidence-Based Recommendations for Immunization: Methods of the NACI, January 2009, CCDR.

What follows is information on 4- to 6-year-old diphtheria, tetanus, pertussis and polio boosters in Canada and vaccines approved for this use; vaccine product options framed based on the question presented to NACI (including relevant epidemiology, efficacy, effectiveness, immunogenicity and safety/adverse event information) along with further information regarding research priorities and surveillance issues.

III. Canadian 4- to 6-year-old Booster Programs

There is some variability in diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type B (Hib) schedules in Canada (see Table 1), for the most part with respect to the inclusion of hepatitis B immunization in infancy and the timing of the adolescent tetanus-diphtheria- acellular pertussis (Tdap) booster. As of 2011, all provinces and territories, with the exception of Québec, gave diphtheria, tetanus, acellular pertussis and polio containing vaccine to 4- to 6- year-olds which contained the same concentrations of these antigens as is included in the infant doses (DTaP-IPV). In April 2011, Québec changed to Tdap-IPV, a product with a lower concentration of diphtheria and pertussis antigens, for the 4- to 6-year-old tetanus-diphtheria- acellular pertussis-polio booster.Footnote 1 See Table 2 for further details.

Table 1: Routine schedules for publicly-funded infant to adolescent pertussis-containing vaccine immunization programs in Canada (2011). Footnote a
Province/ Territory DTaP-HB- IPV-Hib DTaP-IPV-Hib DTaP- IPV Tdap- IPV Tdap

Notes: Personal Communication, Julie Laroche, Manager, Immunization Assessment and Information, Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada

NACI
recommendation
2, 4, 6, 18
months
4-6 years (either product may be used) 10 years after the previous booster (14-16 years in general)
BC 2, 4, 6 months 18 months 4-6
years
Grade 9, Jan 2004
AB 2, 4, 6, 18
months
4-6
years
Grade 9, Sep 2004
SK 2, 4, 6, 18
months
4-6
years
Grade 8, Sep 2003
MB 2, 4, 6, 18
months
4-6
years
14-16 years,
Aug 2003
ON 2, 4, 6, 18
months
4-6
years
14-16 years,
Dec 2003
QC 2, 4,6, 18
months
4-6
yearsFootnote b
Grade 9, Sep 2004
NL 2, 4, 6, 18
months
4-6
years
Grade 9, Sep 1999
NB 2, 4, 6, 18
months
4 years Grade 9 (Sep
2004) changed to
Grade 7 in
(Sep 2012)
NS 2, 4, 6, 18
months
4-6
years
Grade 7, Sep 2007
PE 2, 4, 6, 18
months
4-6
years
Grade 9, Fall 2003
YK 2, 4, 6 months 18 months 4-6
years
Grade 9, Spring 2004
NT 2, 4, 6, 18
months
4-6
years
Grade 9, Oct 2000
NU 2, 4, 6, 18
months
4-6
years
Grade 9 (14-16 years), Sep 2002

Following the Quadracel®  shortage, which began in the winter of 2012, all Canadian provinces and territories, except for Saskatchewan and the Northwest Territories, changed to Tdap-IPV for the 4- to 6-year-old tetanus, diphtheria, acellular pertussis and polio booster. See Table 2.

Table 2: Post Quadracel® Shortage (as of June 2013) routine schedules for publicly- funded infant to adolescent pertussis-containing vaccine immunization programs in Canada Footnote a Footnote b
Province/ Territory DTaP-HB- IPV-Hib DTaP-IPV-Hib DTaP- IPV Tdap- IPV Tdap

Notes:

NACI recommendation 2, 4, 6, 18
months
4-6 years (either product may
be used)
10 years after the previous booster (14-16 years in general)
BC 2, 4, 6 months 18 months 4-6
years
Grade 9
AB 2, 4, 6, 18
months
4-6
years
Grade 9
SK 2, 4, 6, 18
months
4-6
years
Grade 8
MB 2, 4, 6, 18
months
4-6
years
14-16 years
ON 2, 4, 6, 18
months
4-6
years
14-16 years
QC 2, 4, 18
months
6 months 4-6
years
Third year of high school
NL 2, 4, 6, 18
months
4-6
years
Grade 9
NB 2, 4, 6, 18
months
4 years Grade 7
NS 2, 4, 6, 18
months
4-6
years
Grade 7
PE 2, 4, 6, 18
months
4-6
years
Grade 9
YK 2, 4, 6 months 18 months either 4-6 years either 4-6 years Grae 9
NT 2, 4, 6, 18
months
4-6
years
Grade 9
NU 2, 4, 6, 18
months
4-6
years
Grade 9 (14-16 years)

IV. Vaccines

Characteristics of vaccines approved for use in Canada for the 4-6 year old diphtheria, tetanus, acellular pertussis and polio booster are shown in Table 3 below. Note that Boostrix®-Polio and Adacel®-Polio received notice of compliance in the 4 to 6 year age group in 2008 and 2010, respectively.Footnote 2Footnote 3

Table 3: Preparation(s) authorized for use in Canada (e.g. description, composition) Footnote *
Brand name Quadracel® Adacel® -Polio Boostrix® -Polio I
Infanrix™ -IPV

Legend: Diphtheria tetanus, acellular pertussis (DTaP), Diphtheria, tetanus, whole cell pertussis (DTwP), Pertussis Toxin (PT), micrograms(µg) Filamentous Hemagglutinin (FHA), Pertactin (PRN), Fimbriae Antigen (FIM), Limit of flocculation (Lf), D-antigen units (DU).

Antigens DTaP-IPV Tdap-IPV Tdap-IPV DTaP-IPV
Manufacturer Sanofi Sanofi GSK GSK
Authorization -primary and booster immunization 2 months up to 6 years of age (prior to 7th birthday) -booster dose 4 years of age and above
-in children 4 to 6 years of age, may be considered as an alternative for the 5th dose of DTaP-IPV
-booster dose 4 years of age and above
-not intended for primary immunization
- booster dose up to and including 6 years of age, who have previously been immunized with three or four doses of DTaP vaccine or DTwP vaccine
PT (µg) 20 2.5 8 25
FHA (µg) 20 5 8 25
PRN (µg) 3 3 2.5 8
FIM 2/3 (µg) 5 5 - -
Diphtheria Antigen (Lf) 15 2 2.5 25
Tetanus (Lf) 5 5 5 10
Polio 1/2/3 Antigens (DU) 40/8/32 40/8/32 40/8/32 40/8/32

Further information on the antigens can be found in section V.3 (page 9) of this statement.

V. Should There Be a Preferential Recommendation for Either Lower or Higher Concentration of Antigen Products for Children at 4 to 6 Years of Age?

V.1 Epidemiology of Pertussis in Canada

Pertussis is a cyclical disease, which peaks at two to five year intervals. With the introduction of the whole-cell pertussis vaccine in 1943, the incidence of pertussis decreased significantly in Canada, from an average of 165 cases per 100,000 population from 1933 to 1943 to a low annual average of 6.7 cases per 100,000 from 2001 to 2011.Footnote 4  A resurgence of pertussis was observed beginning in 1990. This was likely due to a combination of factors, including the low effectiveness of the combined adsorbed diphtheria-tetanus-pertussis whole-cell vaccine given to children in Canada between 1981 and 1998, waning immunity from the previous vaccine among adolescents and adults, as well as increased physician awareness and improved diagnosis and reporting of pertussis infection.Footnote 5 The whole cell vaccines were replaced with acellular vaccines made from purified antigens of B. pertussis in 1997/98 in Canada.

