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The Pertussis Problem Stanley A. Plotkin Department of Pediatrics, University of Pennsylvania, Philadelphia
Pertussis is resurgent, and many cases are occurring in vaccinated children and adolescents. In countries using acellular vaccines, waning immunity is at least part of the problem. This article discusses possible improvements in those vaccines. Keywords. pertussis; pertussis toxin; adjuvants; waning immunity; Th1 responses.
Pertussis is resurgent. After being largely controlled in children after the advent of routine pertussis immunization with whole-cell vaccine in the 1940s, and continuing control when a switch was made to acellular vaccines in the 1990s, recent reports from around the world suggest that more cases of pertussis are occurring than can be explained by better observation and better diagnostic methods [1]. Although the epidemiologic situation is unclear in some geographical areas, there is little doubt that pertussis incidence has risen in North America, Europe, and Australia, both in school children and adolescents [2, 3]. Pertussis has increased in practically every state in the United States and in some to epidemic proportions [4, 5]. The situation in adults is uncertain, as pertussis has always been common in that age group owing to the impermanence of immunity to Bordetella pertussis [6]. Five factors appear to be playing a role, although experts differ as to what weight to give each one: strain change in the presence of vaccine immunity; local collections of unvaccinated and therefore susceptible children; lower efficacy of acellular vaccines relative to whole-cell vaccines; waning immunity after acellular vaccines; and the predilection of those vaccines to induce Th2 rather than Th1 responses. A sixth possible factor is suggested by the recent finding that acellular vaccine does not
Received 18 October 2013; accepted 8 December 2013; electronically published 20 December 2013. Correspondence: Stanley A. Plotkin, MD, 4650 Wismer Road, Doylestown, PA 18902 ([email protected]). Clinical Infectious Diseases 2014;58(6):830–3 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/cit934
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protect against pertussis infection in a baboon model, although symptoms are prevented [7]. If this is true in humans, circulation of the organism would be intensified in countries using acellular vaccine. Acellular pertussis vaccines contain 1–5 antigens: pertussis toxin (PT), filamentous hemagglutinin, pertactin (PRN), and 2 fimbrial agglutinogens. Strain change has been expressed in several ways: change in circulating organisms over the years in the alleles for each of the antigens [8]; replacement of older promoters of the PT allele with the so-called P3 promotor, which generates more toxin [9, 10]; and the appearance of pertactin-deficient strains [11, 12]. The latter makes vaccines containing PRN less useful. Although most reported cases have occurred in vaccinated children, the presence of substantial numbers of unvaccinated children in a particular area increases the pertussis risk by a factor of 2.5 [13, 14]. Multiple studies, both epidemiological and serological, have confirmed that immunity wanes rapidly after the acellular vaccine booster at age 4–6 years and the preadolescent dose at age 10–12 years [15–18]. Vaccine effectiveness is high for only about 2 years postdose. Moreover, in the many clinical trials conducted in the 1990s, one of the whole-cell pertussis vaccines that was compared with acellular vaccines was poorly immunogenic. In every trial where other whole-cell pertussis vaccines were used, their efficacy was greater than that of the acellular vaccine in the same trial [19]. Although opinions differ as to the correlation of protection with antibody levels, many authorities consider that high levels of PT and PRN antibodies are associated with protection [20, 21]. In addition, studies in mice and in baboons have demonstrated that whereas whole-cell
Table 1. Possible Vaccination Strategies to Control the Resurgence of Pertussis Strategy
Remarks
Return to the use of wcP
Probably unacceptable
Develop less-reactogenic wcP Maternal vaccination to provide transplacental antibody to protect newborn
Not yet done Now generally recommended
Vaccination of newborn contacts (cocoon strategy)
Difficult to obtain complete coverage
More frequent boosters with acP
Costly and difficult to put in place Change antigens in acP to those from Uncertain effect currently circulating strains Increase quantities of current antigens Inactivate PT by genetic mutation or milder chemical
Would require large trials
Add new virulence factors Use stronger adjuvants
Would require large trials May require large trials
Probably advisable to increase immunogenicity
Administer live attenuated Bordetella Early development pertussis intranasally Probably best as a boost strategy Abbreviations: acP, acellular pertussis vaccine; PT, pertussis toxin; wcP, wholecell pertussis vaccine.
