1. Introduction

Pertussis or whooping cough, caused by Bordetella pertussis, is a severe respiratory childhood disease that can be fatal, particularly in very young infants. However, it also represents a significant disease burden in older children, adolescents, and adults [1]. The first pertussis vaccine was developed in 1926 [2] but has only been available for large-scale administration

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

since the middle of the last century. Today, more efficacious vaccines based on key antigens of pertussis have been developed and are available for providing global coverage in vaccination programs [3]. These vaccines are included on the World Health Organization (WHO) Model List of Essential Medicines, as one of the most effective and safe medicines needed in a healthcare system [4]. Nevertheless, the disease is still not under control and today is considered one of the most prevalent vaccine-preventable childhood diseases. The World Health Organization (WHO) records close to 160,700 pertussis-related deaths in children younger than 5 years in 2014 and more than 24.1 million yearly pertussis cases worldwide [5]. Since the 1950s, the incidence and the numbers of pertussis-linked deaths have declined dramatically and reached its lowest point in several countries in the late 1970s, which showed the effectiveness of mass vaccination programs against pertussis. Prior to their implementation, the reported incidence of the disease was as high as 150 cases per 100,000 persons, which was most likely a vast underestimation even in countries like the USA [6]. More recently, the number of cases and associated deaths has again increased in several industrialized countries, reflecting a shortcoming in current vaccination strategies.

Name of aPVs Composition<sup>1</sup> Manufacturers/Distributer

Acel-Imune (PT, FHA, PRN, FIM) +DT+TT Wyeth Pharmaceutics (USA)

Adacel (PT, FHA, PRN, FIM) +DT+TT Sanofi Pasteur

Boostrix-3 (PT, FHA, PRN) +DT+TT Sanofi Pasteur BSc-1 (PT) Biocine Sclavo

CLL-3F2 (PT, FHA, FIM) Sanofi Pasteur (Canada) Certiva (PT)+DT+TT Baxter Laboratory Daptacel (Tripacel) (PT, FHA, PRN, FIM) +DT+TT Sanofi Pasteur

2HCPDT (PT, FHA, PRN, FIM) +DT+TT Sanofi Pasteur (Canada)

JNIM-7 (PT) Japan Nat Inst of Healthy

NIH-6 (PT, FHA) Japan Nat Inst of Healthy

Pentavac (PT, FHA, PRN, FIM) +DT+TT + HB + IPV + Hib Sanofi Pasteur (France)

Triavax (PT, FHA) +DT+TT Sanofi Pasteur (France) Tripedia (PT, FHA) +DT+TT Sanofi Pasteur (USA)

DT (2.5 lf) + TT (5lf). Licensed for use in person with 4 yr age or older. In the USA 10-60 yr older.

10Repevax (PT, FHA, PRN, FIM) +DT+TT + IPV Sanofi Pasteur

Quantitative difference can be found in the aPV compounds formulations.

<sup>4</sup> A 3-in-1 vaccine approved for individuals aged ≥10 yr including those aged ≥65 yr.

HCPDT is the "hybrid" formulation of Tripacel, evaluated in 1993 Stockholm trial.

11SKB-2 was an experimental two-company DTaP evaluated in the 1992 Stockholm trial.

Table 2. Source and composition of acellular pertussis vaccines studied and producers.

JNIH-6 and 7 were the aPV used in the 1986 Swedish trial.

(pertussis), polio and Hib disease (Haemophilus influenzae type b).

DTaP-HB-IPV-Hib PT, FHA, PRN, FIM) +DT+TT + HB + IPV + Hib MGM Vacines Co (Merck/Sanofi)

Infanrix (PT, FHA, PRN) + DT+TT Glaxo Smith Klein (Rixensant, Belgium)

LPB-3P (PT, FHA, PRN) Wyeth Lederle Vaccines and Pediatric

MIch-2 (PT, FHA) Michigan Department of Public Health

Por-3F2 (PT, FHA, FIM) Speywood (Porton) Pharmaceuticals

SSVI-1 (PT) Swiss Serum and Vaccine Institute 11SKB-2 PT, FHA) +DT+TT SmithKline Beecham Biologicals

A 3-in-1 vaccine, differ from Infanrix by containing reduced quantities of PT (8 μg) + FHA (8 μg) + PRN (2,5 μg) +

The 6-in-1 vaccine is given to babies as a series of 3 doses. The first dose is given at 2 months of age, the second at

The 5-in-1 vaccine was used in the UK for many years. In late September 2017 the UK replaced it with a 6-in-1 vaccine for all babies born on or after 1st August 2017. Both vaccines give protection against diphtheria, tetanus, whooping cough

Abbreviations: PT, pertussis toxin; FHA, phytohemagglutinin; PRN, pertactin; FIM, fimbriae (mixture of FIM-2 and FIM-3); TT, tetanus toxoid; DT, diphtheria toxoid, HB, Hepatitis B; IPV, Inactived Polio; Hib, Haemophilus influenzae type b.

