The solid black line with circle markers indicates overall incidence of pertussis among all age groups combined.
A, Pertussis incidence, 1990-2014. B, Rate ratios of pertussis incidence, 1990-2014. Vertical dashes represent the breakpoints in segmented regression analysis (1990-2004 as the pretetanus toxoid, reduced diphtheria toxoid, and acellular pertussis [Tdap] period, 2005-2009 as the post-Tdap [whole-cell pertussis–primed] period, and 2010-2014 as the post-Tdap [transition to fully acellular pertussis–primed] period).
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Skoff TH, Martin SW. Impact of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccinations on Reported Pertussis Cases Among Those 11 to 18 Years of Age in an Era of Waning Pertussis Immunity: A Follow-up Analysis. JAMA Pediatr. 2016;170(5):453–458. doi:10.1001/jamapediatrics.2015.4875
There is accumulating literature on waning acellular pertussis vaccine–induced immunity, confirming the results of studies assessing the duration of protection of pertussis vaccines.
To evaluate the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine’s effect over time among those 11 to 18 years old, while accounting for the transition from whole-cell to acellular pertussis vaccines for the childhood primary series.
Design, Setting, and Participants
Extended, retrospective analysis of reported pertussis cases between January 1, 1990, and December 31, 2014, in the United States. The analysis included all nationally reported pertussis cases.
US Tdap vaccination program and the transition from whole-cell to acellular pertussis vaccines.
Main Outcomes and Measures
Rate ratios of reported pertussis incidence (defined as incidence among 11- to 18-year-old individuals divided by the combined incidence in all other age groups) modeled with segmented regression analysis and age-specific trends in reported pertussis incidence over time.
Between 1990 and 2014, 356 557 pertussis cases were reported in the United States. Of those, 191 914 (53.8%) were female and 240 665 (67.5%) were white. Overall incidence increased from 1.7 in 100 000 to 4.0 in 100 000 between 1990 and 2003, while latter years were dominated by epidemic peaks. Incidence was highest among infants younger than 1 year throughout the analysis period. Pertussis rates were comparable among all other age groups until the late 2000s, when an increased burden of pertussis emerged among children 1 to 10 years old, resulting in the second highest age-specific incidence. By 2014, 11- to 18-year-old individuals once again had the second highest incidence. While slope coefficients from segmented regression analysis showed a positive impact of Tdap immediately following introduction (slope, −0.4959; P < .001), a reversal in trends was observed in 2010 when rates of disease among 11- to 18-year-old individuals increased at a faster rate than all other age groups combined (slope, 0.5727; P < .001).
Conclusions and Relevance
While the impact of Tdap among adolescents looked promising following vaccine introduction, our extended analysis found that trends in adolescent disease were abruptly reversed in 2010, corresponding directly to the aging of acellular pertussis–vaccinated cohorts. Despite the apparent limitations of Tdap, it remains the best prevention against disease in adolescents.
Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines were licensed in the United States in 2005 for use as a booster dose among adolescents and adults. The primary goal of Tdap vaccination was to reduce the growing burden of disease among adolescents. Early field evaluations conducted shortly after vaccine introduction revealed 66% to 78% effectiveness of Tdap among adolescents,1-3 and vaccination coverage increased steadily in the years following introduction. By 2014, Tdap coverage among those aged 13 to 17 years reached 87.6% in the United States.4 Shortly following the introduction of Tdap vaccines, the effects of vaccination among the target adolescent age group looked promising. Although elevated, reported rates of pertussis among 11- to 18-year-old individuals decreased more quickly than rates of disease among all other age groups in the years immediately following Tdap introduction, suggesting that the targeted use of Tdap reduced the burden of pertussis preferentially in the adolescent age group.5
Despite high or increasing coverage with both Tdap and the childhood pertussis vaccination series (diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine [DTaP]), the United States has been experiencing a pertussis resurgence in recent years, with notable changes in the epidemiology of disease. Since the early 1990s, significant epidemics have been reported nationally in the United States, with the largest postvaccine introduction peak in 2012, when more than 48 000 cases were reported in the United States, the largest number of cases since the mid-1950s. Many factors are likely contributing to the resurgence in disease including changes in diagnostic testing and reporting, increased awareness of pertussis among health care professionals and the general public, molecular evolution of the organism, and, most importantly, waning of vaccine-induced immunity. Although pertussis vaccines have demonstrated excellent short-term effectiveness, the protection of both DTaP and Tdap wanes quickly in the years following vaccination.6-8 This waning is consistent with the epidemiological shift toward the emergence of disease among recently vaccinated children and adolescents.
