Canada Communicable Disease Report
Vol. 23 (ACS-3)
15 July 1997

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

STATEMENT ON PERTUSSIS VACCINE

PREAMBLE

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health 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. Persons administering or using the vaccine(s) 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 licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monograph(s).

INTRODUCTION

Pertussis (whooping cough) is a highly communicable infection of the respiratory tract caused by Bordetella pertussis.  The disease can affect individuals of any age; however, severity is greatest in young infants. The goal of pertussis control is to reduce the incidence and severe morbidity of pertussis among young children.  Pertussis has been controlled in Canada through immunization; during the last 40 years, the incidence of pertussis has decreased by over 90% although outbreaks of pertussis continue to occur.  Over the past 10 years, the annual number of reported cases has ranged from 1,000 to 10,000 cases, although these figures likely underrepresent the true incidence because of incomplete reporting.  Hospitalizations for pertussis are still common in Canada and several deaths from pertussis occur each year, particularly in unimmunized infants.

PREPARATIONS USED FOR IMMUNIZATION

Whole-cell pertussis vaccines

Until recently, all pertussis vaccines available in Canada were so-called whole-cell pertussis vaccines.  These vaccines are suspensions of killed B. pertussis organisms.  Whole-cell pertussis vaccines are usually given combined with other agents, either adsorbed diphtheria and tetanus toxoids (DPT), adsorbed diphtheria and tetanus toxoids plus inactivated polio vaccine (DPT-Polio), or DPT or DPT-Polio combined with Haemophilus influenzae type b (Hib) conjugate vaccine (DPT-Hib, DPT-Polio-Hib). They are also available as a single, non-absorbed preparation.  In combined vaccines, the whole-cell pertussis component potentiates the antibody response to diphtheria and tetanus antigens.

Acellular pertussis vaccines

Because of the frequency of local and systemic adverse reactions associated with whole-cell pertussis vaccines, acellular pertussis vaccines made from purified antigens of B. pertussis have been developed. All of the currently available acellular pertussis vaccines contain pertussis toxoid (PT) and most contain filamentous hemagglutinin (FHA). Other antigens contained in some products are the 69 kilodalton (69 kDa) membrane protein, also known as pertactin, and fimbriae. Although just recently introduced into North America, acellular pertussis vaccines have been in widespread use in Japan for over 15 years.

Like whole-cell vaccines, acellular pertussis vaccines are usually given combined with other agents including diphtheria and tetanus toxoids (DTaP) with or without inactivated polio vaccine (DTaP-Polio) and/or Hib conjugate vaccine (DTaP-Hib, DTaP-Polio-Hib).  Although not available at this time, combinations with hepatitis B vaccine are also under development.

ADVERSE REACTIONS

Whole-cell pertussis vaccines

Whole-cell pertussis vaccine is usually administered in combination with diphtheria and tetanus toxoids; it is responsible for most of the reactions to DPT.  Minor local reactions, such as transient pain, redness, swelling, and systemic reactions, such as fever, and fussiness occur in 50% to 75% of vaccine recipients, but are self-limited.  Drowsiness and anorexia are also common.  The incidence and severity of fever and irritability can be significantly reduced by the administration of acetaminophen (15 mg/kg/dose) at the time of inoculation and again at 4 and 8 hours after vaccination.  Reducing fever may also minimize the occurrence of febrile convulsions associated with pertussis vaccine in susceptible children.  Hence, acetaminophen prophylaxis is particularly recommended for children with a personal or family history of convulsions upon receiving whole-cell pertussis vaccine.

Persistent, inconsolable crying lasting ³ 3 hours (1%) and high-pitched, unusual screaming (0.1%) have also been reported after pertussis vaccination.  Convulsions and a hypotonic- hyporesponsive state have each been reported to occur at a frequency of about 1:1,750 injections of DPT⁽¹⁾. Most convulsions are brief, generalized, self-limited, and are usually associated with fever. Convulsions associated with pertussis vaccine are not associated with a subsequent seizure disorder.  Complete recovery has been observed, without persistent neurological or developmental defects, on follow up of hypotonic-hyporesponsive episodes or convulsions.

