REVIEW published: 03 July 2019 doi: 10.3389/fimmu.2019.01344 Pertussis Prevention: Reasons for Resurgence, and Differences in the Current Acellular Pertussis Vaccines Susanna Esposito 1*, Paola Stefanelli 2 , Norman K. Fry 3 , Giorgio Fedele 2 , Qiushui He 4,5 , Pauline Paterson 6 , Tina Tan 7 , Markus Knuf 8,9 , Carlos Rodrigo 10,11 , Catherine Weil Olivier 12 , Katie L. Flanagan 13,14,15 , Ivan Hung 16 , Iria Lutsar 17 , Kathryn Edwards 18 , Miguel O’Ryan 19 and Nicola Principi 20 for the World Association of Infectious Diseases and Immunological Disorders (WAidid) and the Vaccine Study Group of the European Society of Clinical Microbiology and Infectious Diseases (EVASG) 1 Edited by: Department of Surgical and Biomedical Sciences, Paediatric Clinic, Università degli Studi di Perugia, Perugia, Italy, 2 Luciana Leite, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy, 3 Immunisation and Countermeasures Division, Instituto Butantan, Brazil Public Health England–National Infection Service, London, United Kingdom, 4 Institute of Biomedicine, University of Turku, Turku, Finland, 5 Department of Medical Microbiology, Capital Medical University, Beijing, China, 6 Department of Infectious Reviewed by: Disease Epidemiology, The Vaccine Confidence Project TM, London School of Hygiene & Tropical Medicine, London, Camille Locht, United Kingdom, 7 Division of Pediatric Infectious Diseases, Department of Pediatrics, Northwestern University Feinberg Institut National de La Santé et de la School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States, 8 Children’s Hospital, Recherche Médicale Helios HSk, Wiesbaden, Germany, 9 Department of Pediatrics, University Medicine, Mainz, Germany, 10 Department of (INSERM), France Pediatrics, Vall d’Hebron University Hospital, Barcelona, Spain, 11 School of Medicine-Germans Trias i Pujol University Carmen Alvarez-Dominguez, Hospita, Universidad Autónoma de Barcelona, Barcelona, Spain, 12 Retired, Neuilly-sur-Seine, France, 13 School of Medicine, Instituto de Investigación Marques de College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia, 14 School of Health and Biomedical Science, valdecilla (IDIVAL), Spain RMIT University, Melbourne, VIC, Australia, 15 Department of Immunology and Pathology, Monash University, Melbourne, VIC, Kingston H. Mills, Australia, 16 Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China, Trinity College Dublin, Ireland 17 Department of Microbiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia, *Correspondence: 18 Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, Susanna Esposito United States, 19 Microbiology and Mycology Program, Faculty of Medicine, Institute of Immunology and Immunotherapy, susanna.esposito@unimi.it University of Chile, Santiago, Chile, 20 Retired, Milan, Italy Specialty section: This article was submitted to Pertussis is an acute respiratory disease caused by Bordetella pertussis. Due to its Vaccines and Molecular Therapeutics, frequency and severity, prevention of pertussis has been considered an important public a section of the journal health issue for many years. The development of the whole-cell pertussis vaccine (wPV) Frontiers in Immunology and its introduction into the pediatric immunization schedule was associated with a Received: 24 February 2019 Accepted: 28 May 2019 marked reduction in pertussis cases in the vaccinated cohort. However, due to the Published: 03 July 2019 frequency of local and systemic adverse events after immunization with wPV, work on Citation: a less reactive vaccine was undertaken based on isolated B. pertussis components Esposito S, Stefanelli P, Fry NK, Fedele G, He Q, Paterson P, Tan T, that induced protective immune responses with fewer local and systemic reactions. Knuf M, Rodrigo C, Weil Olivier C, These component vaccines were termed acellular vaccines and contained one or more Flanagan KL, Hung I, Lutsar I, pertussis antigens, including pertussis toxin (PT), filamentous haemagglutinin (FHA), Edwards K, O’Ryan M and Principi N (2019) Pertussis Prevention: Reasons pertactin (PRN), and fimbrial proteins 2 (FIM2) and 3 (FIM3). Preparations containing up for Resurgence, and Differences in the to five components were developed, and several efficacy trials clearly demonstrated that Current Acellular Pertussis Vaccines. Front. Immunol. 10:1344. the aPVs were able to confer comparable short-term protection than the most effective doi: 10.3389/fimmu.2019.01344 wPVs with fewer local and systemic reactions. There has been a resurgence of pertussis Frontiers in Immunology | www.frontiersin.org 1 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines observed in recent years. This paper reports the results of a Consensus Conference organized by the World Association for Infectious Disease and Immunological Disorders (WAidid) on June 22, 2018, in Perugia, Italy, with the goal of evaluating the most important reasons for the pertussis resurgence and the role of different aPVs in this resurgence. Keywords: acellular pertussis vaccine, Bordetella pertussis, pertussis, whole-cell pertussis vaccine, pertussis prevention INTRODUCTION of more rapid waning of immunity after immunization with the acellular vaccines. Data from the United States document that Pertussis is an acute respiratory disease caused by Bordetella 4,000 cases were reported annually in the 1980s, but increases to pertussis, a Gram-negative bacterial pathogen (1). Before the 25,827, 25,616, 27,500, and 48,277 cases were reported in 2004, availability of