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A multicenter, randomized, double-blind study was undertaken in 2342 infants to evaluate the safety and immunogenicity of 13 acellular and 2 whole cell pertussis vaccines combined with diphtheria and tetanus toxoids. Vaccines were administered to infants at 2, 4, and 6 months of age. Sera were obtained before the first vaccination (age 2 months) and 1 month after the third vaccination (age 7 months). All of the acellular vaccines produced significant increases in antibody for included antigens ; mean antibody levels often exceeded those obtained with the reference whole cell vaccine. The vaccines were well-tolerated. All acellular vaccines were associated with significantly fewer adverse reactions than the control whole cell vaccine.

In Italy, oral polio vaccine and diphtheria and tetanus (DT) and hepatitis B (HB) vaccinations are required by law. At present, infants receive DT and HB by two separate intramuscular injections during one visit, and most receive an additional injection of acellular pertussis vaccine at the same time. Although simultaneous administration of the vaccines has the advantage of only one medical visit, it is time-consuming for staff, very expensive, painful to the infants, and stressful for parents. A much better solution would be to administer a ready-to-use mixture containing all the vaccines, provided that this combination vaccine had good local and systemic safety profiles and clinical and immunologic efficacy. To evaluate such a combination vaccine in healthy infants at 3, 5, and 11 and at 2, 4, and 6 months of age, a multicenter clinical study is underway in Italy.

Clinical Infectious Diseases 2004; 39:29–30 This article is in the public domain, and no copyright is claimed. 1058-4838/2004/3901-0006 Pertussis is the only disease for which children are routinely vaccinated that is not at historically low levels in the United States. The increases seen in pertussis are not due to ineffective vaccines or programs. The effectiveness of acellular pertussis vaccine has been demonstrated to be high in both prelicensure studies and postlicensure evaluations, and coverage among vaccine-eligible age groups remains high. However, pertussis continues to strike those who are susceptible because of waning vaccine-induced immunity and infants who are too young to have completed the primary vaccination series. To address the issue of waning immunity, formulations of acellular pertussis vaccine combined with diphtheria and tetanus toxoids for adolescents and adults (TdaP) are now under development in the United States; TdaP vaccines are already licensed and available in Canada, Germany, France, and Australia and are expected in the United States soon. Because a vaccine to prevent pertussis in older children, adolescents, and adults is likely to be available soon, how should policy makers approach its use? Our recommendations for use of TdaP should be guided by our knowledge, and there are things we know well about pertussis. Outbreaks of pertussis occur in a variety of settings but are most frequently recognized in middle and high schools. Antimicrobial prophylaxis is recommended for close contacts of patients with pertussis, and outbreak response is a complex, costly, and disruptive activity for schools and local health authorities. The rates of hospitalization, serious complications, and death among adolescents are low, but cough illness due to pertussis is prolonged, and the health impact—in terms of medical visits, antimicrobial treatment, and experience of illness—is significant. Currently, these school-based outbreaks are not preventable, and the only strategies for control are identification, isolation, and prophylaxis of contacts.

4 The Evolving Adolescent Immunization Schedule: A Need for Acellular Pertussis Booster Immunizations

Since the introduction of whole cell pertussis vaccine into general use as part of the routine immunization in 1947 under the Preventive Immunization Law, a steady decrease in reported cases of pertussis was noted until 1974. At that time the number of reported cases reached an all time low and no deaths caused by pertussis were reported. The vaccine (diphtheria-tetanus-whole cell pertussis vaccine) had been given to infants 12 weeks old or older in a 0.5-ml dose by deep subcutaneous injection; three doses were given at intervals of 3 to 8 weeks and the fourth dose (booster) was given 12 to 18 months after the third dose. The immunization was completed with those four doses. Because whole cell vaccine appeared to be associated with severe neurologic illnesses, it was temporarily suspended in 1975. The vaccine was resumed soon thereafter but the age of administration was raised to 24 to 48 months. Under these circumstances acceptance rates of pertussis occurred, reaching a peak in 1979. Although whole cell vaccine was used even after temporary suspension, it was considered to be unacceptable by the public. As a result the acellular pertussis vaccine was developed and has totally replaced whole cell vaccine since 1981. A steady decrease in reported cases of pertussis as well as the number of deaths has been noted since 1979 in accordance with increase in vaccine acceptance rates. The national surveillance system begun in 1981 demonstrated also a steady decrease in the incidence of pertussis during the past 9 years.

