Historical Review of Pertussis and the Classical Vaccine

5259 Historical Review of Pertussis and the Classical Vaccine James D. Cherry Department ofpediatrics, UCLA School ofmedicine, UCLA Children's Hospital, and UCLA Center for Vaccine Research, Los Angeles. California Pertussis is an epidemic disease caused by Bordetella pertussis and also to a lesser extent by Bordetella parapertussis. Classical illness lasts 4-8 weeks and is characterized by paroxysms of coughing with posttussive vomiting and whooping; however, 47.4% of primary infections last 4 weeks or less. Whole cell pertussis vaccines are generally highly efficacious. All whole cell vaccines are reactogenic, causing fever and local reactions in many vaccinees. In the past, these vaccines were thought to cause infant deaths and brain damage. However, several large epidemiologic studies indicate that whole cell vaccines do not cause infant deaths or neurologic disease. Recent studies indicate that neither immunization nor infection give long-term immunity. As a result, B. pertussis infections are endemic in adult populations. The future control of B. pertussis will require immunization schedules with new acellular vaccines that include booster doses in older children and adults. Pertussis (whooping cough) has been and remains an endemic disease with significant morbidity and mortality [1-4]. At present, more than 355,000 deaths are caused by pertussis annually, mainly in unimmunized children in developing countries [4]. The disease pertussis and its cause are reviewed along with development and use of classical vaccines and past and present epidemiology of Bordetella pertussis infection, which is the main cause of the disease. Pertussis History. Pertussis (whooping cough) was first recognized in the Middle Ages [5]. It was described as "the kink" (a Scottish term synonymous with fit or paroxysm) and "kindhoest" (a teutonic word meaning child's cough). The first epidemic, described by Guillaume de Baillou, occurred in Paris in 1578 (cited in [6]). In 1906, Bordet and Gengou [7] reported the isolation ofthe causative organism (B. pertussis). Throughout this century, endemic and epidemic disease caused by B. pertussis has occurred in all populations with unimmunized children [1-3, 8]. Causative organisms. Pertussis is caused by gram-negative pleomorphic bacilli of the genus Bordetella [1]. The predominant cause is B. pertussis, but B. parapertussis also causes typical pertussis [9]. B. bronchiseptica, an animal pathogen, can also cause rare instances of illness with chronic cough in humans. Recently, in Germany, during a 4-year laboratory study in conjunctionwith a vaccine efficacytrial, 6% ofculturepositive cases of pertussis were caused by B. parapertussis Financial support: Lederle-Praxis Biologicals; NIH (AJ-15124). Reprints or correspondence: Prof. James D. Cherry, Dept. of Pediatrics, UCLA School of Medicine, 22-442 MDCC, 10833 Le Conte Ave., Los Angeles, CA 90095. The Journal of Infectious Diseases 1996; 174(8uppl 3):8259-63 1996 by The University of Chicago. All rights reserved. 0022~1899/96/74S3-000 I$0 1.00 (unpublished data). It is often stated that Chlamydia trachomatis and certain adenoviruses can cause clinical pertussis. However, it is my view that illnesses caused by these agents are sufficiently different from those caused by B. pertussis so that clinical confusion should not occur. Laboratory diagnosis. The standard laboratory method for the diagnosis ofb. pertussis infection is culture ofthe organism from a nasopharyngeal swab. It is a common beliefthat culture has low sensitivity, but when specimens are collected early in a typical case and transport and laboratory techniques are done correctly, the isolation rate is ~80% [10]. Isolation rates are worse ifspecimens are collected late (cough lasts > 2 weeks), if antibiotics have been administered, if subjects were previously vaccinated, or if they are previously infected adults. Infection with B. pertussis can also be diagnosed serologically by the demonstration of a 4-fold increase in agglutinin titer or a significant increase in IgA or IgG antibody determined by ELISA to B. pertussis antigens when acute- and convalescent-phase serum specimens are compared [3]. In epidemiologic studies, B. pertussis infections can also be diagnosed by significantly high single-agglutinin titers or ELISA antibody values [11]. The B. pertussis antigens used in ELISA for diagnosis are pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (69-kDa outer membrane protein), and fimbriae. B. parapertussis has FHA and an outer membrane protein similar to that of B. pertussis, and therefore infection with B. parapertussis will often result in a rise in antibody levels to these two B. pertussis antigens (unpublished data). Recently, the polymerase chain reaction (PCR) has been used as an additional laboratory method for the identification ofb. pertussis in nasopharyngeal specimens. In a study by my group, PCR increased the identification of subjects with B. pertussis infections by almost 4-fold [12]. Additional identified cases included persons with prior antibiotic treatment, less severe illnesses, and delayed specimen collection. Extreme care in the laboratory with appropriate controls is required to avoid contamination and false-positive results.

