Background: In 1992-1993, a randomized, double-blind, placebo-controlled clinical trial of two 3-component acellular pertussis vaccines was started in 4 of Italy's 20 regions. During the trial, the children had been randomized to receive 3 doses of 1 of 2 acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DT) or of a DT vaccine only, at 2, 4, and 6 months of age. Both diphtheria-tetanus-acellular pertussis (DTaP) vaccines, 1 manufactured by SmithKline Beecham (DTaP SB; Infanrix) and 1 manufactured by Chiron Biocine (DTaP CB; Triacelluvax), contain pertussis toxin (PT), filamentous hemagglutinin, and pertactin. The results of the first period of follow-up, which ended in 1994 (stage 1), showed that both vaccines had a protective efficacy of 84% in the first 2 years of life; when the trial's follow-up was extended under partial blinding until the participating children had reached 33 months of age (stage 2 of the follow-up), these high levels of efficacy had persisted. Therefore, the objective of this study was to estimate the persistence of protection from 3 to 6 years of age of the 2 3-component DTaP vaccines administered as primary immunization in infancy.
Methods: An unblinded prospective longitudinal study of vaccinated and unvaccinated children in 4 Italian regions, with active surveillance of cough, was conducted by study nurses, and Bordetella pertussis infections were confirmed laboratory. The present study (stage 3) included those children who completed stage 2 of the follow-up and were still under active surveillance as of October 1, 1995, accounting for 4217 children who had received DTaP SB (representing 94% of the vaccine's recipients in the initial phase of the trial), 4215 who had received DTaP CB (95% of the original recipients), and 266 who had received DT only (18% of the original recipients). Because the parents of most of the original DT placebo group accepted pertussis vaccination during stage 2 in 1995, an additional 856 children were recruited in the DT group at the initiation of stage 3. These additional children were identified from the census list of children born in the same period and living in the same areas as the trial participants but who had been vaccinated in infancy with DT only. Eligible children were included in stage 3 if they had no history of either pertussis or pertussis vaccination and if a serum sample obtained at the time of enrollment had undetectable immunoglobulin G (IgG) against PT. Parental consent to participate in the study was obtained. Active surveillance for pertussis was conducted in the field by 72 study nurses through monthly contact with each family in the study. A cough episode that lasted >/=7 days was considered to be a laboratory-confirmed infection by Bordetella pertussis if at least 1 of the following 5 criteria (listed in hierarchic order) was met: 1) B pertussis was obtained from nasopharyngeal culture (culture-confirmed infection); 2) the enzyme-linked immunosorbent assay (ELISA) IgG or IgA titer against PT in the convalescent-phase serum sample increased by at least 100% compared with the acute-phase sample; 3) the PT-neutralizing titers in Chinese hamster ovary assay in the convalescent-phase sample increased by at least 4-fold compared with the acute-phase sample; 4) the ELISA IgG or IgA titer against filamentous hemagglutinin in the convalescent-phase sample increased by at least 100% and the culture or the polymerase chain reaction assay on the nasopharyngeal aspirate was negative for B parapertussis; and 5) the ELISA IgG PT titer in 1 of the 2 serum samples exceeded the geometric mean titer computed on convalescent sera of the children with a culture-confirmed B pertussis infection in each study group. Incidence of laboratory-confirmed B pertussis infection, using case definitions that varied in terms of duration and type of cough, was computed and the proportion of cases prevented among DTaP recipients in comparison with DT recipients was calculated.
Results: A total of 391 laboratory-confirmed infections were identified in the 3-year follow-up period (138 DTaP SB, 126 DTaP CB, 127 DT recipients, respectively). The mean duration of cough in children with laboratory-confirmed infection was 48, 47, and 70 days for the DTaP SB, DTaP CB, and DT recipients, respectively; the mean duration of spasmodic cough was 15, 13, and 23 days, respectively. When using the primary case definition (ie, laboratory-confirmed B pertussis infection and >/=14 days of spasmodic cough or >/=21 days of any cough), the efficacy was 78% for the DTaP SB vaccine (95% confidence interval [CI]: 71%-83%) and 81% for the DTaP CB vaccine (95% CI: 74%-85%). When using the case definition based on a more severe clinical presentation (>/=21 days of spasmodic cough), the vaccine efficacy was 86% (95% CI: 79%-91%) for both vaccines. When using the case definition based on milder clinical presentation (any cough for >/=7 days), the efficacy was 76% (95% CI: 69%-81%) for the DTaP SB vaccine and 78% (95% CI: 72%-83%) for the DTaP CB vaccine.
Conclusions: The persistence of protection through 6 years of age suggests that the fourth DTaP dose could be postponed until preschool age in children who received 3-component acellular pertussis vaccines in infancy, provided that immunity to diphtheria and tetanus is maintained. Additional booster doses could be administered at older ages to reduce reactogenicity induced by multiple administrations and to optimize the control of pertussis in adolescents and young adults.