Bordetella pertussis is a Gram-negative, cocobacillus-shaped bacterium and the primary causative agent of pertussis, also known as whooping cough, a highly contagious respiratory disease affecting humans exclusively [1]. The bacterium colonizes the ciliated epithelium of the respiratory tract, where it produces key virulence factors such as pertussis toxin, which disrupts immune signaling and leads to the characteristic paroxysmal coughing fits followed by an inspiratory "whoop" [2]. Transmission occurs via respiratory droplets from infected individuals, particularly during the early catarrhal stage, making it highly infectious, especially in close-contact settings like households and schools [3]. While the disease can affect all age groups, it poses the greatest risk to infants under one year old, who face high rates of complications such as apnea, pneumonia, seizures, and death [4]. Diagnosis is achieved through a combination of clinical evaluation and laboratory methods including polymerase chain reaction (PCR), bacterial culture, and serology, with PCR being the most sensitive in early stages [5]. Treatment primarily involves macrolide antibiotics like azithromycin to reduce transmission and severity, although efficacy diminishes in later stages [6]. Prevention is largely dependent on vaccination, with DTP vaccine and Tdap vaccine regimens significantly reducing disease incidence since their introduction in the 1940s [7]. Despite high vaccine coverage, pertussis has re-emerged in many regions due to waning immunity from acellular vaccines, pathogen adaptation such as pertactin-deficient strains, and gaps in vaccination coverage, prompting ongoing research into improved vaccines and public health strategies [8].

Microbiology and Pathogenesis

Bordetella pertussis is a Gram-negative, cocobacillus-shaped bacterium that is strictly aerobic, non-spore-forming, and non-motile [1]. It is an obligate human pathogen with no known animal or environmental reservoirs, making humans the sole host for this bacterium [1]. The bacterium measures approximately 0.8 µm in diameter and 0.4 µm in length and typically appears singly or in small clusters under microscopy [1]. Its genome is approximately 4.1 million base pairs in size, with a guanine-cytosine (G+C) content of 67.72%, encoding around 3,816 proteins, and it belongs to the family Alcaligenaceae [1].

Morphology and Nutritional Requirements

B. pertussis possesses a capsule that contributes to virulence by aiding in adherence and immune evasion [13]. It expresses surface structures such as fimbriae and filamentous hemagglutinin (FHA), which facilitate attachment to ciliated epithelial cells in the human respiratory tract [14]. The bacterium has specific nutritional requirements and is considered fastidious, requiring nicotinic acid (niacin) as an essential growth factor, although it does not need other vitamins for development [15]. It also requires specific amino acids, though its nutritional profile is relatively simple compared to other Bordetella species [15]. Metabolomic studies indicate that B. pertussis can adapt its metabolism in response to nutrient availability, influencing the global regulation of virulence and the biosynthesis of vaccine antigens [17].

Optimal Culture Conditions

B. pertussis is a strict aerobe and requires enriched media and controlled environmental conditions for cultivation [18]. The most commonly used selective media are Regan-Lowe agar, which contains blood and charcoal and allows for the detection of hemolysis, and Bordet-Gengou agar, originally formulated with 50% defibrinated blood and later modified to 15%, enriched with glycerol and potato [19][20]. Both media are effective, though Regan-Lowe is often considered more sensitive in clinical laboratories [21]. The optimal temperature for growth ranges between 35°C and 37°C, close to human body temperature, although some studies suggest that toxin production is higher at 34°C, which is relevant for vaccine production [22][23]. The optimal pH for growth is between 7.2 and 7.4, with growth inhibited under acidic conditions [22]. Low sodium concentrations (50–75 mM) enhance growth and toxin association with the cell, while higher concentrations (100–140 mM) reduce these effects [23].

Virulence Mechanisms and Immune Evasion

B. pertussis employs a sophisticated array of virulence factors to colonize the respiratory epithelium and evade host immune responses. Key adhesins include filamentous hemagglutinin (FHA), a large 220 kDa protein that binds to lactosylceramide and integrins on epithelial cells and monocytes, facilitating adhesion and immune modulation [26]. Pertactin (P.69), a 69 kDa outer membrane protein containing an Arg-Gly-Asp (RGD) motif, interacts with host integrins to promote adhesion and non-phagocytic cell invasion [27]. Fimbriae (FIM2 and FIM3) enhance bacterial aggregation and adherence to epithelial cells and are important antigenic components in acellular vaccines [28].

To subvert the immune system, B. pertussis produces several immunomodulatory toxins. The pertussis toxin (PT), an AB5 toxin, ADP-ribosylates the alpha subunit of Gi/o proteins in host cells, leading to excessive intracellular cyclic AMP (cAMP) accumulation. This disrupts neutrophil chemotaxis, macrophage activation, and antigen presentation, while also promoting lymphocytosis by altering lymphocyte migration [29]. The adenylate cyclase toxin (ACT) enters phagocytic cells, converting ATP to cAMP, which inhibits phagocytosis, reactive oxygen species production, and apoptosis, allowing bacterial survival [29]. The bacterium also evades the complement system through surface proteins like the autotransporter Vag8, which inhibits complement activation and prevents opsonization and lysis [31]. Additionally, its lipooligosaccharide (LOS) induces a moderate inflammatory response that may be manipulated to favor bacterial persistence without triggering effective immune clearance [32].

