Licensed pertussis vaccines in the United States

Abstract

The United States switched from whole cell to acellular pertussis vaccines in the 1990s following global concerns with the safety of the whole cell vaccines. Despite high levels of acellular pertussis vaccine coverage, the United States and other countries are experiencing large pertussis outbreaks. The aim of this article is to describe the historical context which led to acellular pertussis vaccine development, focusing on vaccines currently licensed in the US, and to review evidence that waning protection following licensed acellular pertussis vaccines have been significant factors in the widespread reappearance of pertussis.

During the 1990s, the United States (US) switched from using whole cell pertussis to solely using acellular pertussis vaccines. Despite high level vaccine coverage with these acellular pertussis vaccine, the US¹ and many countries which exclusively employ acellular pertussis vaccines such as Australia,² Canada,³ United Kingdom,⁴ Ireland⁵ and Norway⁶ have experienced increased incidences or outbreaks of pertussis. The aim of this review is to depict the historical context surrounding both global safety and some effectiveness concerns regarding whole cell pertussis vaccines which led to the development and US license of acellular pertussis vaccines, and to describe how waning protection following acellular pertussis vaccines and decreased long-term protection compared with whole cell pertussis vaccines have been important contributors in the re-emergence of pertussis.

In the US, there are currently two manufacturers of licensed acellular pertussis vaccines: GlaxoSmithKline Biologicals (GSK) and Sanofi Pasteur. The licensed and currently available acellular pertussis vaccines contain either 3 or 5 pertussis antigens, depending on the vaccine (described below).

Whole Cell Pertussis Vaccines Brief History

Whole cell pertussis vaccines developed from suspensions of whole killed organisms were first licensed in the US in 1914. In 1948, the pertussis vaccine was combined with diphtheria and tetanus toxoids and became a diphtheria whole cell pertussis and tetanus toxoid (DTP) vaccine. Widespread use of DTP vaccines in the United States coincided with large decreases in pertussis disease, falling from 115,000–270,000 cases annually prior to the vaccine era to 1,200–4,000 cases annually during the 1980s.⁷

Although most DTP vaccines were highly efficacious (estimated 80–98% effective),^8-13 a few licensed DTP vaccines were associated with poor protection. A US licensed DTP vaccine manufactured by Connaught Laboratories (now Sanofi Pasteur, Toronto) was used exclusively in Canada between 1985 and 1998. Subsequent studies estimated this vaccine's effectiveness as ranging between 49–61%^14-16; use of this DTP vaccine was implicated as a major contributing factor to Canada's pertussis resurgence during the 1990s.¹⁷ A 1993 pertussis outbreak in the US also occurred in a highly DTP-vaccinated population. This study did not directly implicate any specific DTP vaccine, however of the known DTP doses given, 72% were manufactured by Connaught.¹⁸ The licensed Connaught DTP vaccine met all regulatory vaccine potency requirements, yet it was later shown to stimulate very low antibody responses to all of the pertussis antigens tested,¹⁹ highlighting the difficulty in predicting which DTP vaccines would be more or less effective. Sweden also saw resurgence in pertussis during the 1970s, thought to be the result of earlier changes to Sweden's DTP manufacturing process.²⁰ The fact that selected DTP were poorly effective raised some questions regarding the utility of all DTP vaccines.²¹

Further complicating public perceptions, DTP vaccines were very reactogenic and concern regarding DTP safety grew in the 1970s and 1980s. A high proportion of infants experienced significant injection site reactions following DTP immunization (redness [37%], swelling [41%], and pain [51%]).²² Fever occurred within hours after DTP in many infants: 47% of infants had temperatures >38°C and 6% had temperatures >39°C.²² DTP vaccines were also associated with serious systemic reactions, including febrile seizures, hypotonic hyporesponsive episodes (temporary shock-like state), persistent crying and whole limb swelling. Although none were associated with serious long-term sequelae,²³ these adverse events contributed to increasing public concerns about the safety of the vaccine.²⁴ Especially concerning was the suggestion that some serious cases of encephalopathy were attributable to DTP; these were referred to as “pertussis vaccine encephalopathy.” Studies ultimately detected no true association between DTP and encephalopathy.²⁵ Subsequent genetic analysis studies which identified de novo mutations in the sodium channel gene SCN1A in patients with alleged pertussis vaccine-induced encephalopathy,²⁶ and which were replicated in five additional cases of alleged vaccine-induced encephalopathy,²⁷ have cast further doubt on such an association.

