2. Resurgence, vaccine design, and new targets

In 2008, there was an estimated incidence of 16 million cases of pertussis infection worldwide that resulted in approximately 195,000 children deaths, making pertussis one of the leading causes of vaccine-preventable deaths in children under 5 years of age [30, 31]. Most of pertussis deaths occur in developing countries. However, pertussis has not only persisted in countries with high vaccination coverage but has resurged with a number of epidemic episodes being recorded [32–34]. The resurgence of pertussis as a deadly childhood disease is a major public health concern that reflects changes in its epidemiology but is also affected by a growing attitude among parents to delay or even refuse vaccination of their children, which highlights the urgent need for new integrated approaches to control the spread and impact of whooping cough. Several explanations have been presented to enlighten the resurgence of pertussis disease over the past few decades in which most of them is associated with the aPVs currently in use: (i) the decrease of vaccine effectiveness over time (declining immunity) [35, 36], (ii) the selection of mutants that can escape the immunity induced by a vaccine [37, 38], and/or (iii) failure of the vaccine to induce sterilizing immunity to the pathogen that avoids transmission [20]. However, perhaps the most significant contributing factor is our relative lack of understanding the basics of pertussis infection, immunity, and disease. We are still unsure of which specific immune responses are protective against B. pertussis infection and disease in humans and how to elicit protective responses through vaccination.

integrity of the bacteria in the vaccine [40]. A major challenge over the next few years will be the implementation of a reproducible process that can produce consistent lots under good manu-

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

http://dx.doi.org/10.5772/intechopen.75055

51

In recent years, extensive research efforts have elucidated that natural infections and immunizations with wPVs predominantly induce IFN-γ-secreting T-helper 1 cells (Th1) and IL-17 secreting Th17 cells [41–44]. By contrast, it has been shown that aPVs induce a qualitatively different immune response, characterized by the induction of Th2 immunity [39, 43–45]. This difference in the immune response, along with the chemical inactivation of the pertussis toxin antigen in aPVs, may account for the apparent lack of aPV protection against colonization by subsequent B. pertussis infections and suboptimal T-cell priming that has been observed as a

Since current aPVs mainly elicit a Th2 response, several solutions have been proposed to improve the Th1/Th17 responses. One possibility is to combine these vaccines with Th1 driving adjuvants, at least for the priming doses [46, 51]. The development of such a candidate vaccine based on a single-immunization platform consisting of three immune stimulators is in progress [47], namely, (i) host defense peptides, (ii) polyphosphazenes (a family of inorganic molecular hybrid polymers based on a phosphorus-nitrogen backbone substituted with organic side groups with very diverse properties), and (iii) the synthetic oligonucleotides containing CpG-ODN (oligodeoxynucleotides) combined with poly(I:C), (polyinosinic-polycytidylic acid) an agonists of Toll-like receptor 9 (TLR9). This last immune stimulatory compound associated with dacarbazine, a therapeutic agent, has been successfully used to promote antitumor immu-

In the case of pertussis, the inclusion of these immune stimulators resulted in a humoral immune response from a single application in neonatal mice and pigs that was 100- to 1000 fold stronger than a licensed aPV [47]. The onset of immunity occurred more quickly with a predominantly Th1 response. Importantly, immunity persisted for more than 2 years and appeared to be highly effective even in the presence of maternal antibodies. To address the contribution of chemically inactivating pertussis toxin to vaccine performance, a strain of B. pertussis was engineered as a source for genetically detoxified Ptx for the formulation of a new aPV. In Thai adolescents, its safety was like Adacel, a trivalent aPV combined with diphtheria and tetanus compounds produced by Sanofi Pasteur (see Table 2) with an

Substantial evidence has been accumulated in the last 2 years that immunity induced by aPVs is much shorter lived than immunity induced by wPV [10]. Additionally, using refined techniques of peptide microarray, it has been demonstrated that qualitative differences within the humoral response of individuals vaccinated with wPV and aPVs exist. Using a microarray technique, it was shown that animals immunized with wPV recognize qualitatively a major number of B epitopes in the PTx than mice immunized with aPV [49]. Another study using a similar approach compared the recognition pattern of sera from children immunized with different pertussis vaccines (17 B. pertussis proteins) and concluded that 11% of the individuals displayed a private humoral response [50]. All these studies are important to guide the rational

improved induction of neutralizing antibodies against PTx [47].

development of new vaccines.

reduction in the efficiency for the generation of an immune memory repertoire.

facturing practice conditions.

nity [48].

