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Pertussis vaccines
See also Vaccines
General information
Note on abbreviations
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DT = Diphtheria + tetanus toxoids
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DTP = Diphtheria + tetanus toxoids + pertussis
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DTaP = Diphtheria + tetanus toxoids + acellular pertussis
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DTwP = Diphtheria + tetanus toxoids + whole cell pertussis
Drug studies
Acellular pertussis vaccine
Whole-cell and acellular pertussis vaccines have been reviewed, with emphasis on the protectivity of the various virulence factors and antigens [ ]. The authors summarized their review as follows: although Bordetella pertussis has at least five proteins required for virulence and an additional two “toxic” components, only serum neutralizing antibodies to pertussis toxin have been shown to confer immunity to pertussis.
Quality control of acellular pertussis vaccines presents particular problems related to the various methods used for preparation of the active components, the different compositions of the final formulations, and different amounts of antigen. Researchers in the National Institute for Biological Standards and Control in the UK have presented a strategy capable of addressing the key problem areas likely to be encountered with all existing types of acellular pertussis vaccines and combinations [ ]. Their proposal could be considered as a starting point for improvement of quality control programs for these vaccines.
An overview of clinical trials with a special diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine has been published [ ]. The vaccine contains as pertussis components purified filamentous hemagglutinin, pertactin, and genetically engineered pertussis toxin. The vaccine induces high and long-lasting immunity and is at least as efficacious as most whole-cell pertussis vaccines and similar in efficacy to the most efficacious acellular pertussis vaccines that contain three pertussis antigens. The vaccine is better tolerated than whole cell vaccines and has a similar reactogenicity profile to other acellular vaccines.
A vaccine containing diphtheria and tetanus toxoids and acellular pertussis with reduced antigen content for diphtheria and pertussis (TdaP) has been compared with a licensed reduced adult-type diphtheria–tetanus (Td) vaccine and with an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (ap) [ ]. A total of 299 healthy adults (mean age 30 years) were randomized into three groups to receive one dose of the study vaccines. The antibody responses (anti-diphtheria, anti-tetanus, anti-pertussis toxin, anti-pertactin, anti-filamentous hemagglutinin) were similar in all groups. The most frequently reported local symptom was pain at the injection site (62–94%), but there were no reports of severe pain; redness and swelling with a diameter of 5 cm or more occurred in up to 13%. The incidence of local symptoms was similar after TdaP and Td immunization. The most frequently reported general symptoms were headache and fatigue (20–50%). The incidence of general symptoms was similar in the TdaP and Td groups. There were no reports of fever over 39 °C. No serious adverse events were reported.
A retrospective assessment among the population of the Group Health Cooperative from 1997 to 2000 confirmed the safety of DTaP vaccine [ ]. Administrative databases were used to identify medical visits linked with diagnostic codes indicative of injection site reactions, seizures, allergic responses, and febrile episodes after DTaP immunization. During the study 76 133 doses of DTaP were administered, mainly as the fourth or fifth immunization doses. There were 26 injection site reactions; four involved the entire upper arm but were self-limiting. Febrile seizures occurred in 1 per 19 496 immunizations. There was no evidence of allergic responses.
The immune system is partly immature at birth, and therefore immunization schedules for the majority of childhood vaccines including pertussis vaccine do not recommend immunization before 2 months of age. However, the pertussis case fatality rate is highest in infants below 6 months of age. For this reason 45 infants were immunized at birth and at 3, 5, and 11 months of age (group 1) and compared with 46 infants who were immunized at 3, 5, and 11 months of age (group 2) with a trivalent acellular pertussis vaccine (genetically detoxified pertussis toxin, filamentous hemagglutinin, pertactine) [ ]. There were no adverse effects in children in the two groups. After the second dose of vaccine (administered at 3 months) the antibody titers of infants in group 1 were already similar to the titers achieved after the second dose (administered at 5 months) in infants in group 2. The authors concluded that immunization at birth may lead to earlier prevention of pertussis in infants under 6 months of age.