Although there has been a concern about the possible association of severe neurologic illness (including encephalopathy) occurring within 72 hours of the administration of whole-cell pertussis vaccine, the risk of association is so small compared to the background rate of these types of events that the question of causation cannot be answered. Whether there is a risk of permanent brain damage following pertussis vaccination is even more controversial; available studies have been unable to prove causation.

Acellular pertussis vaccines

Reactogenicity of the acellular pertussis vaccines is less than that reported after whole-cell pertussis vaccines.  In phase 2 and 3 studies of acellular pertussis vaccines, the incidence of local adverse reactions including tenderness, erythema, swelling, and general reactions, including fever, irritability, and drowsiness were significantly lower after immunization with acellular pertussis vaccines than whole-cell pertussis vaccines. In a US National Institutes of Health (NIH) sponsored multi-centre phase 2 study⁽²⁾ comparing 13 acellular pertussis vaccines and two whole-cell pertussis vaccines, differences in rates of adverse events were demonstrated between the acellular vaccines; however, no product was consistently less reactogenic.  All were less reactogenic than the whole-cell vaccines.  In the large phase 3 efficacy studies of acellular pertussis vaccines, less common adverse reactions such as persistent crying and hypotonic-hyporesponsive episodes were also less common after acellular pertussis vaccines, and were reported in similar frequency in recipients of non-pertussis containing vaccines.  Convulsions were reported less frequently after acellular pertussis vaccines in some of the efficacy studies but not others. Table 1 presents data from the Swedish efficacy study⁽³⁾ of two acellular pertussis vaccines, an American whole-cell vaccine, and a diphtheria-tetanus toxoid vaccine (DT), and is representative of rates of adverse reactions following pertussis vaccines.

Because of the lower incidence of fever associated with acellular pertussis vaccines, there may be less justification for routine use of prophylactic acetaminophen. Acetaminophen may be considered in children with a high risk of febrile seizures.

Table 1 Adverse reactions associated with pertussis vaccine

IMMUNOGENICITY

There is no known direct correlation between levels of specific pertussis antibodies and protection against pertussis.  For whole-cell pertussis vaccines, vaccine potency and efficacy correlate with a minimum of four international units (IUs) in the intracerebral mouse-protection assay.  Susceptibility of a population to pertussis correlates best with agglutinin antibodies but these do not adequately predict protection in an individual⁽⁴⁾.  Antibody responses to specific pertussis antigens vary widely among different whole-cell vaccines⁽⁵⁾.  Acellular pertussis vaccines prepared from purified pertussis antigens evoke a more predictable antibody response in that they elicit antibodies to all of the vaccine constituents.  In comparative studies of acellular pertussis vaccines, however, the level of antibodies achieved post vaccination does not directly correlate with the antigen quantity of the vaccine⁽⁶⁾.

Table 2 Summary of efficacy studies with acellular pertussis vaccines combined with diphtheria and tetanus toxoids in infants  

EFFICACY

Whole-cell vaccine

Controlled clinical trials of whole-cell pertussis vaccines in the 1940s and 1950s demonstrated efficacy between 70% to 90%. Although no randomized controlled clinical trials had been done over the last four decades, household-contact studies and case-control studies suggested a wider variation in the efficacy of whole cell vaccine ranging from 40% to 100%. The efficacy of the whole-cell vaccine, produced by Pasteur Mérieux Connaught Canada and used in most of Canada, has not been measured in a randomized controlled clinical trial; epidemiologic studies suggest that its efficacy may be below the 70% to 90% efficacy estimates^(7,8). In addition, the efficacy of whole-cell pertussis vaccine diminishes as the time interval since vaccination increases⁽⁹⁾. This may account for the increasing incidence of pertussis in school-aged children and adolescents.

Acellular pertussis vaccines

In the last 2 years, the results of seven studies of the efficacy of eight DTaP vaccines have been reported^(3,10-13). The studies were not designed to compare the efficacy of acellular pertussis vaccines and involved different study designs; therefore few conclusions can be made about the relative merits of the various products. All of the acellular vaccines were efficacious; most were as effective or more effective than the whole-cell DPT vaccines included as a control. Table 2 summarizes the results of the efficacy studies.