Nonetheless, reservations about DTP safety, and to lesser extent, the effectiveness of selected vaccines, had global impact. In the 1970s and 1980s, Japan suspended their pertussis vaccination program because of safety concerns.²⁸ In Sweden, effectiveness concerns led to a suspension of Sweden's pertussis vaccination program.²⁹ Other countries such as the United Kingdom, Italy, Ireland, Australia, West Germany and Russia saw substantially reduced pertussis vaccine acceptance within their populations.^7,24 In the US by the mid-1980s, lawsuits related to vaccine safety led several manufacturers to withdraw their DTP vaccines and paved the way to the US National Childhood Vaccine Injury Act in 1986. This act provides funds to compensate for adverse events following immunization.²¹ Faced with such widespread apprehension surrounding DTP safety, great efforts were made to develop acellular pertussis vaccines.

Acellular Pertussis Vaccines Early Days

Several pertussis antigens were identified for potential inclusion in an acellular pertussis vaccine the 1980s; 13 different acellular pertussis vaccines were initially developed and tested.³⁰ Acellular vaccines containing 1–5 pertussis antigens in various combinations ultimately underwent further testing in randomized clinical trials. The 5 tested Bordetella pertussis antigens were 2 purified hemagglutinins (filamentous hemagglutinin [FHA] and pertussis toxin [PT]), pertactin (PRN; a 69 kDa outer membrane), and 2 fimbria proteins (fimbriae 2 and 3 combined).

Following Japan's suspension of it pertussis vaccine program, Sato and colleagues developed the first acellular pertussis vaccines (containing formaldehyde-treated FHA and formalin-inactivated PT)²⁸; these were initially administered to children 2 y and older. Household contact studies among children 1 y and older estimated efficacies ranging from 78% to 92%,³¹ although estimates varied depending on the number of vaccine antigens and doses, ages of the children and pertussis case definitions. These estimates were generally higher than those subsequently observed in infants (see below). Pertussis incidence in Japan declined following acellular pertussis vaccine use in children,²⁸ but their duration of protection was not reported.

Placebo-Controlled Infant DTaP Trials

Sweden's suspension of its pertussis vaccine program in 1979 meant that it was a suitable country to conduct placebo-controlled efficacy trials of acellular pertussis vaccines.^32-35 The first was a placebo-controlled trial which evaluated the two Japanese acellular pertussis vaccines in infants and estimated an efficacy after 2 doses of 69% for the 2 component (PT and FHA) vaccine and 54% for the single component (PT) vaccine.³² A separate open label trial reported that 3 doses of a PT vaccine appeared effective against pertussis disease 3 y after immunization (cumulative incidence in control children was 20%, while no disease was seen in vaccinated children); however, this study's impact was limited because it lacked a placebo group, relied on retrospective matched controls and could not estimate vaccine efficacy.³⁴ A concurrent placebo-controlled trial of the PT vaccine calculated an efficacy of 71% after 3 doses.³⁵ Vaccine efficacy in both placebo-controlled trials varied considerably when milder clinical endpoints were used.^35,36 None of the placebo-controlled trials included comparator DTP vaccines, which limited widespread acceptance of these vaccines. Further, none of the studies specifically evaluated the duration of protection following immunization.

Infant Placebo Controlled Trials: DTaPand DTP Arms

During the 1990s, there were numerous acellular pertussis vaccine infant efficacy trials conducted in many countries. However, this review will focus mainly on studies that specifically evaluated acellular pertussis vaccines that are currently licensed and available in the US. In particular, there were two large double-blind trials (in Italy and Sweden) which compared DTaP or DTP with DT (placebo). For both trials, infants were immunized at 2, 4 and 6 mo of age and the comparator DTP vaccine was the same lot of the US licensed Connaught vaccine. Pertussis cases were defined according to the WHO case definition of ≥21 d of paroxysmal cough and laboratory confirmation of B. pertussis. Neither study directly compared current US licensed acellular pertussis vaccines with each other, nor did they primarily focus on whether DTaP efficacy changes over time or provides sustained protection against pertussis.