The incidence of pertussis is highest in infants and children, and decreases sharply among those older than 14 years. Average incidence rates from 2007 to 2011 were highest among infants less than 1 year of age at 64.0 cases per 100,000 population, followed by 1- to 4 year olds (20.5 cases per 100,000), and 10- to 14-year-olds (11.6 cases per 100,000).Footnote 4 In the 1990's, an increase in incidence was observed in adolescents and adults due to low vaccine effectiveness in the population cohort that was immunized with the vaccine available between 1981 and 1999.Footnote 5 Adolescents constituted a major reservoir for the disease and were  an important source of transmission to infants. As such, in 2003 the NACI recommended a single dose of the adolescent/adult formulation of the combined diphtheria-tetanus-acellular pertussis vaccine (Tdap). This was incorporated into vaccine programs across Canada by the end of 2004. The incidence of pertussis has decreased in the 15 to 19 year age group from 18.7 cases per 100,000 population in 2003 to 1.7 cases per 100,000 population in 2011.Footnote 4  NACI has also recommended all adults receive one dose of Tdap if not previously immunized in adulthood.

Since the last major peak in 1998, pertussis incidence in Canada had been on a steady decline. However, in 2012, all Canadian provinces and territories reported an increase in pertussis activity with the exception of Saskatchewan, Prince Edward Island, Newfoundland and Labrador and Nunavut. New Brunswick in particular experienced a significant increase in activity following a province-wide outbreak that began in early 2012. Based on preliminary data, 4845 cases were reported in 2012 in Canada, corresponding to a national incidence of 14.1 cases per 100,000 population. Three deaths were reported, all in previously well infants less than seven months of age. The increased incidence occurring across the country is not limited to one specific age group or to those who are unimmunized but instead varies by jurisdiction.Footnote 4

V.2 Effectiveness of 4-6 year-old Pertussis Booster Vaccines

Literature regarding the effectiveness of pertussis-containing pre-school booster vaccines is summarized in Table 7. Two recent studies have suggested a waning of immunity over the five years after the fifth dose of DTaP.Footnote 6 Footnote 7 In Klein and co-authors' study, after the 5th dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year in those vaccinated more than five years before.Footnote 6 Misegades and colleagues investigated the vaccine effectiveness in children after receipt of five doses of pertussis containing vaccine.Footnote 7 Using a case-control design, they showed that vaccine effectiveness declined each year after the 5th dose of DTaP. Their estimates of VE based on time since the 5th dose were for those within one year of receipt 98.1% (95% CI 96.1 - 99.1), 12-23 months since last dose 95.3% (95% CI 91.2-97.5), 24-35 months since last dose 92.3% (95% CI 86.6%-95.5%), 36-47 months since last dose 87.3% (95% CI 76.2-93.2), 48-59 months since last dose 82.8% (95% CI 68.7-90.6) and in those greater than 60 months from last dose of DTaP 71.2% (95% CI 45.8 - 84.8).Footnote 7

Comparative effectiveness of high versus low potency pertussis formulations as a 4- to 6-year- old booster dose has not been studied, and it is not known whether higher antigenic content of the pertussis vaccine is associated with higher levels of protection.

V.3 Immunogenicity of 4- to 6-year old Pertussis Booster Vaccines (including Evidence for Adequacy of Correlates of Immunity)

To provide an understanding of the different antigens and their functions we have included a short primer on humoral antibodies used by the regulator, Health Canada, to assess immune response to pertussis vaccines (in the absence of defined correlates of protection for pertussis). Pertussis toxin (PT) has a few activities including binding to the host cells, induction of lymphocytosis and modifying the immune response. Antibodies to PT develop after natural infection as well as vaccination. Filamentous hemagglutinin (FHA) is a protein that is secreted by B. pertussis. It plays a major role in the adhesion to epithelium cells in a host. Pertactin (PRN) is a highly immunogenic surface protein that promotes binding to host cells. Fimbriae types 2 and 3 (FIM 2/3) are surface components of B. pertussis and are involved in colonization of the nasopharynx. Some or all of  these components are included in various vaccines that are currently used in Canada (please refer to Table 3). Antibodies against each of these components are measured and compared to the immune responses from historical efficacy trials. Protection is likely conferred by the interplay of the above antibodies in conjunction with cell mediated immunity.Footnote 8

Serological correlates of protection have been defined for diphtheria and tetanus.

A number of studies have shown that both higher and lower concentration acellular pertussis products are able to elicit immune responses. Publications obtained with respect to 4- to 6-year- old pertussis booster immunogenicity are shown in Table 7. There are a total of four studies that have investigated the use of ap after priming with aP in the childhood immunization schedule Footnote 9-11. Of these, only two were randomized controlled trials of ap versus aP. In the Ferrara et al. study (2012),Footnote 9 Boostrix®-Polio (GSK) (Tdap-IPV) was compared head to head with Tetravac® (Sanofi), a two-pertussis-component aP product not available in Canada. It should be noted that these children received only three doses of priming, as compared to the Canadian schedule that recommends a three dose primary series and one booster (at 18 months) prior to the 4- to 6- year-old booster dose. The reduced content product provided a non-inferior immune response to the full strength product when immunogenicity was measured to the two common components one month after immunization.Footnote 9 One other study (Langley et al. 2006)Footnote 10 investigated the immunogenicity of lower content pertussis and diphtheria containing vaccine Adacel® (Sanofi) (Tdap) with a higher content pertussis and diphtheria content vaccine Quadracel® (DTap-IPV).Footnote 10 This was a Canadian study; therefore children received three primary doses and 18 month booster prior to immunization at 4-6 years of age. The majority of children in both arms of this study had a four-fold rise in their pertussis antibodies approximately one month after immunization.Footnote 10 The study by Scheifele et al.Footnote 27 used the same two products as the Langley et al.Footnote 10 study and was also done in Canadian children. The study primary objectives related to safety but the investigators also reported on serum antibody concentrations before and 4 weeks after booster immunization. GMC values for PT were significantly higher in the DTaP-IPV group than in the Tdap group while the GMC values for FIM 2/3 were significantly higher in the Tdap group. The clinical significance of this finding is unknown.

Children in the Langley et al.Footnote 10 study were followed for five years after the 4-to 6-year-old booster and PT responses were lower in the ap group versus the aP group at that time (data on file, Sanofi). The responses to other antigens were similar between the two groups, five years after immunization. The clinical significance of these findings are unknown. One other study provided information on long term durability of immune response (Meyer, 2008).Footnote 12 In a subset analysis of about 120 subjects, anti-PT, anti-FHA and anti-PRN antibodies were similar between both Boostrix® (GSK) (Tdap) and Infanrix™ (GSK) (DTaP) at 3.5 years after the 4-to 6-year-old booster.Footnote 12

V.4 Adverse Events Associated with 4- to 6-year-old Pertussis Booster Vaccines

All products approved for use in Canada for the diphtheria, tetanus, pertussis and polio booster dose at 4-6 years of age are safe. Below is a brief summary of the safety data from studies of these vaccines, as well as available Canadian safety data (see Table 7 for details of the studies).