Genetic Evolution and Immune Escape

The genetic evolution of B. pertussis has led to the emergence of strains that may evade vaccine-induced immunity, a phenomenon known as vaccine-driven evolution [8]. A key mechanism is the rise of pertactin-deficient (Prn-negative) strains, which have lost the expression of pertactin, a major component of acellular vaccines. These strains have been increasingly reported in the United States, Australia, and Norway since the widespread use of acellular vaccines, providing a selective advantage in vaccinated populations [8][35]. Additionally, point mutations in vaccine antigen genes, such as ptxP and prn, have led to antigenic variation. The ptxP3 lineage, which produces higher levels of pertussis toxin, has largely replaced older strains, suggesting adaptive fitness [36]. Genomic plasticity, driven by insertion sequences like IS481, facilitates recombination, rearrangements, and deletions, contributing to selective sweeps of advantageous variants [37]. These evolutionary changes challenge the long-term efficacy of current vaccines and underscore the need for genomic surveillance and next-generation vaccine development [38].

Immune Evasion and Implications for Vaccine Design

B. pertussis further evades immunity by surviving intracellularly within epithelial cells, macrophages, and dendritic cells, thus avoiding humoral defenses [39][40]. It modulates phagosome maturation to avoid lysosomal fusion, enabling persistence in a protected niche [41]. The release of outer membrane vesicles (OMVs) acts as immune decoys, diverting antibody responses and modulating host inflammation [42]. These evasion strategies highlight the limitations of current acellular vaccines, which induce predominantly Th2-polarized humoral immunity with limited Th1/Th17 activation, resulting in shorter-lived protection and reduced ability to block transmission [43]. Future vaccines may need to induce mucosal and cellular immunity, include conserved antigens or native OMVs, and use novel adjuvants to promote robust Th1/Th17 responses for more durable and effective protection [44][45].

Clinical Presentation and Diagnosis

Bordetella pertussis infection, commonly known as pertussis or whooping cough, presents in distinct clinical stages with varying symptoms depending on the age and immune status of the patient. The disease typically begins with a catarrhal phase resembling a common cold, progresses to a paroxysmal stage marked by severe coughing fits, and may culminate in a convalescent phase. Diagnosis relies on a combination of clinical suspicion and laboratory confirmation, with different testing modalities offering variable sensitivity and specificity depending on the timing of illness and patient characteristics.

Clinical Presentation: Stages and Symptomatology

The clinical course of pertussis is classically divided into three phases: catarrhal, paroxysmal, and convalescent. The initial catarrhal phase lasts approximately one to two weeks and is characterized by non-specific respiratory symptoms such as rhinorrhea, nasal congestion, sneezing, low-grade fever, mild cough, and general malaise [46]. This stage is highly contagious, as the patient sheds large quantities of B. pertussis through respiratory droplets when coughing or sneezing [2]. The transmission is particularly efficient in close-contact settings such as households, schools, and daycare centers due to the release of infectious droplets into the air [48].

After the catarrhal phase, the disease progresses to the paroxysmal stage, which is defined by intense, violent, and uncontrollable coughing episodes that can last several minutes and severely impair breathing [49]. These paroxysms often culminate in a forceful inhalation that produces a high-pitched, crowing sound known as the "whoop" or inspiratory stridor, which gives the disease its English name [50]. The coughing fits can be so severe that they lead to vomiting, facial cyanosis (bluish discoloration), extreme fatigue, and tearing. They frequently disrupt daily activities and sleep, and in some cases, can result in complications such as rib fractures or hernias. The illness may persist for weeks or even months, earning it the colloquial name "the 100-day cough" [46].

The clinical presentation varies significantly with age. In infants and young children, particularly those under six months, the symptoms can be atypical and more severe. The classic "whoop" may be absent, but the disease can manifest with life-threatening apnea (pauses in breathing), respiratory distress, or feeding difficulties [52]. This atypical presentation increases the risk of delayed diagnosis and severe complications, including pneumonia, seizures, and death [4]. In contrast, adolescents and adults often experience milder symptoms that are frequently mistaken for a persistent cold or bronchitis, which can lead to inadvertent transmission to vulnerable infants [54]. This age-related variation in symptom severity underscores the importance of considering pertussis in the differential diagnosis of prolonged cough, regardless of age.

Diagnostic Approaches: Laboratory Methods and Clinical Algorithms

The diagnosis of B. pertussis infection is achieved through a combination of clinical evaluation and laboratory testing. The choice of diagnostic method depends on the stage of the disease, as the sensitivity of each test varies over time. The three primary laboratory techniques are polymerase chain reaction (PCR), bacterial culture, and serology.

Polymerase chain reaction (PCR) is currently the most sensitive and widely used method for diagnosing pertussis, especially during the first three weeks of illness [5]. PCR can detect as few as 0.5 bacterial genomes per reaction, making it highly effective even in samples with low bacterial load or after the initiation of antibiotic therapy [56]. Its high sensitivity, rapid turnaround time, and ability to provide results within hours make it the preferred test in clinical settings. However, specificity can be affected by the target gene used; for example, the IS481 insertion element, commonly targeted in PCR assays, is also present in other Bordetella species like B. holmesii and B. bronchiseptica, potentially leading to false positives [56]. To enhance specificity, assays targeting unique B. pertussis genes such as the pertussis toxin gene (ptxA-pr) or BP283 are recommended [56].