vaccines induce both Th1 and Th2 responses (and possibly Th17 responses as well), acellular vaccines induce only Th2 cells [22–26]. Retrospective data, though uncontrolled, suggest that the receipt of even 1 dose of whole-cell vaccine in infancy before exposure confers better protection against later exposure than receipt of all acellular pertussis vaccine doses [4, 27–30]. Possible Solutions to Increased Pertussis
What can be done to respond to this situation? Table 1 lists the possibilities. Although it may be possible to make a less reactogenic whole-cell vaccine, it is unlikely that the public in developed countries would accept a return to the whole-cell vaccine formerly used. Maternal vaccination to protect newborns is now recommended and should become widespread, but that will not stop pertussis in older age groups [31]. Although it is tempting to change the alleles in acellular pertussis vaccine to those from circulating strains, that step in itself is unlikely to be the complete answer to the problem. Increasing the dose of PT to generate more and longer-lasting antibodies to the PT could be helpful. Interestingly, Denmark claims to have a low incidence of pertussis and uses a vaccine containing PT only, but in a quantity at least 2-fold higher than formulations used in other countries [32]. More relevant may be the impact of formalin inactivation of PT. Some reports show that PT so inactivated induces antibody that binds PT but is not bactericidal [33]. A PT that had been inactivated genetically but not chemically was tested in the 1990s and produced antibody levels that were much higher
than the formalin-inactivated products [34, 35]. This is an important point, inasmuch as the high antibody levels are likely to give a longer duration of protection even if they wane. Another possible improvement of acellular pertussis vaccine would be the inclusion of additional virulence factors of B. pertussis. The most prominent candidate is adenylate cyclase toxin, an important toxic factor [36]. However, there are numerous other candidate antigens [37–39]. Perhaps the most obvious way of improving the immunogenicity of acellular vaccine is the incorporation of a stronger adjuvant than aluminum salts into the vaccine to drive a Th1 response, assuming that such a response is necessary. Many new types of adjuvants are available, including multiple Tolllike receptor agonists. In fact, an extensive literature exists reporting experiments in animals with adjuvants to improve antibody responses to pertussis antigens [40–44]. A recent report shows that oligosaccharides derived from B. pertussis lipopolysaccharide and conjugated with a protein could induce bactericidal antibody [45]. Last, an attenuated strain of B. pertussis that is administered intranasally has been developed [45]. Whereas that type of administration raises safety concerns in infants, a live vaccine conceivably would be a useful booster after primary acellular pertussis vaccination. In the interim, the main strategy to prevent the worst disease is acellular vaccination of pregnant women in the last trimester to provide the newborn with passive protection [46]. Cocooning (vaccination of family contacts) may provide some additional advantage but is difficult in practice [47]. Boosters with acellular vaccine could be given more often, but that is a costly public health strategy, and at the moment all acellular pertussis vaccine is given in combination with diphtheria and tetanus toxoids. In addition, until the situation is clarified, the gradual switch from whole-cell to acellular vaccines that has been occurring in less affluent countries will probably stop. Difficulties of Vaccine Reformulation
To change the vaccine given to infants in the first 2 years of life is a daunting proposition, both because the requirements for safety data would be large and because the pertussis is often part of combinations with many other valences, thus requiring recertification of many products currently on the market. At a time when pertussis vaccination is recommended throughout the world, it is ethically impermissible to do an efficacy study in infants with an unvaccinated control group. Moreover, the data from outbreaks show reasonable levels of protection through age 6, with the problem coming later in life [15, 16, 18, 28]. Therefore, the focus should be on the booster vaccines given to pre–school age children and in adolescents. However, even for a new booster vaccine, the regulatory pathway is unclear. A classical efficacy study would have to
