Pertussis: Microbiology, Disease, Treatment, and Prevention

Aim of This Review

Despite the recognition of pertussis clinical disease more than 1,600 years ago, Bordetella pertussis continues to be a major global pathogen now known to affect infants, children, and adults. Despite major disease reductions due to the introduction of pertussis vaccines in the 1940s and vaccine improvements in the 1970s, epidemics of pertussis persist. The aim of this review is to provide state-of-the art information on pertussis, including history of the disease and causative organism, pathogenesis, epidemiology and burden of the disease, clinical presentation and complications, prevention and treatment modalities, outbreak control, immunity as a result of vaccination and disease exposure, and future directions.

History of Pertussis and Bordetella pertussis

In the seventh century, during the Sui Dynasty, a pertussis-like illness was described by Chinese medical scholar Yuanfang Chao as “the cough of 100 days” (1, 2). One thousand years later (1578) in France, Guillaume De Baillou provided the first description of whooping cough among children of Paris; he described the illness as “quinte” due to the observed 5-h periodicity of paroxysms seen in acute episodes of disease (3). Recent research suggests that the earliest recorded epidemics of pertussis were noted in Persia (present-day Iran) (4). In Europe, pertussis outbreaks were first described in the 16th century, but recognition of the causative agent did not occur until 300 years later. In 1883, a German scientist, Carl Burger, working at the University of Bonn recognized rods of bacteria in a stained sputum specimen from a patient with clinical pertussis (5). Seventeen years later, Jules Bordet, a Belgian physician-scientist, visualized small Gram-negative bacilli in the sputum of his 5-month-old daughter suffering from whooping cough. However, at the time, Bordet was unable to grow these bacilli in available culture media (6, 7). Six years later, Bordet's son had also suffered from pertussis, and by that time, Bordet and Gengou were successful in isolating and growing B. pertussis for the first time in history (6, 8–10). In 1920, Bordet was awarded the 1919 Nobel Prize in Physiology or Medicine for his work related to antimicrobial immunology, which included extensive study of B. pertussis and set the stage for identification of this organism as the cause of whooping cough (11).

Microbiology of Bordetella Species

Bordetella species are classified under the family Alcaligenaceae and comprise 10 genetically distinct species (Table 1) (12–14). Although B. pertussis has been classically identified as the sole agent responsible for whooping cough, other species (i.e., B. parapertussis and B. holmesii) can also cause coughing that resembles whooping cough (15–28). B. pertussis is a Gram-negative, pleomorphic aerobic coccobacillus that grows optimally on either Bordet-Gengou or Regan-Lowe agar between 35°C and 37°C and can be differentiated from other Bordetella species based on its growth and biochemical characteristics. B. pertussis is a fastidious, nonmotile, catalase- and oxidase-positive species, in contrast with B. parapertussis, which is less fastidious, oxidase negative, and urease positive and produces a brown pigment on heart infusion, Regan-Lowe, or Mueller-Hinton agar (12, 13, 29–32). Bordetella species grow slowly on blood-supplemented medium and on synthetic medium containing appropriate growth factors, such as nicotinamide (30).

Other Bordetella species have been shown to infect humans as well as animals. Although B. parapertussis and B. holmesii have been recognized as causes of whooping cough-like illness, B. parapertussis has been studied more widely than B. holmesii (15, 16, 28, 33–36). Cherry and Seaton analyzed nasopharyngeal specimens submitted for PCR testing from nine states (California, Florida, Illinois, Michigan, New Jersey, Ohio, Texas, Virginia, and Washington) between 2008 and 2010 (27). The results of this study revealed that ∼14% of the culture-positive clinical specimens were identified as B. parapertussis. However, additional studies between 1971 and 2003 have shown wide variation in detection rates for B. parapertussis; rates ranged from 1.4% to 97.7% (24–26, 37–43). These studies differed in geographic location, PCR methods, and the number of clinical samples tested.

In humans, B. parapertussis and B. holmesii can cause disease, although the severity of symptoms tends to be milder than seen with B. pertussis (26, 27, 34, 44–46). B. parapertussis may cause disease in domestic animals, including ovine (sheep) and swine (14, 47), though the strains infecting these mammalian species arise from different lineages and are genetically distinct (48). In addition, B. bronchiseptica has been identified as a cause of disease among immunocompromised persons and has been isolated from traumatized patients and patients with peritonitis (49–52) and from domestic dogs, cats, and pigs (52–54).

Mechanisms of Pathogenesis

Although B. bronchiseptica, B. parapertussis, and B. holmesii can infect a wide range of mammals, including humans, B. pertussis is a human-specific pathogen (55–58). Pertussis results from a coordinated interplay of several virulence factors of B. pertussis, which include toxins such as pertussis toxin (PT), adenylate cyclase toxin (AC), dermonecrotic toxin (DNT), and tracheal cytotoxin (TCT). Other factors that influence the virulence of B. pertussis include surface structures, such as filamentous hemagglutinin (FHA), fimbriae (FIM), pertactin (PRN), the type III secretion system, and lipopolysaccharide (LPS) (59), and metabolic proteins (e.g., BrkA, BapC, and BatB) (Table 2) (60–132). In B. pertussis, the bvgAS genes positively control expression of several virulence factors, including PT, AC, DNT, FHA, TcfA, pertactin, FIM, BrkA, BipA, BcfA, and Vag8. The BvgAS two-component signal transduction system of B. pertussis plays a pivotal role in pertussis pathogenicity (133, 134).

Like that of other bacteria, B. pertussis pathogenesis is influenced by environmental cues (e.g., temperature changes) that dictate virulence factor expression once inside the human host. During transmission from person to person, B. pertussis moves from local environmental temperatures to higher body temperatures which appear to influence regulation of the bvgA and bvgS genes (135). In turn, the regulatory system encoded by bvgA and bvgS can be activated by temperature (as well as sulfate [SO₄] and nicotinate) and regulates expression of virulence factors in B. pertussis and Escherichia coli (136–138). Recent insights by Boulanger et al. suggest that bvgA regulates fim3 gene expression through phosphorylation-mediated control of transcriptional complexes (139). In addition, comparative genomics work by Bart and colleagues examining single nucleotide polymorphisms (SNPs) underscores the importance of genetic changes in B. pertussis that play a role in altered transcription and translation (140).

Clinical observations combined with studies in animal models suggest that the mechanisms of virulence of B. pertussis consist of a cascade of events initiated by the adherence of bacteria via FHA and fimbriae to tracheal epithelium and lungs as an essential primary step (141, 142). Once adherence takes place, B. pertussis cells multiply locally, resist host defense mechanisms (e.g., mucociliary clearance, antimicrobial peptides, and inflammatory cells), and cause local damage to the upper and lower respiratory tracts with systemic manifestations (143–145). The severity of the symptoms depends on several factors, including the patient's age, strength of the immune response, and extent of systemic bacterial dissemination. In infants, for whom disease is severe, bacteria descend from the upper to the lower respiratory tract and, via an unclear mechanism, produce necrotizing bronchitis, diffuse alveolar damage, intra-alveolar hemorrhage, fibrinous edema, macrophage-rich alveolar infiltrates, lymphangiectasia, neutrophilic bronchopneumonia, and fibrin thrombi (142, 143, 146). In more severe cases, these pathological events can lead to pulmonary hypertension, respiratory failure, and even death (142, 147, 148). Pulmonary hypertension develops as an indirect effect of PT through induction of lymphocytosis (hyperleukocytosis), in which the total white blood cell (WBC) count can exceed 1 × 10⁵ cells/mm³. These extremely high WBC counts produce lymphocyte aggregations in the pulmonary vasculature that result in increased pulmonary vascular resistance (149–151). In infants with pertussis, the lymphoid system is also affected. Postmortem biopsies have shown cortical atrophy of the thymus gland, lymph depletion in lymph nodes, and white pulp depletion in spleen (152). In infants who had encephalopathy secondary to B. pertussis infection, brain biopsies showed cerebral hemorrhage and cortical atrophy (153, 154). Although these pathological findings could result from the direct effect of B. pertussis toxins on the brain, they are thought to result from hypoxia (145).