Duration of protection of acellular pertussis vaccines is not known. Long-term follow up is planned for several of the cohorts that participated in these efficacy studies.

RECOMMENDED USAGE

Immunization against pertussis consists of three doses given at intervals of 4 to 8 weeks beginning at 2 months of age, a fourth dose 6 to 12 months after the third dose (most available data are with the fourth dose at 15 to 18 months of age following the third dose at 6 months of age) and a fifth dose at 4 to 6 years of age.

The dosage and route of administration should be as recommended by the manufacturer. Adsorbed vaccines are given intramuscularly. It is important that pertussis vaccination begin and be completed on time to ensure the greatest possible protection to the young infant, in whom the disease can be very serious. Because adverse reactions may be more common and the disease is typically less severe in older children, adolescents and adults, immunization with the whole-cell pertussis vaccine is not recommended for persons ³ 7 years of age. However, older children, adolescents, and adults who develop pertussis are an important source of infection for young infants. For this reason, studies are underway to assess the role of pertussis in adolescents and adult cough illness, and the safety, immunogenicity, and efficacy of acellular pertussis vaccines in adolescents and adults. Immunization in these age groups may be recommended in the future. Acellular pertussis vaccine has been used safely for control of pertussis in defined populations such as school or hospital outbreaks, although data supporting its use is lacking. Should its use be considered for this purpose, it should be undertaken with specific informed consent and with a formal evaluation of its effectiveness.

Either acellular and whole-cell pertussis vaccines may be used for immunization against pertussis. Whole-cell pertussis vaccines are known to cause very high rates of local adverse reactions following the fifth dose⁽¹⁴⁾. Administering this dose with acellular pertussis vaccine results in much lower rates of these adverse reactions. In view of the lower incidence of vaccine associated adverse events with all doses and the possibility that the acellular pertussis vaccines may be more efficacious than the whole-cell pertussis vaccine in widespread use in Canada, the use of acellular pertussis vaccines should be given preference and should be introduced in provincial and territorial immunization programs for all doses as soon as possible. For children who have already begun their immunization series with whole-cell pertussis vaccine, acellular pertussis vaccine should be substituted for the next and all subsequent doses.

Efficacy for most of the acellular pertussis vaccines was demonstrated after three doses of the same vaccine. No data are available regarding the interchangeability of acellular pertussis vaccines; therefore, whenever possible, efforts should be made to complete the first three doses with the same acellular pertussis vaccine. Although data are similarly lacking, the acellular vaccines can be considered interchangeable for the fourth and fifth doses because it may be difficult to ensure supply of the same vaccine during the entire 4- to 6-year immunization period.

Acellular pertussis vaccine is recommended to complete pertussis immunization in children whose series was interrupted because of the more extensive contraindications to pertussis immunization as listed in previous editions of the Canadian Immunization Guide (also see "Conditions Not Considered Contraindications to Pertussis Vaccine" below). Use of the acellular pertussis vaccine should also be encouraged for children in whom pertussis vaccine was removed from their immunization series because of "false contraindications" or parental concerns about adverse reactions associated with the whole-cell pertussis vaccine.

Vaccines which combine antigens against multiple diseases enhance immunization compliance by decreasing the necessary number of injections and visits, and therefore should be encouraged. Both whole-cell and acellular pertussis vaccines are available as pertussis-only vaccines and in combination with diphtheria and tetanus toxoids, as well as with inactivated polio vaccine, and Hib conjugate vaccine. In general, adverse reactions associated with the combination vaccines are no more frequent than those associated with the constituent vaccines. Antibody response to combination antigens is complex; combination vaccines may have increased, decreased, or unaffected immunogenicity when compared to the individual vaccines and the effects may differ among products produced by different manufacturers. As a rule, despite some "immune interference" between antigens, all licensed combination vaccines have demonstrated adequate immunogenicity to each of the constituent vaccines. For this reason, when combination vaccines are available, their use should be encouraged to facilitate vaccine compliance. Conversely, however, the need for multiple injections should not delay implementing of vaccines that provide advantages in safety, immunogenicity, efficacy, or cost.

Acellular or whole-cell pertussis-containing vaccines may be administered simultaneously with other inactivated and live vaccines at different sites. None of the products should be mixed in the same syringe with any other vaccines unless specifically approved and described in the product monograph.