4 months, and the third at 6 months. The vaccine is given at the same time as other childhood immunizations.

10A 3-in1 vaccine indicated for persons from 3 years of age as a booster following primary immunizations.

(Germany)

(PT, FHA, PRN) +DT+TT Chiron Vaccines (USA)

Preventive and Protective Properties of Pertussis Vaccines: Current Situation and Future Challenges

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47

2

2 Acelluvax (Triacelluvax)

3

4

5

6

7

8

9

1

2

3

5

6

7

8

9

No longer available (as of 2013).

Used in Pentacel and Pediacel.

Two types of pertussis vaccines (PVs) are currently available: the first-generation whole-cell vaccines (wPV) and the more recent acellular vaccines (aPVs). While the efficacy of wPV (Table 1) has been demonstrated to be ≥94% after three administrations [7], the occurrence of adverse local and systemic events along with difficulties in production consistency leads to the development of aPVs in the 1980s, currently composed of one to five purified key antigens (Table 2). All available aPVs are combined with tetanus and diphtheria toxoids. Several are also formulated with hepatitis B, inactivated polio, and Haemophilus influenza B polysaccharide [8]. The aPVs clearly have an improved safety profile over wPV, and their short-term efficacy after three administrations was estimated to be 67–70% up to 84%, even those containing three or five B. pertussis components [8]. This value was recently confirmed in a systematic review of meta-analysis data focusing on the short-term protective effect of currently available childhood pertussis vaccines [9]. Because of their improved safety profiles and similar efficacies, most


Table 1. List of whole cell pertussis vaccine manufacturers or distributors.


1 Quantitative difference can be found in the aPV compounds formulations.

2 No longer available (as of 2013).

since the middle of the last century. Today, more efficacious vaccines based on key antigens of pertussis have been developed and are available for providing global coverage in vaccination programs [3]. These vaccines are included on the World Health Organization (WHO) Model List of Essential Medicines, as one of the most effective and safe medicines needed in a healthcare system [4]. Nevertheless, the disease is still not under control and today is considered one of the most prevalent vaccine-preventable childhood diseases. The World Health Organization (WHO) records close to 160,700 pertussis-related deaths in children younger than 5 years in 2014 and more than 24.1 million yearly pertussis cases worldwide [5]. Since the 1950s, the incidence and the numbers of pertussis-linked deaths have declined dramatically and reached its lowest point in several countries in the late 1970s, which showed the effectiveness of mass vaccination programs against pertussis. Prior to their implementation, the reported incidence of the disease was as high as 150 cases per 100,000 persons, which was most likely a vast underestimation even in countries like the USA [6]. More recently, the number of cases and associated deaths has again increased in several industrialized countries,

Two types of pertussis vaccines (PVs) are currently available: the first-generation whole-cell vaccines (wPV) and the more recent acellular vaccines (aPVs). While the efficacy of wPV (Table 1) has been demonstrated to be ≥94% after three administrations [7], the occurrence of adverse local and systemic events along with difficulties in production consistency leads to the development of aPVs in the 1980s, currently composed of one to five purified key antigens (Table 2). All available aPVs are combined with tetanus and diphtheria toxoids. Several are also formulated with hepatitis B, inactivated polio, and Haemophilus influenza B polysaccharide [8]. The aPVs clearly have an improved safety profile over wPV, and their short-term efficacy after three administrations was estimated to be 67–70% up to 84%, even those containing three or five B. pertussis components [8]. This value was recently confirmed in a systematic review of meta-analysis data focusing on the short-term protective effect of currently available childhood pertussis vaccines [9]. Because of their improved safety profiles and similar efficacies, most

reflecting a shortcoming in current vaccination strategies.

46 Pertussis - Disease, Control and Challenges

Table 1. List of whole cell pertussis vaccine manufacturers or distributors.

3 A 3-in-1 vaccine, differ from Infanrix by containing reduced quantities of PT (8 μg) + FHA (8 μg) + PRN (2,5 μg) + DT (2.5 lf) + TT (5lf). Licensed for use in person with 4 yr age or older. In the USA 10-60 yr older.