Despite recent advances in B. pertussis research in the past 2 decades, much remains unknown about the pathogenesis of pertussis (143, 146). For instance, the precise mechanism underlying the paroxysmal cough-associated pertussis “whoops” has not been clearly identified, though some researchers suggest that TCT may be responsible (143). In addition, although several B. pertussis virulence factors have been studied, the interaction and synergistic activity of these factors (e.g., PT, LPS, and TCT), which determines the clinical progression and spectrum of disease across different age groups, require additional study (146). Further studies on the pathogenesis of B. pertussis may also provide the basis for design of novel antimicrobial agents that interfere with newly identified virulence mechanisms.

Global Burden of Pertussis

Pertussis is an endemic disease in developing and developed countries, with frequent outbreaks occurring sporadically at different places around the world. In 1999, Crowcroft et al. estimated the global incidence of pertussis to be 48.5 million cases, with approximately 295,000 deaths reported (155). In 2010, Black et al. reported that 16 million cases of pertussis occurred in 2008 worldwide, resulting in 195,000 deaths (156). A large number of deaths (83,580) were reported from Africa (156, 157). In 2013, an estimated 136,000 cases worldwide were reported (158, 159).

There are several challenges in estimating the global pertussis disease burden. First, many countries have limited surveillance infrastructure, which does not facilitate timely reporting of clinically suspected pertussis cases. Second, in developing countries, laboratory infrastructure to support routine pertussis testing is limited, and molecular diagnostic tests such as PCR are not uniformly available (160). Third, in areas with few trained health professionals, inconsistent clinical identification of pertussis disease may hinder case reporting. In addition, the WHO has noted that the application of a standardized set of pertussis case definitions within an overall surveillance framework for vaccine-preventable diseases or communicable diseases has not been uniform (161, 162).

In 2014, the Strategic Advisory Group of Experts (SAGE) on immunizations charged a pertussis working group to review the current global landscape of pertussis (161). The SAGE review described the epidemiology of pertussis, the effectiveness and safety of various immunization strategies and schedules, and pertussis-related outcomes for 21 countries. For this review, data were collected using a standardized questionnaire consisting of several outcomes and data elements, including incidence of pertussis, clinical case definition, surveillance methods used, pertussis vaccine given, rates of vaccine coverage, and vaccination schedules. The working group found that the evaluation of pertussis incidence is a complex task at the global and country levels. Estimating the burden of pertussis has been a major challenge due to several factors, including changes in surveillance and diagnostic methods over time, changes in national vaccine schedules for and compositions of diphtheria toxoid–tetanus toxoid–whole-cell pertussis (DTP) or diphtheria toxoid-tetanus toxoid-acellular pertussis (DTaP) vaccines, and changes in vaccine manufacturers (161).

A key challenge in estimating the burden of pertussis relates to differences in information reported across different studies and surveillance systems. In some systems, clinically diagnosed pertussis cases (without laboratory confirmation) are reported, while other systems focus on laboratory-diagnosed pertussis. In systems that gather clinically diagnosed pertussis reports, there is potential for overestimating pertussis disease rates. In contrast, other systems that focus on laboratory-confirmed pertussis reports may underestimate true pertussis rates, because substantially less than 100% of clinically suspected pertussis may undergo laboratory testing (163). Underreporting of cases is more likely, and it has been suggested that the true incidence of pertussis is at least three times higher than the official reported rates (164–170). Underreporting is of particular significance with regard to older children and adults, for whom the cough pattern may be atypical. Clinical presentations with atypical cough may result in significant delays in seeking medical consultation (171–173).

For the past several decades, routine pertussis immunization has dramatically reduced disease incidence. In the past, pertussis was primarily a disease affecting children less than 6 years old. However, in the past 20 years there has been a change in the epidemiology of pertussis such that adolescent and adult pertussis continues to be a global concern, even in countries with relatively strong economies and high rates of childhood immunization, such as Australia, Belgium, Canada, Finland, France, Germany, Italy, Japan, The Netherlands, Spain, Switzerland, the United Kingdom, and the United States (174–187).

Burden of Pertussis in Infants and Toddlers

In the vaccine era (from the 1940s to the present), pertussis epidemics have occurred in 3- to 4-year cycles that may have resulted from the cycling of population immunity (188, 189). In the United States, pertussis has become endemic and is currently considered the most common vaccine-preventable disease (190–195). Recent nationwide incidences of pertussis for children less than 6 months, 6 through 11 months, 1 through 6 years, and 7 through 10 years were approximately 160, 40, 22, and 30 per 100,000 population, respectively (196). In 1994 to 1998, ∼13,800 children less than 2 years old were hospitalized as result of pertussis, whereas in 1999 to 2003, the number of hospitalizations was ∼17,000 for the same age group (197). In 2003, 19% of total reported pertussis cases (n = 11,647) occurred in infants aged less than 1 year (198). In 2010, a total of 25 deaths were reported among infants aged less than 6 months (199). In the United States, from 2012 to 2013, 12 pertussis-associated deaths were reported in infants under 3 months of age, and one child died among children aged 1 through 4 years old (200). From 2013 to 2014, seven deaths in infants under 3 months old and one fatality in children 1 through 4 years old were reported (196). Figure 1 shows the reported pertussis incidence by age group from 1990 to 2014.

Pertussis outbreaks have occurred in several states and in all regions of the United States (201–206). In Ohio, from 2009 through 2010, 2,958 cases were reported (205). Additionally, from May 2010 through May 2011, a mixed pertussis and pertussis-like illness outbreak produced 918 cases in Franklin County, Ohio (34). In 2012, Minnesota experienced a large pertussis epidemic in which 4,144 cases were reported (206). Nationwide, during 2012, the total number of reported pertussis cases in all age groups exceeded 48,000, including 20 pertussis-related deaths that occurred primarily in infants aged less than 3 months (207). From 2012 through 2014, 6,231 cases were reported from Washington State. In 2012 alone, a majority (31 of 39) of Washington State counties were affected. In the same year (2012), there were 4,918 total cases (including both confirmed and probable cases), with an overall incidence of 11/100,000 residents (203, 208). During this outbreak, 95 infants were diagnosed with pertussis (incidence, 107/100,000), including 35 children who required hospitalization (208). In 2013 and 2014, while transmission continued, the number of reported pertussis cases declined to 748 and 565 cases, respectively (202, 208). However, in 2015, the number of pertussis cases reported to the Washington State health department through week 48 exceeded 1,300, compared with 456 reported cases through week 48 in 2014 (202). In Michigan, the number of cases reported from 2010 through 2012 exceeded 3,000, with more than half (n = 1,564) of these cases reported in 2010 (204).

From 2010 through 2014, pertussis has been widespread throughout the state of California; 26,566 cases were reported, more than 1,700 of the patients were hospitalized, and there were 15 reported fatalities. In 2014, the number of cases reported (n = 10,831) was the highest of any single year (201). Among them, 376 people were hospitalized, and 85 (23%) of them required intensive care. Of the 376 hospitalized patients, 227 (60%) were infants less than 4 months of age, and four cases were fatal in infants less than 2 months of age. The cumulative pertussis disease burden in California from 2010 to 2014 underscores the ongoing impact of pertussis.