Children who have had natural pertussis can continue to receive pertussis-containing vaccines without risk. Because of concern about adverse reactions associated with whole-cell pertussis vaccine, removal of the pertussis component from subsequent immunizations following culture-positive pertussis was previously recommended because of immunity conferred by infection. Although further data are needed, with the increased safety profile of the acellular pertussis vaccine, elimination of the pertussis component from the vaccine no longer appears necessary, thereby simplifying immunization programs. Continuation of immunization with acellular pertussis vaccine may also confer additional benefit to infants < 6 months of age who often have a sub-optimal antibody response to natural pertussis infection.

CONTRAINDICATIONS AND PRECAUTIONS

Absolute

Pertussis vaccine should not be given to individuals who have had an anaphylactic reaction to a previous dose. Because these events are so rare, it is not known which component of the combined DPT or DTaP (or additional antigens in the combination vaccines) is responsible for allergic reactions. Therefore, no further doses of any of the vaccine components should be given unless assessment implicates the responsible antigen.

Relative

Hypotonic-hyporesponsive episodes are not a contraindication or relative contraindication for the use of acellular pertussis vaccine. Because the incidence of hypotonic-hyporesponsive episodes appears similar between DTaP recipients and DT recipients, it is difficult to attribute causation of hypotonic-hyporesponsive episodes in recipients of DTaP to the pertussis component; continued immunization with all antigens is recommended.

If acellular pertussis vaccine is not available and the incidence of pertussis remains high in the area, whole-cell vaccine can be used in children with a previous hypotonic-hyporesponsive episode. In areas of low incidence, however, it may be prudent to withhold the whole-cell pertussis component and continue vaccination with DT; consultation with the local medical officer of health is recommended.

Deferral

Deferral of pertussis immunization for children with evolving neurological conditions is no longer necessary because of the availability of acellular pertussis vaccines. Specific data using these vaccines are not available in individuals with neurologic diseases and must await post-marketing surveillance. However, since the incidence of adverse events including fever and seizures was no different in recipients of DTaP or DT, it makes little sense to defer the pertussis component of the vaccine.

If acellular pertussis vaccine is not available, deferral of whole-cell pertussis immunization may be considered in children with a progressive, evolving, or unstable neurologic condition in order to prevent confusion of the diagnosis if an adverse event occurs. Such conditions include tuberous sclerosis, poorly controlled convulsions, central nervous system malformations, or neurodegenerative diseases. Continued deferral should be reassessed at each visit; pertussis vaccination should be reinstituted when the condition has resolved, been corrected or controlled, or when acellular pertussis vaccine becomes available. If the individual had proceeded on with the immunization series with the other antigens, pertussis vaccine alone can be used to complete the series.

CONDITIONS NOT CONSIDERED CONTRAINDICATIONS TO PERTUSSIS VACCINE

Certain other events temporally associated with pertussis vaccination are not considered contraindications. However, because of the higher incidence of these events with whole-cell pertussis vaccine, the use of acellular pertussis vaccine is preferred in individuals who have had one of these events with a previous dose.

• High fever within 48 hours of vaccination, attributed to vaccination and not to intercurrent illness, indicates the likelihood of recurrence of fever with subsequent doses. Febrile convulsions may be more likely in a susceptible child who develops high fever. However, there are no long-term sequelae from these convulsions and pertussis vaccination can continue. Acetaminophen prophylaxis reduces the incidence of fever and may reduce febrile convulsions temporally related to pertussis vaccination.
• Afebrile convulsions have not been shown to be caused by pertussis vaccine and are not a contraindication to pertussis vaccination.
• Persistent, inconsolable crying and an unusual high-pitched cry after pertussis vaccine are also not associated with any sequelae and may simply be a pain response at the site of injection in young infants. These reactions do not preclude further pertussis vaccination.
• Onset of encephalopathy temporally related to pertussis vaccination does not indicate that the vaccine was the cause. Encephalopathy itself from whatever cause is not a contraindication to pertussis vaccination.