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compare a new vaccine with a currently accepted one to show noninferiority or superiority. Such studies will be expensive and long, considering that the current vaccines are effective for the first couple of years after administration. Therefore, ideally the licensing authorities should consider other ways of demonstrating vaccine efficacy. Those ways might include protection data in animals such as baboons, human challenge with circulating strains of B. pertussis, or simply serologic data showing higher and more persistent antibody titers. Safety will have to be demonstrated in large numbers, although fewer subjects would be needed if current components are simply updated with analogous alleles or newer inactivation methods, rather than addition of new components. It should be kept in mind that because immunity is not permanent even after natural infection [48], boosters will be necessary even with new vaccines. Last, perhaps the most difficult obstacle is to convince manufacturers to launch development programs for new pertussis vaccines. Large effort and investment was devoted in the 1990s to bring current acellular vaccines to market. Priorities for other new vaccines are pressing and even major manufacturers cannot afford to support multiple simultaneous clinical development programs, so demand from physicians and governments will be crucial to their decisions. In addition, academia and the National Institutes of Health should assist vaccine development by conducting research on the pathogenesis and immunology of pertussis. All of this implies an enormous effort, but I believe that we cannot allow a vaccine-preventable disease to be incompletely controlled, and that a new pertussis vaccine is needed. Note Potential conflicts of interest. The author is a consultant to vaccine manufacturers, including those who manufacture pertussis vaccines, but declares no financial conflict of interest related to this article. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. de Greeff SC, De Melker HE, van Gageldonk PG, et al. Seroprevalence of pertussis in the Netherlands: evidence for increased circulation of Bordetella pertussis. PLoS One 2010; 5:e14183. 2. Kaczmarek MC, Valenti L, Kelly HA, Ware RS, Britt HC, Lambert SB. Sevenfold rise in likelihood of pertussis test requests in a stable set of Australian general practice encounters, 2000–2011. Med J Aust 2013; 198:624–8. 3. Chiappini E, Stival A, Galli L, de Martino M. Pertussis re-emergence in the post-vaccination era. BMC Infect Dis 2013; 13:151. 4. Centers for Disease Control and Prevention. Pertussis epidemic— Washington, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:517–22. 5. Clark TA, Messonnier NE, Hadler SC. Pertussis control: time for something new? Trends Microbiol 2012; 20:211–3. 6. Fine PE, Clarkson JA. Reflections on the efficacy of pertussis vaccines. Rev Infect Dis 1987; 9:866–83.
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7. Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc Natl Acad Sci U S A 2013. Epub ahead of print. 8. Mooi FR, Van Der Maas NA, De Melker HE. Pertussis resurgence: waning immunity and pathogen adaptation—two sides of the same coin. Epidemiol Infect 2013; 1–10. Epub ahead of print. 9. Mooi FR, van Loo IH, van Gent M, et al. Bordetella pertussis strains with increased toxin production associated with pertussis resurgence. Emerg Infect Dis 2009; 15:1206–13. 10. King AJ, van der Lee S, Mohangoo A, van Gent M, van der Ark A, van de Waterbeemd B. Genome-wide gene expression analysis of Bordetella pertussis isolates associated with a resurgence in pertussis: elucidation of factors involved in the increased fitness of epidemic strains. PLoS One 2013; 8:e66150. 11. Bouchez V, Brun D, Cantinelli T, Dore G, Njamkepo E, Guiso N. First report and detailed characterization of B. pertussis isolates not expressing pertussis toxin or pertactin. Vaccine 2009; 27:6034–41. 12. Otsuka N, Han HJ, Toyoizumi-Ajisaka H, et al. Prevalence and genetic characterization of pertactin-deficient Bordetella pertussis in Japan. PLoS One 2012; 7:e31985. 