Recently, Canadian public health officials identified an outbreak of pertussis that began in the Mauricie-Central Quebec region during early October 2015 (209). This outbreak resulted in 151 pertussis cases identified from approximately 12 elementary schools, 2 high schools, and more than 10 day care centers. In 2015, other areas of Canada experienced pertussis outbreaks, including Manitoba, where 51 pertussis cases were reported and the vast majority of those cases were among infants, children, and adults who were unimmunized. In addition, New Brunswick, Canada, reported an outbreak of 56 confirmed pertussis cases. British Columbia, Canada, also reported high numbers of pertussis cases with twice as many cases reported in 2015 as in 2012.

Severe pertussis cases resulting in death have occurred in populations that suffer from health disparities. In 2003, Vitek and colleagues reported pertussis-associated mortality among infants in the United States (210). They found that pertussis-associated deaths were at least 2.6 times higher in Hispanic infants than in non-Hispanic infants during the 1990s. In another study, Murphy et al. investigated the impact of pertussis in American Indian and Alaska native infants from 1980 to 2004 (211). Murphy and colleagues found nearly 500 pertussis-associated hospitalizations among Native American and Alaskan infants, with an annual hospitalization rate of 133 per 100,000 infants. In 2002 to 2004, Murphy et al. estimated that hospitalizations among Native American and Alaskan infants far exceeded those found among the general U.S. infant population (101 per 100,000 versus 68 per 100,000). A number of important factors may explain the higher pertussis burden found in Native Americans, including lower immunization rates than in other populations, the absence of a medical home, and suboptimal living (e.g., household crowding) and socioeconomic conditions that favor pertussis transmission (212–214).

Burden of Pertussis in Adolescents and Adults

Pertussis among adolescents and adults has been reported with increasing frequency during the last 2 to 3 decades (188, 190, 215–233). Population-based studies between 1991 and 1999 estimated an incidence of pertussis in adults of 133 to 507 per 100,000 person-years (167, 171, 234–237), which equates to more than one million cases of pertussis among adults in North America annually (167). In 2013, the nationwide incidences of pertussis among persons 11 to 19 years old and 20 years or older were approximately 28 and 21 per 100,000, respectively (200). Although limited published data exist to describe vaccine uptake coverage stratified by age, city, or state, state-by-state variations in the distribution of pertussis among adolescents and adults have been observed. For example, for 10 years (1989 to 1998), there was an increase in the incidence of pertussis in Massachusetts, where by 1998, 92% of cases reported were among adolescents and adults. In comparison, nationwide, only 47% of cases reported were in this age group (238). In the 2014 pertussis outbreak in California, most reported cases were among adolescents aged 9 to 16 years, and whites were more affected than other racial/ethnic groups (201). The observed increase in reported cases among adolescents and adults has been attributed, in part, to waning immunity that occurs several years after primary childhood immunization (216, 239–246). Such waning immunity likely plays an important role in pertussis transmission among household contacts (218, 247–253).

Seasonality

Unlike the case for other respiratory pathogens, B. pertussis-associated outbreaks do not uniformly show a distinct seasonality. North American studies have shown a predominance of endemic cases during the autumn and winter. In a retrospective study examining pertussis incidence over a 13-year period with over 2,500 confirmed pertussis cases in Toronto, Canada (most [78.4%] were children under 15 years of age), investigators found an autumn and winter seasonal predominance (254). In British Columbia, Canada, Skowronski et al. demonstrated a peak of pertussis among adolescents during August and September 2000 in a population-based study (231). In a recent pertussis outbreak in rural Texas, 34 cases were reported (23 were confirmed and 11 were epidemiologically linked); the first case was reported in late October 2012 (194).

However, in other studies, seasonality of pertussis was not consistent in time or place (181, 255, 256). From 1996 to 2006 in The Netherlands, investigators reported an August peak incidence of pertussis among infants and young children and another peak in November among adolescents (256). Fine and Clarkson described the seasonal pattern of pertussis in England over several decades (255). From 1940 to 1957, peaks of pertussis epidemics were noted in the early or middle months of the year. Between 1958 and 1975, pertussis epidemic peaks were observed predominantly in October through December of each year. For the decade from 1976 through 1985, a bimodal pattern of seasonality (peaks in September and February) was observed. Although studies of pertussis seasonality to date have come largely from countries with temperate climates, limited data are available from tropical/subtropical areas (257). In Senegal, like The Netherlands and England, pertussis has demonstrated a bimodal peak of transmission in some years, with smaller peaks of disease in summer months followed by large epidemic seasons in winter months (258). In Kenya, epidemiological surveillance data from 1974 through 1981 showed a distinct winter seasonality with two pronounced epidemic years (259). In developed and developing countries, climatic factors such as temperature and humidity may play an important role in transmission. In addition, in more developed populations, other factors, such as day care attendance, may act as important drivers for pertussis transmission and seasonal patterns.

Transmission Dynamics of Pertussis

Pertussis is highly contagious and can spread rapidly from person-to-person through contact with airborne droplets. The human nasopharynx can be densely colonized with both commensal bacteria and pathogens, including B. pertussis. Infected individuals aerosolize pertussis-containing droplets by coughing or sneezing (260). Studies of infectious disease transmission estimated the basic reproductive number (R₀) for various infectious diseases, including pertussis. R₀ is defined as the expected number of secondary cases produced by a confirmed primary case in a completely susceptible population (261). Based on R₀ estimates, pertussis is considered far more contagious than polio, smallpox, rubella, mumps, and diphtheria (262, 263). Studies showed that one infected person can transmit B. pertussis to as many as 12 to 17 other susceptible individuals, while R₀ values for polio and smallpox (5 to 7), rubella (6 to 7), mumps (4 to 7), and diphtheria (6 to 7) are substantially lower (261–266). Kretzschmar et al. found that the R₀ for pertussis across five European countries (Finland, Germany, Italy, The Netherlands, and the United Kingdom) during the 1990s was approximately 5.5, which is lower than R₀ estimates in previous studies (267). Moreover, in a recent systematic review, it was estimated that the mean interval from symptom onset in a primary pertussis case to symptom onset in a secondary case is 22.8 days (268). Similarly, the secondary attack rate is estimated to be at least 80% (171, 269, 270).

As in many other countries, the United States had experienced a decline in reported pertussis since the introduction of pertussis vaccines. Nevertheless, a nationwide reemergence of pertussis occurred and continued. In 2011, Rohani and Drake analyzed pertussis notifications in the United States in the period from 1951 to 2010 (271). For this analysis, data were obtained from the National Notifiable Disease Surveillance System, and the goal of the study was to explore the timing, spatial pattern, and consistency of resurgence across the country. Their results showed that a pertussis resurgence occurred at different times in different states, spread out over a transition period of nearly 30 years. Despite this spatial variation, broad patterns in pertussis epidemiology can be summarized as two dominant phases: a period of decline ending in the mid-1970s, followed by nationwide resurgence. The causes of these fluctuations in the epidemiology of pertussis are still a topic of controversy, though the findings of Rohani and Drake (271) suggest that evolution of the B. pertussis bacterium, loss of immunity and persistent transmission among adults, availability of better diagnostics (PCR), and demographic drivers are more probable explanations than changes in reporting or the switch from whole-cell to acellular pertussis vaccines. Another key factor that may play a role in the observed resurgence is the rise of pockets of underimmunization, leading to a build-up of susceptibility from which outbreaks arise. In addition, variable immune responses among target groups for tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) immunization (i.e., pregnant women and adolescents) may translate into some individuals experiencing waning of protective levels of antibody over time.