An outbreak of pertussis occurred in one room of a residential facility where 19 children aged 5 to 36 months were residing. They were prospectively surveyed to estimate the efficacy of acellular pertussis vaccine. Among the 19 residents, 9 were immunized with acellular pertussis vaccine. Among the 19 residents, 9 were immunized with acellular DTP vaccine and 10 were unimmunized. The spread of pertussis was surveyed bacteriologically and serologically for 2 months. Among the 9 immunized, 7 children acquired the laboratory-confirmed pertussis and 1 of the 7 developed the typical symptoms (whooping or paroxysmal coughing attack lasting for 14 days or more). Among the 10 unimmunized, 7 children acquired the laboratory-confirmed pertussis and 6 of the 7 developed the typical symptoms. There was no difference in the rate of secondary infection (7/9:7/10), but there was a significant difference in the rate of development of the typical symptoms (1/7:6/7 p less than 0.05). The point estimate of protective efficacy of the acellular DTP vaccine against typical pertussis was (6/10 - 1/9)/(6/10) x 100 = 81%. It was concluded from these findings that acellular DTP vaccine could not prevent the infection of Bordetella pertussis, but could prevent the development of the typical symptoms.

A diphtheria/tetanus/acellular pertussis– Haemophilus influenzae type b vaccine (DTaP–Hib), introduced to the UK in 1999, was associated with poor primary Hib responses1 and a resurgence of Hib disease in the population.2 Consequently, in 2003, the UK Department of Health undertook a campaign to immunise children aged 6 months–4 years with an additional dose of Hib. We have previously shown a significant rise in Hib titres following an additional Hib dose, given before one year, in infants with very low primary responses.3 Here we describe how that response persists. …

To the Editor. —The information regarding SmithKline Beecham's diphtheria-tetanus—acellular pertussis (DTaP) vaccine, Infanrix, as well as Tripedia (manufactured by Connaught Laboratories, Inc), presented in a Medical News & Perspectives 1 article is misleading on several counts. The efficacy attributed to Tripedia is not in agreement with the manufacturer's own package insert, which states that, when adjusted for confounding factors, efficacy was calculated to be 80%. 2 According to the Food and Drug Administration (FDA), Tripedia has been estimated to be between 69% and 80% effective, depending on the study. 3 The article also implies that Tripedia has been granted licensure for a fifth dose following priming with Tripedia. The FDA has, in fact, requested more data before considering approval of the fifth dose for children primed with Tripedia. Regarding Infanrix, the article refers to an increase in rates of reactogenicity with successive doses without reference to what is known about

Hviid A, Stellfeld M, Wohlfahrt J, et al . Childhood vaccination and type 1 diabetes. N Engl J Med 2004;350:1398–404. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Q Are routinely administered childhood vaccines associated with an increased incidence of type 1 diabetes mellitus in a cohort of Danish children? ### ![Graphic][5] Design: a cohort study of children followed up from birth to a mean age of 6.4 years. ### ![Graphic][6] Setting: Denmark. ### ![Graphic][7] Participants: 739 694 children born in Denmark from January 1990 to December 2000. ### ![Graphic][8] Risk factors: vaccinations with any of 6 groups of vaccines including Haemophilus influenza type b; diphtheria, tetanus, and inactivated poliovirus; diphtheria, tetanus, acellular pertussis, and inactivated poliovirus; whole cell pertussis; measles, mumps, and rubella; and oral poliovirus (data from vaccination reports of the National Board … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DHviid%26rft.auinit1%253DA.%26rft.volume%253D350%26rft.issue%253D14%26rft.spage%253D1398%26rft.epage%253D1404%26rft.atitle%253DChildhood%2BVaccination%2Band%2BType%2B1%2BDiabetes%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa032665%26rft_id%253Dinfo%253Apmid%252F15070789%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa032665&link_type=DOI [3]: /lookup/external-ref?access_num=15070789&link_type=MED&atom=%2Febnurs%2F7%2F4%2F121.atom [4]: /lookup/external-ref?access_num=000220562500006&link_type=ISI [5]: /embed/inline-graphic-1.gif [6]: /embed/inline-graphic-2.gif [7]: /embed/inline-graphic-3.gif [8]: /embed/inline-graphic-4.gif

To the Editor. We wish to comment on the recently published article1 that evaluates the impact of observer bias on the estimate of clinical efficacy of one acellular pertussis vaccine. The authors report that, in the Erlangen trial, the observed incidence in unblinded unvaccinated children (DT) was only 13%, compared with an expected figure of approximately 40%. To determine potential observer bias, the authors analyzed the trial physicians' cough referral rates and used these rates to divide the physicians into three categories indicating their compliance to the trial protocol, which required referral of any cough lasting >7 days. Physicians who had reported an at least 20% incidence of cough were classified as “highly compliant.” The authors then recalculated vaccine efficacy for each compliance category and found that the estimated efficacy greatly varied among the categories and that it was inversely proportional to the physician's referral rate, concluding that a bias had occurred. Because no correlation was found between the cough referral rate and the proportion of unvaccinated (DT) children in each physician's study subject group, the authors concluded that the bias did not depend on unblinded conditions and that a similar bias was thus likely to have occurred in all of the recently conducted pertussis trials. Although the evidence for the Erlangen trial is convincing, extending the conclusions …

Economic Evaluation of Diphtheria, Tetanus, and Acellular Pertussis (DTaP) Vaccine in the United States: A Cost-Benefit and Cost-Effectiveness Model with Visual Basic Application

