Vaccine-Preventable Diseases

Pertussis

Pertussis (whooping cough) is a highly contagious infectious disease caused by Bordetella pertussis. The illness is characterized by severe coughing spasms which may or may not be associated with the classic inspiratory whoop. Pertussis is most severe and complications are most frequent in children < 1 year of age. Morbidity and mortality are generally reported to be higher in females than males. Complications include apnea, pneumonia, seizures, encephalopathy, and death. Death is estimated to occur in one in 200 cases for those < 1 year of age. Infection with B. pertussis produces long-term immunity from the disease but may not prevent further infection. Infection rates in immunized persons may be high, but clinical illness is infrequent and mild when it occurs.

Pertussis incidence in Canada peaked at 182 cases per 100,000 population in 1934, which was prior to the introduction of the whole-cell vaccine that was among the first to be introduced in Canada in 1943. Significant reductions in incidence and mortality have been achieved since the introduction of routine vaccination. Overall, the average annual incidence has decreased by approximately 90%, from 157 cases per 100,000 population (17,463 cases) in the immediate pre-vaccine era to 17 cases per 100,000 (4,900 cases) for 1986 through 1995. The reporting of pertussis in Canada is believed to be highly underestimated; rates based on passive reporting were underestimated by as much as 14-fold in one study.

The highest age-specific incidence is reported in infants (mean of 168 cases per 100,000 population for the last decade). In a recent analysis of pertussis cases of children < 2 years of age who were admitted to tertiary-care pediatric centres in the IMPACT surveillance network, 75% were < 6 months of age. Almost 20% of the cases had illness severe enough to warrant admission to an intensive-care unit. Overall, 10% of the cases had secondary pneumonia, and 5% had neurologic complications (mostly seizures); a case-fatality rate of 0.7% was reported. In comparison to infants and young children, the reported incidence of pertussis is relatively low among adolescents and adults (< 10 per 100,000 population in those > 15 years of age). They usually develop mild disease only; however, they pose a significant problem because they are a reservoir of infection for susceptible younger children.

In recent years the incidence of pertussis has increased across Canada and epidemics have increased in size. The reported incidence in 1994 to 1995 (34.7 and 35.2 per 100,000 population, respectively) has been the highest in a decade, which makes it difficult for Canada to reach its 1997 disease-reduction target. Continuing epidemics of pertussis may be due in part to suboptimal immunization coverage which is documented in several parts of the country. Pertussis has the lowest coverage of all the vaccine-preventable diseases. This is mainly because of parental fears of serious adverse reactions to the whole-cell vaccine in addition to the practice of health-care providers who omit pertussis vaccination because of perceived "contraindications." Omitted or delayed vaccination has its greatest impact among infants because the highest incidence and greatest severity of the disease occurs in this age group. This should always be taken into consideration when a decision is being made to immunize a child according to a schedule other than the recommended routine one.

The whole-cell vaccine currently used in Canada may be another contributing factor to continuing pertussis epidemics. A number of studies have shown that it has only low to moderate effectiveness in preventing clinical illness. The vaccine is still believed to be highly effective in reducing the frequency and severity of complications. Newer, safer, and possibly more efficacious acellular vaccines are currently licensed in Canada for the fourth and fifth booster doses. These vaccines are likely to become more acceptable to parents and health-care providers when they are licensed for the primary series; coverage levels will be higher and the disease will be better controlled.

1998 Update:  The cyclical increase in pertussis rates, which began in the late 1980s, continued in 1998 with 7519 reported pertussis cases, an incidence of 25.1/100,000 (Figure 5). The highest age-specific incidence occurred in the younger than one-year-old age group at 166.9/100,000 (606 cases), followed by 127.3/100,000 (2608 cases) in the five- to nine-year olds and 100.2/100,000 (1556 cases) in the one- to four-year-old age group. The cases are distributed almost equally between the sexes.

Figure 5) Crude incidence of pertussis reported in Canada, 1924 to 1998

Pertussis remains the least controlled vaccine-preventable disease for which routine childhood immunization is available. Contributing factors to this include a reluctance to seek vaccination and the suboptimal protection offered by the whole cell vaccine. New and improved acellular vaccines were licensed in Canada in 1996, and adopted by all provincial and territorial vaccine programs by mid-1998. Close monitoring will help assess the effectiveness of this new vaccine in decreasing the incidence of pertussis over time.

