**2.3. Current situation around the world**

In the USA, notable increases in pertussis disease occurred in 2004 (25,827 cases, 27 deaths), in 2010 (27,550 cases, 27 deaths), and, more recently, in 2012, when more than 41,000 cases and 18 deaths have been reported, the largest number of cases in the USA since 1959. In addition, the epidemiological characteristics of whooping cough have changed in recent years with an increased load of disease among fully vaccinated children and adolescents [28].

In 2012 when whooping cough was epidemic in the USA, there was an incidence of 103 cases per 100,000 inhabitants in Vermont. These evidences suggest a resurgence of pertussis in the USA [3, 26].

According to the WHO SAGE pertussis working group report in April 2014 [3], the data from the USA suggest a decrease in immunity after aP vaccine replaced wP, but no impact was observed on overall infant mortality. It also indicates the limited duration of the protection for pertussis in adolescents, pointing to the need for booster vaccination in adolescents who received the aP vaccine compared to those who had at least one dose of wP. There was no resurgence of the disease in Canada, but the periodic cycle had a higher peak in 2012 than in the previous two cycles. An increase in reported cases was limited to certain regions and happened over short periods. In general, the situation in the country is very heterogeneous with multiple causes for increase in pertussis cases (low vaccine coverage, decreasing immunity, previous wP vaccine with low efficacy), but there is no evidence that aP has contributed to the most recent increase in cases. The data suggest that the immunity induced by aP vaccines decreases before the booster dose of adolescence. Therefore, it can be concluded that the timing of adolescent's vaccination is important and that the age in which the third booster is commonly ministered (14–16 years old) may be too late.

**2.1. Loss of immunity**

28 Pertussis - Disease, Control and Challenges

the natural infection [3, 25].

symptomatic pertussis [26].

USA [3, 26].

**2.2. Pertussis genetic changes**

**2.3. Current situation around the world**

Neither vaccination nor disease induces long-term protection against pertussis. Loss of protection occurs from 4 to 12 years after the last dose of vaccine and from 7 to 20 years after an episode of disease. The duration of protection of the whole-cell vaccine corresponds to that of

The protection evoked by the vaccine tends to get lost over time. Predicted time of the drop of antibody protective levels after vaccination to pre-vaccine levels varies according to different antigens: 15.3 years for pertactin, 11 years for fimbria types 2 and 3, 5 years for pertussis toxin (PT), and 9.5 years for filamentous hemagglutinin. Adolescent vaccination has a good costbenefit, since it leads to a significant reduction in costs with the disease, but yet not all developed countries provide the booster dose for individuals aged between 10 and 17 years. There is evidence that immunization of adolescents also does not provide long-term protection, which may lead to the risk of adults and elderly people being more affected by infection. This raises the issue that adults should also receive booster doses, since adolescents and adults only have protection for a few years, and should receive booster doses every 10 years [20].

The antibodies to pertactin are correlated to the protection of the disease, but nowadays there is an increase of non-pertactin producing *B. pertussis* strains. In developed countries that use the acellular vaccine (which has pertactin as one of its components), loss of immunity may occur, as well as failure to prevent colonization by pertussis. However, other components of the vaccine (pertussis toxin, filamentous hemagglutinin, or fimbriae) also seem to prevent

Genetic changes in *B. pertussis* may be one of the factors that have contributed to the recent reappearance of whooping cough. In the USA, isolated cases of *Bordetella pertussis* without pertactin have increased from 14% in 2010 to 85% in 2012. The effectiveness of the acellular vaccine appears to remain the same, but surveillance for the adaptations and mutations of the

In the USA, notable increases in pertussis disease occurred in 2004 (25,827 cases, 27 deaths), in 2010 (27,550 cases, 27 deaths), and, more recently, in 2012, when more than 41,000 cases and 18 deaths have been reported, the largest number of cases in the USA since 1959. In addition, the epidemiological characteristics of whooping cough have changed in recent years with an

In 2012 when whooping cough was epidemic in the USA, there was an incidence of 103 cases per 100,000 inhabitants in Vermont. These evidences suggest a resurgence of pertussis in the

According to the WHO SAGE pertussis working group report in April 2014 [3], the data from the USA suggest a decrease in immunity after aP vaccine replaced wP, but no impact was

bacteria must be enhanced, as new genotypes have been reported [26, 27].

increased load of disease among fully vaccinated children and adolescents [28].

