Supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories

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Volume II, Issue 3 - March 1997

In 1991 and 1992 safety and immunogenicity of 13 acellular pertussis vaccines were evaluated by National Institutes of Health (NIH) sponsored phase 1 and 2 trials to determine which vaccines to be included in two NIH-sponsored efficacy trials conducted in Stockholm, Sweden and Italy.(7,8) These trials were completed in 1995.(9,10) In addition, efficacy trials were conducted in Göteberg, Sweden by the NIH and by various pharmaceutical companies in Munich, Erlangen and Mainz, Germany and in Senegal (Table 2).(11-13) These trials differed in several aspects, including which pertussis antigens and antigen concentrations were used, study design, immunization schedules, controls, and case definitions.

Because of these differences, direct comparison of results among the studies is not appropriate. In aggregate the acellular pertussis vaccines were associated with lower rates of minor reactions and fewer moderate to severe reactions including hypotonic/hyporesponsive episodes; persistent, inconsolable crying; and temperatures of 40.5 degrees C or higher. The acellular pertussis products generally showed equal efficacy and immunogenicity to the whole-cell vaccines.

When used for the primary series in infants, the immunogenicity of the antigens [pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN) and fimbria (FIM)] in various diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines generally was similar to or higher than the same antigens contained in the diphtheria and the tetanus toxoids and whole-cell pertussis (DTwP) vaccines.(8-10) In none of the trials could antibody responses be correlated directly with protection against pertussis. Although antibody studies are useful for comparing immune response to antigens in various vaccines, pertussis vaccine efficacy studies are necessary to measure clinical protection.

Currently three acellular pertussis vaccines (Tripedia, ACEL-IMUNE and Infanrix) have been licensed for the first three doses recommended in the routine immunization schedule in the US. Information on the efficacy of Tripedia was derived from studies in Sweden and Munich, Germany.(11,14) Additional safety and immunogenicity data were obtained from studies in the US (package insert).(15) Data on the efficacy of ACEL-IMUNE were derived from studies in Erlangen, Germany (11) and on the efficacy of Infanrix from studies in Italy and Germany.(9,13)

In the Munich study, 16,780 infants received DTaP, DTwP, or DT at 2, 4, and 6 months of age. The clinical efficacy of the acellular pertussis vaccine, which contained PT and FHA, was 80% (95% CI, 59 to 90). The efficacy of three doses of DTwP vaccine manufactured in Germany was 87% (95% CI, 33 to 97). Comparison of efficacy estimates between the two groups should not be made due to differences in enrollment of infants in the study.

In Erlangen, Germany, 12,495 doses of whole-cell pertussis vaccine (DTwP) manufactured in the US and 12,651 doses of a four component (PT, FHA, PRN, and FIM) acellular vaccine (DTaP) were administered at 2, 4, 6, and 15 to 18 months of age. The efficacy of the acellular product was 81% (95% CI 73 to 87) and the whole-cell product was 91% (95% CI 85 to 95).

In Italy, 4348 infants received DTwP, 4481 received the approved three component (PT, FHA, PRN) acellular vaccine, and 1470 received DT administered at 2, 4, and 6 months of age. Another 4452 infants received another three component acellular pertussis vaccine which is not yet approved. The efficacy of the approved acellular product was 84% (95% CI 76 to 89) and the whole-cell product efficacy was 36% (95% CI 14 to 52).

Adverse reactions associated with administration of pertussis vaccines can be considered under the following categories. First are minor reactions (erythema, induration, pain and tenderness at the injection site, drowsiness, irritability, anorexia, and temperature over 101 degrees F). The second category is precautions to administration of further pertussis immunization (hypotonic/hyporesponsive episode, persistent inconsolable crying for 3 or more hours, temperature over 40.5 degrees C, and a convulsion with or without fever). The third classification is contraindications to pertussis immunization (encephalopathy not associated with another identifiable cause occurring within 7 days or an immediate anaphylactic reaction) (Table 3).