<sup>4</sup> A 3-in-1 vaccine approved for individuals aged ≥10 yr including those aged ≥65 yr.

5 The 6-in-1 vaccine is given to babies as a series of 3 doses. The first dose is given at 2 months of age, the second at 4 months, and the third at 6 months. The vaccine is given at the same time as other childhood immunizations. 6 Used in Pentacel and Pediacel.

7 HCPDT is the "hybrid" formulation of Tripacel, evaluated in 1993 Stockholm trial.

8 JNIH-6 and 7 were the aPV used in the 1986 Swedish trial.

9 The 5-in-1 vaccine was used in the UK for many years. In late September 2017 the UK replaced it with a 6-in-1 vaccine for all babies born on or after 1st August 2017. Both vaccines give protection against diphtheria, tetanus, whooping cough (pertussis), polio and Hib disease (Haemophilus influenzae type b).

10A 3-in1 vaccine indicated for persons from 3 years of age as a booster following primary immunizations.

11SKB-2 was an experimental two-company DTaP evaluated in the 1992 Stockholm trial.

Abbreviations: PT, pertussis toxin; FHA, phytohemagglutinin; PRN, pertactin; FIM, fimbriae (mixture of FIM-2 and FIM-3); TT, tetanus toxoid; DT, diphtheria toxoid, HB, Hepatitis B; IPV, Inactived Polio; Hib, Haemophilus influenzae type b.

Table 2. Source and composition of acellular pertussis vaccines studied and producers.

developed countries have replaced wPV with an aPV. Globally, wPVs are still the most used vaccines due the higher cost of aPVs, which are difficult to afford in resource-poor countries.

Such a vaccine is currently under development based on a live attenuated B. pertussis strain. Named BPZE1, it has been genetically modified to affect the activity of three different toxins such that they are absent, inactive, or minimally active [24]. This strain has been documented to be safe in preclinical models and genetically stable over at least 1 year of continuous passaging in vitro and in vivo in mice [25]. It can induce a strong protection against challenge infections after a single intranasal administration, which lasted at least for up to 1 year. This contrasts with the protection conferred by aPV that can begin to wane after only 6 months. The strain BPZE1 has successfully completed a Phase I clinical trial that showed its safety profile in young male volunteers with a single intranasal dose of up to 107 colony-forming units suspended in 100 μl. This trial also showed that BPZE1 can transiently colonize the human nasopharynx and induce B. pertussis-specific antibody responses in all colonized individuals. At 6 months, follow-up studies measured antibody titers against all antigens tested to be at least at the same level as detected at 1 month postvaccination. One concern with the trail was the observation that not all subjects showed colonization by BPZE1, even at the highest dose tested, since colonization was found to be essential for the induction of an immune response. A possible reason of the absence of colonization in some individuals may have been their prior contact with wild-type B. pertussis, which could have prevented a response to the vaccine. Consistent with this hypothesis is the detection of preexisting antibody titers in the noncolonized individuals that were significantly higher than the pre-vaccination titers of individuals that displayed colonization, especially against pertactin. Additional studies are needed to test the influence of a prior exposure to wild-type B. pertussis on BPZE1 colonization and to eliminate the possibility for a previously imperceptible subclinical disease. New clinical trials are in progress to test the hypothesis that the presence of preexisting antibodies prevents colonization by the vaccine strain and to determine if their activity can be neutralized by

Preventive and Protective Properties of Pertussis Vaccines: Current Situation and Future Challenges

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Realistically, it would require many more years of research and regulatory approval before a new pertussis vaccine could be available for general use. In the interim, efforts are being made to optimize the application of current vaccines. A promising observation is the protection afforded to newborns, less than 2 months of age, from the immunization of their mothers with aPV during the 28–38th week of gestation. In a recent pertussis outbreak in the UK, the effectiveness of this vaccination schedule was shown to be greater than 90% [26]. Several countries have now made recommendations for providing aPV during pregnancy. However, many issues remain unresolved. For example, the impact of maternal immunization on the immune responses in infants following their primary vaccination is unclear. Several studies have observed a reduction in the primary antibody response to B. pertussis antigens following a maternal vaccination [27]. Another issue is the observation that the adoptive caring immunity is effective to prevent disease but does not prevent pertussis infections in neonates [28]. This suggests that the maternal levels of preexisting pertussis-specific antibodies cannot transfer complete protection against infection. The maternal immune system can be activated in response to pertussis and generates a recall response from memory B cells that increases the levels of milk IgA, but the clinical relevance remains to be determined. Lastly, in a mouse model, challenge studies also have shown that antibodies resulting from maternal vaccinations interfere with the

functionality of antibodies induced from a subsequent vaccination [29].

increasing the vaccine dosage.