8260 Cherry lid 1996; 174 (Suppl 3) Also extremely useful in the diagnosis ofb. pertussis infection is the occurrence of absolute lymphocytosis [1]. Such lymphocytosis is caused by PT (also called lymphocytosispromoting factor) and occurs during primary infections in persons without antibody to PT. A lymphocyte count of 10,000 cells/mnr' in a child with a cough or an infant with apnea virtually always indicates B. pertussis infection. Pathogenesis ofb. pertussis infection. The transmission of infection from one person to another is presumed to be airborne from the cough of an infected person to the respiratory epithelium ofthe new host, where the organisms attach to the cilia ofepithelial cells [13]. Important adhesions for attachment are PT, FHA, and pertactin. Fimbriae may also playa role in continued attachment. After attachment, host immune-effector cell function and bacterial clearance is disrupted by adenylate cyclase toxin and PT. Local tissue damage, which presumably is the cause of symptoms, is likely to result from tracheal cytotoxin and perhaps dermonecrotic toxin. Pertussis is a unique illness in that systemic manifestations rarely occur [1]. Convulsions and encephalopathy are most likely caused by anoxia resulting from respiratory damage. It is possible, however, that they result from systemic toxin. In infection, there is both lymphocytosis and hyperinsulinism caused by dissemination of PT. Therefore, it is possible that both seizures and encephalopathy could result from hypoglycemia due to PT; however, at present, no data support this hypothesis. In 1979, it was suggested that pertussis was a disease caused by PT alone [14]. This idea is still prevalent but is not credible because an illness identical to that caused by B. pertussis is caused by B. parapertussis, and the latter organism does not liberate PT [9]. Clinical illness from B. pertussis infection. Classical pertussis follows an incubation period of 6-20 days. The onset of most cases is 7-10 days after exposure [1]. It is an illness of three stages (catarrhal, paroxysmal, and convalescent) and lasts 4-8 weeks and occasionally longer. Initially, illness starts like a cold with coryza and mild cough. The cough becomes more prominent with paroxysms, posttussive vomiting, and posttussive whooping. Typically there is no fever, no signs or symptoms of systemic illness, and no pharyngitis. Lymphocytosis occurs. These manifestations occur during primary infection in previously unimmunized children. Atypical illnesses occur in both children and adults who have previously been vaccinated or infected [1, 10, 11]. In addition, neonates and young infants with primary infections may present with apnea and seizures without apparent paroxysmal cough [15]. The usual clinical manifestations of B. pertussis infection in adults seem to differ in those who were vaccinated in childhood and in those whose initial exposure to the organism in childhood was by infection [11, 16]. In all adults, the main manifestation is persistent paroxysmal cough, which is largely unresponsive to conventional treatments. The correct diagnosis is rare; the most common incorrect diagnosis is bronchitis. Reinfections in adults not immunized during childhood are more likely to be typical of classical pertussis (with whooping). Recently it was noted that a significant number of primary infections with B. pertussis in unimmunized children do not result in classical pertussis. In a study in Germany, physicians were encouraged to send in cultures for B. pertussis in all respiratory illnesses with cough, regardless ofwhether the illnesses were thought to be pertussis [10]. In this study, 47.4% of 247 children with culture-confirmed B. pertussis infections had illnesses that lasted ~4 weeks; in 25.5%, the illnesses persisted ~3 weeks. Vaccines History. After the isolation of B. pertussis in 1906, the possibility of vaccine development was considered because pertussis was such a devastating disease [1]. In 1933, Madsen [17] reported some degree of protection in vaccinees who received a vaccine