In the 5 years since our original analysis of the early impact of Tdap,5 the landscape of pertussis epidemiology has changed. Waning of vaccine-induced immunity from DTaP has been well documented, particularly as cohorts of children who received an acellular vaccine for all 5 doses of their childhood series age.6,7,9 In light of these changes and findings, we sought to update our previous analysis, looking at the impact of Tdap among those 11 to 18 years of age by including 5 additional years of data (2010-2014), allowing us to assess the effect of Tdap among acellular-primed adolescent cohorts.
Question Accounting for the transition from whole-cell to acellular pertussis vaccines for the childhood primary series, what is the effect of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine among cohorts of adolescents and young adults over time?
Findings In this analysis of reported cases of pertussis in the United States between 1990 and 2014, the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines had an impact among adolescents following its introduction in 2005, there was a reversal in disease trends in 2010, when reported pertussis incidence among adolescents began to increase at a faster rate than disease among all other age groups.
Meaning Our findings are consistent with recent literature suggesting a diminished effect of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine among acellular pertussis vaccine–primed cohorts of adolescents.
This analysis is an extension of our earlier retrospective analysis of pertussis cases reported through the National Notifiable Diseases Surveillance System.5 For this analysis, cases with a cough onset date between January 1, 1990, and December 31, 2014, were classified by state and local health departments according to the Council of State and Territorial Epidemiologists case definition for pertussis. Cases with a confirmed, probable, or unknown case status were included in the analysis. Because this was a retrospective analysis of nationally notifiable surveillance data, institutional review board approval was not needed.
Cases were stratified by the following age groups for the trend over time analysis: younger than 1 year, 1 to 10 years, 11 to 18 years, and 19 years and older. Overall and age-specific incidence rates were calculated using cases reported through the National Notifiable Diseases Surveillance System as numerators and population estimates from the National Center for Health Statistics as denominators (bridged-race, intercensal population estimates were used for 1990-1999 and 2014 postcensal vintage estimates for 2000-2014).
Segmented regression analysis was used to model rate ratios of reported pertussis incidence (defined as incidence among those aged 11 to 18 years divided by the combined incidence in all other age groups), while accounting for temporal variability in disease trends. For the model, the pre-Tdap period was defined as 1990 to 2004 and the post-Tdap period as 2005 to 2014. Additionally, we used 2010 as a second break point to model the transition to acellular DTaP vaccines for the entire childhood series; by 2010, all 11-year-old children were born after the Advisory Committee on Immunization Practices recommendation in 1997 to administer DTaP for all 5 doses of the childhood series. Changes in proportions and risk ratios were used for the comparison of proportions; P < .05 was considered statistically significant.
A total of 356 557 pertussis cases were reported through the National Notifiable Diseases Surveillance System between January 1, 1990, and December 31, 2014; 200 401 (56%) of the cases occurred between 1990 and 2009. Case characteristics are summarized in Table 1.
Between 1990 and 2003, the overall incidence of pertussis increased gradually from 1.7 in 100 000 population to 4.0 in 100 000 (135% increase, P ≤ .001). Following this increase, the latter years were dominated by prominent epidemic peaks in 2004 (8.8 in 100 000), 2005 (8.7 in 100 000), 2010 (8.9 in 100 000), and 2012 (15.4 in 100 000) (Figure 1). Additionally, the number of reported cases during the trough in 2013 was higher than the number of cases reported during the prior peak years of 2004, 2005, and 2010 (Figure 1).
When stratified by age group, rates of disease were consistently highest among infants younger than 1 year compared with the other age groups, ranging from a low of 26.4 in 100 000 in 1991 to a high of 127.2 in 100 000 in 2012 (Figure 2). Pertussis incidence remained comparable among the other age groups until the late 2000s, when an increased burden of pertussis emerged among children 1 to 10 years; between 2007 and 2011, children 1 to 10 years had 1 to 2 times higher incidence of reported pertussis than adolescents 11 to 18 years. While incidence increased dramatically across all age groups between 2011 and 2012, the largest relative increases were observed among those aged 11 to 18 years (267.5%), followed by those aged 1 to 10 years (156.8%). By 2014, a slight increase was observed among adolescents 11 to 18 years of age, surpassing the rate of reported pertussis among those aged 1 to 10 years (Figure 2).
As our previous analysis showed, prior to the introduction of Tdap in 2005, the incidence of pertussis among adolescents aged 11 to 18 years increased gradually before reaching a peak during the 2004 epidemic (slope, 0.2917; P < .001) (Figure 3A). Following the peak, the incidence of pertussis came down in all age groups but declined at a significantly faster rate among adolescents than among all other age groups combined (slope, −0.4959; P < .001) (Figure 3B). However, beginning in 2010, this trend was reversed. Once again, the incidence of disease among adolescents increased at a faster rate than the other age groups, similar to what was observed prior to the introduction of Tdap in the United States but at a much steeper incline (slope, 0.5727; P < .001) (Figure 3B).