In Brazil, a country that still uses wP vaccines, national vaccination coverage in infants under 1 year of age with DTP3 (diphtheria-tetanus-pertussis) vaccine was high (>95%) between 2001 and 2011. From 2006 to 2012, the number of municipalities with coverage above 95% decreased from 83 to 55%, resulting in a heterogeneous coverage throughout the country. The causes for the decline were mainly operational issues due to supply and social problems. In Brazil, the number of pertussis cases increased from 2001 to 2012, with a large increase in morbidity and mortality among infants under 1 year old. This increase was attributed in part to improvements in surveillance sensitivity. Between 2007 and 2012, 51% of reported cases of whooping cough in children under 6 months of age did not receive any dose of vaccine, 37% received only one dose against whooping cough, and 12% received 2 or more doses. The majority of deaths, 342 (97%), occurred in children younger than 1 year of age. The increase in fatal cases among children under 6 months of age led the country to introduce the aP vaccine in pregnant women and also to recommend a cocooning strategy. The recurrence of the natural cycle, the drop in vaccination coverage, and the increase in laboratory tests may be responsible for the increase in the number of cases. There is no evidence of diminishing immunity, as cases are predominant in young infants not yet immunized, supported by the fact that the increase is not observed in older age groups, and the change in disease activity does not exceed what would normally be expected in epidemic cycles [3, 29].