In the Italian acellular pertussis vaccine efficacy trial, 14,751 infants were randomized to receive 1 of 2 three-component DTaP (DTaP₍₃₎), DTP or DT (placebo) vaccines and followed for an average of 17 mo after the third dose. One DTaP₍₃₎ contained 25 μg of glutaraldehyde and formalin-inactivated PT, 25 μg of FHA and 8 μg PRN (Infanrix™, GSK, Rixensart, Belgium), while the other DTaP₍₃₎ contained 5 μg genetically detoxified PT, 2.5 μg FHA, and 2.5 μg PRN (Chiron Biocine [now Novartis], Siena, Italy). Compared with placebo, the efficacy of both DTaP₍₃₎ vaccines was 84% (95% confidence interval [CI]: 76–89 for GSK; 95% CI: 76–90 for Chiron). Surprisingly (at the time), the efficacy of DTP compared with placebo was only 36% (95% CI 14–52).³⁷

In the parallel Swedish study (Sweden 1992 Efficacy Trial), 9829 enrolled infants received a two-component DTaP (DTaP₍₂₎) vaccine containing 25 μg of glutaraldehyde and formalin-inactivated PT and 25 μg of FHA (GSK, Rixensart, Belgium), a five-component DTaP (DTaP₍₅₎) vaccine containing 10μg of glutaraldehyde-inactivated PT, 5 μg of FHA, 5μgof fimbriae 2 and 3 combined, and 3μg of PRN (Daptacel, Sanofi Pasteur), DTP, or DT (placebo). This trial followed subjects for an average of 21 to 23.5 mo after the third dose and reported efficacies of 59% (95% CI 51–66) for the DTaP₍₂₎ and 85% (95% CI 81–89) for the DTaP₍₅₎ vaccine. Similar to the Italian study, DTP efficacy was 48% (95% CI 37–58).³⁸

These two trials appeared to clearly demonstrate that DTaP efficacy was substantially better than that of at least some DTPs. The results were met with optimism and enthusiasm,³⁹ and helped pave the way for DTaP's widespread use in infants. However, the high expectations surrounding DTaP's success were based on only 1.5 to 2 y of follow up after the 3rd dose and its long-term duration of protection was not known at that time. Further complicating the trials’ interpretation was the studies’ finding that the DTP vaccine was suboptimal; as discussed above, the comparator Connaught DTP vaccine chosen for these two clinical trials was unfortunately not efficacious or representative of the efficacy of most other DTP vaccines.^21,23,40-42 At the time, whether the exclusive use of DTaP in infants would provide sustained protection against pertussis and whether its efficacy would change over time were raised as relevant unresolved questions, but given DTaP's apparent greater efficacy (vs. DTP) in these clinical trials and improved safety profile, they were not considered as critical prior to licensure in infants.

US Licensed DTaP Vaccines

The US first licensed DTaP vaccines for use in infants in 1996 (DTaP₍₂₎ [Tripedia, Sanofi Pasteur] and DTaP₍₄₎ [Acel-Imun, Wyeth-Lederle]). As neither are currently available nor used in the US (Sanofi Pasteur stopped manufacturing Tripedia in 2011), they will not be discussed further. DTaP₍₃₎ (Infanrix, GSK) was licensed in 1997 and DTaP₍₅₎ (Daptacel, Sanofi Pasteur) in 2002. In 1997, the Advisory Committee on Immunization Practices (ACIP) recommended that DTaP vaccines replace DTP vaccines for the first 3 doses in infants.⁴³ This recommendation followed the ACIP's earlier 1992 recommendation to use DTaP for the 4th and 5th doses for ages 15 mo through 6 y.⁴⁴ In 2006, the ACIP further recommended that all adolescents should receive a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine as a booster dose.⁴⁵