Although Tdap had a positive impact among adolescents in the 4 years immediately following vaccine introduction, our extended analysis of data through 2014 revealed a reversal in disease trends in 2010, when reported pertussis incidence among adolescents began to increase at a faster rate than disease among all other age groups. Our extended analysis of additional years of surveillance data supports the accumulating literature on waning of acellular vaccine–induced immunity and offers an additional perspective by confirming the results of published case-control and cohort studies assessing the duration of protection of pertussis vaccines. The United States transitioned from whole-cell pertussis (wP) vaccines to acellular DTaP vaccines for the childhood series during the 1990s; in 1992, the Advisory Committee on Immunization Practices recommended DTaP for the fourth and fifth doses of the childhood series, given at 15 to 18 months and 4 to 6 years, respectively, and in 1997, further recommendations were made to transition the primary doses of the series, given at 2, 4, and 6 months of age, to acellular pertussis vaccine.10,11 By 2014, all cohorts of children younger than 16 years should have received acellular vaccine for all 5 doses of the childhood series (Table 2). While our previous analysis showed a strong impact of Tdap among the target adolescent age group, the analysis only included data up through 2009, which captured adolescent cohorts that had received greater than 1 wP dose for the childhood series. Data from the past few years have shown that Tdap duration of protection wanes more quickly among adolescents primed with DTaP than with wP formulations and that at least a single dose of wP vaccine as part of the 5-dose childhood series, especially when administered as the first dose, results in greater Tdap-induced protection.12-14 We observed an abrupt shift in the direction of rate ratios in 2010, the very year that children aged 11 years would have been the first cohort born after the 1997 transition from wP to acellular vaccines to have received acellular vaccines for all doses of the childhood series.
There are many hypotheses surrounding the recent resurgence of pertussis in the United States and abroad. While waning immunity from acellular vaccines is thought to be a driving factor, especially among school-aged children and adolescents, the cause is likely multifactorial. Changes in diagnostic testing, surveillance, and reporting are likely playing a role in the resurgence. However, similar trends in diagnostic test use, with a transition away from culture to polymerase chain reaction, have been observed across age groups.15 More importantly, changes in diagnostic tests and/or reporting do not explain the strong cohort effect of increasing pertussis incidence that has been observed among birth cohorts of acellular-primed adolescents.9,16 In recent years, a rapid increase in pertactin-deficient Bordetella pertussis strains has also been observed in the United States.17 Pertactin is a key B pertussis antigen thought to be involved in bacterial adhesion and is included in all acellular pertussis vaccines used in the United States. Vaccine pressure combined with imperfect and waning vaccine-induced immunity in children and adolescents may have enabled evolution of the bacterium to allow for more efficient transmission among highly vaccinated cohorts.
Given what our analysis and other publications have shown, recommending Tdap for an additional dose among the general population is unlikely to have a significant effect on disease burden in the United States. With modest effectiveness of Tdap vaccines and significant waning of protection within 2 years of vaccine receipt, susceptible individuals will continue to accumulate in the population. A 2016 cost-effectiveness model looking at additional doses of Tdap among a theoretical cohort of persons 11 to 30 years of age found that the fraction of pertussis disease prevented never exceeded 10% with an additional dose of Tdap administered at 16 or 21 years of age.18 While more than 1 dose of Tdap may be considered for high-risk populations pending licensure of additional doses, for now, the Advisory Committee on Immunization Practices recommends more than 1 dose of Tdap only among pregnant women to provide direct protection through maternal antibody transfer to infants who are at increased risk for severe pertussis-related morbidity and mortality.19 Strategies such as early detection and treatment of pertussis should be used in addition to vaccination to optimize the control of pertussis among adolescents and reduce transmission within the general population and to high-risk groups.
Pertussis vaccines continue to protect against severe disease and death, offering major benefits to their recipients. Therefore, maximizing current pertussis vaccination strategies remains the best defense against disease in the short term until pertussis vaccines with extended duration of immunity are developed and made available. Emphasis should be placed on ensuring on-time pertussis vaccination and increasing Tdap coverage among pregnant women to provide protection to infants, those at highest risk for disease.
Corresponding Author: Tami H. Skoff, MS, Meningitis and Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, US Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS C-25, Atlanta, GA 30329 (firstname.lastname@example.org).
Accepted for Publication: December 16, 2015.
Published Online: March 28, 2016. doi:10.1001/jamapediatrics.2015.4875.
Author Contributions: Ms Skoff had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Both authors.
Acquisition, analysis, or interpretation of data: Both authors.
Drafting of the manuscript: Both authors.
Critical revision of the manuscript for important intellectual content: Both authors.
Statistical analysis: Both authors.
Administrative, technical, or material support: Skoff.
Study supervision: Martin.
Conflict of Interest Disclosures: None reported.
Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.