UNANSWERED QUESTIONS

A number of questions about acellular pertussis vaccines remain to be answered. More data are needed on the interchangeability of the various acellular pertussis vaccine products. The optimal number of doses (duration of protection) and the role of pertussis immunization in adolescents and adults needs to be clarified as does the result of cumulative doses of acellular pertussis vaccines on the adverse event profile. Estimates of the rates of adverse reactions in special populations are needed, including individuals with neurologic abnormalities and children after natural infection. Careful studies are needed to assess the effect of implementing acellular pertussis vaccine on the epidemiology of pertussis in Canada, with particular attention on young infants and school-aged children. These studies are particularly important in view of the fact that the efficacy studies of acellular pertussis vaccine were performed with DTaP whereas the implementation of the vaccine will include combinations with additional antigens.

LICENSED VACCINES

Table 3 summarizes the names, manufacturers, constituents, and indications for licensed whole-cell and acellular pertussis vaccines.

Table 3 Summary of Licensed Vaccines and Indications

Acellular vaccines are discussed below, following the list of whole-cell pertussis vaccines.

Whole-Cell Pertussis

Vaccines Pasteur Mérieux Connaught Canada

• Pertussis Vaccine: pertussis (P)
• DPT Adsorbed: diphtheria, pertussis, and tetanus (DPT)
• DPT-Polio Adsorbed: diphtheria, pertussis, tetanus, and polio (DPT-Polio)
• DPT-Hib: diphtheria, pertussis, tetanus, and Hib conjugate (DPT-Hib)
• PENTA^TM : diphtheria, pertussis, tetanus, polio, and Hib conjugate (DPT-Polio-Hib)

Wyeth-Ayerst Canada Inc.

• TRI-IMMUNOL®: diphtheria, pertussis, and tetanus (DPT)
• TETRAMUNE: diphtheria, pertussis, tetanus, and Hib conjugate (DPT-Hib)

Acellular Pertussis Vaccines

Pasteur Mérieux Connaught Canada

• TRIPACEL^TM : component pertussis vaccine combined with diphtheria and tetanus toxoids, adsorbed (DTaP)
• QUADRACEL^TM : component pertussis vaccine, combined with diphtheria and tetanus toxoids, adsorbed, combined with inactivated polio vaccine (DTaP-Polio)
• PENTACEL^TM : component pertussis vaccine, combined with diphtheria and tetanus toxoids, adsorbed, combined with inactivated polio vaccine and Hib conjugate vaccine (DTaP-Polio-Hib).

TRIPACEL^TM is an acellular pertussis vaccine combined with diphtheria (15 Lf) and tetanus (5 Lf) toxoids. The pertussis components (20 mg PT, 20 mg FHA, 5 mg fimbriae combined agglutinogens types 2 and 3, 3 mg 69 kDa membrane protein) are individually purified, adsorbed on aluminum phosphate (0.33 mg per 0.5 mL dose), and preserved with 0.6% 2-phenoxyethanol. QUADRACEL^TM contains the same pertussis, diphtheria, and tetanus constituents with the addition of inactivated poliovirus vaccine (Type 1 Mahoney, Type 2 M.E.F.1, Type 3 Saukett). PENTACEL^TM is the combination of QUADRACEL^TM and Hib conjugate vaccine Act-HIB® (tetanus protein-conjugate) made by using QUADRACEL^TM to reconstitute Act-HIB® immediately prior to vaccination. TRIPACEL^TM , QUADRACEL^TM , and PENTACEL^TM are licensed for the primary and booster immunization of infants and children < 7 years of age.