Large local reactions are the primary safety concern with DTaP-containing vaccinesFootnote 13-17 Footnote 27 although the frequency with which they occur is variable, depending on the study. The highest rate of large local reaction seen in studies of DTaP-IPV was reported by Nilsson.Footnote 14  In this study of 416 Italian and Swedish 4-6 year olds, "any large swelling reaction" (at least one of: > 50mm, diffuse swelling, or swelling to ≥ 1 adjacent joint) occurred in 13.5% of DTaP-IPV recipients and 17.4% of DTaP recipients.Footnote 14   Four studies compared the safety of aP versus ap products (Ferrera, Meyer, Langley, Scheifele)Footnote 9 Footnote 10 Footnote 12 Footnote 27 and in all of these, the proportion of children who experienced  signs and symptoms of  local  reaction  was  smaller  in the ap groups.  Overall frequency of local reactions and differences between aP and ap groups varied across studies.Footnote 9 Footnote 10 Footnote 12 Footnote 27

Systemic reactogenicity was similar among children who received DTaP-IPV and those who received Tdap+/-IPV in the four trials comparing aP to ap products.Footnote 9 Footnote 10 Footnote 12 Footnote 27 Fever was generally the most common systemic reaction and frequency of its occurrence ranged from < 10% to > 20%. There were no vaccine-attributable serious adverse events in these four studies.

The Québec provincial Adverse Events Following Immunization Surveillance System detected an increased frequency of large local reactions with the 4-6 year DTaP-IPV booster. This was consistent with clinical trials that had shown greater reactogenicity with the higher antigen product. Due to increasing reports of large local reactions when children who received primary immunization with exclusively acellular pertussis-containing vaccine were given the 4-6 year booster, that province decided to change to Tdap-IPV for the 4-6 year booster in 2011, prior to the Quadracel® shortage.Footnote 1 Since then, as expected, there has been a decrease in the number of reports of immunization site reactions experienced after the 4-6-year booster dose (personal communication, Eveline Toth, ministère de la Santé et des services Sociaux du Québec).

Data from the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) is consistent with pre- and post-marketing studies that show that DTaP-IPV is very safe. Looking at reporting trends over time in CAEFISS it is clear that adverse events are much less frequently reported following acellular pertussis products than they were when whole cell pertussis products were used. Hospitalizations for large local reactions, which may be diagnosed as cellulitis, are not frequently reported to CAEFISS.Footnote 18

Based on review of the available literature, there appears to be waning immunity after the 4-to 6-year-old DTaP booster, as demonstrated by recent studies of vaccine effectiveness. In trials comparing ap versus aP boosting among children primed with aP vaccines, the high concentration product produces a greater antibody response. The clinical significance of this is unknown given the lack of correlates of protection. Local reactogenicity is less common with ap versus aP.

VI. Recommendations

Please note that provinces and territories must consider economic factors and other local programmatic/operational factors, as well as local epidemiology when considering inclusion of the following recommendations in publicly funded immunization programs.

"Should there be a preferential recommendation for either low or high dose pertussis product for children at 4-6 years of age?"

Recommendation: Either DTaP-IPV or Tdap-IPV vaccines may be used for the 4- to 6-year-old booster in children. NACI does not preferentially recommend one vaccine over the other.

As outlined in this statement, NACI did a thorough review of issues related to safety, effectiveness and immunogenicity. Adverse events are less common with Tdap-IPV than with DTaP-IPV, however DTaP-IPV may elicit a higher and more durable immune response although the correlates of protection for pertussis are not definitive. Based on this level of uncertainty, it would be important to consider the epidemiology in a province/territory and the public's response to local reactions following vaccination when determining which product to choose.

NACI recommendation Grade C

VII. Research Priorities

Research to address the following outstanding questions is encouraged:

  • Establishment and better understanding of pertussis correlates of protection;
  • Further investigation into longevity of protection provided by pertussis containing vaccines and whether the adolescent dose should be given sooner;
  • Comparison of various pertussis-containing products (i.e. ap vs. aP) with respect to vaccine effectiveness, duration of protection, immunogenicity and safety, including the impact of using different products for both priming and boosting on duration of protection;
  • Better understanding of pertussis immunity through serosurveys or studies of infected and uninfected household contacts of cases of pertussis;
  • Improved understanding of the natural history of pertussis immunity; and
  • Development of vaccines with greater effectiveness.

VIII. Surveillance Issues

Ongoing and systematic data collection, analysis, interpretation and timely dissemination are fundamental to planning, implementation, evaluation, and evidence-based decision-making. Tetanus, diphtheria, pertussis and polio are nationally notifiable. To support such efforts, NACI encourages surveillance improvements in the following areas:

  1. Epidemiology
    • Further investigation into the role of waning immunity in the epidemiology of pertussis.
  1. Laboratory
    • Improved laboratory methods for pertussis detection including the use of serology and oral fluid diagnosis;
      Contribution of non-Bordetella pertussis species (e.g. Bordetella holmesii).
  2. Vaccine
    • Immunization registry to improve accuracy of coverage reporting;
    • Vaccine effectiveness;
    • Ongoing, timely vaccine safety surveillance.
Table 4. Levels of Evidence Based on Research Design
Level Description
I Evidence from randomized controlled trial(s).
II-1 Evidence from controlled trial(s) without randomization.
II-2 Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.
Table 5. Quality (internal validity) Rating of Evidence
Quality Rating Description
Good A study (including meta-analyses or systematic reviews) that meets all design specific criteriaFootnote * well.
Fair A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterionFootnote * but has no known "fatal flaw".
Poor A study (including meta-analyses or systematic reviews) that has at least one design- specificFootnote * "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
Table 6. NACI Recommendation for Immunization -- Grades
Grade Recommendation
A NACI concludes that there is good evidence to recommend immunization.
B NACI concludes that there is fair evidence to recommend immunization.
C NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization; however other factors may influence decision-making.
D NACI concludes that there is fair evidence to recommend against immunization.
E NACI concludes that there is good evidence to recommend against immunization.
F NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making.

List of Abbreviations

ap
Acellular pertussis (low concentration pertussis)
aP
Acellular pertussis (high concentration pertussis)
CIG
Canadian Immunization Guide
DTaP
Diphtheria, tetanus, acellular pertussis vaccine (high concentration diphtheria and pertussis)
DTaP-IPV
Diphtheria, tetanus, acellular pertussis, inactivated polio vaccine (high concentration diphtheria and pertussis)
DTaP-IPV-Hib
Diphtheria, tetanus, acellular pertussis, inactivated polio, Haemophilus influenza type b vaccine (high concentration diphtheria and pertussis)
GPEI
Global Polio Eradication Initiative
IPV
Inactivated polio vaccine
OPV
Oral poliovirus vaccine
Tdap
Tetanus, diphtheria, acellular pertussis vaccine (low concentration diphtheria and pertussis)
VAPP
Vaccine associated paralytic poliomyelitis
WPV
Wild poliovirus

Table7. Summary of Evidence for NACI Recommendations

Evidence
STUDY DETAILS SUMMARY
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality
No efficacy or effectiveness studies found in literature search.
Evidence for Effectiveness
STUDY DETAILS SUMMARY
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality
Study Vaccine: DTaP-IPV (Infanrix™-IPV, GSK) or DTaP (Infanrix™, GSK)+IPV
Torvaldsen S et al. Pediatr Infect Dis J 2003Footnote 19 DTaP
(may be DTaP-IPV or DTaP + IPV,
not stated in paper) Infanrix™- IPV or Infanrix™+IP V