composed of suspended organisms (10 X 10 9 ; ml) in phenolyzed saline. In the 1930s, pertussis vaccines were used both to prevent pertussis and for treatment. During this period, many different types of vaccines were experimented with, and some were found to be efficacious [18]. Types of vaccines investigated were whole cell preparations, which were washed or unwashed, mixed vaccines that also contained other bacteria of the upper respiratory tract flora, fractionated vaccines (extracted, crude acellular products), "detoxified vaccines," and vaccines enriched with "toxic factors." In early studies, it was found that to obtain a good antibody response and protection after immunization, the total bacterial count in the vaccine needed to be high. However, because of toxicity, the number of organisms in a single dose was limited [1]. Studies with whole cell vaccines in the United States (US) in the late 1930s and early 1940s revealed marked differences in efficacy; however, in four large studies (>500 children), the efficacies were 91.5%, 87.7%, 91.5%, and 53% [18]. Large trials in the United Kingdom (UK) after World War II also demonstrated marked differences in efficacy between vaccines [1, 2]. In 1947, Kendrick et al. [19] described the mouse intracerebral challenge protection test for vaccine standardization. In the UK trials, a three-dose series of vaccines containing 4 protective units (as defined by Kendrick et al.) had an efficacy of 80% against home exposure [20]. Conventional whole cell vaccines. Whole cell vaccines are manufactured in many countries. Although their basic preparation procedures are similar, the vaccines frequently elicit markedly different immune responses to various B. pertussis antigens. In general, B. pertussis is grown in bulk culture, harvested, concentrated by centrifugation, and suspended in a buffered saline solution [1]. Concentrated bacteria are killed and partially detoxified by heat or a chemical agent or by a combination of these methods. The pertussis component is

JID 1996; 174 (Suppl 3) Pertussis and the Classical Vaccine S261 combined with diphtheria and tetanus toxoids, which have been adsorbed onto an aluminum adjuvant. Immunization schedules. There are many different immunization schedules in use throughout the world, but few were developed on the basis of scientific efficacy information [1]. However, it is apparent that even scientifically less-than-optimal schedules are effective. Often vaccination schedules have been determined on the basis of perceived and real reactogenicity. Immunogenicity data indicate that a primary series should consist ofthree doses and that booster doses are necessary at ages 2 and 4-6 years. The apparent success of schedules that include only three doses in the first year oflife can be explained by the failure in older children of recognition ofvaccine-modified pertussis (see discussion on epidemiology) [2]. There is a reluctance to give booster doses in many countries because of excessive local reactions at the site of injection. Such reactions are at variance with postbooster reactions in the US, where a five-dose schedule is routine. A major reason for this difference is that the content of diphtheria toxoid in vaccines used in many countries other than the US is more than necessary [21]. The local reactions are, to a large extent, immunologic because of the diphtheria toxoid in the vaccine and not the pertussis component. Real and perceived vaccine reactions. All whole cell pertussis vaccines contain both endotoxin and other active toxins, so it is not surprising that reactions occur. In addition, adverse events, such as an Arthus reaction, can be mediated immunologically after a booster dose. Reactions can be caused by the vaccine or perceived from the temporal association between an immunization and an unusual event. Transient local and systemic reactions. Although reactions have been noted in association with pertussis immunization since the first vaccines were tested >60 years ago, only recently were quantitative controlled studies done [1, 