In the 2010 pertussis outbreak in California, a longer time since receipt of a fifth dose of DTaP was associated with an elevated risk of acquiring pertussis among children who had received all recommended acellular pertussis vaccines. In this study, the risk of pertussis increased by 42% each year after the fifth DTaP dose. If DTaP effectiveness is initially 95%, so that the risk of pertussis in vaccinated children is only 5% that of unvaccinated children, then the risk would increase after 5 years by a factor of 1.425 to 29% that of unvaccinated children. The corresponding decrease in DTaP effectiveness would be from 95% to 71%. The amount of protection remaining after 5 years depends heavily on the initial effectiveness. If the initial effectiveness of DTaP was 90%, it would decrease to 42% after 5 years. Regardless of the initial effectiveness, the protection from disease afforded by the fifth dose of DTaP among fully vaccinated children who had exclusively received DTaP vaccines waned substantially during the 5 years after vaccination.

The results of clinical trials evaluating the duration of protection conferred by DTaP vaccines after three or four doses suggested that protection against pertussis was sustained 5 to 6 years after vaccination.12-14 Other studies showed some waning of protection,15-17 and several showed that increasing time since DTaP vaccination was a risk factor for vaccine failure, observations that are consistent with our findings.17-19 Disease-free intervals after pertussis vaccination have decreased over the past two decades in Massachusetts.20 A study in Canada showed that the transition from whole-cell pertussis vaccines to DTaP was associated with an increased incidence of pertussis among children who received only DTaP.21 Taken together, these studies indicate that protection is less enduring with DTaP than with whole-cell pertussis vaccines. 22 The recent California epidemic provides data from a large population of children who only received acellular vaccines and for whom enough time had passed that we could quantify the extent to which DTaP protection waned.

The incidence of pertussis was highest among the population of children who were 8 to 11 years of age and who had received the full five-dose series of DTaP in childhood, suggesting that the waning efficacy of the fifth dose among school-age children played a key role in both allowing and sustaining the recent pertussis outbreak. This observation was surprising because it is not until children reach their teenage years that they are usually considered to be a reservoir for pertussis,23 and teenagers have been disproportionately affected in previous pertussis outbreaks.20 Figure 1 shows that on a population basis, the incidence of pertussis decreased very sharply at 12 to 15 years of age, precisely the same ages of children who were likely to have received whole-cell pertussis vaccines as infants. These ecologic data show that the risk of pertussis was lower among older adolescents, who were likely to have previously received at least one dose of the whole-cell pertussis vaccine than among younger adolescents, who had exclusively received DTaP.

Most children in this study received their fifth dose of DTaP between 4 and 6 years of age. Thus, age and time since vaccination were highly collinear (r=0.97), and we were unable to fully separate out these two variables in the primary analysis involving PCR-negative controls. We could not entirely rule out the possibility that the incidence of pertussis among older children was higher because they were older rather than because of waning protection. The sharp increase in the incidence of pertussis among children 8 to 11 years of age, followed by a sharp decrease at 12 to 15 years (Figure 1), is not characteristic of the epidemiology of pertussis in unvaccinated persons or in previous outbreaks. Furthermore, the secondary analyses involving controls who were closely matched for age showed that the association between the time since vaccination and the risk of pertussis was similar to that in the primary analysis. Therefore, it is more plausible to attribute the increased incidence of pertussis in children between 8 and 11 years of age to the waning effectiveness of DTaP rather than to aging.

The Centers for Disease Control and Prevention recommends routine administration of Tdap beginning at 11 years of age, with vaccination of children as young as 7 years of age in certain circumstances.24 The limited duration of DTaP protection raises the question of whether routine administration of Tdap in younger children (e.g., 8-year-old children) is warranted. However, several issues must be clarified, including the effectiveness and duration of protection of Tdap, the possibility of increased local reactions with more frequent administration of Tdap, the increased cost and burden associated with earlier Tdap boosting (particularly since no other vaccines are routinely given at this age), and the risk of transmission to infants posed by mild-to-moderate pertussis infections that could be prevented with earlier Tdap boosting. Prevention of future outbreaks will be best achieved by developing new pertussis-containing vaccines that provide long-lasting immunity.

The large population in the health plan allowed controls to be matched to PCR-positive children on many potential confounders, and matched controls were more similar to PCR-positive children than were PCR-negative controls on all measured potential confounders. However, matched controls were probably not as similar to PCR-positive children as PCR-negative controls were with respect to unmeasured potential confounders, such as the propensity to have undergone a PCR test to detect pertussis. Because we believe that such unmeasured confounders were probably a greater source of bias than the ones we were able to measure, we considered the analysis involving PCR-negative controls to be more informative.

Our study has several important strengths. One was that we compared PCR-positive children with two sets of controls and obtained similar results with each comparison. Another was that we had precise histories regarding the number of doses of vaccine received and the timing of vaccination and nearly complete demographic data for PCR-positive children and controls. Finally, we observed that older age was associated with an increasing proportion of positive PCR tests (Figure 2); this supports our inference that the increase in the incidence of pertussis reflected a true increase in the incidence of disease rather than increased testing for pertussis.

Our study has limitations. First, although we estimated that the fifth dose of DTaP became 42% less effective each year, we could not anchor this estimate to the initial effectiveness of the vaccine because of the absence of an unvaccinated population. Second, it is possible that PCR testing misclassified a small fraction of persons (i.e., false positive and false negative tests). Since it was highly unlikely that such potential misclassification depended on the time since immunization, misclassification would imply that DTaP effectiveness may have waned even more than we estimated.

In conclusion, our evaluation of data from a large pertussis outbreak in California showed that protection from disease after a fifth dose of DTaP among children who had received only DTaP vaccines was relatively short-lived and waned substantially each year. Our findings highlight the need to develop new pertussis-containing vaccines that will provide long-lasting immunity.