All of the acellular pertussis vaccine containing combinations are safer and more immunogenic than their whole-cell pertussis counterparts. A formulation of TRIPACEL^TM containing one-half the quantity of PT and one-fourth the quantity of FHA was included in the Swedish efficacy study. In over 7,600 doses, the rate of all adverse reactions was significantly less than that of a whole-cell pertussis vaccine produced by the American Connaught Laboratories (DTaP #2, Table 1). In phase 2 studies involving over 2,000 infants, there were no substantive differences between this formulation and the formulation used in TRIPACEL^TM (15). In a study of TRIPACEL^TM at 17 to 19 months after a three-dose primary series with a whole-cell DPT vaccine produced by the Canadian Connaught Laboratories, local reactions were reported after 6% to 29% of injections and systemic reactions after 5% to 49% of injections(16-18). In another study of 126 children 4 to 6 years of age receiving their fifth dose with TRIPACEL^TM , local reactions were reported after 10% to 43% of injections and systemic reactions after 8% to 10% of injections(19). In all cases, rates of adverse reactions were lower than in children given the whole-cell pertussis vaccine produced by the Canadian Connaught Laboratories. TRIPACEL^TM induces a good antibody response to all the pertussis antigens when given as the primary or booster immunization. Antibody response in the infants in the Swedish trial given the TRIPACEL^TM -like formulation exceeded that of recipients of the whole-cell pertussis vaccine for all antigens. The antibody response to the formulation contained in TRIPACEL^TM meets or exceeds these levels⁽¹⁵⁾. In over 300 children, 17 to 19 months of age, previously immunized with three doses of the Canadian Connaught Laboratories whole-cell vaccine and receiving their fourth dose with TRIPACEL^TM , antibody levels were equivalent (PT, FHA) or higher (69 kDa membrane protein, fimbriae) than those following four doses of the Canadian Connaught Laboratories whole-cell pertussis vaccine^(17,18). There are no data yet available on the efficacy of TRIPACEL^TM ; however, an efficacy of 85% was demonstrated in a study of over 2,500 children in Sweden using the formulation of the vaccine containing the lower antigen quantity⁽³⁾. Protective efficacy of TRIPACEL^TM given as the fourth and fifth doses is not known.

The combination TRIPACEL^TM with inactivated polio vaccine (QUADRACEL^TM ) and inactivated polio vaccine and Hib conjugate vaccine (PENTACEL^TM ) do not significantly increase the adverse events or diminish the immunogenicity⁽²⁰⁾. The only exception was a decreased tetanus antitoxin level in recipients of PENTACEL^TM ; however, all children achieved protective levels in excess of 0.01 IU/mL and 10-fold these levels following the 18-month dose. There are no data on the protective efficacy of QUADRACEL^TM or PENTACEL^TM .

Wyeth-Ayerst Canada Inc.

• Acel-PTM: acellular pertussis vaccine, adsorbed (aP)
• ACEL-IMUNE^TM: diphtheria and tetanus toxoids, and acellular pertussis vaccine, adsorbed (DTaP)

Acel-P^TM is a monovalent alum-adsorbed acellular pertussis vaccine using the Lederle-Takeda acellular pertussis vaccine. ACEL-IMUNE^TM is the same acellular pertussis vaccine combined with diphtheria (7.5 Lf) and tetanus (5 Lf) toxoids. The pertussis component is isolated by a copurification process (ammonium sulfate fractionation and sucrose density gradient centrifugation) and contains approximately 41 mg pertussis antigens per 0.5 mL dose (86% FHA, 8% PT, 4% 69 kDa membrane protein, 2% fimbriae [agglutinogen type 2]). The final product is detoxified with formaldehyde and preserved with thimerosal.

ACEL-IMUNE^TM is recommended for children 15 months to 6 years of age who have also not started or not completed their primary series with diphtheria and tetanus toxoids. Acel-P^TM is recommended for primary and booster immunization in children 15 months to 6 years of age whose pertussis immunization was interrupted or deferred, e.g. because of concerns about the adverse effects of pertussis vaccine. ACEL-IMUNE^TM and Acel-P^TM are not yet approved in Canada for use in children < 15 months of age. When inactivated polio vaccine or Hib conjugate vaccine are indicated, they must be given as separate injections at different sites.