Economic Impact of Pertussis

B. pertussis infection can lead to severe disease in adults, resulting in lost work time, clinic or emergency department visits, or hospitalization (226, 238, 272–275). Consequently, the direct and indirect pertussis-related costs are high. Lee et al. estimated total societal costs (medical and nonmedical costs) related to pertussis to be approximately $800 and $1,950 per case in adolescents and adults, respectively (275). In that study, the medical cost related to health service utilization (i.e., number of physician visits, antibiotic treatment, laboratory tests, chest radiograph, and hospitalization) was approximately $240 per case among adolescents and $330 among adults. These medical costs per case would double if postexposure prophylaxis (PEP) for close contacts had been included in the analysis. The average nonmedical cost per case (i.e., days missed from work for adult patients and parents of children, or from school, and other out-of-pocket costs such as those for transportation to doctor visits, for babysitting, and for over-the-counter medications) was estimated to be $155 for adolescents and $447 for adults. Unit costs for services were based on reimbursement rates from the Medicare Fee Schedule and the Physician Fee Schedule (275). In a family-based study, Lee and Pichichero estimated the costs of pertussis for 87 individuals in 69 households (276). They found that the average medical cost for an infant, child, adolescent, and adult was approximately $2800, $300, $250, and $180, respectively. Parents lost an average of six work days to care for an ill child; for these parents, costs associated with work loss averaged $767 per family. Even for parents who did attempt to work while a family member suffered from pertussis, nearly 60% reported decreased work productivity, ranging from 25% to 99%. In that study, work-related costs contributed more than 60% of the overall costs of pertussis (276).

Nonmacrolide Treatments

Trimethoprim-sulfamethoxazole (also known as co-trimoxazole) is used as an alternative to macrolides but should be used only in children older than 1 month and in adults when macrolides are not well tolerated (278). Because of the potential risk for kernicterus among infants, co-trimoxazole should not be administered to pregnant women, nursing mothers, or infants aged less than 2 months (278).

Ampicillin, cephalosporin, tetracycline, chloramphenicol, and fluoroquinolones have not demonstrated acceptable effectiveness in treating pertussis among infants, children, and adults. Furthermore, tetracyclines, chloramphenicol, and fluoroquinolones have potentially harmful side effects in children (350–352). Therefore, none of these antimicrobial agents is recommended for treatment or PEP of pertussis (278). Little is known about the effectiveness of antimicrobial therapy to treat B. parapertussis or B. holmesii, but some in vitro data suggest that macrolides would be effective (353).

Treatment of pertussis symptoms using corticosteroids (354–357), bronchodilators (355, 358–360), antitussives, antitoxin (pertussis immunoglobulin) (361, 362), or antihistamines (360, 363) has not been adequately evaluated. Thus, these therapeutics are not generally recommended.

Exchange transfusion for severe cases of pertussis, however, showed potential therapeutic benefit and promising results, particularly when applied early in the disease course. Infants with severe pertussis usually present with hyperleukocytosis and develop refractory hypoxemia and pulmonary hypertension that is unresponsive to maximal intensive care (364). This may reflect a hyperviscosity syndrome from the elevated WBC count. Several case reports suggested improved outcomes using exchange transfusion to reduce the WBC count (151, 306, 364–370).

Antimicrobial Resistance

Antimicrobial resistance to B. pertussis has been reported sporadically over 2 decades (351). It has been estimated that the occurrence of B. pertussis resistance to macrolides is less than one percent (371). Fry et al. proposed that the mechanism of resistance is due to a mutation of the erythromycin binding site in 23S rRNA (372).

In May 1994 in Yuma County, Arizona, susceptibility testing for Bordetella species was introduced (373). Among 70 pertussis cases reported to the U.S. CDC from Arizona, a highly erythromycin-resistant B. pertussis strain was recovered from a 2-month-old infant (374). The MIC for this drug-resistant isolate was >64 μg/ml; the normal range of MIC for erythromycin against B. pertussis is 0.02 to 0.1 μg/ml (351, 374). In a study of 47 B. pertussis strains isolated at the Primary Children's Medical Center in Salt Lake City, UT (1985 to 1997), one erythromycin-resistant isolate had an MIC of 32 μg/ml (375).

In Australia between 1971 and 2006, 99 isolates of B. pertussis and five isolates of B. parapertussis were collected. None of the B. pertussis isolates was erythromycin resistant, but all five isolates of B. parapertussis were found to have significantly reduced susceptibility to erythromycin and azithromycin (376). In the United Kingdom between 2001 and 2009, no B. pertussis resistance to erythromycin, clarithromycin, or azithromycin was found among 583 isolates tested (372). In 2012, Minnesota experienced the largest pertussis outbreak since 1940 (206). In that epidemic, 265 isolates were collected, and none of the isolates was macrolide resistant (377).

Since the introduction of macrolides as the first line of treatment for pertussis through 2012, only seven erythromycin-resistant isolates have been reported worldwide (373, 375, 378–381). Five of those resistant isolates were identified in the Unites States, with one each from Arizona, California, Georgia, Minnesota, and Utah. One case of erythromycin resistance was reported from Taiwan and one from France. Despite the infrequency of drug-resistant pertussis strains identified to date, continued surveillance of pertussis remains a high priority, in part to maintain vigilance for the emergence of drug resistance in B. pertussis (375, 378). Unfortunately, widespread use of PCR for pertussis diagnosis has led to markedly fewer cultures being obtained for pertussis diagnosis, which has resulted in a lack of data on antimicrobial susceptibility of B. pertussis (376).

Other Bordetella species, such as B. parapertussis, B. holmesii, and B. bronchiseptica, can be treated with macrolides, but resistant strains of B. parapertussis and B. bronchiseptica have been reported (145, 382). Although macrolide-resistant strains are uncommon in many countries and the current therapeutic guidelines are appropriate, screening for antimicrobial resistance is still needed for surveillance and in settings where there is evidence of macrolide failure (372, 376).

Vaccine-Induced Immunity

IgG or IgA enzyme-linked immunosorbent assays (ELISAs) were used to measure antibody to PT, FHA, PRN, or FIM in acellular pertussis vaccine trials involving adolescents and adults (236, 403–405). In 2000, Van der Wielen et al. tested the immunogenicity and safety of acellular pertussis vaccines in 299 adults (403). Prior to vaccination, baseline IgG antibody titers to PT, FHA, and PRN were 73.1%, 98.2%, and 74.5%, respectively. One month after vaccine administration, the IgG titers to PT, FHA, and PRN were 96.8%, 100%, and 98.9%, respectively. In 2007, Guiso et al. conducted a serological follow-up study to assess humoral and cell-mediated immunity in children who had received primary and booster vaccination with either the whole-cell pertussis vaccine or the three-component acellular pertussis vaccine (PT, FHA, and PRN) (406). In this study, for both groups, 3- and 6-year serological and cell-mediated immunity follow-up was performed after a booster dose of either vaccine in the second year of life. At 6 years of follow-up, there was a significant difference in seropositivity between the two groups, in which the anti-PRN IgG level was higher in the acellular vaccine group (95.1%) than in the whole-cell vaccine group (66.7%). The stimulation index (SI) range was also compared: at 3 years of follow-up, the percentage of children with positive cell-mediated immunity (SI ≥ 3) was higher for all three antigens in the acellular pertussis vaccine group. At 6 years of follow-up, the SI was still higher for two antigens (FHA and PT) in the acellular pertussis vaccine group. No difference between groups was detected for PRN. The investigators concluded that the protection provided by three-component acellular pertussis vaccines was as good as that provided by efficacious whole-cell pertussis vaccines.