13. Glanz JM, Narwaney KJ, Newcomer SR, et al. Association between undervaccination with diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccine and risk of pertussis infection in children 3 to 36 months of age. JAMA Pediatr 2013; 167:1060–4. 14. Atwell JE, Van OJ, Zipprich J, et al. Nonmedical vaccine exemptions and pertussis in California, 2010. Pediatrics 2013; 132:624–30. 15. Misegades LK, Winter K, Harriman K, et al. Association of childhood pertussis with receipt of 5 doses of pertussis vaccine by time since last vaccine dose, California, 2010. JAMA 2012; 308:2126–32. 16. Baxter R, Bartlett J, Rowhani-Rahbar A, Fireman B, Klein NP. Effectiveness of pertussis vaccines for adolescents and adults: case-control study. BMJ 2013; 347:f4249. 17. Klein NP, Bartlett J, Fireman B, Rowhani-Rahbar A, Baxter R. Comparative effectiveness of acellular versus whole-cell pertussis vaccines in teenagers. Pediatrics 2013; 131:e1716–22. 18. Tartof SY, Lewis M, Kenyon C, et al. Waning immunity to pertussis following 5 doses of DTaP. Pediatrics 2013; 131:e1047–52. 19. Edwards KM, Lawrence E, Wright PF. Diphtheria, tetanus, and pertussis vaccine. A comparison of the immune response and adverse reactions to conventional and acellular pertussis components. Am J Dis Child 1986; 140:867–71. 20. Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998; 16:1907–16. 21. Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998; 16:1901–6. 22. Higgs R, Higgins SC, Ross PJ, Mills KH. Immunity to the respiratory pathogen Bordetella pertussis. Mucosal Immunol 2012; 5: 485–500. 23. Warfel JM, Beren J, Kelly VK, Lee G, Merkel TJ. Nonhuman primate model of pertussis. Infect Immun 2012; 80:1530–6. 24. Warfel JM, Merkel TJ. Bordetella pertussis infection induces a mucosal IL-17 response and long-lived Th17 and Th1 immune memory cells in nonhuman primates. Mucosal Immunol 2013; 6:787–96. 25. Mascart F, Hainaut M, Peltier A, Verscheure V, Levy J, Locht C. Modulation of the infant immune responses by the first pertussis vaccine administrations. Vaccine 2007; 25:391–8. 26. Ross PJ, Sutton CE, Higgins S, et al. Relative contribution of Th1 and Th17 cells in adaptive immunity to Bordetella pertussis: towards the rational design of an improved acellular pertussis vaccine. PLoS Pathog 2013; 9:e1003264. 27. Sheridan SL, Ware RS, Grimwood K, Lambert SB. Number and order of whole cell pertussis vaccines in infancy and disease protection. JAMA 2012; 308:454–6.
28. Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning protection after fifth dose of acellular pertussis vaccine in children. N Engl J Med 2012; 367:1012–9. 29. Liko J, Robison SG, Cieslak PR. Priming with whole-cell versus acellular pertussis vaccine. N Engl J Med 2013; 368:581–2. 30. Witt MA, Arias L, Katz PH, Truong ET, Witt DJ. Reduced risk of pertussis among persons ever vaccinated with whole cell pertussis vaccine compared to recipients of acellular pertussis vaccines in a large US cohort. Clin Infect Dis 2013; 56:1248–54. 31. Centers for Disease Control and Prevention. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep 2013; 62:131–5. 32. Thierry-Carstensen B, Dalby T, Stevner MA, Robbins JB, Schneerson R, Trollfors B. Experience with monocomponent acellular pertussis combination vaccines for infants, children, adolescents and adults—a review of safety, immunogenicity, efficacy and effectiveness studies and 15 years of field experience. Vaccine 2013; 31:5178–91. 33. Ibsen PH. The effect of formaldehyde, hydrogen peroxide and genetic detoxification of pertussis toxin on epitope recognition by murine monoclonal antibodies. Vaccine 1998; 14:359–68. 34. Rappuoli R. The vaccine containing recombinant pertussis toxin induces early and long-lasting protection. Biologicals 1999; 27: 99–102. 35. Buasri W, Impoolsup A, Boonchird C, et al. Construction of Bordetella pertussis strains with enhanced production of genetically-inactivated pertussis toxin and pertactin by unmarked allelic exchange. BMC Microbiol 2012; 12:61. 36. Dunne A, Ross PJ, Pospisilova E, et al. Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis. J Immunol 2010; 185:1711–9. 37. Marzouqi I, Richmond P, Fry S, Wetherall J, Mukkur T. Development of improved vaccines against whooping cough: current status. Hum Vaccin 2010; 6:543–53.