Cohort (nationally notifiable diseases surveillance system)

Pertussis case definition: lab- confirmed, or epi-linked to lab-confirmed, or fulfilled clinical case definition without laboratory tests

All residents of Australia, 1993-2001

Fifth dose of pertussis-containing vaccine introduced 1994 (initially 4-5 years of age, from 1996 4 years of age). In 1999, all doses changed from wP to aP

Findings:
"from the time that 5- to 9-year-olds have been eligible to receive the 5th dose, their notification rates have become progressively lower"

Comparing 1997 and 2001 epidemic years:
- ≥ 100/100 000 notifications per year among all of 5-7 years of age in 1997 (only 5 & 6 years of age eligible for 5th dose) whereas < 50/100 000 notifications per year among same age groups (all eligible for 5th dose) in 2001

II-2

n/a (surveillance study)

Study Vaccines: DTaP-IPV (Infanrix™-IPV, GSK and Quadracel®, Sanofi Pasteur) or DTaP (Infanrix™, GSK andDaptacel®, Sanofi Pasteur)+IPV
Klein et al.,
New England
J Med
Sept 2012Footnote 6
DTaP with
and without
combined
IPV. Both
GSK and
Sanofi
products
used
(confirmed
with study
authors).

Retrospective
Case-control,
single health
maintenance
organization
(HMO)*

Cases:
pertussis
PCR+ Jan
2006-June
2011; had
received DTaP
between 47-84
months of age;
aP primed

Controls:
1) PCR - and
had 5th dose
DTaP
2) Matched
controls (sex,
age, race,
clinic), had 5th
dose DTaP

*Also used entire HMO cohort to calculate incidence

n=277 cases
age 4-12
years, 2006-
2011

n=3318 PCR-
controls

n=6086
matched
controls
Objective: examination of DTaP
waning immunity in highly-
vaccinated school-aged population
who had only received aP
products; in setting of 2010
California pertussis outbreak

Key Findings:
Pertussis incidence 2006-2011:
< 1 year: 115/100 000/ year
5 year: 29/100 000 / year
10 &11 years of age: 226/100
000/year

Time since fifth DTaP (cases versus  PCR- controls):
1699 days (95% CI: 1627, 1772) vs
1028 days (95% CI: 1003, 1053)
p < 0.001

Odds of pertussis per year after
fifth DTaP:
Cases vs. PCR- controls: OR 1.42
(95% CI: 1.21, 1.66)
Cases vs. Matched controls: OR
1.50 (95% CI: 1.13, 2.00)
II-2 Good
Misegades et al. J Amer Med Assoc 2012Footnote 7 DTaP with and without combined IPV.
Assumed both GSK and Sanofi products as both licensed in USA.

Case-control (retrospective and prospective), 15 California counties
Jan 1st to Dec 14th, 2010.

Cases: suspected, probable, and confirmed pertussis cases among 4-10 year olds
Controls: 4-10 year olds who received care from same clinicians as cases

n=682 cases, 4-10 years,
2010

n=2016
controls,
4-10 years,
2010

Objective: assess association between pertussis disease and receipt of 5 doses of aP-containing vaccine by time since 5th dose

Key findings:
Estimated VE ([1-OR] x 100%) for 5 doses aP = 88.7% (95% CI: 79.4, 93.8)

< 12 months from receipt of 5th dose, estimated VE 98.1% (95%
CI: 96.1, 99.1)
≥ 60 months from receipt of 5th dose, estimated VE = 71.2% (95%
CI: 45.8, 85.4)

Estimated decline in VE from < 12 months to ≥ 60 months since 5th aP was 27.4%

II-2 Good
Evidence for Immunogenicity
STUDY DETAILS SUMMARY
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality
Study Vaccine: DTaP-IPV (Infanrix™-IPV, GSK)
Nilsson et al. Scand J Infect Dis 2005Footnote 14 DTaP-IPV
(Infanrix™- IPV) vs DTaP (Infanrix™+ IPV)
Open, randomized
-7 sites in Italy and Sweden
n =416
- 4-6 years (previously received 3 dose primary series)

Outcomes: Evaluation of immunogenicity of DTaP-IPV vs. DTaP + IPV prior to and one month post-immunization

Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml Poliovirus ≥ 1:8
Seropositivity defined as: Pertussis (PT, FHA, PRN)
≥ 5 EL.U/ml
Vaccine response to pertussis (PT, FHA, PRN) defined as: seropositivity in those seronegative at baseline or 2-fold increase in antibody concentrations in those seropositive at baseline

Key findings: Seroprotection/positivity one month after vaccine, DTaP-IPV vs.
DTaP+IPV, % (95% CI)

Anti-diphtheria:
99 (96.6-99.9) vs. 100 (98.1-100)

Anti-tetanus:
100 (98.2-100) vs. 100 (98.1-100)
Anti-PT:
100 (98.2-100) vs. 99.5 (97.1-100)

Level I Fair
Marshall et al. Vaccine Aug 2006Footnote 20 DTaP-IPV
(Infanrix™- IPV) vs DTaP (Infanrix™) + IPV
Open-label, randomized, non-inferiority, Phase IIIb
- 3 Australian Centres
n=366 (362
vaccinated)
-4-6 years

Outcomes:
Evaluation of immunogenicity of DTaP-IPV+MMR vs. DTaP
+IPV+MMR, pre- and 21 to 48 days post immunization; also examined MMR immunogenicity

Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml Poliovirus ≥ 1:8
Seropositivity defined as: Pertussis (PT, FHA, PRN)
≥ 5 EL.U/ml
Measles > 150mIU/ml Mumps ≥ 231 U/mL Rubella ≥ 4 and ≥ 10 IU/ml Key findings:
Seroprotection/positivity 21-48 days after vaccine, DTaP- IPV+MMR vs. DTaP+IPV+MMR, % (95% CI)
Anti-diphtheria:
100 (97.8-100) vs. 100 (97.7-100)
Anti-tetanus:
100 (97.8-100) vs. 100 (97.7-100)
Anti-PT:
99.4 (96.7-100) vs. 100 (97.7-100)
Anti-FHA:
100 (97.9-100) vs. 100 (98-100)
Anti-PRN:
100 (97.8-100) vs. 100 (97.7-100)
Anti-polio1:
100 (97.7-100) vs. 100 (97.6-100)
Anti-polio2:
100 (97.6-100) vs. 100 (97.6-100)
Anti-polio3:
100 (97.6-100) vs. 100 (97.5 -100)
Anti-measles:
100 (97.8-100) vs. 99.4 (96.6-100)
Anti-mumps:
100 (97.6-100) vs. 100 (97.7-100)
Anti-Rubella ≥ 4 IU/mL:
100 (97.8-100) vs. 100 (97.7-100)
Anti-Rubella ≥ 10 IU/mL:
100 (97.8-100) vs. 100 (97.7-100)

Level I Fair
Black et al. Pediatr Infect Dis J April 2008Footnote 17 DTaP-IPV
(Infanrix™- IPV) vs.
DTaP
(Infanrix™)
+IPV
Open randomized Phase III randomized study
-24 US centers
N=4209

Outcomes: DTaP-IPV vs. DTaP+IPV post booster subjects seroprotected
Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml Poliovirus ≥ 1:8
Pertussis ≥ 5 EL.U/ml Measles ≥ 150mIU/ml Mumps ≥ 1:28
Rubella ≥ 10 IU/ml

