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ARCHIVED - Statement on the recommended use of pentavalent and hexavalent vaccines

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Canada Communicable Disease Report

Canada Communicable Disease Report
Volume 33 • ACS-1
1 February 2007

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)*†

PDF Version
16 Pages - 1.26 MB PDF


Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada 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 Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Combination vaccines against diphtheria, pertussis, polio, tetanus and Haemophilus influenzae type b (Hib) infections have become the standard for routine primary immunization of infants in Canada 1. Since the approval of such vaccines containing acellular pertussis antigens in 1997, only one manufacturer (sanofi pasteur) has provided this combination vaccine to Canadians, as Pentacel®. In 2000, Pediacel®, also manufactured by sanofi pasteur, was approved for use in Canada but has not been marketed. Like its monovalent constituent vaccines, Pentacel® has been highly successful in controlling these infectious diseases in Canada but has the additional benefit of fewer injections. However, in 2004, serious supply difficulties arose in Canada because of production problems experienced by sanofi pasteur.

In 2004, GlaxoSmithKline (GSK) received approval in Canada for two multivalent vaccines: a pentavalent (InfanrixTM-IPV/Hib) vaccine and a hexavalent (InfanrixTM -hexa) vaccine that also protects against hepatitis B. These products have been available for years in most European Union countries and more recently in Australia. The approval of a second manufacturer supplying infant combination vaccines in Canada now provides choice among products for vaccination programs and has the potential to safeguard against supply shortages that could result if there is a problem with one of the manufacturer's products. The decision to use a particular manufacturer's product and the possibility of product interchangeability require comparison of their efficacy, effectiveness and safety.

This statement reviews the composition and clinical evidence for efficacy of the multivalent products from the two manufacturers and provides recommendations for their use. It also updates information provided in the 1 February, 2005, NACI Statement on the Interchangeability of diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae type b combination vaccines presently approved for use in Canada for children < 7 years of age2.

Pentavalent and hexavalent preparations approved for use in Canada

In Canada, two manufacturers, sanofi pasteur (Pentacel® and Pediacel®) and GSK (InfanrixTM-IPV/Hib), supply combined pentavalent vaccines against diphtheria, tetanus, pertussis, polio and Hib. GSK supplies a hexavalent vaccine against these infections and hepatitis B (InfanrixTM-hexa). The composition of the four products is shown in Table 12 . The pentavalent vaccines are thimerosal-free (thimerosal is used in the manufacture of hepatitis B vaccine, and trace amounts may be present in InfanrixTM-hexa), and all the pentavalent and hexavalent vaccines must be stored between +2o C and +8o C. Given the similarities among different vaccines, their trade names will be used in this statement to minimize product confusion.

Pentacel®

Since 1997, Pentacel® has been used in Canada for the three-dose primary series (2, 4 and 6 months of age) and 18-month booster dose1. It is approved for use in children from 2 months of age until their 7th birthday. Pentacel® is reconstituted immediately before administration by combining a lyophilized powder containing polyribosyl ribitol phosphate conjugated to tetanus protein (PRP-T) vaccine (Act-Hib®) with Quadracel®, a liquid product containing acellular pertussis vaccine, adsorbed diphtheria and tetanus toxoids, and inactivated polio vaccine. The pertussis vaccine has five antigens: pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN) and fimbrial proteins 2 and 3 (FIM2 and FIM3). The diphtheria and tetanus toxoids are detoxified with formaldehyde. The three poliovirus types are propagated in human diploid cells and formalin inactivated.

Table 1. Composition of penta/hexavalent vaccines licensed for routine immunization
of infants in Canada*

Contents
(for each 0.5 mL dose)

Pentacel®
(Sanofi
Pasteur)

Pediacel®
(Sanofi
Pasteur)

InfanrixTM-IPV/Hib
(GlaxoSmithKline)

InfanrixTM-hexa
(GlaxoSmithKline)

Diphtheria toxoid

15 Lf

15 Lf

25 Lf (30 IU)

25 Lf (30 IU)

Tetanus toxoid

5 Lf

5 Lf

10 Lf (40 IU)

10 Lf (40 IU)

Pertussis:

 

 

 

 