In Chile, the quality of data was improved in 2012, since the laboratory methods were previously not ideal. The resurgence of whooping cough observed in 2011 and 2012 was preceded by a drop in vaccine coverage and thus may be partly linked to this fall [3]. In Cuba, the notification is based only on the clinical definition, without laboratory confirmation. The country's data is therefore not comparable with data from other countries, thereby limiting its usefulness [3]. In Mexico, the data quality has serious limitations, and the sensitivity of the surveillance system is low. The increase in cases may be related to the low and heterogeneous vaccination coverage. The use of a more sensitive laboratory method (PCR) may explain the recent increase in cases, an idea supported by the dissociation of the total infant cases from whooping cough and infant mortality in 2012 [3]. In the European Union (EU), 40,727 cases of whooping cough were notified in 29 countries in 2014. The reporting rate was 9.1 cases per 100,000 inhabitants, higher than in 2013 but lower than in the epidemic year of 2012 [18]. Germany reported 12,339 cases (15.3 cases per 100,000 inhabitants) in 2014. Rates were highest among children under 1 year of age (51.6 cases per 100,000 individuals), followed by 10–14 years (24.4 per 100,000) and 15–19 years (19.7 per 100,000). The German data is of good quality; therefore, the hypothesis of resurgence of the disease can be discarded. A low overall incidence and low numbers of hospitalizations are observed despite the years of recurrent outbreaks. The increase in incidence may be due to the greater number of serological tests in adolescents [3, 18]. Spain has had a higher mortality rate and hospitalization for whooping cough in children under 3 months of age in 2010 (142.55/100,000) [30–32]. The situation in Denmark is stable, with an observed increase in cases occurring by natural recurrent cycles of the disease and by the use of serological diagnosis. Denmark is the only country with the exclusive use of monovalent aP vaccine: primary immunization begins at 3 months of age, followed by doses at 5 and 12 months. Since 2004, the total number of reported cases has remained relatively stable since the introduction of the aP vaccine, contrary to what has been reported by other countries that have used long-term aP vaccines [3, 5]. The observed epidemiology of Finland is explained by naturally occurring cycles. The situation is stable; no statistically significant change in trends is identified after 2003–2004. Since the aP vaccine was introduced in 2005, the time elapsed is still short to allow observation of possible resurgence of the disease due to the decrease in aP-related immunity. In France, there was no resurgence of the disease, with the aP vaccine being used in the past 10 years with a high coverage. Available data suggest a recent increase in incidence in the age range between 5 and 10, which may reflect an increasing decrease in protection in cohorts exclusively vaccinated with aP. New strategies, such as adult reinforcement and cocooning, have not had a major impact, and their level of implementation remains low [3]. The incidence of pertussis in Belgium at all ages was estimated from 24.2 to 30.8 per 100,000 individuals in 2014. In a study with identification of *B. pertussis* with real-time PCR, the culture of these cases was positive in 30%. In this same study, 60% of the cases were positive in serology with anti-PT antibodies, two serology samples were required, and rare cases were positive for both methods, with which it was demonstrated that diagnosis may require both microbiological and immunological methods [3, 25, 33]. In Portugal, there was a significant increase in incidence in infants under 1 year of age, suggesting a true resurgence of the disease, although the increased incidence may also be associated with the increased use of the PCR test. Pertussis infant mortality was very high in 2012, while mortality from the period 2000 to 2011 was similar to that of other countries. There is likely underreporting in the older age groups. The whole-cell vaccine was replaced by acellular vaccine in 2006. In Sweden there has been no resurgence of pertussis to date, and there have been no major outbreaks since 2004. There has been a successive reduction in the overall incidence of whooping cough since the reintroduction of the vaccine against pertussis after a 17-year period without the vaccine [3]. In the UK, evidence suggests a resurgence of whooping cough. Although the incidence has declined in the last 20 years, there has been no interruption of the natural epidemic cycle, which happens every 3–4 years. A real increase over the natural cycle was observed in infants younger than 3 months of age in 2011 and 2012. An increase in reported cases, hospitalizations, and the number of deaths in young infants was observed. The actual resurgence of pertussis was recorded 7 years after the introduction of the aP vaccine, coinciding with the peak of the natural epidemic cycle [3]. In Eastern European countries, there have been several outbreaks, whose incidence varied from 0.01 to as high as 96 per 100,000 inhabitants. The highest index was found in Estonia [34]. The data available in Israel do not provide clear evidence of the resurgence of pertussis. Possible explanations for the increase in child cases include greater awareness of whooping cough and the availability of better laboratory tests. Vaccination coverage is high in Israel, which has been using aP (ranging from 3 to 5 components) for the past 7 years [3]. Incidence data for children under 6 years of age in Japan were highest in 2000. The most recent data (2010) show an increase in cases of adults over 20 years. This increase was surprisingly not reflected in young infants, and only a small increase can be observed among older children. No data were obtained concerning hospitalizations and deaths related to whooping cough in Japan. There is no evidence of resurgence, although data are limited [35]. The quality of the data is good in Singapore, and there is no evidence of the resurgence of whooping cough [3]. The data does not allow drawing conclusions about the sudden increase in pertussis in 2007 among those unimmunized or with incomplete immunization, which may be due to the introduction of PCR or whether it was a real increase with case duplication in 2007. Despite the two peaks in 2007 and 2011, the overall incidence was low. The recent rise in whooping cough began shortly after moving from wP to aP vaccine in 2006. Data quality is limited in Thailand, since cases are underreported and there is a low sensitivity of the surveillance system. There is no evidence of a resurgence of whooping cough: incidence remained low between 2009 and 2014. Thailand uses only wP vaccination [3, 36]. In Australia, there was a resurgence of whooping cough between 2008 and 2012 in children under 10 years of age, in particular at 2–4 and 7–9 age ranges. Pertussis is an important public health issue in Australia, with continuous increases observed over a long period of time. The increase was observed at first in adults, related to the availability of serological tests, and then in adolescents, which was related to a history of low coverage of vaccines. More recently, increase of pertussis was observed in younger children, consistent with declining immunity in the context of increased availability and use of tests. Withdrawal of the booster dose in early childhood (at 18 months of age) appears to have made an important contribution to the resurgence of the disease in children aged 2–4 years, with decreasing immunity after the last dose of acellular vaccine at 6 months. The 18-month vaccine was reintroduced in 2015. As in the USA, Australia had large

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increases of the disease in children over 6 years of age [3, 37, 38].