Bacterial culture remains the gold standard for diagnosis due to its high specificity, as it allows for the isolation and phenotypic characterization of viable B. pertussis [59]. However, its sensitivity is significantly lower than PCR, ranging from 12% to 60%, and it is highly dependent on proper specimen collection, transport, and the use of selective media such as Regan-Lowe or Bordet-Gengou agar [60]. The long incubation period required for culture (7–10 days) limits its utility for timely clinical decision-making, although it is invaluable for epidemiological surveillance and antibiotic resistance testing.

Serology is most useful in the later stages of the disease, beyond two to three weeks from symptom onset, when bacterial load in the nasopharynx has declined and PCR and culture become less sensitive [61]. The most specific serological marker is IgG against pertussis toxin (IgG-PT), as this toxin is produced exclusively by B. pertussis [62]. In contrast, antibodies against other antigens like filamentous hemagglutinin (FHA) can be less specific, as they may also be induced by vaccination or infection with other Bordetella species [63]. For single serum samples, a cutoff of 50–120 IU/mL for IgG-PT is often used as a diagnostic criterion, provided the clinical and vaccination history is considered [64].

The Centers for Disease Control and Prevention (CDC) defines a confirmed case of pertussis based on laboratory criteria, including isolation of B. pertussis by culture, a positive PCR test, or serological evidence of infection [65]. A probable case is defined clinically as a cough lasting at least two weeks with paroxysms, inspiratory whoop, or post-tussive vomiting, without another explanation [65]. An algorithmic approach to diagnosis is recommended: PCR is the test of choice in the early stages, while serology is reserved for late presentations. In infants, where atypical symptoms like apnea may be the only sign, a high index of clinical suspicion and prompt PCR testing are critical for early intervention [67].

Indications for Hospitalization and Monitoring

Hospitalization is strongly indicated for pediatric patients with suspected or confirmed pertussis, particularly for infants under six months of age, who are at the highest risk for severe complications and mortality [68]. This vulnerability stems from their incomplete vaccination status and immature immune system [69]. Key clinical criteria for hospitalization include age under six months, difficulty breathing (e.g., tachypnea, retractions, nasal flaring), apnea (pauses in breathing of 20 seconds or more), cyanosis during coughing episodes, inability to maintain oral hydration, and associated complications such as pneumonia or seizures [70]. Additionally, hospitalization is necessary for isolation to prevent the spread of infection, as pertussis is highly contagious through respiratory droplets [71].

Supportive respiratory care should be initiated proactively in hospitalized infants. Criteria for initiating respiratory support include documented hypoxemia (oxygen saturation persistently <94% on room air), recurrent apnea or bradycardia associated with coughing paroxysms, signs of respiratory fatigue, or the development of pneumonia requiring mechanical ventilation [72]. Continuous monitoring of pulse oximetry, heart rate, and respiratory pattern is essential in the pediatric intensive care unit (PICU) to detect early signs of decompensation [73]. Given the potential for rapid clinical deterioration, especially in neonates who may present with apnea as the sole symptom, a low threshold for hospitalization and intensive monitoring is warranted to improve clinical outcomes and reduce mortality [71].

Treatment and Antibiotic Resistance

The treatment of Bordetella pertussis infection primarily involves the use of antibiotics, with macrolides being the first-line therapy. The most commonly prescribed macrolide antibiotics include azithromycin, erythromycin, and clarithromycin [6]. These antibiotics are effective in eliminating the bacteria, reducing the severity and duration of symptoms, and preventing transmission to others. Among these, azithromycin is often preferred, particularly for infants under six months of age, due to its favorable safety profile and simpler dosing regimen, typically administered over five days [76]. Erythromycin and clarithromycin are also viable options for older children and adults, although they may be associated with a higher incidence of gastrointestinal side effects.

The effectiveness of antibiotic treatment is highly dependent on the timing of administration. Antibiotics are most beneficial when initiated during the early, catarrhal stage of the illness—within the first one to two weeks after symptom onset—before the onset of severe paroxysmal coughing [77]. When administered early, antibiotics can prevent the progression to the more severe phases of the disease. However, if treatment is delayed beyond three weeks, the clinical benefit in terms of symptom reduction diminishes, although antibiotics still play a crucial role in eradicating the bacteria and reducing contagiousness [78]. Patients are generally considered non-contagious after five days of appropriate antibiotic therapy, whereas untreated individuals may remain infectious for up to 21 days from the onset of symptoms [79].

In severe cases, particularly among infants and young children, hospitalization may be necessary to provide supportive care. This can include oxygen therapy, intravenous hydration, and close monitoring for complications such as apnea or respiratory distress [80]. For individuals who have been in close contact with a confirmed case—especially those at high risk, such as infants, pregnant women, or healthcare workers—prophylactic antibiotics may be recommended to prevent infection [76]. Azithromycin is typically the preferred agent for prophylaxis due to its efficacy and tolerability.

Antibiotic Resistance and Emerging Challenges

Despite the widespread use of macrolides, there is growing evidence of antimicrobial resistance in circulating strains of Bordetella pertussis. Resistance to macrolides, particularly to azithromycin, erythromycin, and clarithromycin, has been increasingly reported worldwide [82]. In China, for example, over 90% of clinical isolates analyzed between 2020 and 2024 exhibited macrolide resistance, linked to a specific point mutation in the 23S rRNA gene (A2037G) [82]. Similar trends have been observed in Japan, Finland, and other countries, where resistant strains have been identified during ongoing outbreaks [84][85]. The spread of resistant clones, such as the MR-MT28 lineage, highlights the global nature of this emerging threat [86].