vaccines, pertussis was a frequent cause of 2005, 2010, and 2012, respectively (19–21). In 2016, 17,972 cases morbidity and mortality, particularly in infants and young were reported, with an incidence rate of 70.9 per 100,000 in children. The introduction of pertussis-containing vaccines children <6 months, 31.9 per 100 000 in 6 to 11 month-olds, into the immunization schedule of infants and children has and 13.7, 14.8, and 16.3 for those aged 1–6, 7–10, and 11–19 reduced pertussis incidence, although sporadic outbreaks remain years, respectively (23). However, the under-reporting of mild relatively common. In a recent publication (2), it was projected cases would be lower these rates. that in 2014, 24. One million cases of pertussis occurred around Trends that are not substantially different have been registered the world in children aged <5 years with ∼160,000 deaths and in other areas. In Europe, 48,446 pertussis cases were reported many hospitalization admissions, some to pediatric intensive care to the European Surveillance System by 30 EU/EEA countries in units. Due to its frequency and severity, pertussis prevention 2016. This number was slightly higher than that reported in 2012 has been considered an important public health issue for many (42,572), the year of peak pertussis incidence in Europe. As in the years. The development of the whole-cell pertussis vaccine USA, rates were higher among children <1 year. In this younger (wPV) and its introduction into the pediatric immunization group, the notification rate was 73.6 cases per 100,000 population, schedule was associated with a marked reduction in pertussis a value significantly higher than that reported in 2014 (51.6 per cases in the vaccinated cohort (3). With widespread use of wPV, 100,000 population). Moreover, children between 10 and 14 years reporting of pertussis declined significantly worldwide, and both of age were reported to have the second highest incidence rates of hospitalization rates and deaths due to pertussis were greatly pertussis, ∼30 cases per 100,000 population (24). reduced. However, due to the frequency of local and systemic The reasons for pertussis resurgence have been investigated, adverse events after immunization with wPV, many parents and several possibilities have been considered. This paper reports were refusing vaccination for their children and lawsuits against the results of a Consensus Conference organized by the World the vaccine manufacturers were forcing many of them to stop Association for Infectious Disease and Immunological Disorders producing the vaccine (4–6). Currently, wPV is no longer being (WAidid) on June 22, 2018, in Perugia, Italy, with the goal used in most developed countries, but remains in use in most low of evaluating the most important reasons for the pertussis and middle income countries (LMIC) (4, 7–9). resurgence and the role of different aPVs in this resurgence. Work on a less reactive vaccine was undertaken based on the isolation of B. pertussis components that induced protective immune responses with fewer local and systemic reactions. These component vaccines were termed acellular vaccines and were LABORATORY METHODS FOR PERTUSSIS composed of one or more pertussis antigens, including pertussis DIAGNOSIS toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN), and fimbrial proteins 2 (FIM2) and 3 (FIM3). Preparations Several reports indicate that resurgence of pertussis might containing up to five components were developed, and several be due, at least in part, to an artifact, resulting from efficacy trials clearly demonstrated that the aPVs were able to an incomplete identification of pertussis cases in the past confer comparable short-term protection to the most effective (Figure 2). The sole use of cultures to confirm B. pertussis wPVs with fewer local and systemic reactions (10–15) (Figure 1). infection has contributed to this phenomenon. Although the With this enhanced safety profile and despite being more culture method has 100% specificity, its sensitivity is very low expensive than wPVs, aPVs were included in the pediatric (25). Moreover, nasopharyngeal samples for culture have to immunization schedules of many countries, particularly in the be collected within the first 15 days of the disease, when industrialized world (16, 17). After over a decade of use, a rise symptoms are frequently non-specific, and such a diagnosis is in pertussis incidence was demonstrated in several industrialized rarely suspected. Furthermore, isolation can become difficult countries, including Australia and the United States (18–22). if the patient has recently been treated with antibiotics that Some of this apparent increase may also be due to improved are active against B. pertussis (26). In addition, pertussis diagnostic methods, such as the use of molecular techniques to cases occurring outside the first year of age (including in diagnose pertussis, but most experts think that it is also a result adulthood) frequently present as only prolonged cough and are Frontiers in Immunology | www.frontiersin.org 2 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines FIGURE 1 | Efficacy of pertussis vaccines against World Health Organization-defined typical pertussis. FIGURE 2 | Reasons for underestimation of pertussis incidence and mortality. undiagnosed, resulting in an underestimation of the true disease not require viable bacteria, they are more sensitive (70–99% incidence (25, 26). vs. 12–60%). However, similar to culture, they