There are few publications on pertussis in Africa, and most of them do not contain surveillance data and epidemiological trends. In addition we have lack of laboratories capable of adequate diagnosis [39]. Based on the WHO data, the number of cases of pertussis in Africa decreased from 2000 to 2010, except in 2011, when an increase occurred [40]. The WHO in 2016 reported 139,535 cases of pertussis in the world, and in Africa we had only 1425 reported cases [21]. Nigeria, on the other hand, had a peak in whooping cough activity in 2009, reporting the second largest number of cases worldwide, and the diagnosis was made primarily clinical as there are few laboratories for the research [40]. In some African countries, wP vaccine coverage is very low, as measured in Chad (22%), Equatorial Guinea (33%), Gabon (45%), Nigeria (47%), Liberia 49%), Ethiopia (51%), Central African Republic (54%), Guinea (59%), Cote d'Ivoire (62%), and Cameroon (68%) [40]. The WHO African Regional Office (AFRO) is working on reducing missed opportunities for vaccination in 20 priority countries representing 30% (5.9 million) of the unvaccinated or partially vaccinated global birth cohort [41].

Country-specific data provided no evidence of a widespread resurgence of whooping cough globally. The increase in the number of pertussis cases observed in recent years has been attributed to cyclical patterns in most countries, probably amplified by increased disease Possible explanations for the increase in child cases include greater awareness of whooping cough and the availability of better laboratory tests. Vaccination coverage is high in Israel, which has been using aP (ranging from 3 to 5 components) for the past 7 years [3]. Incidence data for children under 6 years of age in Japan were highest in 2000. The most recent data (2010) show an increase in cases of adults over 20 years. This increase was surprisingly not reflected in young infants, and only a small increase can be observed among older children. No data were obtained concerning hospitalizations and deaths related to whooping cough in Japan. There is no evidence of resurgence, although data are limited [35]. The quality of the data is good in Singapore, and there is no evidence of the resurgence of whooping cough [3]. The data does not allow drawing conclusions about the sudden increase in pertussis in 2007 among those unimmunized or with incomplete immunization, which may be due to the introduction of PCR or whether it was a real increase with case duplication in 2007. Despite the two peaks in 2007 and 2011, the overall incidence was low. The recent rise in whooping cough began shortly after moving from wP to aP vaccine in 2006. Data quality is limited in Thailand, since cases are underreported and there is a low sensitivity of the surveillance system. There is no evidence of a resurgence of whooping cough: incidence remained low between 2009 and 2014. Thailand uses only wP vaccination [3, 36]. In Australia, there was a resurgence of whooping cough between 2008 and 2012 in children under 10 years of age, in particular at 2–4 and 7–9 age ranges. Pertussis is an important public health issue in Australia, with continuous increases observed over a long period of time. The increase was observed at first in adults, related to the availability of serological tests, and then in adolescents, which was related to a history of low coverage of vaccines. More recently, increase of pertussis was observed in younger children, consistent with declining immunity in the context of increased availability and use of tests. Withdrawal of the booster dose in early childhood (at 18 months of age) appears to have made an important contribution to the resurgence of the disease in children aged 2–4 years, with decreasing immunity after the last dose of acellular vaccine at 6 months. The 18-month vaccine was reintroduced in 2015. As in the USA, Australia had large increases of the disease in children over 6 years of age [3, 37, 38].