The primary genetic mechanism of resistance involves a single nucleotide mutation (A2037G) in the 23S rRNA gene, which prevents macrolides from binding effectively to the bacterial ribosome [82]. This mutation confers high-level resistance and has been associated with treatment failure, where patients continue to shed the bacteria and remain contagious despite antibiotic therapy [88]. The expansion of resistant strains poses significant clinical and public health challenges, as it undermines the effectiveness of first-line treatments and complicates outbreak control.

In cases where macrolide resistance is suspected or confirmed, alternative antibiotics must be considered. Trimethoprim-sulfamethoxazole (cotrimoxazole) is a recommended alternative for patients over two months of age, although its clinical efficacy against resistant strains is still under evaluation [89]. Tetracyclines, such as doxycycline, may be used in adults but are contraindicated in young children due to the risk of tooth discoloration and bone growth inhibition [80]. The detection of resistance is critical for guiding treatment decisions, and molecular techniques such as real-time polymerase chain reaction (PCR) can be used to identify resistance-associated mutations directly from clinical specimens, enabling rapid and targeted interventions [91].

Implications for Public Health and Future Directions

The emergence of antibiotic-resistant Bordetella pertussis strains underscores the need for enhanced global surveillance and genomic monitoring. The integration of whole-genome sequencing (WGS) into public health systems allows for the tracking of resistant clones and the identification of transmission patterns, which is essential for outbreak response [92]. The Organization of the Pan-American Health (PAHO) has called for strengthened vaccination and surveillance efforts in response to the spread of resistant strains [93].

While antibiotics remain a cornerstone of treatment, their limitations in the face of resistance highlight the importance of preventive strategies. vaccination with the DTP vaccine and Tdap vaccine continues to be the most effective means of controlling pertussis, reducing both disease incidence and the potential for resistant strains to spread [38]. However, as current vaccines do not fully prevent colonization or transmission, ongoing research is focused on developing next-generation vaccines that induce stronger mucosal immunity and provide longer-lasting protection. In the interim, a comprehensive approach that combines timely diagnosis, appropriate antibiotic use, resistance monitoring, and high vaccination coverage is essential to mitigate the impact of antibiotic resistance and control the resurgence of pertussis.

Vaccines and Immunity

The prevention and control of Bordetella pertussis infection rely heavily on vaccination, which has dramatically reduced the global burden of pertussis since the mid-20th century. The primary vaccines used are the DTP vaccine (diphtheria, tetanus, and whole-cell pertussis) and the Tdap vaccine (tetanus, diphtheria, and acellular pertussis), both of which are critical components of national immunization programs [7]. The acellular vaccine (aP), introduced to replace the whole-cell (wP) version due to its lower reactogenicity, contains purified antigens such as pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn), and fimbriae (Fim2 and Fim3), each playing a distinct role in inducing protective immunity [96]. The PT component is particularly crucial, as it generates neutralizing antibodies that block the toxin’s effects on immune signaling, while FHA and pertactin inhibit bacterial adhesion to respiratory epithelial cells [97].

Despite high vaccination coverage, immunity conferred by acellular vaccines wanes significantly over time, with protection declining by 2% to 10% annually after the final childhood dose [98]. This phenomenon, known as waning immunity, results in increased susceptibility among adolescents and adults, who can then serve as reservoirs for transmission to vulnerable infants [99]. In contrast, natural infection or vaccination with whole-cell vaccines induces a more durable immune response, characterized by robust activation of T helper 1 (Th1) and T helper 17 (Th17) cells, which are essential for effective mucosal and cellular immunity [100]. Acellular vaccines, however, predominantly elicit a Th2-polarized response, which is less effective at preventing bacterial colonization and transmission, even if it protects against severe disease [43].

Maternal Vaccination and Cocooning Strategies

To protect infants during their most vulnerable period—before they complete their primary immunization series—maternal vaccination with Tdap during pregnancy has become a cornerstone of public health strategy. Administering the vaccine between 27 and 36 weeks of gestation enables the transfer of protective IgG antibodies across the placenta, providing passive immunity to the newborn [102]. This approach has proven highly effective, with studies showing over 90% protection against pertussis in infants under two months of age and significant reductions in hospitalization and mortality [103]. Despite its proven benefits, coverage remains uneven, with disparities linked to socioeconomic status, access to prenatal care, and vaccine hesitancy [104].

Complementary to maternal immunization is the "cocooning" strategy, which involves vaccinating close contacts of newborns—such as parents, siblings, and caregivers—with Tdap to create a protective barrier against exposure [105]. However, the effectiveness of cocooning has been limited by logistical challenges and low adherence rates among adult populations, leading many health authorities to prioritize maternal vaccination as a more reliable and scalable intervention [106].

Booster Doses and Lifelong Protection

To sustain population-level immunity and interrupt transmission cycles, booster doses of Tdap are recommended for adolescents and adults. The Centers for Disease Control and Prevention (CDC) advises a single Tdap dose at age 11–12, followed by Td (tetanus and diphtheria) boosters every 10 years [107]. For adults who have never received Tdap, a one-time replacement of a Td booster with Tdap is recommended, particularly for those in close contact with infants [108]. These booster strategies are essential for maintaining herd immunity, which requires vaccination coverage of 70% to 90% to be effective [109]. Despite these recommendations, adult booster rates remain suboptimal in many countries, contributing to the persistence of pertussis outbreaks.