Although the vaccines together have saved millions of people since its introduction, it has been estimated that their effectiveness appears to decrease between 2 and 10% per year [1, 10]. This rate of decrease has been observed in countries that continue to administer wPV. Yet, it has become apparent that the immunity induced by aPV declines substantially faster than that induced by wPV [11, 12], which led the WHO to recommend that countries considering a switch from wPV to aPV should expect further guidance [4]. Multiple studies, both epidemiological and serological, have confirmed that immunity wanes rapidly after the aPV booster at age 4–6 years and the preadolescent dose at age 10–12 years [13–18]. Nonetheless, it appears that the waning immunity induced by aPV, or wPV, is not the only reason for the observed resurgence in pertussis infections.

Another possible mechanism is asymptomatic transmission. Mathematical modeling of the incidence rates of pertussis in the USA and UK supports a role for undetectable transmission in the recent increase cases [19]. The potential for an essentially silent transmission is also supported by observations in a baboon model recently developed for studying B. pertussis infections. Vaccinations with aPV did not prevent transmission of B. pertussis. Virulent B. pertussis continued to establish infections in animals vaccinated with either aPV or wPV, even though both vaccines protected against disease. A major difference observed between the two vaccines was that infections cleared more rapidly in wPV-vaccinated baboons [20]. All vaccinated animals showed a lower total bacterial load compared to naïve animals suggesting that both vaccines have a positive impact to limit the progression of an infection. Yet, it appears that this impact may not be sufficient to control the circulation of B. pertussis within a population and could lead to the generation of vaccine escape mutants, which have indeed been observed in several countries where aPV is in use. A likely explanation is the observed increase in the isolation of strains not producing pertactin, due to selective pressure [21]. Conversely, there is no apparent major difference in the pathogenesis of whooping cough in children infected with pertactin-deficient strains compared to pertactin-producing strains. This indicates that pertactin is not required for infection by B. pertussis or for the development of the disease, suggesting a role of pertactin in the immune response following vaccination.

In contrast to vaccination with either aPV or wPV, a natural infection by B. pertussis is able to induce sterilizing immunity in baboons [20]. This fact is intriguing since studies in human have shown that infection-induced immunity is longer lived than vaccine-induced immunity [22], although probably not lifelong as reinfections have been reported to occur. While the second attacks are very rare, they are usually much milder than the primary infections [23]. Since B. pertussis is strictly a mucosal pathogen, it is conceivable that its restricted localization could influence the immunity induced from a natural infection. Although the protective role of mucosal immunity has so far attracted little attention, it may contribute to the differences observed between the protection obtained by a vaccine and a natural infection. These observations suggest that a vaccination approach that more closely mimics a natural infection without resulting in disease may be more successful to ultimately control pertussis.

Such a vaccine is currently under development based on a live attenuated B. pertussis strain. Named BPZE1, it has been genetically modified to affect the activity of three different toxins such that they are absent, inactive, or minimally active [24]. This strain has been documented to be safe in preclinical models and genetically stable over at least 1 year of continuous passaging in vitro and in vivo in mice [25]. It can induce a strong protection against challenge infections after a single intranasal administration, which lasted at least for up to 1 year. This contrasts with the protection conferred by aPV that can begin to wane after only 6 months. The strain BPZE1 has successfully completed a Phase I clinical trial that showed its safety profile in young male volunteers with a single intranasal dose of up to 107 colony-forming units suspended in 100 μl. This trial also showed that BPZE1 can transiently colonize the human nasopharynx and induce B. pertussis-specific antibody responses in all colonized individuals. At 6 months, follow-up studies measured antibody titers against all antigens tested to be at least at the same level as detected at 1 month postvaccination. One concern with the trail was the observation that not all subjects showed colonization by BPZE1, even at the highest dose tested, since colonization was found to be essential for the induction of an immune response. A possible reason of the absence of colonization in some individuals may have been their prior contact with wild-type B. pertussis, which could have prevented a response to the vaccine. Consistent with this hypothesis is the detection of preexisting antibody titers in the noncolonized individuals that were significantly higher than the pre-vaccination titers of individuals that displayed colonization, especially against pertactin. Additional studies are needed to test the influence of a prior exposure to wild-type B. pertussis on BPZE1 colonization and to eliminate the possibility for a previously imperceptible subclinical disease. New clinical trials are in progress to test the hypothesis that the presence of preexisting antibodies prevents colonization by the vaccine strain and to determine if their activity can be neutralized by increasing the vaccine dosage.