Booster - 4X pre-vaccination Ab level

Key Findings: seroprotection one month after vaccine, DTaP-IPV vs. DTaP+IPV, % (95% CI)
Anti-diphtheria:
100 (99.6-100) vs. 100 (98.6-100)
Anti-tetanus:
100 (99.6-100) vs. 100 (98.6-100)
Anti-PT:
99.8 (99.2-100) vs. 100 (98.6-100)
Anti-FHA:
100 (99.6-100) vs. 100 (98.6-100)
Anti-PRN:
100 (99.6-100) vs. 100 (98.6-100)
Anti-polio1:
99.9 (99.3-100) vs. 100 (98.5-100)
Anti-polio2:
100 (99.6-100) vs. 100 (98.5-100)
Anti-polio3:
100 (99.5-100) vs. 100 (98.5-100)

Level I Fair
Klein et al. Vaccine Jan 2012Footnote 21 DTaP-IPV
(Infanrix™- IPV)
Open-label, randomized, non-inferiority, Phase IIIb
- 11 US
Centres
n =478
(461
completed active phase)
- 4-6 years

Outcomes:
Evaluation of immunogenicity of DTaP-IPV+ MMR + V vs. DTaP-
IPV + MMR, pre and one month post; did not study immunogenicity of MMR or V
Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml Poliovirus ≥ 1:8
Pertussis (PT, FHA, PRN)
≥ 5 EL.U/ml

Booster response defined as: Diphtheria and tetanus ≥ 0.4 IU/ml in those seronegative at baseline and ≥ 4 times pre-vaccination anti- body in those seropositive at baseline
Poliovirus presence of antibodies in those seronegative at baseline or ≥ 4 times baseline antibody in those with pre-booster antibodies ≥ 1:8 Pertussis (PT, FHA, PRN) ≥ 20EL.U/ml in those seronegative at baseline;  ≥ 4 times baseline antibody in those with baseline antibodies between ≥ 5 EL.U/mL and < 20 EL.U/mL; ≥ 2 times baseline in those with baseline antibodies ≥ 20 EL.U/mL
Key Findings: Seroprotection one month after immunization, DTaP- IPV + MMR + V and DTaP-IPV +
MMR groups combined
% (95% CI)
Anti-diphtheria: 100 (98.3-100)
Anti-tetanus: 100 (98.3-100)
Anti-PT: 100 (98.3-100)
Anti-FHA: 100 (98.3-100)
Anti-PRN: 100 (98.3-100)
Anti-polio1: 100 (98.3-100)
Anti-polio2: 100 (98.3-100)
Anti-polio3: 100 (98.3-100)
Key Findings: Booster response one month after immunization, DTaP-IPV + MMR + V vs. DTaP- IPV + MMR  % (95% CI)
Anti-diphtheria:
99.1 (96.6-99.9) vs. 99.0 (96.6-99.9)

Anti-tetanus:
98.6 (95.9-99.7) vs. 97.6 (94.5- 99.2)

Anti-PT:
95.0 (91.2-97.5) vs. 95.7 (92.0- 98.0)
Anti-FHA:
98.6 (96.0-99.7) vs. 99.5 (97.4-100)
Anti-PRN:
100 (98.3-100) vs. 98.6 (96.0-99.7)
Anti-polio1:
98.1 (95.3-99.5) vs. 96.7 (93.2- 99.6)
Anti-polio2:
95.3 (91.6-97.7) vs. 98.1 (95.2- 99.5)
Anti-polio3:
99.1 (96.7-99.9) vs. (95.2-99.5)

Level I Fair
Study Vaccine: Tdap-IPV (Boostrix®-Polio, GSK)
Sanger et al. Eur J Pediatr Dec 2007Footnote 11 Tdap-IPV (Boostrix®- Polio) vs. Tdap (Boostrix®)
+IPV
Partially blinded, randomized controlled trial (one injection vs. two injections not blinded)
-59 centers in Germany
n=959
4-8 years subset n=566 for one year follow up
Outcomes:
Evaluation of immunogenicity of Tdap-IPV vs. Tdap+IPV pre and one month post, subset with 1 year follow-up
Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml Poliovirus ≥ 1:8
Pertussis (PT, FHA, PRN) 2 fold rise in Ab titres in initially seropositive subjects and appearance of antibodies (cut-off 5 EL.U/mL) in initially seronegative subjects
Key Findings: Seroprotection one year post immunization,
Tdap-IPV vs. Tdap+IPV,
% (95% CI)
Anti-diphtheria:
100 (99-100) vs. 100 (94.4-100)
Anti-tetanus:
99.8 (98.8-100) vs. 98.8 (93.3-100)
Anti-PT :
81.2 (77.4-84.6) vs. 75.3 (64.5- 84.2)
Anti-FHA:
100 (99.2-100) vs. 98.8 (93.3-100)
Anti-PRN:
98.1 (96.4-99.1) vs. 97.5 (91.4- 99.7)
Anti-polio1:
100 (99.2-100) vs. 100 (95.4-100)
Anti-polio2:
100 (99.2-100) vs. 100 (95.4-100)
Anti-polio3:
99.8 (98.8-100) vs. 98.6 (92.4-100)
Level I Fair
Ferrera et al. Hum Vaccin Immuno-ther March 2012Footnote 9 Tdap-IPV (Boostrix®- Polio)
Vs. DTaP- IPV
[Tetravac] (PT &FHA
containing Sanofi product, not available in Canada) both co- adminstered with MMRV
Randomized controlled trial
-multicentered Italy
n=305
5-6 year olds

Outcomes: Evaluation of immunogenicity of Tdap-IPV vs. TDaP-IPV pre and one month post booster
Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml Poliovirus ≥ 1:8
Pertussis (PT, FHA, PRN) 2 fold rise in Ab titres in initially seropositive subjects and appearance of antibodies (cut-off 5 EL.U/mL) in initially seronegative subjects.

Non-inferior seroprotection defined as: upper limit of standardized asymptotic 95% CI on group difference ≤ 10% (diphtheria, tetanus, polio)
Key Findings: Tdap-IPV vs. DTaP- IPV, seroprotection one month post booster

Seroprotection with anti-diphtheria, anti-tetanus, anti-polio(1,2,3), anti- PT and anti-FHA in all subjects (anti-FHA in 99.3% of Tdap-IPV group)
Diphtheria, tetanus, polio (1,2,3) all non-inferior
Key Findings: Tdap-IPV vs. DTaP- IPV, pertussis, one month post- booster
GMC/T (95%CI)
Anti-PT:
59.8 (52.2-68.5) vs. 75.9 (65.7-87.7)
Anti-FHA:
556.2 (491.4-629.5) vs. 613.5 (547- 688.2)
Anti-PRN:
354.8 (280.2-449.4) vs. 7.8 (6.5- 9.2)