Challenges in Vaccine Efficacy and Pathogen Evolution

The resurgence of pertussis in highly vaccinated populations has raised concerns about the long-term efficacy of current vaccines and the adaptive evolution of B. pertussis. Notably, there has been a global increase in the prevalence of pertactin-deficient (Prn-negative) strains, which are no longer recognized by antibodies induced by acellular vaccines that include pertactin as a key antigen [8]. This antigenic divergence is believed to result from vaccine-driven selective pressure, allowing these strains to evade immune detection and circulate more efficiently [111]. Additionally, polymorphisms in the ptxP promoter region have led to the dominance of the ptxP3 lineage, which produces higher levels of pertussis toxin and may enhance bacterial fitness [36].

These evolutionary changes underscore the limitations of current vaccines and highlight the need for next-generation formulations. Candidates under investigation include whole-cell pertussis vaccines with improved safety profiles, live attenuated vaccines administered intranasally to stimulate mucosal immunity, and vaccines based on outer membrane vesicles (OMVs) that present a broader array of native antigens [45]. Such innovations aim to induce more durable and comprehensive immune responses that can better control both disease and transmission.

Equity and Public Health Policy

Significant global inequities persist in pertussis vaccine coverage, particularly in low- and middle-income countries where access to routine immunization services is limited. In 2023, over 14 million infants worldwide did not receive any doses of the DTP vaccine, leaving them highly vulnerable to infection [114]. Barriers include geographic isolation, lack of healthcare infrastructure, socioeconomic disparities, and vaccine hesitancy fueled by misinformation [115]. To address these gaps, public health policies must prioritize equitable access through strengthened primary care systems, community engagement, and culturally appropriate education campaigns [116]. The integration of pertussis vaccination into routine prenatal care and school-based immunization programs can further enhance coverage and sustainability.

In conclusion, while current vaccines have been instrumental in reducing pertussis morbidity and mortality, challenges related to waning immunity, pathogen evolution, and global inequities necessitate ongoing improvements in vaccine design, delivery strategies, and public health communication. The future of pertussis control lies in developing more effective and durable vaccines and ensuring their equitable distribution across all populations.

Epidemiology and Global Trends

Bordetella pertussis remains a significant global public health concern despite the widespread availability of effective vaccines. The epidemiology of pertussis, or whooping cough, is characterized by cyclical outbreaks, a resurgence in many high-income countries, and persistent transmission in regions with suboptimal vaccination coverage. The global landscape has been further complicated by the temporary decline in cases during the COVID-19 pandemic due to non-pharmaceutical interventions, followed by a dramatic rebound, highlighting the fragile nature of disease control [117].

Global Resurgence and Recent Outbreaks

Following a period of reduced transmission between 2020 and 2022, a sharp global resurgence of pertussis has been observed. In 2024, approximately 977,000 cases were reported worldwide, a substantial increase from the 151,000 cases reported in 2018 [117]. The Americas have been particularly affected, with over 66,000 cases reported in 2024 compared to just 4,139 in 2023 [119]. Countries such as Brazil, the United States, Mexico, and Peru have experienced significant outbreaks. For instance, Mexico saw a dramatic increase from 19 cases in early 2024 to 288 in the same period of 2025 [120]. In Europe, cases surged by up to tenfold in the first quarter of 2024, with over 32,000 cases reported in the EU/EEA [121]. This resurgence has been attributed to a combination of factors, including waning immunity from acellular vaccines, pathogen evolution, and disruptions to routine childhood immunization programs during the pandemic [122].

Regional Variations in Incidence and Patterns

The epidemiology of pertussis varies significantly by region, largely influenced by vaccination policies and coverage. In the European Union and the European Economic Area, cyclical epidemics occur every three to five years, although a strict seasonal pattern is not established [123]. In contrast, countries like Australia have observed peaks during autumn and summer [124]. The Union for the Mediterranean and other regions have also reported outbreaks, indicating a global trend. The global coverage for the third dose of the DTP vaccine (DTP3), a key indicator of childhood immunization, was 84% in 2023 [125]. While this represents a relatively stable figure, it means that around 14.5 million children worldwide did not receive any doses of the vaccine in 2023, creating large pools of susceptible individuals [125].

Impact of Vaccination Coverage and Waning Immunity

The level of vaccination coverage is a primary determinant of pertussis incidence. Countries with high coverage, such as many in North America and Europe, have successfully reduced disease in young children but continue to experience outbreaks among adolescents and adults. This shift in the age distribution of cases is largely due to the phenomenon of waning immunity. The protection provided by acellular pertussis vaccines, while highly effective in the short term, diminishes significantly over time, with efficacy decreasing by 2% to 10% per year after vaccination [38]. This allows previously vaccinated individuals to become susceptible again and act as reservoirs for transmission, particularly to vulnerable infants. In countries with lower coverage, such as Mexico (estimated at 78%), the increase in cases has been more dramatic and directly linked to gaps in vaccination [128]. The concept of herd immunity for pertussis is complex, requiring 70% to 90% population immunity to be effective, but it is less robust than for other vaccine-preventable diseases due to the inability of current vaccines to completely prevent asymptomatic colonization and transmission [109].