developed countries have replaced wPV with an aPV. Globally, wPVs are still the most used vaccines due the higher cost of aPVs, which are difficult to afford in resource-poor countries. Although the vaccines together have saved millions of people since its introduction, it has been estimated that their effectiveness appears to decrease between 2 and 10% per year [1, 10]. This rate of decrease has been observed in countries that continue to administer wPV. Yet, it has become apparent that the immunity induced by aPV declines substantially faster than that induced by wPV [11, 12], which led the WHO to recommend that countries considering a switch from wPV to aPV should expect further guidance [4]. Multiple studies, both epidemiological and serological, have confirmed that immunity wanes rapidly after the aPV booster at age 4–6 years and the preadolescent dose at age 10–12 years [13–18]. Nonetheless, it appears that the waning immunity induced by aPV, or wPV, is not the only reason for the observed

Another possible mechanism is asymptomatic transmission. Mathematical modeling of the incidence rates of pertussis in the USA and UK supports a role for undetectable transmission in the recent increase cases [19]. The potential for an essentially silent transmission is also supported by observations in a baboon model recently developed for studying B. pertussis infections. Vaccinations with aPV did not prevent transmission of B. pertussis. Virulent B. pertussis continued to establish infections in animals vaccinated with either aPV or wPV, even though both vaccines protected against disease. A major difference observed between the two vaccines was that infections cleared more rapidly in wPV-vaccinated baboons [20]. All vaccinated animals showed a lower total bacterial load compared to naïve animals suggesting that both vaccines have a positive impact to limit the progression of an infection. Yet, it appears that this impact may not be sufficient to control the circulation of B. pertussis within a population and could lead to the generation of vaccine escape mutants, which have indeed been observed in several countries where aPV is in use. A likely explanation is the observed increase in the isolation of strains not producing pertactin, due to selective pressure [21]. Conversely, there is no apparent major difference in the pathogenesis of whooping cough in children infected with pertactin-deficient strains compared to pertactin-producing strains. This indicates that pertactin is not required for infection by B. pertussis or for the development of the disease, suggesting a role of pertactin in the immune response following

In contrast to vaccination with either aPV or wPV, a natural infection by B. pertussis is able to induce sterilizing immunity in baboons [20]. This fact is intriguing since studies in human have shown that infection-induced immunity is longer lived than vaccine-induced immunity [22], although probably not lifelong as reinfections have been reported to occur. While the second attacks are very rare, they are usually much milder than the primary infections [23]. Since B. pertussis is strictly a mucosal pathogen, it is conceivable that its restricted localization could influence the immunity induced from a natural infection. Although the protective role of mucosal immunity has so far attracted little attention, it may contribute to the differences observed between the protection obtained by a vaccine and a natural infection. These observations suggest that a vaccination approach that more closely mimics a natural infection without

resulting in disease may be more successful to ultimately control pertussis.

resurgence in pertussis infections.

48 Pertussis - Disease, Control and Challenges

vaccination.

Realistically, it would require many more years of research and regulatory approval before a new pertussis vaccine could be available for general use. In the interim, efforts are being made to optimize the application of current vaccines. A promising observation is the protection afforded to newborns, less than 2 months of age, from the immunization of their mothers with aPV during the 28–38th week of gestation. In a recent pertussis outbreak in the UK, the effectiveness of this vaccination schedule was shown to be greater than 90% [26]. Several countries have now made recommendations for providing aPV during pregnancy. However, many issues remain unresolved. For example, the impact of maternal immunization on the immune responses in infants following their primary vaccination is unclear. Several studies have observed a reduction in the primary antibody response to B. pertussis antigens following a maternal vaccination [27]. Another issue is the observation that the adoptive caring immunity is effective to prevent disease but does not prevent pertussis infections in neonates [28]. This suggests that the maternal levels of preexisting pertussis-specific antibodies cannot transfer complete protection against infection. The maternal immune system can be activated in response to pertussis and generates a recall response from memory B cells that increases the levels of milk IgA, but the clinical relevance remains to be determined. Lastly, in a mouse model, challenge studies also have shown that antibodies resulting from maternal vaccinations interfere with the functionality of antibodies induced from a subsequent vaccination [29].