GSK's current US licensed acellular pertussis vaccines for children under the age of 7 y are DTaP₍₃₎ (Infanrix contains 25 μg PT, 25 μg FHA and 8 μg PRN, 25 Lf diphtheria toxoid and 10 Lf tetanus toxoid), DTaP_(3)-inactivated poliovirus-hepatitis B virus (DTaP₍₃₎-IPV-HBV; Pediarix) and DTaP₍₃₎-IPV (Kinrix). The pertussis, diphtheria and tetanus components of DTaP₍₃₎-IPV-HBV and DTaP₍₃₎-IPV vaccines are identical to those in Infanrix. In addition, DTaP₍₃₎-IPV contains 40 D-antigen Units (DU) of Type 1 poliovirus (Mahoney), 8 DU of Type 2 poliovirus (MEF-1), and 32 DU of Type 3 poliovirus (Saukett).⁴⁶ DTaP₍₃₎-IPV-HBV contains identical poliovirus antigens as DTaP₍₃₎-IPV, and also includes 10 μg of HBV surface antigen.⁴⁷

Sanofi Pasteur's current US licensed acellular pertussis vaccines for infants and children are DTaP₍₅₎ (Daptacel contains 10 μg PT, 5 μg FHA, 3 μg PRN, and 5 μg FIM types 2 and 3, 15 Lf diphtheria toxoid and 5 Lf tetanus toxoid), licensed for under 7 y, and the combination vaccine DTaP₍₅₎-IPV-Hemophilus influenza type b (Hib) (Pentacel) for children 6 wk to under 5 y. DTaP₍₅₎-IPV-Hib contains the same amount of PRN, FIM, diphtheria and tetanus toxoid as Daptacel, but higher amounts of PT and FHA (20 μg each).⁴⁸

In general, for all the licensed acellular vaccines, antibody responses to pertussis antigens in infants have all been considered acceptable without significant evidence of immunological interference with other concomitant licensed vaccines.^48-54 A detailed discussion of immune responses following licensed acellular pertussis vaccines is beyond the scope of this review (see^{21, 43,46,47}).

Acellular Pertussis Vaccines Duration of Protection: Clinical Trials

Efficacy estimates for licensed DTaP vaccines were limited not only by the short follow up time period, but also by use of the strict WHO case definitions which are known to overestimate vaccine efficacy, presumably because severe cases are more likely to meet the WHO definition and the vaccine may attenuate severity without preventing disease altogether.^21,41 Using a milder case definition of cough >7 d, the efficacy of DTaP₍₃₎ compared with placebo decreased to 71% (95% CI 60–78) in the Italian trial,³⁷ and the efficacy of DTaP₍₅₎ declined to 78% (95% CI 72–82) in the Sweden 1992 Efficacy Trial.³⁸

Follow up studies to assess DTaP's protection beyond the original 1.5 to 2 y were conducted. No study directly compared DTaP₍₃₎ with DTaP₍₅₎. To estimate DTaP₍₃₎'s duration of protection, children in the original Italian efficacy trial were followed for an additional 9 mo (average follow up of 27 mo after the 3rd dose). Using the WHO case definition, DTaP₍₃₎'s efficacy during just the additional 9 mo was 78% (95% CI 62–87), which decreased to 70% (95% CI 53–81) using the milder criteria of cough >7 d.⁵⁵ A successive Italian study assessed original trial subjects from ages 3 through 6 y (for an average follow up of 31 mo during this period). For cases defined as >14 d of paroxysmal cough or > 21 d of any cough and laboratory-confirmation of B. pertussis, this study reported that DTaP₍₃₎ had an efficacy of 78% (95% 71–83) during this 2.5 y period; the more stringent WHO definition yielded the higher estimate of 86% (95% CI 79–91).⁵⁶ This study concluded that 3 doses of DTaP in infancy provided ongoing pertussis protection which lasted 5 to 6 y and provided evidence for some countries to abandon the toddler booster dose of DTaP.⁵⁷

The Sweden 1992 Efficacy Trial did not conduct similar long-term follow up studies, although other studies in Sweden sought to estimate the duration of protection following infant receipt of DTaP. These studies evaluated differing DTaP formulations, combinations, and vaccine schedule than are used in the US (e.g., vaccine were administered 3, 5 and 12 mo), thus it is not possible to directly compare results of these long-term studies in Sweden with those of the Italian follow up studies.