Immunological studies from the past 15 to 20 years suggest that cellular immunity has a fundamental role to play in the immune response for all pertussis-containing vaccines (whole-cell and acellular vaccines) (407–410). In particular, Toll-like receptor 4 (TLR4) in concert with CD4-positive type 1 T-helper cells (Th-1) and interleukin-17 (IL-17)-producing T-helper cells (Th-17) appear to play a central role in mediating protective immunity after whole-cell pertussis vaccination (408, 411), whereas Th-1 cells alone mediate the protective immune response after recovery from B. pertussis infection (409, 411). In infants, conventional whole-cell pertussis vaccines elicited a higher level of CD3 T-lymphocyte proliferation than did the low-lipopolysaccharide-content whole-cell vaccine (412). Other molecules playing a role in protection against pertussis include interferon gamma, which appears to protect against systemic dissemination (413), IL-12, which induces Th-1 cells (414), and tumor necrosis factor alpha (TNF-α), which enhances macrophage phagocytosis of B. pertussis (415).

In contrast, acellular pertussis vaccines appear to induce a predominantly Th-2 CD4-positive cellular immune response (408, 411, 416–418). However, in other studies, a Th-1 or a mixed Th-1/Th-2 response was also observed after three-component acellular pertussis vaccination (406, 411, 419–424). It has been demonstrated that the Th-2 immune response is not as effective as the Th-1/Th-17 response (425). Thus, the absence of a Th-1/Th-17 cellular immune response after immunization with acellular pertussis vaccines might explain the lower long-term protection of acellular vaccines (426). Other factors, noted in the foregoing section addressing changes in transmission dynamics for pertussis, may also play a role in lower long-term acellular vaccine protection, including the buildup of susceptible individuals in pockets of underimmunization and variable immune responses in select groups such as pregnant women or adolescents. For this reason, the addition of a TLR4 ligand as an adjuvant has been suggested as a strategy to improve Th-1 and Th-17 responsiveness to acellular pertussis vaccination (193, 425, 426). Development of new acellular pertussis vaccines with multiple components or whole-cell pertussis vaccines with detoxified LPS has been suggested as options to enhance immunogenicity and safety (45).

In recent years, there has been an emerging controversy regarding the existence of herd immunity (herd protection) induced by acellular pertussis vaccines. Warfel et al. (427–429) argue that current acellular pertussis vaccines fail to prevent nasopharyngeal colonization and transmission of B. pertussis. To test this hypothesis, they vaccinated nonhuman primates (infant baboons) at 2, 4, and 6 months of age with acellular pertussis or whole-cell pertussis vaccine and challenged them with B. pertussis at 7 months of age. After infection, they quantified B. pertussis colonization in nasopharyngeal washes and monitored leukocytosis and pertussis symptoms. The investigators concluded that acellular pertussis vaccines protected against the development of clinical pertussis but did not protect against colonization and transmission of B. pertussis infection, indicating that herd immunity from acellular pertussis vaccines is doubtful.

Although the existence of herd protection induced by acellular pertussis vaccines has been challenged, population-based epidemiological surveillance for pertussis in Sweden following introduction of the acellular vaccine demonstrated herd protection among infants too young to receive a vaccine and older infants unvaccinated against pertussis (430). In addition, epidemiological modeling based on a model originally conceived by Rohani et al. suggests that achieving the observed reductions in pertussis would be impossible in the absence of herd protection (431, 432). For DTP vaccines, Jackson and Rohani demonstrated that herd protection can be achieved from DTP vaccines (433). They showed that the nationwide use of DTP vaccine in the routine immunization schedule over several decades had reduced the number of pertussis outbreaks in the United Kingdom. Moreover, the interval between pertussis outbreaks was prolonged, indicating that DTP vaccines prevented disease and reduced B. pertussis transmission. Although limited animal model data suggest that acellular vaccines do not produce herd protection, real-world epidemiological data in a large population as well as additional modeling data provide compelling evidence for herd protection. Additional studies to document herd protection in other infant and childhood immunization programs will be valuable to further quantify the extent of herd protection induced by acellular pertussis vaccines.

Vaccination and Prophylaxis for Outbreak Control

Current guidelines for DTaP immunization of infants and children as well as guidelines for the use of Tdap for older children, pregnant women, and adults provide important information on the use of pertussis-containing vaccines in populations affected by an outbreak (195, 333). Whenever possible, individual immunization histories should be reviewed to identify children who may need additional vaccines and adolescents or adults who may need their first or repeat doses of Tdap (468, 469). Recent guidelines for the use of Tdap in pregnant women suggest that all pregnant women should have immunization histories reviewed and vaccine offered to protect the mother at the time of delivery and to protect their babies after delivery (195, 242, 469, 470). In addition to providing pertussis vaccines to eligible individuals, PEP can be used to protect close contacts of confirmed or suspected pertussis cases. If possible, all household contacts of a pertussis case should receive PEP (278). The U.S. CDC recommends administration of PEP to asymptomatic household contacts within 21 days of onset of cough in the index patient (459). In determining the need for PEP, attention to persons with high-risk conditions (e.g., young infants, women in their third trimester of pregnancy, and those with preexisting health conditions) should lead to prompt evaluation by health professionals (459).

In health care institutions, reducing the potential for pertussis transmission can be achieved by reducing exposure to respiratory droplets from coughing or sneezing. For this reason, placement of patients with pertussis in a private room is advised. If no private rooms are available or if several patients have pertussis, then cohorting of pertussis patients is an option. Administration of postexposure chemoprophylaxis to household contacts and HCWs who have had prolonged exposure to respiratory secretions is also recommended (471, 472).

DTP and DTaP Vaccines for Infants and Young Children

Prior to the 1940s, in excess of 200,000 pertussis cases were reported in the United States annually. In 1934, the greatest number (n = 260,000) of annual cases was reported (473). In the United States, DTP vaccines were first licensed in 1914 and became available for routine infant immunization in 1948 (473). In 1976, the number of pertussis cases reported to the U.S. CDC reached its nadir at approximately 1,000 (144, 271, 474–476). In the United States, the whole-cell pertussis vaccine has been administered to children in combination with diphtheria and tetanus toxoids. Whole-cell pertussis vaccines, consisting of suspensions of inactivated B. pertussis, elicit humoral immunity to pertussis following intramuscular injection (477). Based on that concept, the first evidence of DTP vaccine efficacy was obtained from a clinical trial conducted during the 1929 pertussis outbreak in the Faroe Islands of Denmark (478, 479). In the 1930s, many steps were taken to improve DTP vaccines, including increasing the number of inactivated B. pertussis bacteria in the vaccine, standardizing the methods used to grow and kill the bacteria, and using fresh, rapidly growing phase one bacteria as the inoculum (62, 480). As a result, a variety of DTP vaccines were produced in the United States, which varied in their methods of production and generated different levels of antibody response (480, 481). Previous observational studies and clinical trials showed 70% to 90% efficacy of DTP vaccines to prevent serious pertussis disease (158, 482–484). To enhance the immunogenicity of the vaccine and reduce its adverse effects, vaccine was adsorbed onto an aluminum salt (284).