Pertussis toxoid

20 μg

20 μg

25 μg

25 μg

Filamentous hemagglutinin

20 μg

20 μg

25 μg

25 μg

Pertactin

3μg

3 μg

8 μg

8 μg

Fimbriae (agglutinogens 2 & 3)

5 μg

5 μg

none

none

Polio:

 

 

 

 

Type 1

40 DU

40 DU

40 DU

40 DU

Type 2

8DU

8 DU

8DU

8 DU

Type 3

32 DU

32 DU

32 DU

32 DU

Hepatitis B

 

 

 

 

AgHBs recombinant

none

none

none

10 μg

Hib:

 

 

 

 

PRP

10 μg

10 μg

10 μg

10 μg

Binding protein

20 μg
tetanus toxoid

20 μg
tetanus toxoid

30 μg
tetanus toxoid

30 μg
tetanus toxoid

Format

Lyophilized powder

Pre-mixed in ampoule with other components

Lyophilized powder

Lyophilized powder

Other contents

 

 

 

 

Aluminum

1.5 mg Al3PO4

1.5 mg Al3 PO4

0.5 mg Al(OH)3

0.7 mg
Aluminum salts

2-phenoxyethanol

0.6% v/v

0.6% v/v

2.5 mg

2.5 mg

Tween 80

10 ppm (by calculation)

Less than 0.1% (by calculation)

 

 

Other

Bovine serum:

  • ≤ 50 ng
  • trace amounts of formaldehyde
  • Trace amounts of polymixin B and neomycin may be present from the cell growth medium

Bovine serum:

  • ≤ 50 ng
  • trace amounts of formaldehyde
  • Trace amounts of neomycin, streptomycin and polymyxin B may be present in the final product

 

Lactose (as stabilizer):

  • 12.6 mg
  • sodium chloride: 4.5 mg.
  • Residual formaldehyde, polysorbate 80, M199 (as stabilizer), potassium chloride, disodium phosphate, monopotassium phosphate,glycine and trace amounts of neomycin sulfate and polymyxin sulfate

Lactose (as stabilizer):

  • 12.6 mg
  • sodium chloride: 4.5 mg.
  • Residual formaldehyde, polysorbate 80, M199 (as stabilizer), potassium chloride, disodium phosphate, monopotassium phosphate, glycine, and trace amounts of neomycin sulfate and polymyxin sulfate

* Adapted from NACI 2 .
PRP = polyribosyl ribitol phosphate, Lf = limits of flocculation, DU = D-antigen units.
Note:
The Hib component of Pentacel® and Infanrix™-IPV-HIB are alsomarketed separately as Act-Hib® and Hiberix™respectively. When used separately, a diluent is provided. When used as part of the pentavalent product, Act-HIB™ is reconstituted with Quadracel® to make Pentacel®, and Hiberix™ is reconstituted with InfanrixTM-IPV to make Infanrix™-IPV-Hib.When used as part of the hexavalent product, Hiberix™ is reconstituted with Pediarix™ (DTaP-HBV-IPV).
All four vaccines have to be stored between +2o C and +8o C. The vaccines have to be discarded if frozen.


Pediacel®

Pediacel® was approved for use in Canada in 2000 for the three-dose primary series and 18-month booster dose. It is approved for use in children from 2 months of age until their 7th birthday. It differs from Pentacel® in that the Hib component is pre-mixed in a liquid formulation with the other components in an ampoule. Therefore reconstitution is not required before vaccine administration.While the concentrations and types of the three poliovirus strains in Pediacel® are identical to those in Pentacel®, they are grown in vero monkey kidney cell lines. The pertussis vaccine contains the five component antigens at the same concentrations as in Pentacel®; the amounts of tetanus and diphtheria toxoids are also the same.