are maximally In recent years, more attention has been given to the sensitive during the first 2–3 weeks of disease (29). Finally, to epidemiology of pertussis disease in all age groups. New criteria confirm B. pertussis infection beyond this period in previously for the clinical definition of pertussis according to age have undiagnosed patients, serologic methods detecting anti-pertussis been suggested (27). The enhanced identification of pertussis toxin IgG in serum and saliva have been developed and cases using molecular methods, particularly in adolescents validated (30). and adults, has increased the total number of reported cases The availability of reliable tests for pertussis diagnosis to significantly (28). The molecular techniques, particularly real- physicians was rapidly associated with a relevant increase in time-polymerase chain reaction (RT-PCR), are widely available their use and in the number of pertussis cases being reported. in clinical practice and can be completed in a few hours, allowing In Australia, the use of both both PCR and serology in patients rapid diagnosis of pertussis. Moreover, since the techniques do with pertussis-like symptoms increased from 0.5% in the period Frontiers in Immunology | www.frontiersin.org 3 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines from April 2000 to March 2004 to 1.7% in the period between (38) who, exploring the inter-epidemic period and fade-out- March 2010 and March 2011. At the same time in Australia, frequency with a mathematical model, concluded that more the proportion of pertussis notifications with a PCR-confirmed than 10% of individuals lose protection within 10 years diagnosis increased from 16.3% in the period from April 2000 from infection whereas others are protected for more than to March 2004 to 65.3% in the period between April 2010 and 30 years. March 2011 (31). In Canada, the availability of a more sensitive A similar or only slightly reduced duration of protection has PCR assay was associated with a concomitant 6-fold increase been calculated after immunization with wPV. Lambert (39) in specimen submissions and a 5-fold increase in pertussis studied a pertussis outbreak that occurred in 1962 in Kent incidence (32). County, Michigan, USA. He found that the incidence of pertussis Assessing the impact of the enhanced diagnostic methods in vaccinated persons was directly related to the interval since to the resurgence of disease is difficult, given the periodicity the last immunization with wPV. Among the 210 vaccinated of naturally occurring pertussis, the different control measures individuals with pertussis, attack rates were 21, 47, and 65% in and reporting standards for different countries, and the different groups of people who had received the vaccine within the last 4, vaccines and schedules recommended in each country. However, 4 to 7 years earlier and 8–11 years earlier, respectively. Jenkinson a study carried out by a working group of the WHO seems (40) conducted a 10 year study of pertussis in a discrete general to indicate that although improved diagnosis may play a role, practice community in the UK and reported that protection due a real increase in pertussis incidence has occurred in recent to immunization with wPV was still effective in 85% of children years (33). The group prepared a questionnaire to obtain 4 years after immunization, but was reduced to 50% in the information on pertussis incidence, vaccination coverage and following 3 years. schedules, surveillance methods, case definitions, and the type In contrast, the duration of immunity after immunization of vaccine used. The questionnaire was widely distributed to with aPVs appears to be shorter, independent of the schedule countries thought to have achieved long-standing high vaccine used, the numbers, and concentrations of antigens included in coverage and effective disease control. Resurgence was defined each vaccine and the methods used to prepare the vaccines. as evidence of a burden of disease higher than that expected Reports also suggested that pertussis occurred significantly when compared to previous reporting cycles in the same setting. earlier in subjects fully vaccinated with aPV than in those A total of 19 countries participated. Although the increased given wPV (41–43). Clark et al. (41) in 2012 reported that pertussis incidence could be ascribed to cyclic patterns amplified children who were fully immunized during infancy with an by detection bias in most of these countries, in five of them aPV had pertussis more often in the first years of school, while (Australia, Chile, Portugal, USA, and UK), the presence of a true those given a wPV were at higher risk later, mainly during resurgence of pertussis in recent years was clearly demonstrated. adolescence. Similar differences were demonstrated by Vickers Only one country using a wPV, Chile, reported a resurgence. et al. (43), who found that children who had received an aPV However, this resurgence was mainly ascribed to decreased of during infancy were already at risk of pertussis within the vaccine coverage, variable coverage within the various districts, first 4 years of life, whereas those vaccinated with wPV did changes in the surveillance practices, and problems with the not contract pertussis until 5–9 years. Finally, Klein et al. (44) specificity of diagnostic tests. The WHO group concluded that demonstrated that most of the pertussis cases diagnosed in pertussis resurgence was not observed in any country using