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

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.

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.

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}

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 5^th dose of DTaP. Their estimates of VE based on time since the 5^th 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 vaccines^{Footnote 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.

2. 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).
3. Vaccine
   • Immunization registry to improve accuracy of coverage reporting;
   • Vaccine effectiveness;
   • Ongoing, timely vaccine safety surveillance.

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

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