Vulnerable Populations and Transmission Dynamics

The most vulnerable population to severe and fatal pertussis is infants under six months of age, particularly those under two months who have not yet begun their primary vaccination series [130]. This group faces the highest risks of complications such as apnea, pneumonia, seizures, and death [131]. The primary source of infection for these infants is often a close household contact, with studies indicating that up to 80% of cases in infants originate from parents, siblings, or other caregivers [132]. This transmission dynamic underscores the critical role of strategies like maternal vaccination and the "cocooning" approach, where close contacts of newborns are vaccinated to create a protective barrier [105]. The reemergence of pertussis in well-vaccinated populations is also influenced by the evolution of B. pertussis strains, including the emergence of pertactin-deficient strains that may evade vaccine-induced immunity [8]. This evolutionary pressure, combined with waning immunity and vaccination gaps, creates a perfect storm for sustained transmission and periodic epidemics, necessitating a multifaceted public health response [99].

Prevention Strategies and Public Health Measures

The prevention of infection by Bordetella pertussis, the causative agent of pertussis (also known as whooping cough), relies on a multifaceted approach that combines widespread vaccination, targeted public health interventions, and robust epidemiological surveillance. Despite the availability of effective vaccines, the reemergence of pertussis in recent decades has highlighted the need for sustained and adaptive strategies to protect vulnerable populations and maintain herd immunity [2].

Vaccination as the Primary Prevention Strategy

Vaccination remains the cornerstone of pertussis prevention, significantly reducing the incidence and severity of the disease since the introduction of the DTP vaccine in the 1940s [7]. Two primary types of vaccines are used globally:

  • DTaP vaccine: This acellular vaccine is administered to children under seven years of age. The complete primary series consists of five doses, given at 2, 4, and 6 months, between 15 and 18 months, and a final dose between 4 and 6 years of age [138]. It contains purified antigens such as pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn), and fimbriae (Fim2/Fim3), which stimulate a protective immune response [96].

  • Tdap vaccine: This booster vaccine is designed for preadolescents, adolescents, adults, and pregnant women. It is recommended at age 11 or 12, and for adults who have not previously received it. A Tdap booster is also recommended every 10 years, particularly for individuals in close contact with infants, such as parents, caregivers, and healthcare workers [140].

The transition from whole-cell (wP) to acellular (aP) vaccines has improved safety by reducing reactogenicity, but it has also led to challenges related to waning immunity. Acellular vaccines provide strong initial protection, but efficacy declines significantly after 4 to 9 years, contributing to increased susceptibility in adolescents and adults [38]. This waning immunity allows for asymptomatic or mild infections in older individuals, who can then transmit the bacteria to unvaccinated or partially vaccinated infants.

Maternal Vaccination and Cocooning Strategy

Protecting newborns, who are most vulnerable to severe complications such as apnea, pneumonia, and death, is a critical public health priority [4]. Since infants do not receive their first dose of DTaP until 2 months of age, they rely on indirect protection through maternal vaccination and the "cocooning" strategy.

  • Maternal vaccination: Administering the Tdap vaccine during each pregnancy, ideally between 27 and 36 weeks of gestation, allows for the transplacental transfer of protective IgG antibodies to the fetus [143]. This strategy has been shown to be over 90% effective in preventing pertussis in infants under 2 months of age and significantly reduces hospitalizations and mortality [103]. The safety of Tdap vaccination during pregnancy is well-established, with no increased risk of adverse outcomes such as preterm birth or congenital anomalies [145].

  • Cocooning strategy: This approach involves vaccinating all close contacts of a newborn—parents, siblings, grandparents, and caregivers—with Tdap to create a protective "ring" around the infant [105]. While conceptually sound, the effectiveness of cocooning has been limited by challenges in achieving high vaccination coverage among adult contacts. As a result, maternal vaccination is now considered the more reliable and practical method for protecting newborns [106].

Addressing Waning Immunity and Pathogen Adaptation

The resurgence of pertussis in populations with high vaccination coverage is attributed to several interrelated factors:

  • Waning immunity: As mentioned, the protection from acellular vaccines diminishes over time, leading to increased susceptibility in adolescents and adults. This has prompted public health authorities to recommend routine Tdap boosters for these age groups to maintain herd immunity and reduce transmission [143].

  • Pathogen evolution: Bordetella pertussis has undergone genetic changes in response to vaccine pressure, a phenomenon known as vaccine-driven evolution. Notably, there has been a global increase in the prevalence of pertactin-deficient (Prn-negative) strains, which are not recognized by antibodies induced by current acellular vaccines [8]. Additionally, mutations in the ptxP promoter gene have led to the dominance of the ptxP3 lineage, which produces higher levels of pertussis toxin and may enhance bacterial fitness [36].

These evolutionary changes underscore the need for ongoing genomic surveillance and the development of next-generation vaccines that target conserved antigens or induce broader immune responses, such as those involving Th1 cells and Th17 cells, which are more effective at clearing the infection than the Th2-dominated response elicited by current acellular vaccines [43].

Public Health Interventions and Surveillance

Effective control of pertussis requires a comprehensive public health infrastructure that includes case detection, outbreak response, and community education.

  • Epidemiological surveillance: Robust surveillance systems are essential for monitoring disease trends, detecting outbreaks early, and guiding vaccination policies. The implementation of polymerase chain reaction (PCR) testing has greatly improved diagnostic sensitivity, allowing for faster and more accurate case confirmation [5]. However, challenges remain, including underdiagnosis in mild or atypical cases, particularly in adolescents and adults, and underreporting in regions with limited healthcare access [153].