InfanrixTM-IPV-Hib

InfanrixTM-IPV-Hib is approved for use in children between 6 weeks and < 5 years of age. It is a pentavalent vaccine and requires reconstitution before administration. This is done by combining a lyophilized powder containing PRP-T vaccine (Hiberix®) with InfanrixTM-IPV, a product composed of acellular pertussis, adsorbed diphtheria and tetanus toxoids, and inactivated polio vaccines. This vaccine differs from the sanofi pasteur vaccines in that the pertussis portion is derived from three antigens: PT, PRN and FHA. The concentration of each of these antigens is 5 μg greater than in the five-component pertussis vaccines manufactured by sanofi pasteur. The vaccine contains no FIM2 or FIM3. The tetanus and diphtheria concentrations are 5 Lf and 10 Lf (limits of flocculation) greater per dose respectively than in the sanofi pasteur products.

InfanrixTM-hexa

InfanrixTM-hexa is approved for use in children between 6 weeks and 2 years of age. This hexavalent combined diphtheria and tetanus toxoid, acellular pertussis, recombinant hepatitis B virus (HBV), inactivated poliomyelitis and PRP-T Hib vaccine requires reconstitution before administration. This is done by mixing a single-dose, pre-filled syringe of Pediarix™ (DTaP-HBV-IPV suspension for injection) and single dose vial of powdered Hib conjugate (Hiberix® lyophilized powder).

Assessment of efficacy

Literature search

In order to identify prospective clinical trials evaluating the efficacy of the four approved vaccines a systematic search of MEDLINE (January 1966 to August 2006) and EMBASE (January 1966 to August 2006) was conducted. Keywords included both the trade names of the vaccines and the widely recognized abbreviations for their components. A total of 82 full text articles were identified and reviewed. Studies involving preparations not approved for use in Canada were excluded. Articles containing both primary series vaccination and/or first booster dose results were selected for detailed data extraction. A total of 20 publications reporting 22 clinical trials' results on the immunogenicity and/or reactogenicity of Pentacel®, Pediacel®, InfanrixTM-IPV/ Hib and InfanrixTM-hexa were retained for the purpose of this report3-22.

Evidence for vaccine efficacy

No single clinical trial has compared a full series of the different pentavalent products produced by the two manufacturers. One study randomized booster dosing using Pentacel® and InfanrixTM- IPV-Hib in infants and toddlers previously immunized with three doses of Pentacel® and found similar immunogenicity20. A direct assessment between these two products as primary series has not been performed, and an evaluation of vaccine efficacy is primarily dependent on assessment of serologic responses in different studies. A large number of clinical trials and long-term field epidemiologic data have demonstrated high efficacy/effectiveness of different DTaP-based combination vaccines23. The efficacy of the other components, particularly Hib when given in combined vaccines, is a subject of continued scientific discussion24-28. Important short- and medium-term effectiveness of at least three out of the four vaccines of interest, excluding Pediacel®, have been reported29,30. Taking into consideration the very close similarity of Pediacel® and Pentacel®, one can expect comparable effectiveness. It should be noted that trials have not been conducted in selected populations, such as the Canadian Aboriginal population, and further data are needed.

Serologic response to component antigens

Diphtheria: One month after completion of the three-dose primary vaccination series, ≥ 97% of vaccinees in all studies achieved at least ≥ 0.01 IU/mL of antibodies against diphtheria, the level considered protective, regardless of the type of vaccine used. Across studies, antibody geometric mean concentration (GMC) varied from 0.1 IU/mL to 9.6 IU/mL, and GMC < 1 IU/mL was observed in only three studies3,8,31 with three different vaccines (Pediacel®, InfanrixTM-IPV-Hib and InfanrixTM-hexa). In these three studies, the vaccines were administered at 2, 3 and 4 months of age. The highest antibody titres (9.6 IU/mL) were observed in a study with InfanrixTM-hexa15, when the vaccine was administered using a 2, 4 and 6 month schedule. In all studies assessing booster response, 100% of vaccinees had an antibody titre superior to 0.1 IU/mL (GMC range 3.4 to 6.9 IU/mL) 1 month after the booster dose, regardless of the type of vaccine used.

Tetanus: One month after completion of the three-dose primary series, at least 99% of vaccinees had an antibody titre of ≥ 0.1 IU/mL, the level considered protective, regardless of the type of vaccine used. Only in one study5 with Pentacel® vaccine given at 2, 4 and 6 months of agewas theGMC < 1 IU/mL (0.9 IU/mL). In this study, Pentacel® was administered concurrently with the HBV vaccine, given in different limbs (thighs), and serologic testing was performed 8 weeks after the third dose. In all the other studies antibody titres varied from 1.5 IU/mL to 5.7 IU/mL. In booster studies, antibody titres did not appear to depend on the primary series schedule or type of vaccine used. Observed seroprotection rates were 100% in all studies, regardless of the primary vaccination schedule or type of vaccine used.