Level I Fair
Study Vaccine: Tdap-IPV (Adacel®-Polio, Sanofi Pasteur)
Hendrikx, LH et al. Vaccine Nov 2009Footnote 22 Tdap-IPV (Adacel®- Polio) vs DTaP-IPV
(Infanrix™- IPV)
Convenience sample n=69 (aP
primed) and received 4 year olds booster
Outcomes: IgG levels (pooled) 28 days post booster
Key Findings: Tdap-IPV vs. DTaP- IPV, IgG level (95%)
Anti-PT:
44.7 (31-64.5) vs. 192.3 (144-
256.7)
Anti-FHA:
182.3 (99.0-335.7) vs. 518 (429.4- 624.9)
Anti-PRN:
629.1 (264.5-1496) vs. 1273.5
(932.5-1739)
Anti-Fim2/3: 2.7 (1.3-5.5) vs. 1.2
(1.0-1.4)
Level II-3 Fair
Kitchin N et al. Vaccine Aug 2009Footnote 23 Adacel®-Polio (Tdap-IPV) Randomized controlled trial but presenting only one arm n=77
3.5-4.5 year olds (primed with DTaP- IPV-Hib)

Outcomes: Evaluation of immunogenicity of Tdap-IPV pre and one month post booster (GMC/GMT)
Key Findings: GMC/GMT pre vs. post booster, GMC/GMT (95% CI)

Diphtheria GMC:
0.041(0.029 - 0.057) vs. 7.95
(4.97-12.73)
Tetanus GMC:
0.43 (0.3-0.61) vs. 7.26 (5.69-9.26)

Pertussis: Anti-PT:
3.71 (2.89-4.75) vs. 94.84 (71.89- 125.11)
Anti-FHA:
7.05 (4.91-10.12) vs. 103.14
(78.03-136.33)
Anti-PRN:
3.93 (3.07-5.02) vs. 127.42 (96.31- 168.58)
Anti-FIM:
9.66 (7.13-13.10) vs. 671.33
(499.6-902.1)
Anti-polio1:
37 (25.16 - 54.41) vs. 10173.24
(6887.35-15026.79)
Anti-polio2:
51.75 (32.18-83.21) vs. 5272.46
(3856.83-7215.89)
Anti-polio3:
47.18 (33.16-67.13) vs. 11221.8
(7755.59 -16237.18)

Level I Fair
Study Vaccine: Tdap (Boostrix®, GSK)
Meyer CU et al. Hum Vaccin May- Jun 2008Footnote 12 Tdap (Boostrix®) vs. DTaP (Infanrix™) vs. Td (Novartis product) Randomized single blind trial n=422
4-6 year olds

Outcomes: Evaluation of immunogenicity of Tdap vs. DTaP vs. Td pre, one month and 3.5 years post booster. (Also subset with cell-mediated immunity testing, not shown)
Seroprotection defined as: Diphtheria ≥ 0.016 IU/ml or ≥ 0.1 IU/ml
Pertussis (PT, FHA, PRN) ≥ 5 El.U/mL in initially seronegative (< 5 El.U/mL) and two-fold increase in initially seropositive

Key Findings: Tdap vs DTaP, seroprotection 3.5 years after booster, %
Anti Diphtheria: 100 vs. 100 Anti tetanus: 100 vs.100 Anti-PT: 58.7 vs. 60.6
Anti-FHA: 100 vs. 100
Anti-PRN: 99.2 vs. 100

Level I Fair
Study Vaccine: Tdap (Adacel®, Sanofi Pasteur)
Scheifele et al. 2005Footnote 27 Tdap-IPV (Quadracel®) vs. Tdap (Adacel®) Randomized controlled trial
2 Canadian centers
N=290
N=145 Tdap

Outcome measures:
Evaluation of immunogenicity of Tdap vs. DTaP-IPV, pre and 4 weeks after immunization.
Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml

Pertussis PT %≥ 10EU/ml, FHA
%> 10EU/ml, FIM 2/3 %≥ 16EU/ml, PRN %≥ 7EU/ml
Key findings:
Tdap vs. DTaP-IPV post booster GMC (95% CI)
Tetanus 9.8 (8.5-11.3) vs. 8.0 (6.9- 9.2)
Diphtheria 3.8 (3.2-4.4) vs. 6.4
(5.3-7.7)
PT 61.7 (54.3-70) vs. 118.8 (105-135)
FHA133 (116-152) vs. 167.6 (147-191)
Fim2/3 982.7 (843-1145) vs. 640.6
(542-757)
PRN 187.3 (152-230) vs. 162.8
(135-196)

Level I Fair
Langley et al. Vaccine Jan 2007Footnote 10 Tdap (Adacel®) + IPV(4-6wk
later) vs DTaP-IPV
(Quadracel®)
Single blinded randomized controlled trial
8 Canadian centers
n=593
children between 4-7 years of age who completed primary series with fourth dose of pentacel

Outcome measures:
Evaluation of immunogenicity of Tdap vs. DTaP-IPV, pre and 4-6 weeks after immunization.

Seroprotection defined as: Diphtheria and tetanus ≥ 0.1 IU/ml, four-fold rise also used
Pertussis (PT, FHA, FIM, PRN), four-fold rise over pre-vaccination titres

Key Findings:
Non-inferiority between vaccines
-diphtheria and tetanus antibody level > 0.10IU/ml
-> 1.0IU/ml to diphtheria and tetanus similar between two groups
-majority of participants achieved four-fold rise

Proportion with four-fold rise Tdap vs. DTaP-IPV, % (95% CI)
Anti diphtheria:
89.8 (85.5-93.2) vs. 93.7 (89.9- 96.3)
Anti tetanus:
94.3 (90.8-96.8) vs. 93.7 (89.9- 96.3)
Anti-PT:
91.9 (87.8-94.9) vs. 96.8 (93.8- 98.6)
Anti-FHA:
88.1 (83.6-91.8) vs. 92.8 (88.9- 95.7)
Anti-FIM:
94.6 (91.2-97.0) vs. 87.6 (82.9-91.5)
Anti-PRN:
94.3 (90.7-96.7) vs. 92.0 (88.0-95.1)

Level I Fair
Evidence for Safety
STUDY DETAILS SUMMARY
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality
Study vaccine: DTaP-IPV (Infanrix™-IPV, GSK)
Gold MS et al. Med J Australia Aug 2003Footnote 13

Infanrix™
(DTaP)

(nb: Australia changed from DTwP to DTaP between Aug 1997 and Dec 1998)

Passive, population- based AEFI surveillance

Retrospective review of AEFIs reported

Children given immunizations by practitioners who report to Southern Australia Immunisation Coordination Unit between 1997 and 2000

Not a study of 4-6 years but illustrates increased risk of local reactogenicity with more DTaP doses.

166 380 DTaP/DTaP-HepB
vaccines given; 41 459 were 4th dose

581 AEFI reports during the time period; 138 (23.4%) were local reactions after pertussis-containing vaccines

Jan 1998-Dec 2000:
Median age of those with local reaction 19.5 months; relative risk local reaction at fourth dose versus first dose = 36 (95% CI: 8.78, 146). Rate of local reaction at fourth dose 171/100 000. Risk of local reaction greater in those primed with DTaP vs. DTwP

II-2 n/a (surveillance study)
Nilsson et al. Scand J Infect Dis 2005Footnote 14 DTaP-IPV
(Infanrix™- IPV) vs DTaP (Infanrix™) + IPV
Open, randomized
- 7 sites in Italy and Sweden

n =416
- 4-6 years (previously received 3 dose* primary series)

*nb: Canadian children receive a 4- dose primary series whereas children in this study received only 3 priming doses

Outcomes: Evaluation of safety of DTaP-IPV vs. DTaP +IPV. Solicited local and systemic adverse events day 0 to day 3. Any other AE up to day 30.

Key Findings:
No statistically significant differences between groups.