Japanese studies of acellular vaccines
The first generation of the new acellular vaccines was developed in Japan in the late 1970s (Sato). Since late 1981, acellular vaccines have replaced the whole-cell pertussis vaccines for use in the Japanese immunization program. Two types of acellular pertussis vaccine have been produced by six Japanese manufacturers [ , ]. No doubt as a result of these measures the rate of reported serious reactions has decreased in Japan. During the period 1975–81, when whole-cell vaccines were given, the rate was 0.4 per million doses, compared with a rate of 0.25 per million doses during the period 1982–84 [ ]. In 1988, Kumura and Kuno-Sakai summarized the experience gained in Japan since the introduction in 1981 of the new DTP vaccines containing acellular pertussis components [ ]. Acellular vaccines seem to be effective in Japan, since in parallel with their wider use the numbers of reported cases of pertussis and pertussis deaths have declined. Reactogenicity (as expressed by fever or local reactions) was very low. Kimura and Kuno-Sakai cited reports of Quincke’s edema-like swelling of the whole arm following the third injection (0.17% of vaccinees) and the booster injection (2.61%), respectively. Data on more severe adverse events have been collected from 1970 to 1986 in the framework of the National Adverse Reaction Compensation System.
European studies of acellular vaccines
The epidemiological circumstances in Sweden and in parts of Germany and Italy, where the immunization programs against pertussis using whole-cell vaccine had been discontinued or reduced because of public concern about rare severe adverse events, offered good opportunities to assess the clinical efficacy and safety of acellular pertussis vaccines. In Germany, both controlled field trials and a household contact study were carried out. Different mono-component and multi-component acellular vaccines from European and US manufacturers were used in European trials. They comprised a mono-component vaccine composed only of detoxified pertussis toxin (toxoid); a two-component vaccine composed of pertussis toxin and filamentous hemagglutinin; a three-component vaccine composed of pertussis toxin, filamentous hemagglutinin, Pertactin; and another five-component vaccine composed of pertussis toxin, filamentous hemagglutinin, Pertactin, and fimbriae antigens 2 and 3. In some instances they were compared directly with whole-cell pertussis vaccines. In general, the acellular vaccines were found to be immunogenic, epidemiologically effective, and less reactogenic than the whole-cell pertussis-component vaccines as assessed in terms of fever, pain, fretfulness, and local reactions at the injection site. Based on the results, acellular pertussis vaccines have since been licensed in many countries of the world both for primary and booster immunization. Details regarding the results and conclusions of the large-scale field trials completed in 1994 and 1995 in Germany, Italy, and Sweden have been reviewed [ ], as have reports on other clinical trials using acellular pertussis vaccines [ ]. The optimal composition of acellular vaccines has not yet been determined: the number of antigens still varies from one to five, and antigen amounts are also different. Post-licensing studies will therefore be of the utmost importance in studying the induction of herd immunity and possible rare events.
Local reactions to acellular vaccines: effect of number of injections
Data on the use of a single DTaP vaccine for four-dose or five-dose series are limited, but the available data show a substantial increase in the frequency and magnitude of local reactions with successive doses. The accompanying tables show reactions after the fourth dose ( Table 1 ) and fifth dose ( Table 2 ). The original data and references are included in the supplementary recommendations of the Advisory Committee on Immunization Practices (ACIP) on the use of DTaP vaccines in a five-dose series [ ]. Reports from Alberta and British Columbia provinces, Canada, have suggested that the incidence rates of severe local adverse reactions may increase with each dose (third, fourth, fifth) in preschool children [ ].
Table 1
Reactions after the fourth dose of DTaP given at 2 or 3 years of age
| Reaction | ACEL-IMUNE | Tripedia | Infanrix a | Certiva |
|---|---|---|---|---|
| Pain | 19% | 26% | 19 | |
| Erythema | 10%, ≥ 2.4 cm | 30%, ≥ 2.54 cm | 14%, ≥ 2 cm | 6%, ≥ 3 cm |
| Swelling | 29%, ≥ 2.54 cm | 11%, ≥ 2 cm | 5%, ≥ 3 cm | |
| Induration | 9%, ≥ 2.4 cm | |||
| Tenderness | ||||
| Fever = 38 °C | 26% | 26% | 6.3% | |
| Fever = 38.3 °C | 5.5% |
a To be compared with reactions after the first dose: pain 2%, erythema 0%, swelling 0%, fever ≥ 38 °C 6.3%.