adolescents during an outbreak were seen in individuals fully wPVs, suggesting that a link between aPV use and increased immunized during infancy with an aPV, rather than in those pertussis reporting existed (33). who had received wPV. Individuals receiving only aPV had five times higher odds of pertussis disease than those receiving wPV (OR 5.63, 95% CI 2.55–12.46). When aPV effectiveness (VE) was measured over time, its effectiveness was lower than REASONS FOR PERTUSSIS RESURGENCE that expected after wPV or natural infection (44). Early waning AFTER ACELLULAR PERTUSSIS VACCINE of immunity was reported regardless of the schedule used for INTRODUCTION immunization (44). The addition of booster doses of aPV to prolong protection Waning of Immunity was also assessed. Although there was transient protection As is the case with immunization, natural B. pertussis infection afforded by additional booster doses, the protection waned does not assure permanent protection against pertussis. Several rapidly. A meta-analysis of 11 studies (45) that measured long- studies have documented that a second episode of pertussis term immunity to pertussis after three or five doses of diphtheria- can occur some years after the first one. Current estimates tetanus-aP (DTaP), according to the schedules used in many of the duration of protection due to natural infection range European countries and in the USA, respectively, did not reveal from 7 to 10 years (34, 35) to 20 years (36), but there is a significant difference between the annual odds of pertussis evidence that it can be as short as 3.5 years (37). Differences for the three or five dose regimens. It was calculated that for may be due to methods used to evaluate protection and every additional year after the last dose of DTaP, the risk of pertussis epidemiology in different countries. However, duration pertussis increased 1.33 times (95% CI 1.23–1.43), leading to of protection due to natural B. pertussis infection can vary the conclusion that 8.5 years after the last aPV dose, only 10% from subject to subject as evidenced by Wearing and Rohani of children were still protected against disease. Similar results Frontiers in Immunology | www.frontiersin.org 4 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines were reported in another meta-analysis including studies of duration of protection compared to both wPV vaccination and aPVs administered according to the USA schedule (46). VE was natural infection. compared after the childhood series (five doses) and after an Clear differences between systemic immune response after adolescent booster dose (sixth dose). Relative VE was defined natural infection and aP and wP vaccines. Natural infection and as VE in the population given prior doses of an aPV and wPvs induce antibodies of the IgG1, IgG2, and IgG3 subclasses, absolute VE was defined as VE in an aPV-naïve population. with marginal production of IgG4 (55), suggesting a strong Th1 Absolute VE after the childhood series was 91% (95% CI 87– response. In contrast, the immune response after aPVs evoke a 95%) but declined annually by 9.6% (46). Initial relative VE mixed Th2 and Th17 response (56). APVs evoke the production after adolescent boosting was 70% (95% CI: 54 to 86%) and of IgG1 and IgG4 antibodies, which is consistent with a Th2 declined by 45.3% annually. The absolute VE of the full six- response. Furthermore, aPVs evoke CD4+ T-cells that produce dose aPV series was estimated to be 85% (95% CI: 84–86%) in high concentrations of IL-4 and IL-5 and low amounts of IFNγ, the first year after series completion. However, it declined by again consistent with a Th2 response (57). 11.7% (95% CI: 11.1 to 12.3%) per year, and at 18 years of age, Since Th1 cytokines play an important role in protection protection was limited to 28.2% of immunized patients (95% CI: against pertussis (58, 59), this finding can further explain 27 to 29%) (46). the better protection offered by wPVs and natural infection. Wang et al. (47) studied 279 children aged 5 to 15 years who Studies carried out in children who have received infant presented to primary care with a persistent cough of 2 to 8 weeks series of either wPV or aPVs have shown children given duration. Evidence of recent B. pertussis infection based on a aPVs exhibited higher pertussis-specific antibody levels and high oral fluid anti-pertussis toxin IgG titer was demonstrated in higher memory B- and T-cell responses (5, 60–63). Although 215 children who had been fully vaccinated. Risk was higher in no correlates of antibody protection for pertussis have been those who had been immunized ≥7 years earlier, but in 12% of established (64), the higher IgG levels in aPV-immunized these cases, chronic cough was demonstrated in patients given an children could lead to the conclusion that better humoral aPV <7 years before. Further evidence of waning immunity after protection was afforded by the aP rather than wP vaccines. recent aPV immunization was reported by Principi et al. (48) However, the antigens measured were only those included who documented B. pertussis infection in 18.7% (95% CI 11.5– in the aPVs and not the additional antigens included in 28.0) of children and adolescents with chronic cough who had the wPs. been immunized with an aPV a few years previously (<2 years in These differences in immune responses persist over time, some cases). even after booster aPVs (65, 66). The administration of aPV booster doses at 4 and 9 years of age was associated with an increase