To address the resurgence, new vaccination strategies have been explored such as the "cocooning strategy" and maternal immunization. Cocooning refers to the vaccination of mothers and others with direct contact to newborns and infants. Cost-effective cocooning would be difficult to implement since a successful program requires a very high number of contacts be vaccinated to attain a significant impact on the incidence of severe infant pertussis [39]. Currently, there is a growing evidence for effectiveness of immunization of women during pregnancy rather than during the immediate postpartum period. This approach has been found to be more cost-effective than cocooning with a level of vaccine effectiveness against infant deaths that reach an estimated 95% [27]. Alongside the vaccination of contacts, an alternative option under consideration is to advance the vaccination schedule for newborns to 6–8 weeks of age. However, this approach still does not provide protection to infants during their most susceptible period for potentially deadly pertussis infections. A missing element to refinements in the application of available vaccines is an improved surveillance for pertussis. Improvements in the detection of infections and the immune response can positively contribute to evaluations on vaccine efficacy that will help advance our understanding of performance and duration of a pertussis vaccine to provide protection in the field.

Since the 1950s, the toxicity of traditional wPV has been associated with the presence of lipopolysaccharides (LPS), the major constituents of the bacterial outer membranes. To improve on traditional wPVs, the Butantan Institute in Brazil recently produced a wPV with reduced quantities of LPS that removed ≥80% of the endotoxin-related toxicity in comparison to traditional wPV production methods using a chemical extraction of lipo-oligosaccharide (LOS) from the outer membrane. The process maintained the main protective immunogens as well as the integrity of the bacteria in the vaccine [40]. A major challenge over the next few years will be the implementation of a reproducible process that can produce consistent lots under good manufacturing practice conditions.

2. Resurgence, vaccine design, and new targets

50 Pertussis - Disease, Control and Challenges

humans and how to elicit protective responses through vaccination.

pertussis vaccine to provide protection in the field.

In 2008, there was an estimated incidence of 16 million cases of pertussis infection worldwide that resulted in approximately 195,000 children deaths, making pertussis one of the leading causes of vaccine-preventable deaths in children under 5 years of age [30, 31]. Most of pertussis deaths occur in developing countries. However, pertussis has not only persisted in countries with high vaccination coverage but has resurged with a number of epidemic episodes being recorded [32–34]. The resurgence of pertussis as a deadly childhood disease is a major public health concern that reflects changes in its epidemiology but is also affected by a growing attitude among parents to delay or even refuse vaccination of their children, which highlights the urgent need for new integrated approaches to control the spread and impact of whooping cough. Several explanations have been presented to enlighten the resurgence of pertussis disease over the past few decades in which most of them is associated with the aPVs currently in use: (i) the decrease of vaccine effectiveness over time (declining immunity) [35, 36], (ii) the selection of mutants that can escape the immunity induced by a vaccine [37, 38], and/or (iii) failure of the vaccine to induce sterilizing immunity to the pathogen that avoids transmission [20]. However, perhaps the most significant contributing factor is our relative lack of understanding the basics of pertussis infection, immunity, and disease. We are still unsure of which specific immune responses are protective against B. pertussis infection and disease in