  • Outbreak control: When outbreaks occur, public health measures include identifying and treating cases with antibiotics such as azithromycin or erythromycin, providing chemoprophylaxis to close contacts, and implementing vaccination campaigns to boost immunity in affected communities [154]. Isolation of infected individuals for at least five days after starting antibiotic treatment is recommended to prevent further transmission [68].

  • Antibiotic resistance: Emerging resistance to macrolide antibiotics, particularly due to the A2037G mutation in the 23S rRNA gene, poses a growing threat to treatment efficacy [82]. This necessitates enhanced surveillance for resistant strains and the development of alternative treatment protocols, such as the use of trimethoprim-sulfamethoxazole in macrolide-allergic or resistant cases [80].

Promoting Vaccine Equity and Acceptance

Achieving and maintaining high vaccination coverage requires addressing both structural and social barriers. Globally, an estimated 14.5 million children did not receive any doses of the DTP vaccine in 2023, leaving them highly vulnerable to pertussis [125]. Inequities are particularly pronounced in rural, marginalized, and indigenous communities, where access to healthcare services is limited by distance, cost, and cultural factors [115].

To overcome these challenges, public health policies must focus on:

  • Equitable access: Integrating vaccination into primary healthcare and prenatal care, using mobile clinics, and ensuring free or low-cost access to vaccines.
  • Community engagement: Working with local leaders and using culturally appropriate communication to build trust and address vaccine hesitancy.
  • Risk communication: Combating misinformation through clear, evidence-based messaging that emphasizes the safety and importance of vaccination, particularly for pregnant women and caregivers [160].

Maternal and Infant Protection

Infants, particularly those under six months of age, are the most vulnerable population to severe and life-threatening complications from Bordetella pertussis infection, including apnea, pneumonia, seizures, encephalopathy, and death [131]. This vulnerability arises because their immune systems are immature and they have not yet completed the primary series of the DTP vaccine, which begins at two months of age [69]. Consequently, protection during this critical window must come from indirect sources, primarily through maternal immunization and the vaccination of close contacts, a strategy known as "cocooning" [105]. The most effective strategy for preventing pertussis in newborns is maternal vaccination with the Tdap vaccine during pregnancy, which provides passive immunity to the infant through the transplacental transfer of protective antibodies [102].

Maternal Vaccination with Tdap

The cornerstone of infant protection is the administration of the Tdap vaccine to pregnant women. This strategy is recommended during each pregnancy, ideally between weeks 27 and 36 of gestation [102]. This timing optimizes the transfer of maternal IgG antibodies across the placenta, ensuring that the newborn has a high level of protective antibodies at birth, which wane over the first few months of life [166]. The effectiveness of this approach is substantial; studies have shown that maternal Tdap vaccination is over 90% effective in preventing pertussis in infants under two months of age and up to 89% effective in preventing hospitalizations [103]. This protection is critical, as the classical "whoop" may be absent in newborns, and the disease can present atypically with apnea, cyanosis, or bradycardia as the primary symptoms [168]. The safety of the Tdap vaccine during pregnancy has been extensively studied and is supported by major health organizations like the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), with no significant association found between vaccination and adverse pregnancy outcomes [169].

Cocooning and Adolescent/Adult Booster Vaccination

The "cocooning" strategy aims to create a protective ring of immunity around the newborn by vaccinating all close contacts, including parents, siblings, grandparents, and caregivers, with the Tdap vaccine [105]. This approach is designed to reduce the risk of transmission from asymptomatic or mildly symptomatic individuals who may be reservoirs of Bordetella pertussis [171]. However, the effectiveness of cocooning is limited by the practical difficulty of achieving high vaccination coverage among all adult contacts [106]. Therefore, it is most effective when combined with maternal vaccination. The foundation for successful cocooning is the routine administration of Tdap booster doses to adolescents and adults. The waning immunity from childhood vaccines means that adolescents and adults are susceptible to infection and can transmit the bacteria to vulnerable infants [143]. National immunization schedules typically recommend a single Tdap booster at 11-12 years of age, followed by a Td (tetanus and diphtheria) booster every 10 years, with the Tdap dose replacing one of these [174]. This sustained booster strategy is essential for maintaining community immunity and protecting the youngest members of society.

Clinical Management and Hospitalization of Infants

Given the high risk of severe complications, infants with suspected or confirmed pertussis often require hospitalization, especially those under six months old [68]. Key criteria for hospitalization include apnea, cyanosis, difficulty breathing, an inability to maintain hydration, and signs of pneumonia [71]. In the hospital setting, infants are placed in isolation to prevent transmission, and their respiratory status is monitored continuously with pulse oximetry to detect episodes of hypoxemia or apnea [70]. Supportive care is the mainstay of treatment and may include oxygen therapy for hypoxemia, intravenous fluids for dehydration, and suctioning of respiratory secretions [68]. In severe cases, mechanical ventilation in a pediatric intensive care unit (PICU) may be necessary [71]. Antibiotic treatment with a macrolide, such as azithromycin, is initiated immediately upon suspicion to eradicate the bacteria and reduce contagiousness, although its impact on the clinical course of the illness is limited once the paroxysmal coughing phase has begun [180]. The prompt diagnosis and management of pertussis in infants are critical for improving outcomes and reducing mortality in this high-risk group.