Poliovirus: In all but one study, 1 month after completion of the three-dose primary series at least 95% of vaccinees had a seroprotective level ( ≥ 1:8 reciprocal dilution) of antibodies against all three types of poliovirus. The exception was a study using Pentacel® administered concurrently with the HBV vaccine at 2, 4 and 6 months of age, given in different limbs (thighs), in which serologic testing was performed 8 weeks after the third dose5. Between 85% and 92.5% of subjects had a seroprotective level of antibodies against the three types of poliovirus. In this study, Prevnar® was also given, at 3, 5 and 7 months of age. It is important to note that serologic testing was performed at 8 weeks rather than 4 weeks in this study. At 8 weeks, antibody levels are beginning to decline, making comparisons with studies in which testing was performed at 4 weeks more difficult5. Variations in geometric mean titre (GMT) were observed among different studies and for different poliovirus types. These variations may be due to differences in vaccination schedules, study populations, laboratory techniques or interpretation of results. However, despite the variation, high neutralizing antibody GMTs against all three types of poliovirus were observed in all studies. In studies assessing booster response, seroprotection rates to the three polioviruses 1 month after the booster dose were 99% to 100% regardless of the type of vaccine used. Antibody GMTs were in the high ranges (976 NA/mL to 3,697 NA/mL).

Haemophilus influenzae type b: On the basis of antibody levels in study children who do not develop invasive Hib disease, it is estimated that an antibody level of 0.10 μg/mL or 0.15 μg/mL at the time of Hib exposure is necessary in order to be protected from invasive disease. Given the demonstrated waning of antibody levels over time, it is suggested that a post-immunization level of 1 μg/mL is required for long-term protection, to ensure that there is a minimal level of 0.10 μg/mL during the second year of life. It is increasingly questioned, however, whether these benchmark levels, derived from studies of unconjugated PRP vaccines, are equally applicable to antibody responses produced by conjugated vaccines. Not only do the conjugated vaccines stimulate higher antibody responses but as well there is an associated maturation of the immune response (i.e. increased functional capacity of the antibodies) that results in increased avidity of the antibodies before and after the booster challenge. Moreover, the levels obtained with the DTaP-based Hib combinations are still within the broad range of antibody titres achieved with other approved Hib conjugates administered separately.

One month after the third dose of vaccine, the seroconversion rates to PRP (≥ 0.15 μg/mL anti-PRP) varied between 78% and 100% in 19 studies; the rate was ≥ 95% in all but four studies3,5,6,31. In two of these studies the vaccine used was Pentacel®5,6, and it was given at 2, 4 and 6 months of age. In both of the studies, vaccine was given concurrently with HBV vaccine, and 78% and 83% of subjects respectively achieved protective levels. In the two other studies with < 95% response rates to PRP, the vaccination schedules were at ages 2, 3 and 4 months, and response rates were 93% with Pediacel®and 91% with InfanrixTM- hexa6,31 . In general, higher vaccine response rates, of 95% to 100%, were observed in studies with a 2, 4 and 6 month schedule as compared with compressed schedules of either 2, 3 and 4 months or 3, 4 and 5 months. An anti-PRP level of ≥ 1 μg/mL was achieved by 43% to 97% of vaccinees. A lower proportion of children vaccinated according to the compressed schedules (60% to 77%) achieved this antibody level than those vaccinated according to a 2, 4 and 6 months schedule (82% to 97%). The exception was the study discussed previously that used a 2, 4 and 6 month schedule in which Pentacel® was given concurrently with HBV vaccine and serologic testing was performed at 8 weeks5. Only 43% achieved an anti-PRP level of ≥ 1 μg/mL. The anti-PRP GMT ranged from 0.6 μg/mL to 11.4 μg/mL in all studies, depending on the schedule and the population. In studies assessing booster response, the anti-PRP antibody level of ≥ 0.15 μg/mL was observed in 99% to 100% of vaccinees after a booster dose, independently of the vaccine originally used in the primary series or as booster dose. The proportion of vaccinees with an anti-PRP level ≥ 1.0 μg/mL was reported in four booster studies and varied from 94% to 100%. In studies with InfanrixTM administered in a 2, 4 and 6 months primary series schedule, 99% to 100% of vaccinees achieved an anti-PRP level of ≥ 1.0 μg/mL after a booster dose. In a Canadian study on the interchangeability of two vaccines following a three-dose Pentacel® series, 98.4% and 100% (p value > 0.05) in the Pentacel®and InfanrixTM- IPV/Hib booster groups respectively had an anti-PRP titre of ≥ 1.0 μg/mL20. In this study the InfanrixTM-IPV/Hib group had lower GMC than the Pentacel®booster group (19.1 μg/mL vs 29.0 μg/mL respectively).