were highest among children under 1 year of age (51.6 cases per 100,000 individuals), followed by 10–14 years (24.4 per 100,000) and 15–19 years (19.7 per 100,000). The German data is of good quality; therefore, the hypothesis of resurgence of the disease can be discarded. A low overall incidence and low numbers of hospitalizations are observed despite the years of recurrent outbreaks. The increase in incidence may be due to the greater number of serological tests in adolescents [3, 18]. Spain has had a higher mortality rate and hospitalization for whooping cough in children under 3 months of age in 2010 (142.55/100,000) [30–32]. The situation in Denmark is stable, with an observed increase in cases occurring by natural recurrent cycles of the disease and by the use of serological diagnosis. Denmark is the only country with the exclusive use of monovalent aP vaccine: primary immunization begins at 3 months of age, followed by doses at 5 and 12 months. Since 2004, the total number of reported cases has remained relatively stable since the introduction of the aP vaccine, contrary to what has been reported by other countries that have used long-term aP vaccines [3, 5]. The observed epidemiology of Finland is explained by naturally occurring cycles. The situation is stable; no statistically significant change in trends is identified after 2003–2004. Since the aP vaccine was introduced in 2005, the time elapsed is still short to allow observation of possible resurgence of the disease due to the decrease in aP-related immunity. In France, there was no resurgence of the disease, with the aP vaccine being used in the past 10 years with a high coverage. Available data suggest a recent increase in incidence in the age range between 5 and 10, which may reflect an increasing decrease in protection in cohorts exclusively vaccinated with aP. New strategies, such as adult reinforcement and cocooning, have not had a major impact, and their level of implementation remains low [3]. The incidence of pertussis in Belgium at all ages was estimated from 24.2 to 30.8 per 100,000 individuals in 2014. In a study with identification of *B. pertussis* with real-time PCR, the culture of these cases was positive in 30%. In this same study, 60% of the cases were positive in serology with anti-PT antibodies, two serology samples were required, and rare cases were positive for both methods, with which it was demonstrated that diagnosis may require both microbiological and immunological methods [3, 25, 33]. In Portugal, there was a significant increase in incidence in infants under 1 year of age, suggesting a true resurgence of the disease, although the increased incidence may also be associated with the increased use of the PCR test. Pertussis infant mortality was very high in 2012, while mortality from the period 2000 to 2011 was similar to that of other countries. There is likely underreporting in the older age groups. The whole-cell vaccine was replaced by acellular vaccine in 2006. In Sweden there has been no resurgence of pertussis to date, and there have been no major outbreaks since 2004. There has been a successive reduction in the overall incidence of whooping cough since the reintroduction of the vaccine against pertussis after a 17-year period without the vaccine [3]. In the UK, evidence suggests a resurgence of whooping cough. Although the incidence has declined in the last 20 years, there has been no interruption of the natural epidemic cycle, which happens every 3–4 years. A real increase over the natural cycle was observed in infants younger than 3 months of age in 2011 and 2012. An increase in reported cases, hospitalizations, and the number of deaths in young infants was observed. The actual resurgence of pertussis was recorded 7 years after the introduction of the aP vaccine, coinciding with the peak of the natural epidemic cycle [3]. In Eastern European countries, there have been several outbreaks, whose incidence varied from 0.01 to as high as 96 per 100,000 inhabitants. The highest index was found in Estonia [34]. The data available in Israel do not provide clear evidence of the resurgence of pertussis.

30 Pertussis - Disease, Control and Challenges

There are few publications on pertussis in Africa, and most of them do not contain surveillance data and epidemiological trends. In addition we have lack of laboratories capable of adequate diagnosis [39]. Based on the WHO data, the number of cases of pertussis in Africa decreased from 2000 to 2010, except in 2011, when an increase occurred [40]. The WHO in 2016 reported 139,535 cases of pertussis in the world, and in Africa we had only 1425 reported cases [21]. Nigeria, on the other hand, had a peak in whooping cough activity in 2009, reporting the second largest number of cases worldwide, and the diagnosis was made primarily clinical as there are few laboratories for the research [40]. In some African countries, wP vaccine coverage is very low, as measured in Chad (22%), Equatorial Guinea (33%), Gabon (45%), Nigeria (47%), Liberia 49%), Ethiopia (51%), Central African Republic (54%), Guinea (59%), Cote d'Ivoire (62%), and Cameroon (68%) [40]. The WHO African Regional Office (AFRO) is working on reducing missed opportunities for vaccination in 20 priority countries representing 30% (5.9 million) of the unvaccinated or partially vaccinated global birth cohort [41].