Revised case definitions for diseases under national surveillance will be published as a supplement to the Canada Communicable Diseases Report in the fall of 1999.

Pertussis Vaccine

Only acellular vaccines made from purified antigens of B. pertussis are now available in Canada, and whole-cell preparations are no longer in use. Acellular vaccines have been developed to reduce the frequency and severity of both local and systemic adverse reactions associated with whole-cell pertussis vaccines. All the currently available acellular vaccines contain pertussis toxoid, filamentous hemagglutinin and pertactin. Although recently introduced into North America, acellular pertussis vaccines have been widely used in Japan for over 15 years.

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 licensed in Canada at this time, combinations with hepatitis B vaccine are in use in other countries.

The dTap adolescent/adult formulation of acellular pertussis vaccine is combined with tetanus and diphtheria toxoids adsorbed on aluminum phosphate. The antigen content of this vaccine (including the pertussis content) is lower than the one found in the vaccines used in preschool children.

Efficacy and Immunogenicity

In 1995-1996, the results of seven studies of the efficacy of eight DTaP vaccines were reported. The studies were not designed to compare the efficacy of the various acellular pertussis vaccines and involved different study designs; therefore, few conclusions can be drawn about the relative merits of the various products. All the acellular vaccines were efficacious, and most were as effective or more effective than the whole-cell DPT vaccines included as controls. All acellular pertussis vaccines licensed in Canada have an estimated efficacy of approximately 85%; a detailed summary of the products and the results of the studies can be found in the 1997 NACI statement on acellular pertussis vaccines.

The duration of protection afforded by acellular pertussis vaccines is not known, but the data seem to indicate that protection does not decline during the first 4 years of follow-up. Long-term follow-up will continue for several of the cohorts that participated in the efficacy studies.

As discussed in the NACI statement in 2000, there are limited data about the efficacy of a single dose of adolescent/adult pertussis vaccine given to previously immunized adolescents or adults in the prevention of pertussis infection, disease and transmission. However, it has been shown that a single dose of this vaccine increased their pertussis antibody levels far in excess of those observed in infants in Sweden who received three doses of acellular pertussis vaccine. As the efficacy demonstrated in the Swedish trial was 85%, it is reasonable to expect that the protection against severe disease in adolescents and adults would be of the same order.

The only study conducted to directly assess vaccine efficacy, by Ward et al., found that a single dose of a tri-component acellular pertussis vaccine gave significant protection. The point estimate of vaccine efficacy for the primary case definition was 78%; however, there were so few cases meeting this case definition that the confidence interval was very wide. De Serres et al. have provided another, indirect, piece of evidence supporting the protective efficacy of a single dose of dTap with data showing the efficacy of a single booster dose of acellular pertussis vaccine in infants or preschool-aged children.

Recommended Usage

Acellular pertussis vaccine is recommended for all children >= 2 months of age for whom there are no contraindications. Children who have had natural pertussis should continue to receive pertussis-containing vaccines. Because of concern about the adverse reactions associated with whole-cell pertussis vaccine, it was previously recommended that the pertussis component be removed from subsequent immunizations after a finding of positive culture, because of the immunity conferred by infection. Although further data are needed, the increased safety profile of the acellular pertussis vaccine makes elimination of the pertussis component no longer necessary and thereby simplifies immunization programs. As well, continuation of immunization with acellular pertussis vaccine may confer additional benefit to infants < 6 months of age, who often have a suboptimal antibody response to natural pertussis infection.

In children >= 7 years of age who have not had a primary pertussis immunization or for whom the immunization status is unknown (e.g., immigrant children), adolescent/adult dTap should be considered.

Pertussis Vaccine

Interchangeability

The efficacy of most of the acellular pertussis vaccines has been 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 vaccine. Although data are similarly lacking, the acellular vaccines can be considered interchangeable for the fourth and fifth doses, since it may be difficult to ensure supply of the same vaccine during the entire 4-6 year immunization period.

Outbreak control

Acellular pertussis vaccine has been used safely for the control of pertussis outbreaks in defined populations, such as in schools or hospitals, although data supporting its effectiveness are lacking. Ensuring the complete immunization of all children remains the most important preventive measure in maximizing control of pertussis. Updating the immunization of daycare, school and community contacts should be undertaken by public health authorities.