in the production of IgG4, regardless of the type of Immune Responses to Pertussis Vaccines vaccine used for priming, but was significantly higher in aPV- and Natural Infection primed children (66). IgG4 antibodies are unable to activate Studies that have compared immune responses after natural B. the complement system and lead to a suboptimal inflammatory pertussis infection and the administration of both wPVs and aPVs response with impaired phagocytosis and antimicrobial defense, have clearly shown that the immune stimulation evoked by aPVs another potential mechanism for the lower efficacy of aPVs is different from that due to natural infection and wPVs (49– compared to wPVs (67). Moreover, the evidence that production 51). Natural infection evokes both mucosal and systemic immune of IgG4 after immunization with aPV increases with each responses, while aPVs induce only a systemic immune response. dose seems to indicate that the protection offered by aPVs As B. pertussis is a mucosal pathogen and only exceptionally tends to be as shorter with each subsequent boosters (68, 69). causes infection outside the respiratory tract, this difference is of Preadolescent booster vaccination with an aPV was found to particular importance in pertussis control. Mucosal immunity is induce lower B-cell and Th1 cell responses in aPV-primed essential to prevent colonization and transmission of B. pertussis compared with wPV-primed children, resulting in significantly organisms. Consequently, preventive measures such as aPVs that lower Th1/Th2 ratios. Confirming this, it has been shown that do not induce a valid mucosal response can prevent disease wPv or aPV primary immunizations in infancy determines but cannot avoid infection and transmission. Animal studies adolescent cellular immune profiles, showing a beneficial Th1- have shown that natural infection is associated with a strong dominated response after wP-priming (69). These findings secretory IgA response in both the upper and lower airways of a preferential Th1 response were also shown in the and induction of resident memory T cells (TRM) (52, 53). baboon model, with aPV vaccines preventing disease after Moreover, it has been recently reported (54) that IL-17 and natural pertussis challenge, but not preventing transmission IFN-γ-secreting CD69+CD4+ TRM cells were expanded in the of pertussis organisms (70). All these findings indicate that respiratory tract after B. pertussis challenge of mice immunized although aPVs are as individually protective as wPVs in with wP, but not aP vaccines. However, natural infection was the first years after priming, they induce shorter long-term associated with the most persistent protection against nasal protection than wPVs and a different profile of pertussis- colonization and this correlated with potent induction of nasal specific immunity. tissue TRM cells. These animal data suggest that the lack Finally, aPV pertussis vaccines do not prevent colonization. of mucosal immune response after aPV administration might Consequently, they do not reduce the circulation of B. explain its lower efficacy when compared to wPVs and the shorter pertussis and do not exert any herd immunity effect. Frontiers in Immunology | www.frontiersin.org 5 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines These findings at least partly explain the resurgence In conclusion, aPV use seems to favor adaptation of B. of pertussis. pertussis strains with emergence of mutated strains. However, the role of genetic modification in reducing aPV protection remains unclear with future studies needed. Genetic Modifications of Bordetella pertussis ROLE OF ANTIGENS INCLUDED IN Circulation of B. pertussis strains with modified or absent antigens included in the aPV have been reported in both the PRESENTLY AVAILABLE VACCINES IN pre-vaccine era and the aPV era (71–73). Moreover, strains with CONDITIONING PROTECTION polymorphisms of the PT gene resulting in the production of Although pertussis resurgence has been demonstrated to be greater amounts of this protein have been detected (74–79). independent of the type of aPV used, it is theoretically possible Although it cannot be excluded that this phenomenon might that the composition of vaccines and the immunization strategies simply be derived from the natural evolutionary course of B. may have played a role in modifying the pertussis incidence. pertussis, it has been proposed that it might be a consequence of However, estimates of aPV efficacy and comparisons between B. pertussis adaptation to aPV use (80). different aPVs are very problematic for several reasons. First, Genes encoding antigens included in the aPV vaccines have the criteria for the diagnosis of pertussis used in the various evolved at higher rates than other non-vaccine surface protein- aPV effectiveness trials have not been uniform. In some cases, encoding genes soon after the introduction of aPVs into the significant underestimations of the real pertussis incidence may pediatric immunization schedule (81). The most compelling data have limited the reliability of final results. When the WHO’s have been the evolution of PRN-negative B. pertussis strains clinical case definition of pertussis as prolonged paroxysmal according to the use of vaccines PRN-containing vaccines. With cough is used, it is highly likely that most of the mild cases are some exceptions (82–84), studies have demonstrated that the not included. Second, study designs, administration schedules, emergence of PRN-deficient