Pertussis: There is no agreement on serologic correlates of protection for pertussis. Different interpretations of the serologic response to pertussis antigens have been used in analyzed studies. In addition to issues surrounding non-standardized and non-validated serologic assessment of efficacy, vaccine components differ among manufacturers. Sanofi pasteur products contain PT, FHA, PRN, and FIM2 and FIM3. GSK products only include PT, FHA and PRN, but each component is at a 5 μg higher concentration. While clinical trial data suggest comparable efficacy between three- and five-component monovalent pertussis vaccines against culture-confirmed pertussis with at least 21 days of cough, five-component vaccines may provide enhanced protection against milder disease32. No published clinical trials have directly compared the clinical efficacy of a full series of different pentavalent vaccines containing either three or five acellular pertussis components.

The vaccine response (VR) was determined as appearance of antibodies in subjects seronegative before vaccination or, at a minimum, maintenance of pre-vaccination antibody concentrations in subjects who were initially seropositive, or a four-fold rise in antibody titres. The VR in all studies except one was greater than 90% and 95% to PT and PRN respectively. The VR to FHA varied from 77% to 100%. The exception was a study using Pentacel® administered concurrently with the HBV vaccine at 2, 4 and 6 months of age, given in different limbs (thighs), in which serologic testing was performed 8 weeks after the third dose5. The VR to PT, PRN and FHA was 80%, 78% and 57% respectively. Published results seem to indicate a higher GMC to PT in those vaccinated with Pediacel® and higher GMC to PRN and FHA in those vaccinated with InfanrixTM-IPV/Hib and InfanrixTM-hexa. The anti-pertussis FIM2 and FIM3 levels were reported in two studies involving Pediacel®10,11. A 4-fold increase of FIM2 and FIM3 antibody level was observed in 100% of subjects. GSK products do not contain FIM2 and FIM3, and therefore antibody responses to these antigens have not been assessed. In studies assessing booster response, VR varied from 91% to 100%, 90% to 100% and 95% to 100% for PT, FHA and PRN respectively. In these studies, the antibody GMC to PT, FHA and PRN varied from 12 EU/mL to 100 EU/mL, 132 EU/mL to 521 EU/mL and 167 EU/mL to 664 EU/mL respectively.

Hepatitis B: Seroprotection rates against hepatitis B were measured in several studies with pentavalent vaccines (Pentacel® and InfanrixTM-IPV-Hib) in which hepatitis B vaccine (Recombivax-HB® or Engerix®-B) was administered concurrently in different limbs (thighs) and in studies with InfanrixTM-hexa5,8. HBV antibody levels ≥ 10 mIU/mL are considered protective. Seroprotection rates in all studies varied between 95% and 100% regardless of the type of vaccine used. The GMC varied from 169 mIU/mL to 439 mIU/mL when Recombivax® 5 μg vaccine was used concurrently with Pentacel® vaccine5 or when vaccines were administered according to the compressed schedule (2, 3 and 4 months)11,31. In studies that used a 2, 4 and 6 month schedule, the GMC varied between 867 mIU/mL and 1,827 mIU/mL. In these latter studies Engerix®-B 10 μg vaccine was used concurrently with InfanrixTM-IPV-Hib or as a component part of InfanrixTM-hexa. In two studies assessing booster response, after three doses of InfanrixTM-hexa, rates of seroprotection were 96% and 98% for hepatitis B, and after the fourth booster dose of InfanrixTM-hexa they were 99% to 100%, and high anti-HBs (antibody to hepatitis B surface antigen) GMCs (5,754 to 6,539 mIU/mL) were observed13,31.