Country-specific data provided no evidence of a widespread resurgence of whooping cough globally. The increase in the number of pertussis cases observed in recent years has been attributed to cyclical patterns in most countries, probably amplified by increased disease awareness, increased global laboratory tests, and increased sensitivity of diagnostic methods, as well as by the use of PCR amplification. Recurrent natural cycles may be more visible in countries where surveillance is more sensitive and where disease control in recent years has generally been good.

diminishes before the age of 6 years old, whereas those who use wP offer a protection that lasts for 6 years or more. A second booster dose should be given from 4 to 6 years of age for

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National programs currently administering wP vaccination should continue to use wP vaccines for the primary vaccination series. National programs currently using the aP vaccine may continue to use this vaccine but should consider the need for additional booster doses and additional strategies, such as maternal immunization in case of pertussis resurgence. Only the aP vaccine can be administered in individuals from the age of 7 onward. Vaccination at this age must be based on cost-effectiveness mindset, since the priority is always to main-

The acellular vaccine was introduced in 1992 in the American calendar, and in 1997 it was already part of the entire childhood calendar (2, 4, 6, and 15 months and 4–6 years). In 2006, a booster dose was introduced at 11–12 years old. Despite this, there was a large outbreak in 2012 in children vaccinated with the acellular vaccine, probably due to the loss of immunity, lower immune response induced by the aP, increased awareness and notification, as well as

One of the reasons for the increase in pertussis is the loss of immunity induced by the vaccine or by infection among adolescents and adults. This leads to the discussion about the need for changes in the vaccine calendars of adolescents and adults. In countries with high vaccination coverage, there has also been an increase in pertussis cases in adolescents and adults in recent years, which is one of the causes of the onset of diseases in young infants, so a vaccine booster in adolescence and adulthood is recommended in order to reduce the spread of the disease

The duration of immunity of the wP vaccine is 4–12 years, and the aP protection begins to diminish after 4–5 years. This led to the need of a booster dose in the adolescence (from 8 to 11 years), because adolescents present low levels of antibodies, which increase later in life

Although a booster dose in adolescence has been shown to decrease the disease in adolescents, this is generally not recommended as a means of controlling disease in infants. Introduction of reinforcements in adolescents and/or in adults should only be done after evaluation of local epidemiology [16, 43]. Adult vaccination in most countries with high vaccination coverage is done with dT, and even when done with dTap, as in the USA, this occurs in only 14.2% of

One of the risk factors associated with pertussis in young infants is the presence of a household contact, usually parents, siblings, or caregivers, with a cough for 5 days or more [46].

One of the strategies to reduce the transmission of pertussis to young infants, especially less than 6 months of age, is the introduction of Tdap vaccination in pregnant women between 27

improved diagnostic techniques, and possibly genetic alterations of the bacteria [26].

tain high vaccination coverage in the first years of life [16].

**3.3. Adolescents and adults: booster schedule**

(from 12 to 15 years) due to natural infection [44].

adults who have done so in the last 7 years [45].

**3.4. Pregnant women: booster doses**

both vaccines [16, 43].

among young infants [20].

Data from only five of these countries (Australia, Chile, Portugal, the USA, and the UK) supported the hypothesis of a real resurgence in pertussis-related morbidity in recent years compared to previous periods of time. Only one country that used wP vaccine against pertussis, Chile, reported a resurgence. For the time being, the increase in cases can be attributed to a sustained decrease in vaccine coverage, to variable coverage at the district level, to changes in surveillance practices, as well as to problems with the specificity of diagnostic tests. The increase in infant cases was noteworthy and associated with increased disease mortality. However, since this was based on fluorescent antibody test data alone (which is known to have problems with specificity), more data will be needed for a better characterization of the problem [3, 39].