To address the resurgence, new vaccination strategies have been explored such as the "cocooning strategy" and maternal immunization. Cocooning refers to the vaccination of mothers and others with direct contact to newborns and infants. Cost-effective cocooning would be difficult to implement since a successful program requires a very high number of contacts be vaccinated to attain a significant impact on the incidence of severe infant pertussis [39]. Currently, there is a growing evidence for effectiveness of immunization of women during pregnancy rather than during the immediate postpartum period. This approach has been found to be more cost-effective than cocooning with a level of vaccine effectiveness against infant deaths that reach an estimated 95% [27]. Alongside the vaccination of contacts, an alternative option under consideration is to advance the vaccination schedule for newborns to 6–8 weeks of age. However, this approach still does not provide protection to infants during their most susceptible period for potentially deadly pertussis infections. A missing element to refinements in the application of available vaccines is an improved surveillance for pertussis. Improvements in the detection of infections and the immune response can positively contribute to evaluations on vaccine efficacy that will help advance our understanding of performance and duration of a

Since the 1950s, the toxicity of traditional wPV has been associated with the presence of lipopolysaccharides (LPS), the major constituents of the bacterial outer membranes. To improve on traditional wPVs, the Butantan Institute in Brazil recently produced a wPV with reduced quantities of LPS that removed ≥80% of the endotoxin-related toxicity in comparison to traditional wPV production methods using a chemical extraction of lipo-oligosaccharide (LOS) from the outer membrane. The process maintained the main protective immunogens as well as the In recent years, extensive research efforts have elucidated that natural infections and immunizations with wPVs predominantly induce IFN-γ-secreting T-helper 1 cells (Th1) and IL-17 secreting Th17 cells [41–44]. By contrast, it has been shown that aPVs induce a qualitatively different immune response, characterized by the induction of Th2 immunity [39, 43–45]. This difference in the immune response, along with the chemical inactivation of the pertussis toxin antigen in aPVs, may account for the apparent lack of aPV protection against colonization by subsequent B. pertussis infections and suboptimal T-cell priming that has been observed as a reduction in the efficiency for the generation of an immune memory repertoire.

Since current aPVs mainly elicit a Th2 response, several solutions have been proposed to improve the Th1/Th17 responses. One possibility is to combine these vaccines with Th1 driving adjuvants, at least for the priming doses [46, 51]. The development of such a candidate vaccine based on a single-immunization platform consisting of three immune stimulators is in progress [47], namely, (i) host defense peptides, (ii) polyphosphazenes (a family of inorganic molecular hybrid polymers based on a phosphorus-nitrogen backbone substituted with organic side groups with very diverse properties), and (iii) the synthetic oligonucleotides containing CpG-ODN (oligodeoxynucleotides) combined with poly(I:C), (polyinosinic-polycytidylic acid) an agonists of Toll-like receptor 9 (TLR9). This last immune stimulatory compound associated with dacarbazine, a therapeutic agent, has been successfully used to promote antitumor immunity [48].

In the case of pertussis, the inclusion of these immune stimulators resulted in a humoral immune response from a single application in neonatal mice and pigs that was 100- to 1000 fold stronger than a licensed aPV [47]. The onset of immunity occurred more quickly with a predominantly Th1 response. Importantly, immunity persisted for more than 2 years and appeared to be highly effective even in the presence of maternal antibodies. To address the contribution of chemically inactivating pertussis toxin to vaccine performance, a strain of B. pertussis was engineered as a source for genetically detoxified Ptx for the formulation of a new aPV. In Thai adolescents, its safety was like Adacel, a trivalent aPV combined with diphtheria and tetanus compounds produced by Sanofi Pasteur (see Table 2) with an improved induction of neutralizing antibodies against PTx [47].

Substantial evidence has been accumulated in the last 2 years that immunity induced by aPVs is much shorter lived than immunity induced by wPV [10]. Additionally, using refined techniques of peptide microarray, it has been demonstrated that qualitative differences within the humoral response of individuals vaccinated with wPV and aPVs exist. Using a microarray technique, it was shown that animals immunized with wPV recognize qualitatively a major number of B epitopes in the PTx than mice immunized with aPV [49]. Another study using a similar approach compared the recognition pattern of sera from children immunized with different pertussis vaccines (17 B. pertussis proteins) and concluded that 11% of the individuals displayed a private humoral response [50]. All these studies are important to guide the rational development of new vaccines.