In a study that compared two whole-cell and 13 acellular pertussis vaccines, the rates of minor side effects were lower in all of the acellular groups when compared to the whole-cell groups.7 None of the acellular pertussis vaccines consistently caused the least or most reaction. All of the recently completed trials, including the ones in which Tripedia, ACEL-IMUNE, and Infanrix were used, showed significantly fewer side effects in infant recipients of acellular pertussis vaccines compared to whole-cell products. Table 4 shows minor side effects occurring within 72 hours following immunization of 672 infants with Tripedia (DTaP) or Connaught DTwP at 2 months of age. Immunizations at 4 and 6 months of age produced similar results.

In the Italian trial hypotonic/hyporesponsive episodes and persistent crying for greater than or equal to 3 hours were significantly (P<.01 and .001, respectively) less frequent in the acellular pertussis groups than in the group that received DTwP.9 In the Stockholm trial protracted crying for greater than or equal to 3 hours was significantly less (P<.001) in the two DTaP and DT vaccine groups than in infants who received DTwP vaccines.(10) Munich trial data on these adverse events after DTwP administration were not collected in a manner that permits comparison with the DTaP group. In the Erlangen trial persistent, inconsolable crying was less in infants in the DTaP group than in infants in DTwP group.

The association of acellular pertussis vaccines with serious adverse events (encephalopathy and immediate anaphylaxis) is unknown due to the rare occurrence of these events (less than or equal to 1:100,000 immunizations). None of the efficacy trials enrolled a sufficient number of infants to permit evaluation of acellular pertussis vaccines in this category of adverse effect.

The development and testing of pediatric combination vaccines, containing multiple antigens delivered in a single injection, is accelerating at a rapid pace. Table 5 shows commercially available combination vaccines. Combining multiple antigens has been shown to result in a decreased immune response to some of the antigens,(16) indicating the immunogenicity of all antigens must be tested before new combinations are recommended as part of the routine immunization schedule. Currently there are two vaccines that combine DTwP with Haemophilus influenzae b and one that contains acellular pertussis vaccine and H influenzae b. The latter is only approved for the fourth pertussis dose. Food and Drug Administration approval for use in the primary series is pending. These combined products will decrease the number of injections and hopefully lead to a simplified immunization schedule. A product combining hepatitis B and H influenzae b was released in December 1996 for use in infants at 2, 4, and 12 to 15 months of age. The number and different types of combinations is expected to escalate in the next few years.

Adolescents and adults immunized as children against pertussis have waning immunity and serve as reservoirs of infection for unimmunized young children. Studies have shown that 15% of the cases of pertussis in the US occur in adults. In one study the prevalence of pertussis in adults over 18 years of age was 12.4% of individuals with the complaint of cough persisting for 2 weeks or longer.(2) Ongoing studies are evaluating the incidence of pertussis in adolescents and adults; the incidence, severity, and cost of disease; adverse effects of the vaccine; and cost effectiveness of immunizing individuals in this age group. Preliminary results are encouraging.(17) Current recommendations are to limit use of any acellular pertussis vaccine to children <7 years of age unless used as part of a research protocol.(5,6)

Both the AAP and the CDC have recommended all infants routinely be immunized with five doses of a diphtheria, tetanus and pertussis containing vaccine beginning at 6 to 8 weeks of age (Table 1).(5,6) In the US, DTaP is preferred for all doses in the immunization schedule, even for children who begin their primary immunization schedule with DTwP, in whom one of the approved DTaP products can be used to complete the pertussis immunization schedule. There currently are three acellular vaccines approved for use beginning at 2 months of age but others, including combination products, are expected to be available soon.

Larry K. Pickering, M.D.
Center for Pediatric Research
Children's Hospital of The King's Daughters
Eastern Virginia Medical School
Norfolk, Virginia

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