strains has resulted as a consequence and duration of follow-up have not been consistent in the of aPV-induced selection pressure. The rate of PRN-negative effectiveness trials. In many European countries, the primary isolates is significantly correlated with aPV use in the USA (85). series includes only two doses of an aPV with a booster dose at In Denmark, where an aPV without PRN is used, no PRN- ∼1 year. In contrast, in other countries, including the US, the deficient isolates have been detected (86). In Japan where aPVs primary series is based on three doses within the first 6 months with PRN were administered for many years (87), consistent of life, with a booster dose given after the first birthday. Third, rates of PRN-negative strains have been demonstrated over time most, but not all, national immunization schedules include a (2005–2007, 41%; 2008–2010, 35%; and 2011–2013, 25%) (88, booster before entering school and during adolescence. Fourth, 89). However, when these aPV vaccines were replaced with a the composition of the administered aPV can vary. Most of preparation without PRN in November 2012, a marked reduction these studies have been carried out with vaccines containing of PRN-deleted strains was observed (2014–2016, 8%) (90). The three or five antigens, but in earlier studies vaccines with only clinical relevance of PRN-deleted strains has not been precisely PT have been included. In addition, the quantity of antigen can defined (80), but children infected with these strains do not differ among the preparations. For example, GSK DTaP vaccines have more severe pertussis (91, 92), In contrast, B. pertussis contain 25 µg PT, 25 µg FHA, and 8 µg PRN, while the Sanofi strains with the enhanced PT promoter allele PTP3, instead of the common PTP2 allele, were found to produce greater preparation also includes FIM2 and three different amounts of amounts of PT (74) and cause more severe disease in younger PT, FHA, and PRN for the primary and booster doses. Tdap infants (92). contains 10 µg PT, 5 µg FHA, and 3 µg PRN when administered Interesting, B. pertussis strains lacking the PRN gene show alone, but when Tdap is combined with polio, hepatitis B, and increased fitness and/or prolonged infection times in animals Haemophilus influenzae type b, the PT and FHA content is immunized with ACVs (74, 93, 94). This finding suggests that loss increased to 20 µg. In addition, the type of aluminum salt used of PRN could lead to a reduced immune response to aPVs and as an adjuvant and its content vary slightly among between favor pertussis resurgence. However, clinical studies that have vaccines. Finally, there has been no single study that directly evaluated the effectiveness of aPVs containing PRN in the setting compares all aPV vaccines with different numbers and quantities of PRN-deficient pertussis have produced conflicting results. One of included antigens. study in the US (80) assessed the VEs of a five-dose DTaP series among 4–10 year-olds and a Tdap booster among 11–19 year- Role of the Number of Pertussis Antigens olds in an area where >90% of B. pertussis strains were PRN In those studies that directly compared vaccines using similar deficient. It was found that overall DTaP VE was 84% (95% CI 58– vaccine schedules, similar definitions of pertussis disease, and 94%) while that of TdaP was 70% (95% CI 54–81%), which do not comparable durations of follow-up, it can be concluded that the substantially differ than rates reported during the circulation of 3-component aPV (3aPV) and the 5-component aPV (5aPV) PRN-positive strains. In contrast, a second US study revealed that have comparable efficacy. Greco et al. evaluated two 3aPVs in vaccinated persons, the likelihood of suffering from pertussis produced by different pharmaceutical companies (12), and disease was greater if the infecting strain was PRN-negative than Gustafsson et al. (13) studied a 5aPV, with both studies being if it is PRN-positive (85). conducted in children that had received three doses at ∼2, 4, and Frontiers in Immunology | www.frontiersin.org 6 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines 6 months of age and were followed for 2 years. For both 3aPVs, The importance of PRN has already been discussed, and the overall efficacy was 84% (95% CI 75.8–89.4 for the first and whether the lack of PRN in the infecting strain can reduce 76.2–89.7 for the second 3aPV), while that of the 5aPV was 85.2% aPV efficacy remains controversial. Although protection against (95% CI 80.6–88.8) 1 year after first dose (13). pertussis after aPV administration has been correlated with All these vaccines contain PT, which might explain these high serum anti-PRN antibody concentrations, pre-existing PRN relatively similar results. PT seems to be essential for conferring antibodies do not protect against B. pertussis infection (97). protection (95, 96). In Sweden (10) and Denmark (97) a vaccine Further studies are in progress to evaluate the impact of containing only PT demonstrated effectiveness that did not circulating B. pertussis strains lacking pertactin in a systematic differ from that of multivalent aPVs concomitantly used in project among EU countries. other countries. However, lower levels of anti-PT antibodies Fimbriae are adhesins, and the hypothesis of a potential role have been associated with increased susceptibility to B. pertussis reported previously for FHA can also be suggested for Fim2 and infection (95, 96). It has not been determined which type and Fim3. However, data