Contacts

Children exposed to a case should have their immunization status reviewed. If immunization is incomplete and in the absence of contraindications, any necessary doses should be given as follows:

• Children who have received fewer than three doses should receive their additional dose(s) as soon as possible, with an interval of 4 weeks between doses.
• Children who have had three doses may receive their fourth dose as early as 6 months after the third dose.
• A booster dose of vaccine, usually as DTaP, should be given to any child ≤ 6 years of age who has had four doses of vaccine, unless the most recent dose was given within the previous 3 years.

If dTap is considered for people >= 7 years to achieve outbreak control, this should be undertaken with evaluation of its effectiveness.

The role of chemoprophylaxis in the management of contacts is not discussed here.

Schedule and Dosage

Immunization against pertussis routinely consists of three doses given at 2, 4 and 6 months of age, a fourth dose at 18 months of age and a fifth dose at 4 to 6 years of age. When more rapid protection is preferred, the first three doses may be administered at intervals of 4 weeks and the fourth dose given as soon as 6 months after the third dose. It is important that immunization against pertussis begin and be completed on time to ensure the greatest possible protection to the young infant, in whom the disease can be very serious. The dose to be administered is that recommended by the manufacturer.

For children >= 7 years who have not been immunized or immigrants with unknown status, two doses of adolescent/adult dTap with a 4 week interval should be administered and a third dose given at 12 months. Monovalent acellular pertussis vaccine should be administered to children who have been immunized against diphtheria and tetanus but not against pertussis.

Route of Administration

All combined acellular pertussis vaccines are adsorbed vaccines and must be given intramuscularly.

Booster Doses and Re-immunization

Because adverse reactions are 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 people >= 7 years of age. However, pertussis in this group is an important source of infection for young infants. For this reason, studies are under way to assess the role of pertussis in adolescents and adults with cough illness, and the safety, immunogenicity and efficacy of acellular pertussis vaccine in these age groups. A single dose of pertussis vaccine in adolescence or adulthood will provide individual protection, but the duration of its effect and whether it prevents transmission to infants is not known. The combined adolescent/adult formulation of dTap should be used to replace the adolescent booster of Td. Until data about the safety of repeated doses are available, only one dose is currently recommended.

Storage Requirements

Pertussis-containing vaccines should be stored at a temperature between 2o and 8o C and should not be frozen. As with all adsorbed vaccines, pertussis-containing vaccines that have been frozen should not be used.

Simultaneous Administration with Other Vaccines

Vaccines that combine antigens against multiple diseases enhance immunization compliance by decreasing the necessary number of injections and visits, and therefore should be encouraged. Acellular pertussis vaccines are available as a pertussisonly vaccine 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 single constituent vaccines. Antibody responses to combination antigens are complex: the immunogenicity of combination vaccines may be greater, less or the same as that of the individual vaccines, and the effects may differ among products from different manufacturers. As a rule, despite some "immune interference" between antigens, all licensed combination vaccines have demonstrated adequate immunogenicity with each constituent. For this reason, when combination vaccines are available, their use should be encouraged to facilitate compliance. Conversely, however, the need for multiple injections should not delay administration of vaccines that provide advantages of safety, immunogenicity, efficacy or cost.

Vaccines containing acellular pertussis may be administered simultaneously with other inactivated and live vaccines at different sites. Not to do so is a missed opportunity and is likely to result in under-immunization. None of the products should be mixed in the same syringe with any other vaccines unless specifically approved and described in the product monograph.

Adverse Reactions

The rate of reactions to acellular pertussis vaccines is less than that reported with the whole-cell preparations. In clinical trials, the incidence rates of local adverse reactions, including tenderness, erythema, swelling and general reactions of fever, irritability and drowsiness, were significantly lower after immunization with acellular than with whole-cell pertussis vaccines. Less common adverse reactions such as persistent crying and hypotonic-hyporesponsive episodes were also less frequent after administration of acellular pertussis vaccines, and were reported with a frequency similar to that among recipients of vaccines not containing pertussis. Convulsions are unusual and were reported less often after immunization with acellular pertussis vaccines in some of the efficacy studies but not in others. Because of the lower incidence of fever associated with these vaccines, there may be less justification for routine use of prophylactic acetaminophen, as had been recommended with whole-cell pertussis vaccines. Acetaminophen may be considered in children with a high risk of febrile seizures or low pain tolerance.

The size and frequency of local reactions increase with the number of doses administered. These local reactions produce large swelling, but pain is generally limited. The presence of a large, local reaction to a previous dose should not be considered a contraindication to continue the recommended schedule.