However, one 3 y follow-up study which evaluated a cohort of subjects offered some clues. In this study, some children in the cohort received GSK's DTaP₍₃₎, others received 3 doses of Sanofi Pasteur's DTaP₍₅₎, while yet others received various combinations of DTaP vaccines (including single component or DTaP₍₂₎ vaccines). This study found that protection against pertussis overall remained for 5–6 y after the 3rd DTaP dose, but it also suggested that protection may have waned among 6–7 y old children.⁵⁸ An 8 y follow up study similarly noted increased pertussis incidence in 6–8 y old children,⁵⁹ suggesting some waning protection after DTaP. This study combined all DTaP recipients into a single “acellular pertussis vaccine” cohort, and children in the study received varying number of DTaP doses, were vaccinated at different ages, and received different component vaccines than did US children. Furthermore, long-term follow up studies in both Italy and Sweden were likely complicated by high rates of natural disease in the population, which may have stimulated longer-lasting immunity than that induced by vaccination alone. For these reasons, extrapolation of these findings to the US was problematic.

Observational Studies of DTaP

Observational studies offer an additional approach to gaining insights on the duration of protection of currently licensed DTaP vaccines. A Canadian study evaluated the transition from the Connaught DTP to the DTaP₍₅₎ vaccine from 1995 through 2005 using passive surveillance data and observed that the highest pertussis incidence was among 0–4 y old children in birth cohorts that would have received only the acellular vaccine. This study also noted that among children who had received either DTP or mixed DTaP₍₅₎/DTP vaccines, lower pertussis rates were seen in infants and preschool children (ages 0–4 y) than among school age children (ages 5–9 y), while among children who had only received DTaP_(5), the incidence of pertussis was higher among children aged 0–4 y than among those aged 5–9 y _. This study indicated that that transition from DTP to DTaP₍₅₎ in Canada was associated with an increased incidence of pertussis among infants and young children.⁶⁰ However, another Canadian study using active surveillance evaluated pertussis hospitalization during 1991–2004 reported that the change from DTP to DTaP₍₅₎ was associated with decreased pertussis hospitalizations among 4–59 mo old children, results which the authors concluded were not surprising since DTaP₍₅₎ replaced the poorly effective DTP vaccine.⁶¹ Differing results between these two studies may have been related to differences in clinical disease severity (i.e., hospitalizations vs. all reported cases) or case finding methods (active vs. passive surveillance).

Lavine and colleagues examined the duration of protection following pertussis vaccination in Massachusetts from 1990 to 2008.⁶² Massachusetts switched from DTP to DTaP in 1995 (used DTaP₍₂₎ until 2004 and then DTaP₍₃₎ from 2004–2008). The authors observed that while DTP and DTaP offered similar duration of protection for individuals first vaccinated during the late 1990s, the disease-free interval following vaccination has been decreasing over the past 2 decades. Although the observed decrease followed Massachusetts’ transition from DTP to DTaP, the authors proposed this may have been due to a rising force of infection through increased pertussis circulation over time rather than due to waning protection from DTaP because earlier studies reported that DTaP's duration of protection was similar to DTP's in countries with high rates of natural disease.⁶³ However, for the US population in this study with low overall rates of exposure to natural disease, an alternative explanation for the decreasing disease-free interval may have been related instead to DTaP waning.

Studies During Pertussis Outbreaks

Studies conducted during pertussis outbreaks have been an important tool to evaluate DTaP's duration of protection. In general, a number of studies found that increasing time since vaccination was a risk factor for vaccine failure. A case-control study evaluated a 2003 pertussis outbreak in northwest Missouri. Of the total 127 pertussis cases, the majority (83/127) occurred in school age children aged 5–18 y, of whom 51% were 10–14 y old. Cases were more likely than controls to have received the 5th pertussis vaccine dose at a younger age; receipt at age 4 y vs. age 5 y was associated with an increased risk for pertussis (odds ratio [OR] 2.36, 95% CI, 1.20–4.62)_.⁶⁴ The authors reported that for the cases with available pertussis vaccine history (n = 79), vaccine type (DTaP or DTP) was not significantly associated with pertussis, although they did not report vaccine types received. However, age matching of cases and controls minimized potential variations by design and likely resulted in cases and controls being concordant with regard to vaccine type received. With the ACIP's 1992 recommendation that DTaP be used for 4th and 5th doses,⁴⁴ many subjects in this study (i.e., those <15–16 y old at the time of the 2003 outbreak) were of an age that it was likely they received DTaP for at least the 5th dose. For this reason, while this study did not detect evidence that vaccine type (DTaP or DTP) for the 5th dose mattered, since power was limited in this study, it is worth considering that it also did not provide powerful evidence that vaccine type did not matter. While clearly not conclusive, this early study hinted at DTaP waning.