Safety, immunogenicity, and efficacy of Acel-P^TM and ACEL-IMUNE^TM are similar to other acellular pertussis vaccines. In a study of 249 children, 15 months to 6 years of age and given a three-dose primary series with Acel-PTM, local reactions (pain, erythema, and induration) were reported after 13% to 18% and systemic reactions (fever, drowsiness, irritability) after 5% to 12% of the 743 injections given⁽²¹⁾. In 911 children, 17 to 24 months and 4 to 6 years of age, and receiving their fourth or fifth immunization with ACEL-IMUNE^TM after a primary series with the whole-cell pertussis (DPT) vaccine produced by Wyeth-Lederle; local reactions were reported after 7% to 26% of immunizations and systemic reactions after 6% to 19%^(22-24). Acel-P^TM elicited a four-fold or greater antibody rise against its constituent antigens in 93% to 100% of children 15 months to 6 years of age and undergoing primary immunization(21). In nearly 1,000 children receiving their fourth or fifth DPT dose with ACEL-IMUNE^TM, antibody levels were equivalent to (PT, 69 kDa membrane protein, fimbriae) or higher (FHA) than those following the Wyeth-Lederle whole-cell vaccine^(23,24). There are no data describing the immune response to these acellular pertussis vaccines given as the fourth or fifth dose following initial immunization with other whole-cell pertussis-containing vaccines licensed in Canada. Protective efficacy of Acel-P^TM and ACEL-IMUNE^TM given as the fourth and fifth dose is not known. In a non-blinded household-contact study in Japan, efficacy of the Takeda acellular pertussis vaccine after primary immunization in children ³ 2 years of age was 79% (95% confidence interval = 60 to 89)(25). In a recently completed efficacy study in over 10,000 children in Germany, ACEL-IMUNE^TM was shown to have comparable efficacy to the Wyeth-Lederle whole-cell pertussis-containing vaccine (Table 2)⁽²⁶⁾. There are no data available on the efficacy of the monovalent Acel-PTM.

SmithKline Beecham Pharma Inc.

• Infanrix^TM : diphtheria, tetanus, and acellular pertussis vaccine, adsorbed (DTaP)

Infanrix^TM is an acellular pertussis vaccine containing PT (25 mg), FHA (25 mg) and the 69 kDa membrane protein (8 mg), 30 IUs diphtheria toxoid (25 Lf), 40 IUs tetanus toxoid (10 Lf), 0.5 mg aluminum as aluminum hydroxide and 0.5% 2-phenoxyethanol as preservative per 0.5 mL dose.Infanrix^TM is licensed for the primary and booster doses for children < 7 years of age. When inactivated polio vaccine and Hib conjugate vaccine are indicated, they must be given as separate injections at different sites.

The safety, immunogenicity, and efficacy of Infanrix^TM is similar to other acellular pertussis vaccines. In an NIH-sponsored efficacy study in Italy, with a similar design as the Swedish efficacy study, 13,761 doses of Infanrix^TM were given in a primary infant series. Local adverse reactions (including redness > 2.4 cm, swelling > 2.4 cm, and prominent tenderness) were reported by 1.9%, 1.6%, and 0.4% of Infanrix^TM and 9.1%, 9.6%, and 11.4% of the American Connaught Laboratories whole-cell pertussis vaccine recipients, respectively. Fever ³ 38o C was reported by 7.9% of Infanrix^TM and 40.3% of whole-cell pertussis vaccine recipients⁽¹²⁾. Infanrix^TM for a booster dose, after the primary series with Infanrix^TM or whole-cell pertussis vaccine, is also associated with fewer local and systemic adverse reactions than with whole-cell vaccine. As with other acellular pertussis vaccines, non-painful swelling of the entire thigh has occasionally been reported after the booster doses with InfanrixTM. Antibody levels to the pertussis antigens following Infanrix^TM are higher than after the whole-cell pertussis vaccine; over 94% of recipients had an antibody response to the three pertussis antigens⁽¹²⁾. Protective efficacy of Infanrix^TM in over 4,400 infants in the Italian efficacy study was 84%. Protective efficacy of Infanrix^TM given as the fourth and fifth doses is not known.

References

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4. Medical Research Council. Vaccination against whooping cough: the final report to the Whooping Cough Immunization Committee of the Medical Research Council and to the Medical Officer of Health for Battersea and Wandsworth, Bradford, Liverpool and Newcastle. Br Med J 1959;I:994-1000.

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9. Lambert HJ. Epidemiology of a small pertussis outbreak in Kent County, Michigan. Public Health Rep 1965;80:365-69.

10. Edwards KM, Decker MD. Acellular pertussis vaccines for infants. N Engl J Med 1996;334:391-92.

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12. Greco D, Salmaso S, Mastrantonio P et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med 1996;334:341-48.