In 1970s, confidence in DTP vaccines began to decline in several countries after reports of local and systemic reactions surfaced in several locations (Table 6). In addition to reports of local skin reactions at the injection site, other less common but more serious systemic adverse events were linked to DTP, including neurological diseases such as encephalopathy, infantile spasms, and sudden infant death syndrome (485–487). Moreover, growing medical and public anxiety coupled with a heightened molecular structural knowledge of B. pertussis led to production of less reactogenic acellular pertussis vaccines (284). In Japan, Sato et al. designed the first purified-component DTaP vaccine (488). The initial acellular vaccines (Takeda-type vaccines) consisted predominantly of FHA, small amounts of inactivated PT, and, in some cases, fimbrial proteins and PRN. These constructs were followed by development of other acellular (Biken-type) vaccines containing equal amounts of PT and FHA. Newer DTaP vaccines contained purified immunogenic antigens and excluded LPS, which was present in the DTP vaccines (473, 489–493). In addition, the new-generation DTaP vaccines underwent rigorous testing for potential toxicity and potency in mice, while testing for potential adverse events and antibody response was done in children. The results of safety testing were reassuring and revealed that the efficacy of DTaP vaccines exceeded that of whole-cell DTP vaccines. Larger effectiveness trials and pertussis surveillance studies followed and proved that DTaP vaccines were effective and safe (284).

In 1981, Japan introduced DTaP vaccines exclusively into the national immunization schedule. Since then, the reported number of pertussis cases in Japan has been low (494–496). These results from Japan encouraged other developed countries to evaluate Japanese DTaP vaccines and to develop DTaP vaccines with additional antigens. Approximately 24 acellular pertussis vaccines have been designed, many of which were evaluated in large clinical trials (Fig. 2; see Table S1 in the supplemental material). Although acellular pertussis vaccines are now used routinely in the immunization programs of many countries, optimizing the formulation of acellular vaccines has proven to be challenging, in part because no simple method (e.g., use of a correlate of protection) exists to evaluate the protective efficacy of newer pertussis vaccines (188). Therefore, acellular pertussis vaccines vary with respect to manufacturer, number of components, quantity of each component, and methods of purification and toxin inactivation as well as incorporation adjuvants and excipients (492).

Acellular pertussis vaccines have been studied extensively. In 1995, Edwards et al. conducted a large clinical trial to compare the safety and immunogenicity of 13 DTaP vaccines and two DTP vaccines (see Table S1 in the supplemental material) (492, 493). The results of this study showed that all 13 DTaP vaccines were as immunogenic as or more immunogenic than DTP vaccines and were associated with substantially fewer and less-severe adverse reactions than standard commercial DTP vaccines. Another clinical trial was conducted in 1996 by Gustafsson et al. to determine the efficacy and safety of two-component DTaP, five-component DTaP, and DTP vaccines among approximately 10,000 Swedish infants (404). The efficacy of the vaccines was determined to be approximately 60% for the two-component vaccine, 85% for the five-component vaccine, and 48% for the DTP vaccine. Rates of local skin reactions (redness of ≥2 cm, tenderness, and nodule of ≥2 cm) and systemic adverse events (fever of ≥38°C, crying longer than 1 h, weakness, cyanosis, and pallor) were significantly higher after any dose of DTP vaccine than after the three DTaP vaccines.

More recently, in 2012, Zhang et al. conducted a Cochrane review of several clinical trials that evaluated the safety and efficacy of one-, two-, and multicomponent DTaP vaccines in children (489). In this review, the efficacies of multicomponent DTaP vaccines in preventing severe (∼85%) and mild (71% to 78%) pertussis were similar. The estimated efficacies of one- and two-component DTaP vaccines were 59% to 75% to protect against severe pertussis but only 13% to 54% to protect against mild pertussis. In addition, the efficacies of DTP and DTaP have been shown to decrease over time after receipt of the fifth dose of either vaccine. In one study, the efficacy of DTaP vaccine declined from 98% to 71% (one year versus 6 years from fifth-dose completion) (497). In a large population-based study involved 15,286 participants, DTP vaccines yielded protection for 5 to 14 years (393). Although the efficacy of acellular pertussis vaccines in published studies varies by the number of B. pertussis antigens and manufacturer, a meta-analysis of several large pertussis vaccine trials showed no significant differences between DTaP and DTP vaccine efficacy against laboratory-confirmed pertussis (Fig. 2).

In the past 30 years, there has been a substantial increase in disease rates, and several pertussis outbreaks have occurred across the United States despite continued high DTaP vaccination uptake estimates among infants (174, 194, 201, 203–206, 271, 377, 476, 498). In addition, the epidemiology of pertussis has evolved such that pertussis in adolescents and adults continues to be a global concern even in countries with strong economies and high rates of childhood immunization, such as Australia, Belgium, Canada, Finland, France, Germany, Italy, The Netherlands, Spain, Switzerland, the United Kingdom, and the United States (174–187, 302, 499). This change in the epidemiology of pertussis has been reflected in the cases reported to the U.S. CDC and the European Center for Disease Prevention and Control (EUVAC). According to the U.S. CDC 2014 Provisional Pertussis Surveillance Report, the incidence rates of pertussis for the years 2013 and 2014 were approximately 151, 40, 22, 30, 25, and 2 per 100,000 persons for the age groups less than 6 months, 6 to 11 months, 1 to 6 years, 7 to 10 years, 11 to 19 years, and ≥20 years, respectively (500). In the 2010 EUVAC pertussis surveillance report, the incidence rates of pertussis across Europe were 15, 4, 5, 13, 10, and 2 cases per 100,000 persons for the age groups less than 1 year, 1 to 4 years, 5 to 9 years, 10 to 14 years, 15 to 19 years, and ≥20 years of age, respectively (501).

Several factors have been attributed to the increase in incidence rates and the shift in the epidemiology of pertussis, including lower immunization rates among adolescents and adults, waning immunity after receipt of acellular pertussis vaccines, an increase in the awareness of pertussis by health care providers caring for adolescents and adults, improvements in diagnostics and surveillance methods, evolution of B. pertussis, and the spread of other Bordetella species (239–241, 246, 499, 502–513).

Some vaccine experts believe that the relatively short duration of immunity offered by acellular pertussis vaccines is the most important factor that explains the trends of outbreaks, particularly among children 7 to 10 years old (193, 496). For example, during the California outbreak, children primed with DTP vaccines had longer-lasting immunity than those primed with DTaP (502). In Australia, a sustained pertussis epidemic occurred in the past several years, which is thought to be a result of the switch from DTP to DTaP vaccines (514). Other vaccine-preventable disease scientists do not believe that the change in the underlying B. pertussis epidemiology is sufficient to explain the pertussis upsurge in adults but instead believe that increased public awareness and the addition of PCR and single-point serological diagnosis are the major factors for the high rates of cohort cases reported (163, 193, 287). In addition, B. parapertussis is often underdiagnosed and cannot be ignored as a potential cause for pertussis outbreaks, because no vaccine is currently available to protect humans from this species (27).

The prevention of pertussis centers on the provision of pertussis vaccines in routine childhood immunization programs. These programs vary across countries where licensed pertussis vaccines have been administered to infants, children, and adults. In the United States, and based on the guidelines of the Advisory Committee on Immunization Practices (ACIP), the childhood immunization schedule for DTaP vaccine consists of five doses for children less than 7 years of age. These five doses are given at 2, 4, 6, and 15 to 18 months of age, and one booster dose is given at 4 to 6 years of age (515, 516). Although DTaP vaccines became widely used in many countries, including the United States, Canada, and Australia, in some Asian and many European countries, DTP vaccines are still the mainstay of pertussis prevention (182, 432, 517–519).

In the United States, despite great success of public health programs and availability of vaccines for disadvantaged children through the federally funded Vaccines for Children Program, many children in medically underserved areas as well as in minority groups remain partially immunized or nonimmunized (520). Recent (2015) data from Detroit, MI, show that only 40% of children have completed the primary vaccination series and suggest that rates of underimmunization may exceed 50% in some populations (Michigan Care Improvement Registry, unpublished data). Such underimmunization suggests the need for improved local-, state-, and national-level immunization strategies to reach the Healthy People 2020 goals of 95% vaccine coverage for several pediatric vaccines (521).