on the potential ability of these antigens quantity of PT is able to confer the greatest short- and long- to induce protective mucosal immunity are lacking. Serum term protection. Because of its various noxious effects, PT must levels of antibodies against Fim2 and Fim3 have been correlated be detoxified before inclusion in aPVs. Detoxification can be with protection after household exposure to B. pertussis (107). achieved genetically or through chemical treatment. The results Moreover, in a clinical trial, when mild cases of pertussis were of these methods are quite different, as genetic detoxification does included in the case definition, the efficacy of a 5aPV was found not modify the antigenic characteristics of PT and leads to a to be significantly higher than that of a two or three component protein with superior immunogenicity to chemically detoxified aPV. Comparing the relative risk of 3aPV recipients acquiring PT, as clearly demonstrated by an efficacy trial showing that pertussis to those receiving 5aPV was 1.82 (95% CI 1.14–2.90), the PT-9K/129G-based vaccine induces earlier and longer- suggesting a protective role of fimbriae (10, 107). In the presently lasting protection (98). Additionally, lower doses of genetically available vaccines, FIM2 seems to be more important than FIM detoxified PT seem to stimulate comparable protection as higher 3, as demonstrated by data collected during long-term evaluation doses of the chemically detoxified product. In the study by Greco of children included in a study by Olin et al. (108). A slight but et al. (12) in which two 3aPVs were evaluated, the protection significant reduction in 5aPV efficacy was seen over time when offered by the two vaccines was comparable but was achieved compared to 3aPV. During that time period, the expression of with 5 µg of genetically detoxified PT and with 25 µg of fimbriae in circulating B. pertussis changed from predominantly chemically detoxified PT. Fim2 to Fim3; suggesting that the stronger immune responses to Finally, it cannot be forgotten that not all chemical the Fim2 antigen than the Fim3 antigen in the vaccinated subjects treatments have the same impact on PT. Detoxification with was the cause of the reduced long-term efficacy of the 5aPV, formaldehyde, glutaraldehyde, or with combined procedures are suggesting that FIM 2 evokes more relevant protection after 5aPV more destructive of epitopes than detoxification with hydrogen administration (109). peroxide, evoking a lower immune response (50). Confirming this notion, important differences have been evidenced when comparing two aPVs detoxified by different chemical procedures VACCINATION COVERAGE AND VACCINE in terms of long-term B and T-cell immune responses (99, 100). HESITANCY The relevance of FHA for inducing protection is less clear. Several studies in mice suggest that pre-existing serum anti- Although coverage with one dose of diphtheria- tetanus-pertussis FHA antibodies do not protect against pertussis in mice (101). vaccine (DTP1) is extremely high globally with overall levels FHA antibody induced by passive or active immunization did at 90% in 2017, the coverage varies between widely 49 and not protect mice against intracerebral or pulmonary challenge 99%, depending on the country (110, 111). In 2017, the greatest with B. pertussis (102). Finally, human studies conducted in number of cases of pertussis were reported in in India (23,766), Japan suggested that comparable protection was seen after either Germany (16,183), Australia (12,114), and China (10,390), an aPV containing PT and FHA or only an aPV including countries with national vaccination coverage rates of DTP1 all only PT, although the results of this study remain debatable, above 90% and coverage rates for three doses of DTP (DTP3) since the PT and FHA combination vaccine contained only above 88% (112). However, coverage may be high nationally, approximately 50% of the PT in PT only product. In contrast, there can be regional variation leading to sporadic pertussis cases another study in humans found that the relative efficacy of a and disease outbreaks (111). monovalent PT vaccine was significantly less than that seen after Pertussis is an important cause of childhood morbidity combined PT-FHA vaccine during 3 years of passive surveillance and mortality, especially in infants under 6 months of age. (103). However, as FHA is an adhesin that is essential for the Maternal pertussis immunization is an effective strategy to adherence of B. pertussis to the respiratory epithelium, it has protect infants during this vulnerable period, prior to them being been suggested that mucosal antibodies against this antigen protected during their childhood vaccination. Maternal pertussis could block adherence, thereby protecting against colonization, immunization has been included in national recommendations and, consequently, disease (104). This hypothesis is supported across several high-income countries, including the United States by the evidence that FHA delivered to experimental animals in 2011, the United Kingdom in 2012, and in Australia in 2015 intranasally can provide protection against aerosol challenge with (113, 114). Reasons for non-vaccination in pregnant women are B. pertussis (105, 106). context specific, and include a lack of awareness, a lack of access, Frontiers in Immunology | www.frontiersin.org 7 July 2019 | Volume 10 | Article 1344 Esposito et al. Pertussis Prevention With Acellular Pertussis Vaccines a lack of perceived