The National Institutes of Health (NIH) Vaccine and Treatment Evaluation Units (VTEUs) Collaborative Study of a Fifth Sequential Dose of 6 DT Acellular Pertussis (DTaP) Vaccines Compared with One Whole Cell Pertussis (DTwP) Vaccine in 4 to 6 Year-Old Children † 889

Immunogenicity of a combined Diphtheria-Tetanus-Acellular Pertussis(DT-tricomponent Pa)-Hepatitis B (HB)-Inactivated Poliovirus (IPV) admixed with Haemophilus influenzae type b (Hib) Vaccine in Infants♦ 813

Results from several clinical trials involving acellular pertussis vaccines containing one or more pertussis antigens have demonstrated these vaccines to have fewer local and systemic reactions than whole-cell pertussis vaccines. However, true rates of less common serious adverse reactions, e.g. hypotonic-hyporesponsive episodes (HHE), known to be associated with whole-cell vaccines have yet to be determined. In a clinical trial of multicomponent acellular pertussis vaccines in Sweden with 80,000 participants the incidence of HHE requiring hospitalization was about one in 3,000 (Heijbel H et al., Dev Biol Stand 1997:89:101).

Recent attempts to combine DTaP, HIB and IPV have been hindered by significant interactions particularily to the HIB component. We conducted a randomized, controlled trial to compare two pentavalent vaccines in infants aged 2, 4 and 6 months. The acellular pertussis (aP) vaccine was the five component vaccine containing Pertussis Toxoid (PT), Filamentous Haemagglutinin(FHA), Fimbrae 2&3 (FIM), Pertactin (69kDa) which was demonstrated to have 85% efficacy in a Swedish efficacy trial. This acellular pertussis combination, DTaP-IPV//PRP-T, produced excellent responses to all antigens with no clinically significant interactions. Antibody levels to the two pentavalent vaccines at 7 months of age (1 month after dose 3) are below. HIB responses were identical whether the PRP-T was given combined with DTaP-IPV(GMT=4.40) or given separately from DTaP-IPV (GMT=3.83).Table

We disagree with Dr Sepkowitz that examining the Vaccine Adverse Event Reporting System for rare serious events casts doubt on the safety of vaccines. Demonstrating that reported adverse events after the the administration of the acellular pertussis vaccine are (1) rare after millions of doses have been used (vs only thousands used in prelicensure clinical trials) and (2) less common than similar events reported after the administration of the whole-cell pertussis vaccine should help instill public confidence in a vaccine that historically has been the most feared. While controversy remains about whether the whole-cell pertussis vaccine has been proven to be a cause of permanent neurologic damage, 1-3 a consensus exists that the evidence is consistent with a causal relationship between the whole-cell pertussis vaccine and acute encephalopathy, with an attributable risk between 0 and 10.5 cases per million doses of whole-cell pertussis vaccine. 4 As Dr Sepkowitz

In Reply. —The efficacy rate attributed to Tripedia in the article is based on data from a study in Germany 1 reported to the Vaccines and Related Biologics Products Advisory Committee in January 1996. That study used a different case definition of pertussis from the now generally accepted WHO case definition on which the efficacy rate stated in the Tripedia labeling is based. While it is true that Tripedia has not yet been approved for the fifth dose following priming with Tripedia, from the practicing pediatrician's position, the point is moot. Infants who started receiving Tripedia this summer, when the vaccine was licensed for the first 3 doses, will not be candidates for a 5th dose for 4 years. By then, the FDA expects to have accumulated sufficient data to warrant licensure of the fifth dose. There is no question that there are untoward reactions with other acellular vaccines besides Infanrix. But

In the supplement to Pediatrics entitled Report of the Nationwide Multicenter Acellular Pertussis Trial, Edwards et al1 describe the serologic responses to individual antigens in thirteen acellular pertussis vaccines which were evaluated in the phase I/II trials performed by National Institute of Allergy and Infectious Diseases-supported Vaccine Treatment and Evaluation Units. In that article, the authors comment that "postimmunization geometric mean (antibody) titers [against pertussis toxin] differed significantly among the acellular vaccine groups and did not seem to correlate with the pertussis toxin (PT) antigen content of the vaccines."

In a somewhat bizarre coincidence, the typescript of the report by Rosenthal et al, 1 sent to me by our esteemed editor, arrived concurrently with the "Report of the Nationwide Multicenter Acellular Pertussis Trial." 2 The careful and persuasive studies described in the multicenter report cast a shadow on the rather unconvincing methods and conclusions of the article by Rosenthal et al, based on the Vaccine Adverse Event Reporting System (VAERS). The article based on VAERS is problematic in 2 respects: (1) the VAERS enterprise is not adequately described and (2) the report itself has serious methodological infelicities. Editor's Note: We asked Dr Brown to comment on the article in this issue by Rosenthal et al (page 457) because of his interest in vaccine adverse reaction reporting systems. We assured him that candor would not be interpreted as peevishness by the always-perceptive readers of the ARCHIVES . Catherine D. DeAngelis, MD