Two studies measured the immunogenicity of InfanrixTM-hexa using a vaccination schedule of 3, 5 and 11 months of age18,19. One study compared single injections of InfanrixTM-hexa with separate injections of InfanrixTM-IPV-Hib and HBV, and the other single injection InfanrixTM-hexa with separate DTPa-HBV-IPV and Hib vaccines. There was excellent serologic response for all six antigens (diphtheria, tetanus, poliovirus, Hib, pertussis and hepatitis B) in these two studies.

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Co-administration with other vaccines

DTaP combined vaccines may be given at the same time as pneumococcal conjugate and meningococcal conjugate vaccines. Hepatitis B vaccine may be given in adolescence or in infancy, and the schedule varies by province/territory in Canada. The potential for interaction of DTaP-based penta- and hexavalent vaccines with these three vaccines has been studied in several clinical trials.

Schmitt et al.8 compared concurrent administration of InfanrixTM-IPV/Hib and Prevnar® (Wyeth) vaccine at 2, 3, 4 and 11 to 15 months of age with InfanrixTM-IPV/Hib vaccine given at the same age plus Prevnar® “catch-up vaccination” at age 6, 7, 8 and 11 to 15 months (control group). They found that the GMCs of the DTaP-IPV/Hib components were comparable between the two groups. Diphtheria antibody concentrations were higher in the group with concurrent Prevnar® vaccine administration (99% versus 97% ≥ 0.1 IU/mL), and all pertussis component antibody concentrations were lower in the concurrent group than the control group (PT: 84% vs 92%; FHA 69% vs 77%; and PRN: 80% vs 96%). In another study, by Tichmann-Schumann et al.13, the immunogenicity and safety of InfanrixTM-hexa and Prevnar® coadministered at 2, 3 and 4 months of age with a booster at 12 to 23 months of age was compared with the immunogenicity and safety of InfanrixTM-hexa given alone. Immunogenicity analysis yielded similar results in the two groups, and pre-established criteria for non-inferiority were met for all antigens. The concurrent administration of Prevnar® vaccine resulted in higher anti- diphtheria antibody GMC than when InfanrixTM-hexa was given alone (2.34 vs. 1.43 IU/mL). These findings were supported by another study, by Knuf et al.31. Scheifele et al.5 compared Pentacel® and Recombivax-HB® (5 μg) coadministered with Prevnar® at 2, 4 and 6 months or Prevnar® given sequentially at 3, 5 and 7 months and measured serology at 8 weeks after the series. GMCs were comparable between the two groups for pertussis antigens, poliovirus types 1 to 3 and tetanus antitoxin. Sequentially vaccinated subjects had higher antibody levels to diphtheria toxin and hepatitis B surface antigen but lower anti-PRP than concurrently vaccinated subjects. Although the serologic responses to vaccine serotypes contained in Prevnar® are of uncertain significance, in all four studies these responses were not inferior when given concurrently.

Halperin et al.6 compared Pentacel® given at 2, 4, 6 and 15 to 18 months concurrently with either Engerix-B® or Menjugate™ (Novartis Vaccines) vaccine and demonstrated that a protective (≥ 1:8) bactericidal antibody level was achieved in 99% of the meningococcal conjugate vaccine recipients after the first two doses and 100% after the three-dose primary series. Antibody levels to the concomitant vaccine antigens in the group receiving meningococcal vaccine were similar to those in the control group except for higher anti-diphtheria antibody titres, which likely resulted from the diphtheria toxoid carrier used in the meningococcal vaccine. In another study, by Tejador et al. from Spain, InfanrixTM-hexa was given at 2, 4 and 6 months, and meningococcal C conjugate vaccine (Meningitec™,Wyeth Canada) was given either concurrently or separately at 3, 5 and 7 months of age(15). Serologic responses to each of the antigens in InfanrixTM-hexa were similar (98% to 99%) in both groups; 99.5% to 100% of all subjects had meningococcal C bactericidal antibody titres ≥ 1:8, and 99.1% to 99.5% ≥ 1:128.