Evidence from Recent Large Pertussis Outbreaks

California experienced its largest pertussis outbreak in 50 y in 2010–2011.¹ Notably, the majority of cases occurred among school age children aged 8–12 y, a highly vaccinated cohort who had only ever received DTaP vaccines. This setting provided the first opportunity to specifically investigate duration of protection and waning immunity following 5 doses of DTaP among a population of children who had only ever received DTaP vaccines.

We conducted a case-control study within Kaiser Permanente Northern California (KPNC) to investigate the extent of DTaP waning. KPNC is an integrated healthcare delivery system with an annual membership of approximately 3.2 million members which covers a diverse and large geographic area within Northern California (23 counties). We evaluated risk of pertussis according to time since 5th dose of DTaP among children in KPNC born from 2000 onwards (to ensure that they had received only DTaP vaccines); in 2010, these children were between the ages of 4–12 y. Pertussis cases (defined as testing positive for pertussis via polymerase chain reaction [PCR] test) were compared with two sets of controls: those testing PCR-negative for pertussis and closely matched KPNC members. When compared with controls, pertussis positive children were more likely to have received their 5th DTaP earlier than were those in either control group. Compared with PCR-negative controls, this study estimated that the odds of acquiring pertussis increased 42% on average each year after the 5th DTaP dose (OR 1.42, 95% CI 1.21–1.66),⁶⁵ indicating that the protection from pertussis wanes substantially during the 5 y after the 5th doses of DTaP.

How does an average of 42% annual waning (i.e., the risk of “breakthrough” infection in vaccines) translate into vaccine effectiveness? Assuming vaccine effectiveness very shortly after receipt of the 5th dose is 95% (i.e., risk of pertussis in vaccinated children is only 5% that of unvaccinated children), after five years, pertussis risk would increase by a factor of (1.42⁵ x 5%) to 29%. This corresponds to a decrease in DTaP effectiveness from 95% to 71% (i.e., 100–29%) five years after the 5th dose.

In a separate case-control study conducted in California, Misegades and colleagues also found substantial waning after the 5th dose of DTaP.⁶⁶ In this study, cases and controls who had received 5 doses of DTaP were compared with unvaccinated children according to time since completing the 5 dose DTaP series. This study estimated that DTaP effectiveness 12 mo after the 5th dose was 98% (95% CI, 96- 99). By 60 mo or more after the 5th dose, effectiveness had declined to 71% (95% CI, 46–85), a level which closely aligns with estimates of DTaP waning.^65,67

In another study, Tartof, et. al.⁶⁸ investigated pertussis incidence during the 6 y after the 5th dose of DTaP among children born from 1998–2003 in Oregon and Minnesota and found that there was a steady increase in risk of pertussis each year. In Minnesota, the risk of pertussis increased from a risk ratio of 1.9 (95% CI 1.3–2.9) 1 y after the 5th dose to 8.9 (95% CI 6.0–13.0) 6 y after the 5th dose. None of the studies above differentiated between DTaP₍₃₎ and DTaP₍₅₎ vaccines. Whether waning differs between the licensed DTaP vaccines has not been reported.

More recently, Quinn and colleagues evaluated protection following the first 3 doses of DTaP₍₃₎ through age 3 y in Australia and noted substantial waning protection against pertussis following the 3rd dose.⁵⁷ This matched case-control study from 2005 through 2009 (which overlapped with a pertussis epidemic from 2008 through 2011) found that effectiveness against laboratory confirmed pertussis was 53.7% (95% CI 43.8–61.9) after the 1st dose, 80.8% (95% CI 73.5–86.1) after the 2nd dose, and 83.5% (95% CI 79.1–87.0) after the 3rd dose. However, vaccine effectiveness decreased to 79.2% (95% CI 75.0–82.8) at age 1 y, declining further to 59.2% (95% CI 51.0–66.0) at age 3 y. The evidence from this study suggest that DTaP vaccines provide reasonable protection during the first year of life, but protection against pertussis wanes rapidly in young children even before the booster dose between ages 4 to 6 y.