Table 2
Reactions after the fifth dose of DTaP administered at entry to school
| Reaction | ACEL-IMUNE | Tripedia | Infanrix |
|---|---|---|---|
| Severe pain | 2.1% | 1.6% | |
| Erythema | 20%, >2–2.4 cm | 31%, >5 cm | |
| Swelling | 25%, >5 cm | 30%, >5 cm | |
| Induration | 14% | 21%, >5 cm | |
| Tenderness | 38% |
Limb swelling after booster doses of acellular vaccines
Swelling involving the entire thigh or upper arm has been reported after booster doses of different acellular pertussis vaccines, for example in a German study during April 1993 to November 1994 using a fourth dose of Infanrix. There was an increase in thigh circumference in 1.2–3.2% of children; swelling began within 48 hours of a booster dose and the mean duration was 3.9 (range 1–7) days; the mean increase in circumference was 2.2–5.0 cm; in a few children, the swelling interfered with walking.
Similar swelling and substantial local reactions have been observed in fourth-dose and fifth-dose follow-up studies from the Multicenter Acellular Pertussis Trial, which examined 12 different DTaP vaccines, and in recent studies of the fifth dose of Tripedia and Infanrix in Germany. The pathogenesis of both substantial local reactions and limb swelling is unknown. Associations with pertussis toxoid, diphtheria toxoid, or aluminium in the vaccine have been discussed. Because reports to date have suggested that the reactions are self-limited and resolve without sequelae, and in recognition of the benefits of a fifth dose of DTaP, the ACIP has recommended that a history of extensive swelling after the fourth dose should not be considered to be a contraindication to a fifth dose of DTaP. Parents or care-givers of children who receive fourth and fifth doses of a DTaP series should be informed of the increases in reactogenicity that have been observed [ ].
Whole-cell pertussis vaccine
Pertussis whole cell vaccine is an adsorbed suspension of inactivated pertussis bacteria. The vaccine is available in monovalent form or in combination with diphtheria and tetanus toxoids (DTP). DTP vaccine is the preparation of choice in routine immunization practice.
Local reactions are common after DTP immunization (40–70% of the vaccinees) but are usually self-limiting [ ]. A nodule may be palpable at the injection site of adsorbed products for several weeks. Abscess at the injection site has been reported (6–10 per million vaccinees). Mild to moderate fever (38.0–40.4 °C) occurs frequently (about 50% of vaccinated infants), generally within several hours of administration, persisting for 1–2 days. Fever and other systemic symptoms are much less common following immunization with preparations not containing the pertussis component. Arthus-type hypersensitivity reactions occur, particularly after booster doses. Rarely, severe systemic reactions (urticaria, anaphylaxis) have been reported.
Non-neurological adverse reactions to whole-cell immunization have been reviewed [ , ]. The most frequent are mild fever, drowsiness, and reduction in appetite; a very small percentage of vaccinees experience more severe fever, redness, swelling, pain, “fussiness,” or vomiting.
A follow-up study has been carried out in 105 children with collapse (a hypotonic-hyporesponsive episode or a shock-like syndrome) after their first immunization with DTwP + IPV vaccine [ ]. Information about subsequent immunizations, health, and development in 101 of the children was supplied by child health-care units. The parents of one child refused further immunization, 16 children completed their schedule with the combination diphtheria + tetanus + poliomyelitis vaccine (DT-IPV), and the other 84 children received further pertussis vaccine (DTP-IPV), totalling 236 doses; 74 children received the complete series of three additional doses. None of the children had recurrent collapse, and other adverse events were only minor. About half were given paracetamol prophylactically for the first subsequent dose; most of them did not take it for further doses. The authors suggested that it is unnecessary to withhold further doses of pertussis vaccine in a child with collapse after a previous dose. It has been suggested that the threat of natural pertussis in non-immunized children should be taken much more into account than the fear of developing a collapse reaction [ ]. In another study [ ] in the USA, one of the 14 children not completely immunized because of a hypotonic-hyporesponsive episode after a previous dose later developed natural pertussis, which lasted for 3 months and was transmitted to both her parents.
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