13. Schmitt HJ, von Konig CHW, Neiss A et al. Efficacy of acellular pertussis vaccine in early childhood after household exposure. JAMA 1996;275:37-41.

14. Scheifele DW, Meekison W, Grace M et al. Adverse reactions to the preschool (fifth) dose of adsorbed diphtheria-pertussis-tetanus vaccine in Canadian children. Can Med Assoc J 1991;145:641-47.

15. Halperin SA, Eastwood B, Barreto L et al. Safety and immunogenicity of two acellular pertussis vaccines with different pertussis toxoid and filamentous hemagglutinin content in infants two to six months old. Scand J Infect Dis 1995;27:279-87.

16. Connaught Laboratories Ltd. (a Pasteur Mérieux Company). TRIPACEL^TM product monograph. North York, ON: Connaught Laboratories Ltd., 1996.

17. Halperin SA, Mills E, Barreto L et al. Acellular pertussis vaccine as a booster dose for seventeen- to nineteen-month-old children immunized with either whole-cell or acellular pertussis vaccine at two, four, and six months of age. Pediatr Infect Dis J 1995;14, 792-97.

18. Halperin SA, Davies HD, Barreto L et al. Safety and immunogenicity of two inactivated poliovirus vaccines in combination with an acellular pertussis vaccine and diphtheria and tetanus toxoids in seventeen- to nineteen-month-old infants. J Pediatr 1997;130:525-31.

19. Halperin SA, Scheifele D, Barreto L. Comparative safety of a fifth dose of an acellular or whole-cell pertussis vaccine in four- to five-year-old children. Abstracts of the 36th ICAAC, American Society for Microbiology, New Orleans, 1996; G100.

20. Connaught Laboratories Ltd. (a Pasteur Mérieux Company). QUADRACEL^TM product monograph. North York, ON: Connaught Laboratories Ltd., 1997.

21. Stehr K, Heininger U, Uhlenbusch R et al. Immunogenicity and safety of a monovalent, multicomponent acellular pertussis vaccine in 15 month-6-year-old German children. Eur J Pediatr 1995;154:209-14.

22. CDC. Pertussis vaccination: acellular pertussis vaccine for reinforcing and booster use - supplementary ACIP statement. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1992;41(RR-1):1-10.

23. Blumberg DA, Mink CM, Cherry JD et al. Comparison of an acellular pertussis-component diphtheria-tetanus-pertussis (DTP) vaccine with a whole-cell pertussis-component DTP vaccine in 17- to 24-month-old children, with measurement of 69-kilodalton outer membrane protein antibody. J Pediatr 1990;117:46-51.

24. Morgan CM, Blumberg DA, Cherry JD et al. Comparison of acellular and whole-cell pertussis-component DTP vaccines. AJDC 1990;144:41-45.

25. Mortimer Jr. EA, Kimura M, Cherry JD et al. Protective efficacy of the Takeda acellular pertussis vaccine combined with diphtheria and tetanus toxoids following household exposure of Japanese children. AJDC 1990;144:899-904.

26. Uberall M. A comparative efficacy trial in Germany in which infants received either the Lederle/Takeda acellular pertussis component DTP (DTaP) vaccine, the Lederle whole-cell component DTP (DTP) vaccine or DT vaccine. Presented at the International Symposium on Pertussis Vaccine Trials, Rome, Italy, October 30-November 1, 1995.

* Members: Dr. D. Scheifele (Chairman); Dr. J. Spika (Executive Secretary); N. Armstrong (Advisory Committee Secretariat Officer); Dr. P. DeWals; Dr. S. Halperin; Dr. B. Law; Dr. M. Naus; Dr. B. Ward; Dr. I. Gemmill; Dr. W. Schlech III; Dr. P. Orr; Dr. G. DeSerres; Dr. J. Carsley.

Liaison Members: Dr. D. Carpenter (ND); Dr. A. Carter (CMA); Dr. T. Freeman (CFPC); Dr. S. Hadler (CDC); Dr. V. Marchessault (CPS); Dr. J. Waters (ACE); Dr. J. Levingood.

Ex-Officio Members: Dr. P. Duclos (LCDC); Dr. L. Palkonyay (DD); Dr. D. Kertesz (LCDC).

[Canada Communicable Disease Report]