Emerging Challenges and Future Directions

The global landscape of Bordetella pertussis infection continues to evolve, presenting new challenges despite decades of successful vaccination programs. The reemergence of pertussis in regions with high vaccine coverage underscores the limitations of current strategies and highlights the need for innovative approaches in diagnostics, therapeutics, and immunization. Key emerging challenges include pathogen adaptation under vaccine pressure, the rise of antimicrobial resistance, waning immunity from acellular vaccines, and persistent inequities in global vaccine access. Addressing these issues requires coordinated efforts in genomic surveillance, development of next-generation vaccines, and strengthening of public health infrastructure.

Pathogen Evolution and Immune Evasion

Bordetella pertussis is undergoing significant genetic evolution, driven in part by selective pressure from widespread use of acellular vaccines (aP). This phenomenon, known as vaccine-driven evolution, has led to the emergence of strains that may evade vaccine-induced immunity. One of the most documented adaptations is the increasing prevalence of pertactin-deficient strains, where the bacterium no longer expresses the pertactin (Prn) protein, a key component in most acellular vaccines [8]. These Prn-negative strains have expanded clonally in countries like the United States, Australia, and Norway, suggesting a selective advantage in vaccinated populations [35]. The loss of this antigen allows the pathogen to escape neutralizing antibodies, potentially reducing vaccine effectiveness.

Beyond antigen loss, B. pertussis exhibits antigenic variation through point mutations in critical genes such as ptxP and prn. The ptxP3 lineage, which produces higher levels of pertussis toxin, has become dominant worldwide, replacing older strains and possibly contributing to increased virulence [36]. Genomic plasticity, facilitated by insertion sequences like IS481, enables recombination and gene deletions, further driving bacterial adaptation [37]. These evolutionary changes challenge the long-term efficacy of current vaccines and necessitate ongoing genomic surveillance to monitor circulating strains and inform vaccine updates.

Antimicrobial Resistance and Therapeutic Implications

A growing threat to pertussis control is the emergence of antimicrobial resistance, particularly to macrolide antibiotics, which are the first-line treatment for B. pertussis. Resistance is primarily mediated by a point mutation (A2037G) in the 23S rRNA gene, which prevents macrolides like azithromycin and erythromycin from binding to the bacterial ribosome [82]. This resistance has been reported at high levels in China, where over 90% of isolates in some regions are macrolide-resistant [82], and has also been detected in Europe and the Americas [84].

The clinical implications are significant, as macrolide resistance can lead to treatment failure, prolonged infectiousness, and increased risk of outbreaks. Cases of microbiological treatment failure have been documented, where patients continue to shed bacteria despite antibiotic therapy [88]. In such scenarios, alternative antibiotics like trimethoprim-sulfamethoxazole are recommended for patients over two months of age, though their efficacy is still under evaluation [89]. The integration of molecular diagnostics, such as PCR assays that detect resistance mutations directly from clinical samples, is crucial for guiding treatment and outbreak control [91]. Strengthening global surveillance for antimicrobial resistance in B. pertussis is essential to inform clinical guidelines and prevent the spread of resistant clones.

Waning Immunity and the Need for Improved Vaccines

The limited durability of immunity conferred by acellular vaccines is a major factor in the resurgence of pertussis. Unlike whole-cell vaccines, which induce a more balanced Th1/Th17 immune response, acellular vaccines primarily stimulate a Th2 response, leading to shorter-lived protection [43]. Studies show that vaccine effectiveness declines by 2% to 10% per year, with significant waning observed within 4 to 9 years after the last dose [98]. This waning immunity allows adolescents and adults to become susceptible reservoirs, transmitting the infection to vulnerable infants.

To compensate, vaccination strategies now include booster doses with Tdap vaccine in adolescence and adulthood, as well as maternal immunization during pregnancy to provide passive protection to newborns [143]. However, future solutions lie in developing next-generation vaccines that induce longer-lasting and more robust immunity. Promising candidates include vaccines based on outer membrane vesicles (OMVs), which contain multiple native antigens and have shown strong immunogenicity in preclinical studies [194]. Live attenuated intranasal vaccines are also in development, aiming to stimulate mucosal immunity in the respiratory tract, the primary site of infection [43].

Global Inequities and Public Health Strategies

Despite the availability of effective vaccines, significant global inequities in pertussis vaccine coverage persist. In 2023, an estimated 14.5 million children worldwide did not receive a single dose of the DTP vaccine, leaving them highly vulnerable to infection [125]. Low- and middle-income countries face barriers such as inadequate healthcare infrastructure, supply chain limitations, and socioeconomic disparities. Even in high-income countries, marginalized populations, including indigenous communities and migrants, experience lower vaccination rates due to geographic, cultural, and linguistic barriers [115].

Addressing these inequities requires multifaceted public health strategies. The inclusion of Tdap in national immunization programs for pregnant women and adolescents is critical, as demonstrated by high-coverage countries like Uruguay [198]. Community-based interventions, such as mobile vaccination units and culturally competent health workers, can improve access in remote areas. Additionally, combating vaccine hesitancy through effective risk communication and education is essential [160]. The World Health Organization's vaccine equity initiative underscores the need for policies that ensure universal access to life-saving immunizations [116]. Closing these gaps is not only a moral imperative but a public health necessity to achieve sustainable control of pertussis worldwide.

References