Safety and tolerability

Safety and tolerability assessments of DTaP-based penta- and hexavalent vaccines approved for use in Canada have been reported in several studies4-11,13-20,22,31. A summary of systemic and local reactions seen in trials evaluating Pentacel®/Pediacel®and InfanrixTM families of products in primary series and boosters is shown in Table 2. It must be emphasized that no head-to-head comparison studies are available for direct comparison and that the rates reported are dependent, in part, on the varying definitions of the severity of reactions. In addition, the incidence of adverse events seen with placebo or monovalent vaccines needs to be taken into consideration. These rates are not shown in Table 2. Only three studies have been reported using the Pentacel®/Pediacel® family in primary vaccination and one in booster dosing4-7. The only potential difference between the two vaccine families was the higher incidence of fever ≥ 38 oC reported with InfanrixTM vaccines. It is of note, however, that studies reporting this higher incidence were conducted using 2, 3 and 4 month or 3, 5 and 11 month schedules. A tendency to a higher incidence of systemic and local reactions was observed after booster doses compared with the primary vaccination series. The results of one study examining responses to a booster dose of either InfanrixTM-IPV/Hibor Pentacel® among infants previously vaccinated with three doses of Pentacel® (primary series) revealed decreased rates of pain and redness with InfanrixTM-IPV/Hib than with Pentacel®; however, this may have been because it was the participants' first exposure to InfanrixTM-IPV/Hib and fourth exposure to Pentacel® rather than an inherent difference in the reactogenicity of the products20.

Table 2. Incidence of systemic and local reactions reported by vaccine family

Incidence of systemic and local reactions

Primary series

Booster dosing

Pentacel®/Pediacel® family
3 studies 5-7

 

InfanrixTMfamily
13 studies 8-11,13-19,22,31

Pentacel®
1 study

InfanrixTM family 7 studies 8,10,17-20,31

Fever > 38 oC

0.6%-9.7%

11.0%-29.3%

11%

12%-46.9%

Fever > 39.5 oC

0.0%

0.0%-1.4%

1.0%

0.0%-5.4%

Restlessness/unusual crying

18.7%-48.5%

14.4%-39.7%

63%

24.8%-63.0%

Decreased appetite

16.3%-25.8%

0.6%-25.3%

43%

13.6%-40.0%

Drowsiness

12.3%-22.7%

0.9%-39%

13.8%

7.4%-33.7%

Fussiness

14.3%

17.5%-31.6%

N/A

19.1%-31.4%

Incidence of local reactions

4 studies(4-7)

13 studies(8-11,13-19,22,31)

1study

7studies(8,10,17-20,31)

Pain

 

 

 

 

Any

8.3%-23.7%

7.3%-24.0%

52.1%

9.0%-39.4%

Severe

0.0%-1.4%

0.0%-2.5%

6.9%

1.1%-8.9%

Redness

 

 

 

 

Any

14.7%-37.9%

9.0%-43.0%

11.5%

5.6%-48.2%

Severe

0.3%-4.4%

0.0%-4.0%

3.0%

1.0%-10.9%

Swelling

 

 

 

 

Any

10.7%-28.3%

5.7%-36.9%

27.0%

12.1%-30.7%

Severe

0.0%-4.4%

0.3%-6.1%

2.0%

1.0%-3.7%


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Summary

The nature and characteristics of the immunizing agents in the Pentacel®/Pediacel® and the InfanrixTM families of vaccines, although different, have many common qualitative and quantitative components and characteristics. Two vaccines, Pediacel® and InfanrixTM-hexa, have logistical and operational advantages compared with the other two vaccines. Pediacel® does not require reconstitution, and from operational perspectives this will eliminate error during vaccine mixing and will save some administration- related time. InfanrixTM-hexa contains HBV antigen and, if used in provinces or territories where infants are routinely vaccinated against HBV, would reduce the number of injections related to immunization by three as compared with separate administration of hepatitis B vaccine.