Local (DTaP-IPV vs. DTaP)*, % :
-pain: 71% vs. 69%
-redness: 50% vs. 49%
-swelling: 55% vs. 56%
-any large swelling reaction (any of > 50mm, diffuse swelling,
or swelling to ≥ 1 adjacent joint: 13.5% vs. 17.4%
-swelling involving ≥ 1 adjacent joint(s): 0% vs. 1.5%

Systemic (DTaP-IPV vs. DTaP+IPV)*, %:
-fever (axillary T > 38.0 °C):
21% vs. 17%
-drowsiness: 25% vs. 25%
-loss of appetite: 20% vs. 18%
-irritability: 18% vs. 20%

*proportions extrapolated from figure, did not extrapolate 95% CIs

Level I Fair
Black et al. Vaccine Aug 2006Footnote 16 DTaP-IPV
(Infanrix™- IPV) vs.
DTaP
(Infanrix™ + IPV)
Open randomized phase II non- inferiority trial 14 US centers N=400

Outcomes:
-local solicited adverse events (15 days post vaccination)
-general adverse events (15 day post vaccination)

-MMR specific general symptoms (43 days post vaccination)
-unsolicited events (31 days post vaccination)
-serious adverse events within 6 months of vaccination

Key Findings:
DTaP-IPV vs. DTaP, % (95% CI)

Local
-pain: 60.2% (53-67.1) vs.
57.4 % (50.2-64.5)
-redness: 57.1% (49.9-64.2) vs.
50.8% (43.5-58.0)
-swelling: 39.8% (32.9-47) vs.
41% (34-48.3)

Systemic:
-fever: 18.9% (13.7-25.1) vs.
21.6% (16.1-28.1)
-drowsiness: 24.5% (18.6-31.3)
vs. 22.2% (16.5-28.7)
-loss of appetite: 20.9% (15.4-
27.3) vs. 17.5% (12.5-23.6)

Level I Fair
Marshall et al.
Vaccine Aug 2006Footnote 20
DTaP-IPV
(Infanrix™- IPV) vs DTaP (Infanrix™) + IPV
Open-label, randomized, non-inferiority, Phase IIIb
- 3 Australian Centres
n=366
- 4-6 years

Outcomes:
Evaluation of safety of DTaP-IPV (left deltoid) vs. DTaP (left deltoid)
+IPV (right arm), both with concomitant MMR (right arm). Specific local and systemic adverse events (day 0 to day 3); MMR-specific symptoms (day 0 to day 14); unsolicited and serious adverse events up to day 30.

Key Findings:
Local (DTaP-IPV vs. DTaP),
% (95% CI)
-pain: 80.1% (73.3-85.8) vs.
64.1% (56.3-71.3)
-redness: 77.8% (70.8-80.3) vs.
77.25 (70.1-83.4)
-swelling: 60.2% (52.5-67.6) vs.
65.3% (57.5-72.5)
-swelling involving ≥ 1 adjacent joint(s): 6.4% vs. 6.0% Systemic (DTaP- IPV+MMR vs. DTaP+IPV+MMR), up to 15 days, %, 95% CI
-fever (axillary T > 39.0 °C):
4.1% (1.7-8.3) vs. 5.4% (2.5-
10)
-drowsiness: 23.4% (29.2-44.3)
vs. 24% (17.7-31.2)
-loss of appetite: 20.5% (14.7-
25.3) vs. 24% (17.7-31.2) -vaccine-related rash: 2.9%
(1.0-6.7) vs. 3.6% (1.3-7.7)

Level I Fair
Black et al. Pediatr Infect Dis J April 2008Footnote 17 DTaP-IPV
(Infanrix™- IPV) vs.
DTaP
(Infanrix™ + IPV)
Open randomized Phase III randomized study
- 24 US
centers
N=4209

Outcomes:
-local solicited adverse events (4 days post vaccination)
-general adverse events (4 days post vaccination)
-MMR specific general symptoms (15 days post vaccination)
-unsolicited and serious adverse events (6 months post vaccination)

Key findings:
DTaP-IPV vs. DTaP+IPV, % (95% CI)

Local
-pain: 57% (55.2-58.7) vs.
53.3% (50.2-56.4)
-redness: 36.6 (34.9-38.3) vs.
36.6% (33.6-39.6)
-swelling: 26% (24.5-27.6) vs.
27% (24.3-29.8)
-increase in limb circumference: 36% (34.3-37.7) vs. 37.8%
(34.9-40.9)

General
-fever: 16% (14.7-17.4) vs.
14.8 % (12.7-17.2)
-drowsiness: 19.1% (17.7-20.5)
vs. 17.5% (15.2-19.9)
-loss of appetite: 15.5% (14.3-
16.8) vs. 16 %(13.8-18.4)

Level I Fair
Kemmeren et al. Vaccine June 2011Footnote 24 DTaP-IPV
(Infanrix™- IPV)
Cross- sectional study
- Netherlands
n=849 (group who were aP primed)

Outcome measures: local and systemic reactions to DTaP-IPV in wP vs. aP primed 4 year olds children reported in survey returned one week after immunization.
(Results shown below are only for aP primed group.)

Local (n=824)
% (95% CI)
-pain: 45.5% (42.2-49)
-redness: 30.5% (27.5-33.7)
-swelling: 23.1% (20.3-26.1)
-reduced use of arm: 20.4% (17.8-23.3)
-swelling in axilla: 1.5% (0.8-
2.5)

Systemic (n=824)
% (95% CI)
-fever: 10.4% (8.5-12.7)
-headache 5.6% (4.2-7.4)
-pallor 3.5% (2.5-5.0)
-nausea 5.2% (3.9-7.0)
-vomiting 3.3% (2.3-4.7)
-dizziness 1.1% (0.6-2.1)
-abnormal perspiration 6.6%
(5.1- 8.5)
-syncope 0.4% (0.1-1.1)

Level III Not possible to rate quality using Harris criteria
Klein et al. Vaccine Jan 2012Footnote 21 DTaP-IPV
(Infanrix™ IPV)
Open-label, randomized, non-inferiority, Phase IIIb
- 11 US
Centres
n =478

Outcomes:
Evaluation of safety of DTaP-IPV comparing Group 1 (DTaP-IPV + MMR + V simultaneously) and Group 2 (DTaP-IPV + MMR
simultaneously and V one month later). All vaccines given in left arm. Specific local and systemic adverse events (4-day period following immunization) and  unsolicited AEs (day 0-30) and serious AEs (up to 6 months).

Key Findings (Group 1 vs. Group 2)
Local* %
-pain: 66% vs. 70%
-redness: 50% vs. 49%
-swelling: 41% vs. 38%
-diffuse swelling: 1/239 (0.4%) in Group 1 and 6/237 (2.5%) in Group 2
-swelling involving one adjacent joint: 0/239 (0%) in Group 1
and 1/237 (0.4%) in Group 2.