Tdap Immunization for Adolescents and Adults

Even in countries with substantial childhood vaccination coverage (sometimes defined as ≥70%), the protection provided by vaccination tends to decrease over time due to waning immunity (155, 384). In 2003, Crowcroft et al. estimated that the proportion of susceptible children who became infected with B. pertussis was ∼10 percent at 1 year after complete vaccination, 60% by 5 years, and 100% by 15 years (155). It has also been estimated that 80% of the current cases of pertussis occur because of waning immunity in household members who had been immunized against pertussis (522). Such data underscore the importance of booster vaccination among older children, adolescents, and adults. Recent immunization efforts have focused on adults, because the disease in this age group is often overlooked and unrecognized (225, 251, 282, 523). Moreover, adolescents and adults are usually the primary source of B. pertussis transmission to neonates and infants, who are at risk of infection themselves (476, 498, 524–527). As a result, another acellular pertussis vaccine (Tdap) was developed for adolescent and adult use.

Similar to DTaP vaccines, Tdap vaccines have demonstrated high levels of safety and immunogenicity. In a small group of adolescents (n = 123) aged 11 to 18 years who had never received B. pertussis antigen-containing vaccines and had no history of B. pertussis infection, 89% of participants mounted anti-PT antibodies, and all participants had an immune response to at least one B. pertussis antigens (FHA or pertactin) 29 to 49 days after vaccination (528). In 2007, Wei et al. investigated a pertussis outbreak at a private school on the island of St. Croix, U.S. Virgin Islands (n = 499 students, nursery school through twelfth grade) to determine Tdap vaccine effectiveness (529). They determined that the estimated Tdap vaccine effectiveness was approximately 66%. In a large randomized clinical trial involving 802 participants aged 18 to 55 years who had completed childhood vaccination with DTP and were given monocomponent Tdap in that study, the antibodies to PT were mounted in 92% at 1 month after vaccine administration (530). In 2004, Purdy et al. conducted a cost-benefit analysis to determine whether Tdap administration in adolescents and adults would be a good strategy (531). They found that vaccination is most cost-effective among adolescents because they have the highest incidence of pertussis and pertussis-related complications in which disease-related costs were indirect (i.e., lost productivity at work and disrupted social activities). The results of that study revealed that booster immunization for adolescents 10 to 19 years of age would prevent 0.7 to 1.8 million pertussis cases and save 0.6 to 1.6 billion dollars over 10 years. After an extensive review of its cost-effectiveness, Tdap is now recommended by the ACIP for a wide range of the general population. Table 7 presents the ACIP recommendations for the Tdap vaccine.

A few years following release of the ACIP recommendations for Tdap vaccine, Koepke et al. conducted a population-based study to evaluate the effectiveness of Tdap vaccines in adolescents (532). Koepke and colleagues used the Wisconsin Immunization Registry to collect Tdap vaccination histories and reports of laboratory-confirmed pertussis among adolescents during the Wisconsin pertussis outbreak of 2012. The results of their study showed that the effectiveness of Tdap vaccines decreased over a short time regardless of vaccine manufacturer. The estimated effectiveness was ∼75%, 68%, and 35%, and 12% for adolescents who received vaccines during 2012, 2011, 2010, and 2008/2009, respectively, with point estimates differing between the two Tdap vaccine brands. However, in 2015, Decker et al. critiqued the study conducted by Koepke et al., claiming that it was neither randomized nor conducted prospectively (533). In addition, Decker et al. claimed that the authors of that study were unable to control for brand-specific vaccine analyses, which could have been a potent confounding factor (533). While future studies are needed to evaluate the long-term effectiveness of available Tdap vaccines and until a more durable vaccine is produced, clinician scientists have recently suggested that Tdap vaccination should be started at the age of 9 years instead of that currently recommended (11 years of age) (534). They also suggested that a booster of Tdap vaccine should be administered every 5 to 10 years to every person. In addition, a booster of Tdap vaccine every 2 to 3 years during local pertussis epidemics may also be considered. Other experts urge the production of a single-component monovalent acellular pertussis vaccine (i.e., free of diphtheria and tetanus toxoids), which could allow more frequent boosters in adults (535).

In the United States, most Tdap vaccines are administered in outpatient (ambulatory) clinic settings, community pharmacies, or public health departments (536, 537). Although Tdap vaccines are widely available in those settings, overall rates of Tdap immunization are still relatively low, particularly among adults (508). The U.S. CDC showed that the uptake of Tdap vaccine among adults was ∼14% in 2014, while much higher vaccine uptake was reported among adolescents (i.e., ∼80% in 2012), likely because it is required for school enrollment in many states (507, 508).

Tdap Immunization for Pregnant Women

During the last decade, 83% of whooping cough deaths occurred in infants under 3 months of age (538). Experts now recognize that household members were the primary source of pertussis infection for children (247, 249, 251, 524, 539–541). Although the source of infection (SOI) has not been identified in more than 50% of infant cases, mothers were recognized as the main SOI for an estimated 35% of infections in the United States (247, 250, 540). Additional information has emerged in a number of reports from Australia and The Netherlands indicating that older children have become the most common SOI to their infant brothers and sisters (253, 524, 542). In September 2015, Skoff and colleagues used enhanced pertussis surveillance data collected over an 8-year period (2006 to 2013) from seven states (Colorado, Connecticut, Massachusetts, Minnesota, Mexico, New York, and Oregon) to identify the most common source of pertussis infection in the United States (543). The results of this study showed that siblings (mean age, ∼8 years) are the main SOI (35.5%), followed by mothers (20.6%), and fathers (10%).

As a result of ongoing community pertussis transmission to babies who are too young for pertussis vaccination, the ACIP released an updated set of recommendations to protect babies from pertussis. The ACIP concluded that administration of Tdap vaccine during pregnancy is safe and immunogenic (544–547). The ACIP recommended that pregnant women, preferably in the third or late second trimester, and all individuals who come into close contact with babies should receive one dose of Tdap vaccine (544). Nevertheless, as antibody titers decay after 1 year post-Tdap vaccination in healthy adults, maternal antipertussis antibodies also wane rapidly so that there is little persistent antibody in the mother at the time of the next baby, even if the mother is immunized during a prior pregnancy (548–551). Therefore, in 2012, the ACIP revised the recommendations and advised Tdap vaccine for all pregnant women and for each pregnancy irrespective of the interval between pregnancies (545). Studies have shown that efficient antibody transfer occurred from vaccinated mothers to babies via the placenta, although antibody levels are neither optimum nor long-lasting (545, 552, 553).

In October 2012, the United Kingdom introduced Tdap immunization for pregnant women. Since then, several studies have been conducted to evaluate vaccine safety and effectiveness. Based on preliminary data from the United Kingdom and Australia, babies born to vaccinated mothers are at lower risk of acquiring pertussis infection early in their lives than their unvaccinated counterparts (554). In 2014, Donegan et al. used the United Kingdom Clinical Practice Research Datalink to conduct a cohort study to examine the safety of pertussis vaccine in pregnancy (555). More than 20,000 pregnant women who received the pertussis vaccine and a matched unvaccinated control group were observed for development of vaccine-related adverse events. The results of this study showed no evidence of a higher risk of stillbirth in the 2 weeks after vaccination or later in pregnancy. In addition, compared with the cohort of unvaccinated women, there was no evidence of a higher risk of premature delivery, stillbirth, maternal or neonatal death, pre-eclampsia, eclampsia, hemorrhage, fetal distress, low birth weight, or any other serious pregnancy- or delivery-related complications. Another study by Amirthalingam et al. analyzed 82 lab-confirmed infant pertussis cases identified from 2008 to 2013 in the United Kingdom Clinical Practice Research Datalink to assess maternal Tdap vaccine effectiveness (556). Vaccine effectiveness in infants born after 1 October 2012 and younger than 3 months at onset was 91% (95% confidence interval [CI], 84% to 95%). In 2015, Dabrera et al. conducted a case-control study in England and Wales for the period from October 2012 through July 2013 to determine the effectiveness of maternal Tdap vaccine in protecting infants from pertussis (557). PCR or culture was used to confirm pertussis in clinically suspected disease in infants aged less than 8 weeks. Mothers of 10 cases and 29 controls received Tdap in pregnancy. The results in this study showed an adjusted Tdap vaccine effectiveness of 93% (95% CI, 81% to 97%).