Contraindications and Precautions

Pertussis vaccine should not be given to individuals who have had an anaphylactic reaction to a previous dose or to any constituent of the vaccine (see product monographs in the Guide). Because these events are so rare, it is not known which component of the combined DTP 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 an assessment can determine the responsible antigen or other vaccine component. In order to maximize the child's benefit, an assesment should be done rapidly.

Conditions Not Considered Contraindications to Pertussis Vaccine

Certain other events temporally associated with whole-cell pertussis immunization were at one time considered contraindications or precautions to further pertussis immunization. With the use of acellular pertussis vaccine, they are no longer considered contraindications.

• High fever within 48 hours of vaccination, attributed to immunization 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 immunization can continue. Acetaminophen prophylaxis reduces the incidence of fever and may reduce febrile convulsions temporally related to pertussis immunization.
• Afebrile convulsions have not been shown to be caused by pertussis vaccine and are not a contraindication to immunization.
• Persistent, inconsolable crying and an unusual high-pitched cry after pertussis vaccination are not associated with any sequelae and are likely to be pain responses at the site of injection in young infants. These reactions do not preclude further pertussis immunization. Acetaminophen prophylaxis may reduce discomfort with subsequent doses.
• Hypotonic-hyporesponsive episodes are not a contraindication to the use of acellular pertussis vaccine. Because these episodes occur after both DTaP and DT, it is difficult to attribute causation to the pertussis components of DTaP; continued immunization with all antigens is recommended.
• Onset of encephalopathy temporally related to pertussis immunization does not indicate that the vaccine was the cause. Encephalopathy itself, from whatever cause, is not a contraindication to pertussis immunization.
• Deferral of pertussis immunization for children with evolving neurologic conditions is no longer necessary because of the availability of acellular pertussis vaccines. Specific data on the use of these vaccines in individuals with neurologic diseases are not available and must await post-marketing surveillance. However, because the incidence of adverse events, including fever and seizures, is no different in recipients of DTaP and DT, it is unnecessary to defer the pertussis component of the vaccine. Moreover, recent advances in the diagnosis and management of neurologic conditions leave little room for natural disease progressions to be misinterpreted as immunization-related events.

Other Considerations

NACI may change its recommendations on the current schedule, so that the five doses are administered before school entry, and on immunization of adolescents/adults. These changes will be based on evidence about the duration of the protection induced by acellular pertussis vaccine.

Selected References

Decker MD, Edwards KM, Steinhoff MC et al. Comparison of 13 acellular pertussis vaccines: adverse reactions . Pediatrics 1995;96(l):557-66.

De Serres G, Shadmani R, Boulianne N et al. Effectiveness of a single dose of acellular pertussis vaccine to prevent pertussis in children primed with pertussis whole cell vaccine. Vaccine 2001;19:3004-8. 

Edwards KM, Meade BD, Decker MD et al. Comparison of 13 acellular pertussis vaccines: overview and serologic response. Pediatrics 1995;96(l):548-57.

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

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.

Gustafsson L, Hallander HO, Olin P et al. A controlled trial of a two-component acellular, a fivecomponent acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-55.

Halperin SA, Smith B, RusselMet al. An adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults. Pediatr Infect Dis J 2000;19:276-83. 

National Advisory Committee on Immunization. Statement on pertussis vaccine. CCDR 1997;23(ACS-3):1-16. 

National Advisory Committee on Immunization. Statement on adult/adolescent formulation of combined acellular pertussis, tetanus, and diphtheria vaccine. CCDR 2000;26(ACS-1):1-8. 

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.

Stehr K, Cherry JD, Heininger U et al. A comparative efficacy trial in Germany in infants who received either the Lederle-Takeda acellular pertussis component DTP (DtaP) vaccine, the Lederle whole-cell component DTP vaccine, or DT vaccine. Pediatrics 1998;101:1-11

Trollfors B, Taranger J, Lagergard T et al. A placebo-controlled trial of a pertussis-toxoid vaccine. N Engl J Med 1995;333:1045-50.

Ward J, Partridge S, Chang S et al. Acellular pertussis vaccine efficacy and epidemiology of pertussis in adolescents and adults: NIH multicenter adult pertussis trial (APERT).

Acellular Pertussis Vaccine Conference, Bethesda, Maryland, November 12-14, 2000.