Several different schedules of penta- and hexavalent vaccines were tested in clinical trials. Taking into consideration the current epidemiology of these infections in Canada and the data from safety and immunogenicity clinical trials, the schedule of vaccine given at the age of 2, 4 and 6 months with a booster dose at 12 to 23 months appears to be the most appropriate. There are some difference in the ages for which the products have been approved. While none of the of vaccines are approved or recommended in those over 7 years of age, the Pentacel®/Pediacel® family of vaccines is approved for use in children aged 2 months to 7 years. InfanrixTM-IPV/Hib is approved for use for children 6 weeks to < 5 years of age. GSK's quadrivalent vaccine, InfanrixTM-IPV, is approved for use from 6 weeks to 6 years of age and the hexavalent vaccine, InfanrixTM-hexa, is approved for use from 6 weeks to 2 years of age.

No important differences in immune response to diphtheria, tetanus or poliovirus 1, 2 and 3 were observed between Pentacel®/Pediacel® and InfanrixTM vaccines. The anti-PRP response seems to be associated more with age and schedule of vaccine administration than with the type of vaccine.

The immune response (GMTs) to the hepatitis B vaccine component was higher after InfanrixTM-hexa than to separate administration of Pentacel® and Recombivax-HB® vaccines. Higher anti-HBs GMTs with Engerix®-B (component part of InfanrixTM-hexa) than Recombivax-HB® vaccine are reported in numerous other studies with monovalent HBV vaccine.

The response to pertussis remains difficult to interpret because there is no consensus on the protective antibody levels or on the role of different types of antibodies in protection against disease. The response to pertussis in clinical trials is differently interpreted, the number of antigens varies depending on vaccine manufacturer, and the response to PT, FHA and PRN differs depending on the vaccine used. Thus, existing data do not permit conclusions to be made about the higher effectiveness of one or another vaccine of interest. Nevertheless, consistently high response to all pertussis vaccine antigens was observed after the booster vaccination during the second year of life regardless of the vaccine used during primary series or booster administration.

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NACI recommendations

  1. Either Pentacel®/Pediacel® or InfanrixTM-IPV/Hib vaccines may be used for the routine immunization of infants against diphtheria, pertussis, polio, tetanus and Hib infections. A 2, 4 and 6 and 12 to 23 month schedule is recommended. The fourth dose (i.e., booster dose), is generally given at 18 months of age.

  2. The first three doses of the immunization series (i.e. primary series) should, whenever possible, be completed with the same combination product. Either Pentacel®/Pediacel® or InfanrixTM-IPV/Hib may be used interchangeably for the fourth dose (i.e. booster dose).

  3. Where infant immunization for hepatitis B is undertaken, InfanrixTM-hexa may be used as an alternative to separately administered hepatitis B and either Pentacel®/Pediacel® or InfanrixTM-IPV/Hib vaccines. Although InfanrixTM-hexa may be given for all four doses (age 2, 4, 6 and 12 to 23 months), the fourth dose is unlikely to provide significant added protection against hepatitis B but will increase cost. Two alternative strategies are to use InfanrixTM-hexa for the 2, 4 and 6 month doses with either Pentacel®/Pediacel® or InfanrixTM-IPV/Hib given as the 12 to 23 month booster dose or to use InfanrixTM-hexa for the 2, 4 and 12 to 23 month doses with InfanrixTM-IPV/Hib given as the 6 month dose. This latter schedule may be logistically challenging.

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References

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* Members: Dr. M. Naus (Chairperson), Dr. S. Deeks (Executive Secretary), Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. M.-N. Primeau, Dr. B. Tan, Dr. B.Warshawsky.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), E. Holmes (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. D. Money (SOGC), Dr. P. Orr (AMMI Canada), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. J. Smith (CDC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE).

Ex-Officio Representatives: Dr. F. Hindieh (BGTD), Dr. M. Lem (FNIHB), Dr. J.W. Anderson (DND).

† This statement was prepared by Kevin Laupland, Shelley Deeks and Bernard Duval. The primary literature search and study data abstraction were conducted by Vladimir Gilca.


[Canada Communicable Disease Report]