Since the ACIP recommendations for pregnant women were issued, several concerns have been raised. In 2014, Jiménez-Truquehas and Edwards (558) summarized those concerns as follows: (i) the safety profile of Tdap vaccine for both mothers and babies has not been extensively evaluated, (ii) the high concentration of antibodies transmitted transplacentally could minimize an infant's immune response to pertussis-containing vaccine (559), and (iii) serological interference between maternal antibodies and infant antibodies after pertussis-containing vaccine can occur (553). More recent comments about the ACIP recommendations were provided by Boyce and Virk (534), who expressed concern that passive antipertussis immunity will not allow for sufficient herd immunity to protect infants from community exposures. Moreover, they asserted that the duration of protection yielded by maternal antibodies transfer is relatively short-lasting and will not impact the substantial morbidity that pertussis causes outside the period of infancy.

To address some of these concerns, Hardy-Fairbanks et al. conducted a cohort study in which 70 pregnant women were enrolled to evaluate the effect of maternal Tdap vaccination on infant immunological responses to routine pediatric vaccines (553). At delivery, pertussis antibody titers among women receiving Tdap vaccine during pregnancy (n = 16) were approximately 2- to 20-fold higher than those in the control group (unvaccinated women, n = 54). Umbilical cord antibody titers were approximately 3- to 36-fold higher in vaccinated women than in unvaccinated women. They also found that infants whose mothers were vaccinated with Tdap during pregnancy maintained adequate antibody concentrations even after the first dose of DTaP vaccine was administered. However, slight declines in the immune response following the primary series of DTaP vaccine were observed in the Tdap group compared with controls, but no differences in immune response remained following the booster dose.

Additional studies suggest that there is no evidence of the interference between Tdap vaccine-induced maternal antibody and DTaP immunization among infants reported in previous studies of acellular pertussis vaccines (560, 561). In 2014, Munoz et al. conducted a double-blind randomized controlled trial to evaluate the safety and immunogenicity of Tdap vaccine (n = 33) or placebo (n = 15) given during the third trimester of pregnancy, with crossover vaccination postpartum (561). At delivery, antibody titers in women who received Tdap vaccine during pregnancy were higher than those in women who received vaccine after delivery (P < 0.001). Also, infants of mothers vaccinated with Tdap vaccine during pregnancy had higher immune responses at birth (P < 0.001) and at age 2 months (P < 0.001) than those of women who received a placebo in the third trimester. Antibody responses in infants born to mothers vaccinated with Tdap in pregnancy were not different following the fourth dose of DTaP vaccine from those in infants whose mothers were not vaccinated during pregnancy. This trial found no Tdap-associated serious reactions among infants or mothers. Developmental milestones and growth were similar in both infant groups.

In contrast, in 2014, Kharbanda et al. (562, 563) conducted a retrospective cohort study to determine the risk of chorioamnionitis, preterm birth, pregnancy-induced hypertension, and small size for gestational age in 220 women with singleton pregnancies who received Tdap vaccine during the index pregnancy. They found that 6.1% of women exposed to the Tdap vaccine were diagnosed with chorioamnionitis, compared with 5.5% of those who did not receive the vaccine (adjusted relative risk [RR] = 1.19; 95% CI, 1.13 to 1.26). No other statistically significant results were noted. Pertussis experts have encouraged more epidemiological studies and clinical trials to assess the duration of protection that antepartum immunization would offer to infants in order to better understand the immune response to pertussis vaccines and to implement more efficient strategies that would overcome existing barriers to vaccinating pregnant women (410, 564–566). In the efforts to interrupt the circulation of B. pertussis, several options have been suggested, including vaccination of all pregnant women, vaccination of all of an infant's close contacts, lowering the start date of infant immunization, reinstituting use of DTP vaccines, and adding another B. pertussis antigen (e.g., AC or BrKA antigen) to existing DTaP vaccines (193, 287). In 2008, Halasa et al. conducted a randomized controlled trial among 50 neonates aged 2 to 14 days (567). Two subgroups of these neonates received DTaP vaccine either alone or in combination with hepatitis B vaccine. They found that the additional dose of DTaP at birth was safe but was significantly associated with lower responses to several pertussis antigens than in controls.

Despite national recommendations for maternal Tdap vaccination, the Tdap vaccine has been provided to only a fraction of eligible women in the United States. In 2013, data from California Department of Public Health indicated that only 25% of hospital-delivering women received Tdap vaccine during pregnancy (554). Another national report found that fewer than three percent of pregnant women received maternal Tdap vaccination (568). In Michigan, the average uptake of Tdap vaccine among pregnant women who are enrolled in the Medicaid health insurance plan was approximately 14% (569). In a recent commentary, pediatric specialists at the University of California Los Angeles Medical Center (UCLA) observed that most mothers were not vaccinated with Tdap during pregnancy (566). Since that report, the UCLA health system has mandated that obstetrics and gynecology clinics maintain a stock of Tdap vaccine for perinatal vaccination of expectant and new mothers.

Types of Vaccines

Currently, both whole-cell and acellular pertussis vaccines are distributed by manufacturers in Belgium, Bulgaria, France, India, Indonesia, Italy, and South Korea. Whole-cell vaccines are available in combination with conjugate Haemophilus influenzae type b vaccine, enhanced inactivated poliovirus vaccine, or hepatitis B virus vaccine (284). Since 1996, in the United States, only acellular pertussis-containing vaccines are shown in the recommended immunization schedule. There are five U.S. Food and Drug Administration-licensed DTaP vaccines for infants and young children, and they vary in the amount and number of antigens in the vaccine. In addition to diphtheria and tetanus toxoids, the vaccines also contain other pertussis components as follows. Certiva (Baxter Laboratories) is a monocomponent vaccine that contains only PT antigen. Tripedia (Sanofi Pasteur) is a dual-component vaccine containing PT and FHA, while Infanrix (GlaxoSmithKline) is a triple-component vaccine containing PT, FHA, and PRN. In the United States, the combination of Infanrix, hepatitis B vaccine, and inactivated poliovirus vaccine is marketed as Pediarix (GlaxoSmithKline). Pediarix is supplied in single-dose, thimerosal-free vials or prefilled syringes and is licensed for a three-dose primary series in infants born to mothers without hepatitis B surface antigen. Acel-Immune (no longer manufactured) and Daptacel (Sanofi Pasteur) are four-component vaccines that contain PT, FHA, PRN, and FIM2 (Acel-Immune) or PT, FHA, PRN, and FIM2,3 (Daptacel) (163, 284).

Tdap vaccines (under the brand names Adacel and Boostrix) are licensed in the United States for immunization of adolescents and adults. Adacel (Sanofi Pasteur) is a five-component acellular pertussis vaccine. Adacel is licensed for use in the United States in persons 11 to 64 years old and is supplied in thimerosal-free, single-dose vials. Boostrix (GlaxoSmithKline) is a three-component acellular pertussis vaccine. In the United States, Boostrix is licensed for use in persons 10 years of age and older (284).