38. Asensio CJ, Gaillard ME, Moreno G, et al. Outer membrane vesicles obtained from Bordetella pertussis Tohama expressing the lipid A deacylase PagL as a novel acellular vaccine candidate. Vaccine 2011; 29: 1649–56. 39. Alvarez HJ, Erben E, Lamberti Y, et al. Bordetella pertussis iron regulated proteins as potential vaccine components. Vaccine 2013; 31:3543–8. 40. Gracia A, Polewicz M, Halperin SA, et al. Antibody responses in adult and neonatal BALB/c mice to immunization with novel Bordetella pertussis vaccine formulations. Vaccine 2011; 29:1595–604. 41. Moyer MW. New adjuvants aim to give whooping cough vaccine a boost. Nat Med 2012; 18:991. 42. Polewicz M, Gracia A, Garlapati S, et al. Novel vaccine formulations against pertussis offer earlier onset of immunity and provide protection in the presence of maternal antibodies. Vaccine 2013; 31:3148–55. 43. Garlapati S, Eng NF, Kiros TG, et al. Immunization with PCEP microparticles containing pertussis toxoid, CpG ODN and a synthetic innate defense regulator peptide induces protective immunity against pertussis. Vaccine 2011; 29:6540–8. 44. Asokanathan C, Corbel M, Xing D. A CpG-containing oligodeoxynucleotide adjuvant for acellular pertussis vaccine improves the protective response against Bordetella pertussis. Hum Vaccin Immunother 2013; 9. Epub ahead of print. 45. Kubler-Kielb J, Vinogradov E, Lagergard T, et al. Oligosaccharide conjugates of Bordetella pertussis and bronchiseptica induce bactericidal antibodies, an addition to pertussis vaccine. Proc Natl Acad Sci U S A 2011; 108:4087–92. 46. Heininger U, Riffelmann M, Bar G, Rudin C, von Konig CH. The protective role of maternally derived antibodies against Bordetella pertussis in young infants. Pediatr Infect Dis J 2013; 32:695–8. 47. Terranella A, Asay GR, Messonnier ML, Clark TA, Liang JL. Pregnancy dose Tdap and postpartum cocooning to prevent infant pertussis: a decision analysis. Pediatrics 2013; 131:e1748–56. 48. Wendelboe AM, Van RA, Salmaso S, Englund JA. Duration of immunity against pertussis after natural infection or vaccination. Pediatr Infect Dis J 2005; 24(5 suppl):S58–61.
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The Pertussis Problem Stanley A. Plotkin Department of Pediatrics, University of Pennsylvania, Philadelphia
Pertussis is resurgent, and many cases are occurring in vaccinated children and adolescents. In countries using acellular vaccines, waning immunity is at least part of the problem. This article discusses possible improvements in those vaccines. Keywords. pertussis; pertussis toxin; adjuvants; waning immunity; Th1 responses.
Pertussis is resurgent. After being largely controlled in children after the advent of routine pertussis immunization with whole-cell vaccine in the 1940s, and continuing control when a switch was made to acellular vaccines in the 1990s, recent reports from around the world suggest that more cases of pertussis are occurring than can be explained by better observation and better diagnostic methods [1]. Although the epidemiologic situation is unclear in some geographical areas, there is little doubt that pertussis incidence has risen in North America, Europe, and Australia, both in school children and adolescents [2, 3]. Pertussis has increased in practically every state in the United States and in some to epidemic proportions [4, 5]. The situation in adults is uncertain, as pertussis has always been common in that age group owing to the impermanence of immunity to Bordetella pertussis [6]. Five factors appear to be playing a role, although experts differ as to what weight to give each one: strain change in the presence of vaccine immunity; local collections of unvaccinated and therefore susceptible children; lower efficacy of acellular vaccines relative to whole-cell vaccines; waning immunity after acellular vaccines; and the predilection of those vaccines to induce Th2 rather than Th1 responses. A sixth possible factor is suggested by the recent finding that acellular vaccine does not
Received 18 October 2013; accepted 8 December 2013; electronically published 20 December 2013. Correspondence: Stanley A. Plotkin, MD, 4650 Wismer Road, Doylestown, PA 18902 ([email protected]). Clinical Infectious Diseases 2014;58(6):830–3 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/cit934