Long-term Protection: Differences between DTP and DTaP

Although DTaP vaccines wane rapidly, an important issue was whether long-term protection, particularly during pertussis outbreaks, differed among individuals who had only received DTaP and those who received DTP. To address this, we investigated whether pertussis risk during the California epidemic differed among teenagers according to vaccine type (DTP/DTaP) received in infancy and early childhood. This case-control study included subjects born between 1994 through 1999, spanning the transition from DTP to DTaP vaccines, who had received their first 4 pertussis vaccines in KPNC. Teenagers (10–17 y old in 2010) who had received 4 doses of DTaP during the first two years of life were approximately 6 times more likely to be PCR positive for pertussis than were those who had received 4 doses of DTP (OR 5.6, 95% CI 2.6–12.5).⁶⁹ Further, each additional DTaP received instead of DTP was associated with, on average, a 40% increased risk of pertussis (OR 1.4 95% CI 1.2–1.6). This study demonstrated that DTaP provided substantially less long-term protection against pertussis during the California outbreak.

Sheridan and colleagues similarly observed that Australian children born in 1998 during Australia's transition from DTP to DTaP who had received 3 doses of DTaP had higher rates of pertussis during a 2011 outbreak than did children who had received 3 doses of DTP.⁷⁰ While the authors did not report the specific DTaP vaccines used in Australia, somewhat limiting inferences regarding US licensed DTaP vaccines, their results further support that DTaP provides more limited duration of protection that DTP. This study also suggested improved protection from pertussis was associated with receiving DTP for the first dose. Interestingly, an investigation of a 2012 pertussis outbreak in Oregon noted a similar observation. Among children born during the transition from DTP to DTaP from 1997 through 1999, those who began with DTP had a lower pertussis incidence than did those who first received DTaP.⁷¹ Together, these studies provide compelling evidence that for children who have only ever received acellular pertussis vaccines, DTaP vaccines do not offer long lasting protection against pertussis infection.

Conclusion

Disease caused by Bordetella pertussis remains an ongoing challenge which is a testimony to both the complexity of the organism and the difficulties involved in developing safe, efficacious and long-lasting pertussis vaccines. Reservations about whole cell pertussis vaccines’ reactogenicity and associated adverse events, and to a lesser extent, effectiveness of selected DTP vaccines, led to the widespread use of DTaP vaccines in most developed countries. Current licensed DTaP vaccines are safe and provide good short-term protection against pertussis, but fall short in providing long-term protection against disease when compared with efficacious whole cell pertussis vaccines. Yet, it is improbable that the US would return to using DTP; parental hesitancy toward vaccines has only increased in the intervening years since the US and other countries stopped using DTP, and safety concerns would continue to be at least as important today as they were in the 1980s and 1990s. As the cohort of DTaP-only children becomes larger, older, more remote from vaccination, and thus increasingly susceptible to pertussis, we can expect that pertussis outbreaks will be larger and more frequent. To protect young infants in this setting, we should continue strategies to vaccinate pregnant women with Tdap during pregnancy.⁷² We also need to ensure that this DTaP-only cohort of children receive all recommended doses of acellular pertussis vaccines, including a Tdap booster. While a single adolescent dose of Tdap may dampen outbreaks in the short-term, it is unlikely to provide long-term disease control.⁷³ Additional short-term strategies to alleviate future epidemics may need to include extra Tdap doses during outbreaks, and repeat Tdap vaccinations for health care workers and others with exposure to high risk susceptible individuals. Ultimately to achieve widespread protection and disease control in the long-term, new vaccines are needed to provide long lasting immunity against pertussis.

Disclosure of Potential Conflicts of Interest

Nicola P Klein receives research support from GlaxoSmithKline and Sanofi Pasteur, both manufacturers of pertussis vaccines. She also received research support from Pfizer, Novartis, Merck and Co., and the Centers of Disease Control and Prevention.

Acknowledgments

Many thanks to Bruce Fireman and Roger Baxter for critically reviewing this manuscript.