Systemic*
-fever (axillary T > 39.0 °C): 26% vs. 27%
-drowsiness: 25% vs. 26%
-loss of appetite: 25% vs. 24% Unsolicited AEs (event types and relationship to immunization not noted by authors):
Group 1: 31.4 (95% CI: 25.6,
37.7%)
Group 2: 30.4% (95% CI: 24.6,
36.7%)

*proportions extrapolated from figure, did not extrapolate 95% CIs

Level I Fair
Study Vaccine: DTaP (Infanrix™, GSK and Daptacel®, Sanofi Pasteur)
Study Vaccine: Tdap-IPV (Boostrix®-Polio, GSK)
Jackson LA et al.
Pediatrics Mar 2011Footnote 25
DTaP (did not identify formulations/ brands) Retrospective cohort study n=233 616
4-6 year olds children who were enrolled in 1 of 7 managed care organizations (MCOs) participating in Vaccine Safety Datalink (VSD) collaborative project received DTaP between 2002 and
2006

1270 presumptive reactions (based on relevant ICD codes, ex. cellulitis) in first four days after vaccination (0.5% of 233 616 doses)

Chart review completed for 1221/1270 (96%) and 1017/1221
confirmed (83%)

75% of all DTaP given in arm

Higher BMI independently associated with risk of medically- attended local reaction (inadequate IM injection)
Adjusting for age, gender, MCO site, RR medically-attended local reaction 1.78 (95% CI: 1.43, 2.21)
for arm injection vs. thigh injection. When also adjusted for BMI (among subgroup with valid BMI)

II-2 Fair
(retrospec- tive review of MD notes, did not have record of which DTaP
product, not all
presump- tive visits confirmed to be local reactions)
Sanger et al. Eur J Pediatr Dec 2007Footnote 11 Tdap-IPV (Boostrix®- Polio) vs. Tdap (Boostrix®)
+IPV
Partially blinded, randomized controlled trial (one injection vs. two injections not blinded)
- 59 centers in Germany
N=959
- 4-8 years
-Endpoints/Outcomes
-assessed through diary card 15 post vaccination
-local symptoms (redness, pain, swelling, drowsiness, fever, irritability, loss of appetite)
-serious adverse events - 30 days post immunization
-Outcome measures: Tdap-IPV vs. Tdap+IPV Local reactions:
-pain grade III 2.8% vs. 6.6% (p=0.035)
-swelling 44.8% vs. 54.4%) (p=0.041)
-fever >39C 6.0% vs. 1.5% (p=0.036)
-no serious adverse outcomes reported
Level I Fair
Ferrera et al. Hum Vaccin Immuno-ther March 2012Footnote 9 Tdap-IPV (Boostrix®- Polio)
vs DTaP-IPV [Tetravac] (PT &FHA
containing Sanofi product, not available in Canada) both co- adminstered with MMRV
Randomized controlled trial
- multicentered Italy
N=305
5-6 year olds
Endpoints/Outcomes:

-4d symptom diary for
-solicited, unsolicited localized and general adverse events

Outcomes:
DTap-IPV vs. TdaP-IPV Pain (58.9% vs. 61.2%)
Grade III swelling (5.3% - 3.3%)
Fatigue (26.5%-23.7%) Fever (21.2%-19.7%)
No serious adverse events
Study Vaccine: Tdap (Boostrix®, GSK)
Meyer CU et al. Hum Vaccin May- June 2008Footnote 12 Tdap (Boostrix®) vs DTaP
(Infanrix™) vs Td (Novartis
product)
Randomized single blind trial N=422 Outcome measures:
-local solicited adverse events (15 days post vaccination)
-general adverse events (15 day post vaccination)
-unsolicited/serious adverse events within 31 days of vaccination
Key findings:
Local Tdap vs. DTaP
-pain 47.8% vs. 63.3%
-redness 33.9% vs 48.9%
-swelling 32.2% vs 43.3% General Tdap vs DTaP
-diarrhea 10% vs. 8.9%
-irritability 16.1% vs. 21.1%
-loss of appetite 17.8% vs. 17.8%
-fever 20% vs. 22%
-vomiting 7.8% vs. 4.4%
Level I Fair
Study Vaccine: Tdap (Adacel®, Sanofi Pasteur)
Scheifele et al. 2005 Footnote 27 Tdap-IPV (Quadracel) vs. Tdap (Adacel) Randomized controlled trial 2 Canadian centers N=290
N=145 Tdap

Outcome measures:
-30 minutes post immunization
-2 weeks post immunization - SE diary
-home visit at approximately 48 hour post immunization, if reaction noted then telephone interview at 7 days post immunization

Key findings:
Tdap vs. DTaP-IPV group
-erythema ≥ 50mm 6.3% vs. 17.2%
-swelling ≥ 25mm 23.1% vs. 35.9%
-pain (mod/severe) 6.7% vs. 13.1%
-fever 1.4% vs. 6.3% Rates of erythema > 25mm, swelling statistically significant between groups, fever, pain
(moderate/severe) not significant between groups

Level I Fair
Langley et al. Vaccine Jan 2007Footnote 10 Tdap (Adacel®) + IPV(4-6 week later) vs.
DTaP-IPV
(Quadracel®)
Single blinded randomized controlled trial 8 Canadian centers N=593
n=299 DTaP-IPV
n=294 Tdap
-children between 4- 7 years of age who completed primary series with 4th dose of pentacel

Outcome measures:
- 30 minutes post immunization
- 2 weeks post immunization - SE diary
- phone contact day 4 and 15 post immunization
- unsolicited AE up to 6 weeks post immunization

Key findings:
- localized findings less common in Tdap group vs. DTaP-IPV group
- erythema 34.6% vs. 51.7%
- swelling 24.2% vs. 33.8%
-pain 39.6% vs. 67.2%
-fever 8.72% vs. 16.9%
-rates of any or moderate and severe erythema, swelling, pain and fever
- non-inferior b/w vaccines

Level I Fair

Acknowledgments

Footnote *NACI Members: Dr. B. Warshawsky (Chair), Dr. I. Gemmill (Vice-Chair), Dr. N. Crowcroft, Dr. B. Henry, Dr. D. Kumar, Dr. S. McNeil, Dr. C. Quach-Thanh, Dr. M. Salvadori, Dr. B. Seifert, Dr. N. Sicard, Dr. W. Vaudry, Dr. R. Warrington.

Liaison Representatives: Dr. A. Corriveau (Council of Chief Medical Officers of Health), Dr. J. Blake (Society of Obstetricians and Gynaecologists of Canada), Dr. S. Deeks (Canadian Public Health Association), Dr. A. Mawle (Centres for Disease Control and Prevention, U.S.), Dr. D. Moore (Canadian Paediatric Society), Dr. A. Opavsky (Association of Medical Microbiology and Infectious Disease Canada), Dr. A. Pham-Huy (Canadian Association for Immunization Research and Evaluation), Dr. S. Rechner (College of Family Physicians of Canada), Dr. V. Senikas (Society of Obstetricians and Gynaecologists of Canada).

Ex-Officio Representatives: Dr. M. Carew (First Nations and Inuit Health Branch, Health Canada), Dr. (LCol) P. Eagan (Department of National Defence), Dr. P. Huston (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada), Dr. A. Klein (Biologics and Genetic Therapies Directorate, Health Canada), Dr. B. Law (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada), Dr. C. Légaré (Marketed Biologicals, Biotechnology and Natural Health Products Bureau, Health Canada), Dr. B. Raymond (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada/Canadian Immunization Committee), Ms. M. St-Laurent (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada), Dr. E. Taylor (Marketed Health Products Directorate, Health Canada).

*This statement was prepared by Dr. N. Crowcroft, Dr. S. Desai, Dr. A. Hashim, Ms. J. Lourenco, and Dr. A. Wormsbecker and approved by NACI.

NACI gratefully acknowledges the contributions of Dr. M. Naus and Public Health Ontario Library Services to the development of this statement.

References

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