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protect against pertussis infection in a baboon model, although symptoms are prevented [7]. If this is true in humans, circulation of the organism would be intensified in countries using acellular vaccine. Acellular pertussis vaccines contain 1–5 antigens: pertussis toxin (PT), filamentous hemagglutinin, pertactin (PRN), and 2 fimbrial agglutinogens. Strain change has been expressed in several ways: change in circulating organisms over the years in the alleles for each of the antigens [8]; replacement of older promoters of the PT allele with the so-called P3 promotor, which generates more toxin [9, 10]; and the appearance of pertactin-deficient strains [11, 12]. The latter makes vaccines containing PRN less useful. Although most reported cases have occurred in vaccinated children, the presence of substantial numbers of unvaccinated children in a particular area increases the pertussis risk by a factor of 2.5 [13, 14]. Multiple studies, both epidemiological and serological, have confirmed that immunity wanes rapidly after the acellular vaccine booster at age 4–6 years and the preadolescent dose at age 10–12 years [15–18]. Vaccine effectiveness is high for only about 2 years postdose. Moreover, in the many clinical trials conducted in the 1990s, one of the whole-cell pertussis vaccines that was compared with acellular vaccines was poorly immunogenic. In every trial where other whole-cell pertussis vaccines were used, their efficacy was greater than that of the acellular vaccine in the same trial [19]. Although opinions differ as to the correlation of protection with antibody levels, many authorities consider that high levels of PT and PRN antibodies are associated with protection [20, 21]. In addition, studies in mice and in baboons have demonstrated that whereas whole-cell
Table 1. Possible Vaccination Strategies to Control the Resurgence of Pertussis Strategy
Remarks
Return to the use of wcP
Probably unacceptable
Develop less-reactogenic wcP Maternal vaccination to provide transplacental antibody to protect newborn
Not yet done Now generally recommended
Vaccination of newborn contacts (cocoon strategy)
Difficult to obtain complete coverage
More frequent boosters with acP
Costly and difficult to put in place Change antigens in acP to those from Uncertain effect currently circulating strains Increase quantities of current antigens Inactivate PT by genetic mutation or milder chemical
Would require large trials
Add new virulence factors Use stronger adjuvants
Would require large trials May require large trials
Probably advisable to increase immunogenicity
Administer live attenuated Bordetella Early development pertussis intranasally Probably best as a boost strategy Abbreviations: acP, acellular pertussis vaccine; PT, pertussis toxin; wcP, wholecell pertussis vaccine.
vaccines induce both Th1 and Th2 responses (and possibly Th17 responses as well), acellular vaccines induce only Th2 cells [22–26]. Retrospective data, though uncontrolled, suggest that the receipt of even 1 dose of whole-cell vaccine in infancy before exposure confers better protection against later exposure than receipt of all acellular pertussis vaccine doses [4, 27–30]. Possible Solutions to Increased Pertussis
What can be done to respond to this situation? Table 1 lists the possibilities. Although it may be possible to make a less reactogenic whole-cell vaccine, it is unlikely that the public in developed countries would accept a return to the whole-cell vaccine formerly used. Maternal vaccination to protect newborns is now recommended and should become widespread, but that will not stop pertussis in older age groups [31]. Although it is tempting to change the alleles in acellular pertussis vaccine to those from circulating strains, that step in itself is unlikely to be the complete answer to the problem. Increasing the dose of PT to generate more and longer-lasting antibodies to the PT could be helpful. Interestingly, Denmark claims to have a low incidence of pertussis and uses a vaccine containing PT only, but in a quantity at least 2-fold higher than formulations used in other countries [32]. More relevant may be the impact of formalin inactivation of PT. Some reports show that PT so inactivated induces antibody that binds PT but is not bactericidal [33]. A PT that had been inactivated genetically but not chemically was tested in the 1990s and produced antibody levels that were much higher
than the formalin-inactivated products [34, 35]. This is an important point, inasmuch as the high antibody levels are likely to give a longer duration of protection even if they wane. Another possible improvement of acellular pertussis vaccine would be the inclusion of additional virulence factors of B. pertussis. The most prominent candidate is adenylate cyclase toxin, an important toxic factor [36]. However, there are numerous other candidate antigens [37–39]. Perhaps the most obvious way of improving the immunogenicity of acellular vaccine is the incorporation of a stronger adjuvant than aluminum salts into the vaccine to drive a Th1 response, assuming that such a response is necessary. Many new types of adjuvants are available, including multiple Tolllike receptor agonists. In fact, an extensive literature exists reporting experiments in animals with adjuvants to improve antibody responses to pertussis antigens [40–44]. A recent report shows that oligosaccharides derived from B. pertussis lipopolysaccharide and