need for the vaccine, and concerns about its The optimal pertussis vaccine would be one that induced both safety and effectiveness (115). a mucosal and systemic responses similar to those occurring under natural infection, leading to a long-term protection against both disease and infection. Such a vaccine might increase public CONCLUSIONS confidence and result in better vaccine uptake. Meanwhile, the identification of more efficacious vaccination strategies The resurgence of pertussis observed in recent years seems to with currently available vaccines reaching high vaccination be a complex but real phenomenon resulting from a number of coverage rates is required, including the vaccination of pregnant cases, including the use of aPV in many locales. Lack of mucosal women (50). immune responses after aPV administration favor infection, persistent colonization, and transmission of the pathogen. Moreover, earlier waning of protective immunity and the AUTHOR CONTRIBUTIONS circulation of B. pertussis variants depleted of vaccine-included SE proposed the project, coordinated the Study Group, and antigens further favor the increase in pertussis disease. Several wrote the first draft of the study. PS, NF, and GF coordinated different aPVs are available, but it has yet to be determined the sections of the project on Vaccines, Microbiology, and which of them confers the highest and the most-prolonged Immunology, respectively, giving a substantial scientific protection. Further studies are needed to evaluate the importance contribution. QH, PP, TT, MK, CR, CW, KF, IH, IL, KE, and of individual antigens included in aPVs in conferring protection MO gave a substantial scientific contribution. NP co-wrote the against disease, colonization, and transmission. However, present first draft of the manuscript and supervised the project. All knowledge seems to indicate that PT, particularly if genetically authors approved the final submitted version of the manuscript. detoxified, represents the main antigen that ensures protection from disease even if not from infection. 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MK was member of advisory boards for GSK, Pfizer, moiety of Bordetella pertussis filamentous hemagglutinin: adherence, Baxter, Novartis, Astra Zeneca, MedImmune, SPMSD, Sanofi, MSD, Jansen, and immunogenicity, and protective role. Infect Immun. (2002) 70: 4142– performed for these companies presentations during industry symposia. These 7. doi: 10.1128/IAI.70.8.4142-4147.2002 activities were done as a service task for his employer. Personally, he did not 106. Knight JB, Huang YY, Halperin SA, Anderson R, Morris A, receive any fees from companies. There was also no target agreement with his Macmillan A, et al. Immunogenicity and protective efficacy of a employer in this respect. MO has received an investigator initiative research grant recombinant filamentous haemagglutinin from Bordetella pertussis. from Merck to evaluate population perception on hexavalent vs. heptavalent Clin Exp Immunol. (2006) 144:543–51. doi: 10.1111/j.1365-2249.2006.0 vaccines in Chile. KF is on the vaccine advisory boards for Sanofi Pasteur and 3097.x Seqiris and have received honoraria from AstraZeneca and Pfizer for giving talks. 107. Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates PP has received research funding from the National Institute for Health Research of immunity to Bordetella pertussis cough illnesses. Vaccine. (1998) 16:1901– and from GlaxoSmithKline, and has received honorariums from Sanofi Pasteur 6. doi: 10.1016/S0264-410X(98)00226-6 and Pfizer. CR has received consultancy fees and independent research grants 108. Olin P, Rasmussen F, Gustafsson L, Hallander HO, Heijbel H. from GlaxoSmithKline group of companies, Sanofi-Pasteur MSD, Wyeth, Pfizer, Randomised controlled trial of two-component, three-component, and Astra-Zeneca, and Astellas. five-component acellular pertussis vaccines compared with whole-cell pertussis vaccine. Lancet. (1997) 350:1569–77. doi: 10.1016/S0140-6736(97)0 The remaining authors declare that the research was conducted in the absence of 6508-2 any commercial or financial relationships that could be construed as a potential 109. Hallander H, Advani A, Alexander F, Gustafsson L, Ljungman M, Pratt C, conflict of interest. et al. Antibody responses to Bordetella pertussis Fim2 or Fim3 following immunization with a whole-cell, two-component, or five-component Copyright © 2019 Esposito, Stefanelli, Fry, Fedele, He, Paterson, Tan, Knuf, Rodrigo, acellular pertussis vaccine and following pertussis disease in children Weil Olivier, Flanagan, Hung, Lutsar, Edwards, O’Ryan and Principi. This is an in Sweden in 1997 and 2007. Clin Vaccine Immunol. (2014) 21:165– open-access article distributed under the terms of the Creative Commons Attribution 73. doi: 10.1128/CVI.00641-13 License (CC BY). The use, distribution or reproduction in other forums is permitted, 110. WHO. Global and regional immunization profile. Data received as of provided the original author(s) and the copyright owner(s) are credited and that the 21 September 2018. (2018). Available online at: http://www.who.int/ original publication in this journal is cited, in accordance with accepted academic immunization/monitoring_surveillance/data/gs_gloprofile.pdf?ua=1 practice. No use, distribution or reproduction is permitted which does not comply (accessed October 4, 2018). with these terms. Frontiers in Immunology | www.frontiersin.org 11 July 2019 | Volume 10 | Article 1344