conjugated with a protein could induce bactericidal antibody [45]. Last, an attenuated strain of B. pertussis that is administered intranasally has been developed [45]. Whereas that type of administration raises safety concerns in infants, a live vaccine conceivably would be a useful booster after primary acellular pertussis vaccination. In the interim, the main strategy to prevent the worst disease is acellular vaccination of pregnant women in the last trimester to provide the newborn with passive protection [46]. Cocooning (vaccination of family contacts) may provide some additional advantage but is difficult in practice [47]. Boosters with acellular vaccine could be given more often, but that is a costly public health strategy, and at the moment all acellular pertussis vaccine is given in combination with diphtheria and tetanus toxoids. In addition, until the situation is clarified, the gradual switch from whole-cell to acellular vaccines that has been occurring in less affluent countries will probably stop. Difficulties of Vaccine Reformulation
To change the vaccine given to infants in the first 2 years of life is a daunting proposition, both because the requirements for safety data would be large and because the pertussis is often part of combinations with many other valences, thus requiring recertification of many products currently on the market. At a time when pertussis vaccination is recommended throughout the world, it is ethically impermissible to do an efficacy study in infants with an unvaccinated control group. Moreover, the data from outbreaks show reasonable levels of protection through age 6, with the problem coming later in life [15, 16, 18, 28]. Therefore, the focus should be on the booster vaccines given to pre–school age children and in adolescents. However, even for a new booster vaccine, the regulatory pathway is unclear. A classical efficacy study would have to
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compare a new vaccine with a currently accepted one to show noninferiority or superiority. Such studies will be expensive and long, considering that the current vaccines are effective for the first couple of years after administration. Therefore, ideally the licensing authorities should consider other ways of demonstrating vaccine efficacy. Those ways might include protection data in animals such as baboons, human challenge with circulating strains of B. pertussis, or simply serologic data showing higher and more persistent antibody titers. Safety will have to be demonstrated in large numbers, although fewer subjects would be needed if current components are simply updated with analogous alleles or newer inactivation methods, rather than addition of new components. It should be kept in mind that because immunity is not permanent even after natural infection [48], boosters will be necessary even with new vaccines. Last, perhaps the most difficult obstacle is to convince manufacturers to launch development programs for new pertussis vaccines. Large effort and investment was devoted in the 1990s to bring current acellular vaccines to market. Priorities for other new vaccines are pressing and even major manufacturers cannot afford to support multiple simultaneous clinical development programs, so demand from physicians and governments will be crucial to their decisions. In addition, academia and the National Institutes of Health should assist vaccine development by conducting research on the pathogenesis and immunology of pertussis. All of this implies an enormous effort, but I believe that we cannot allow a vaccine-preventable disease to be incompletely controlled, and that a new pertussis vaccine is needed. Note Potential conflicts of interest. The author is a consultant to vaccine manufacturers, including those who manufacture pertussis vaccines, but declares no financial conflict of interest related to this article. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. de Greeff SC, De Melker HE, van Gageldonk PG, et al. Seroprevalence of pertussis in the Netherlands: evidence for increased circulation of Bordetella pertussis. PLoS One 2010; 5:e14183. 2. Kaczmarek MC, Valenti L, Kelly HA, Ware RS, Britt HC, Lambert SB. Sevenfold rise in likelihood of pertussis test requests in a stable set of Australian general practice encounters, 2000–2011. Med J Aust 2013; 198:624–8. 3. Chiappini E, Stival A, Galli L, de Martino M. Pertussis re-emergence in the post-vaccination era. BMC Infect Dis 2013; 13:151. 4. Centers for Disease Control and Prevention. Pertussis epidemic— Washington, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:517–22. 5. Clark TA, Messonnier NE, Hadler SC. Pertussis control: time for something new? Trends Microbiol 2012; 20:211–3. 6. Fine PE, Clarkson JA. Reflections on the efficacy of pertussis vaccines. Rev Infect Dis 1987; 9:866–83.
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