2]. Between 1978 and 1979, reactions in 15,752 diphtheria-tetanus toxoid (DT) pertussis (DTP) recipients were compared with those in 784 DT recipients (table 1) [22]. Nine of 10 reactions listed in table 1 occurred significantly more frequently in DTP vaccine recipients than in DT vaccinees. Local reactions were generally more frequent with increasing doses, whereas systemic reactions, with the exception of fever, were less frequent with increasing doses. The occurrence of fever correlated directly with the vaccine endotoxin content [23]. Reactions varied with different vaccine production lots. In the same study, 9 children experienced hypotonic-hyporesponsive episodes, and 9 children had seizures [22]. In more recent investigations, my group has done studies to determine the cause ofhypotonic-hyporesponsive episodes, seizures, and persistent crying [24]. In these studies, persistent crying was associated with painful local reactions, seizures were characteristic of febrile seizures, and fever most likely resulted from vaccine endotoxin. We found no evidence that PT plays a role in hypotonic-hyporesponsive episodes or seizures. Table 1. Less serious reactions following 15,752 DTP and 784 DT immunizations. Reaction DTP group DT group P Local Redness 5891 (37.4) 60 (7.6) <.001 Swelling 6411 (40.7) 60 (7.6) <.001 Pain 8018 (50.9) 78 (9.9) <.001 Systemic Fever (38 C) 3605 (46.5) 27 (9.9) <.001 Drowsiness 4962 (31.5) 117 (14.9) <.001 Fretfulness 8412 (53.4) 177 (22.6) <.001 Vomiting 977 (6.2) 20 (2.6) <.001 Anorexia 3292 (20.9) 55 (7.0) <.001 Persistent crying 488 (3.1) 5 (0.7).003 High-pitched, unusual cry 17(0.1) 00.3574 NOTE. Data are no. (%). Modified with permission from [22]. * Fever was evaluated 3 and 6 h after diphtheria-tetanus toxoid-pertussis (DTP) and DT immunizations in 7753 and 292 children, respectively. Neurologic illness and death temporally associated with DTP immunization. The first and second doses of DTP are frequently administered at the age of the peak occurrence of the sudden infant death syndrome (SIDS). Therefore, it is not surprising that many SIDS cases occur after immunization in temporal association. However, several excellent controlled studies indicate there is no causative role ofpertussis vaccine in SIDS [1, 3]. Neurologic events after pertussis immunization have been recognized since the early days ofpertussis immunization [1, 3]. These events were initially called "pertussis vaccine encephalitis" and more recently' 'pertussis vaccine encephalopathy." However, when cases of so-called vaccine encephalopathy are examined, the illnesses are characteristic of the first seizures in infantile epilepsy and not different from illnesses in nonvaccinated children of similar ages [1]. In recent years, five large epidemiologic studies have been done and their results analyzed (with some reanalyzed extensively) [25-29]. From these studies, it has been concluded that "pertussis vaccine encephalopathy is a myth" [30]. Pertussis vaccine causes the first febrile seizure in prone children and accelerates the occurrence of the first seizure of infantile epilepsy. This latter event is most clearly demonstrated in infantile spasms [31], but other infantile epilepsies also result from preexisting but unrecognized brain damage and can be accelerated by pertussis immunization. Vaccine efficacy. Whole cell pertussis vaccines in use today are clearly efficacious despite the use of less-than-optimal immunization schedules in many countries. Efficacy can be demonstrated in several ways. The most graphic is the resurgence of epidemic pertussis in a country after discontinuation or marked reduction in vaccine use. Epidemic pertussis was relatively controlled in the UK, Japan, and Sweden in the early 1970s [1]. In the UK and Japan, immunization was markedly disrupted, and epidemic disease occurred. In both countries,

S262 Cherry JID 1996; 174 (Supp1 3) pertussis was subsequently brought under control with the renewed use of pertussis vaccines. In contrast with the UK and Japan, pertussis immunization was discontinued in Sweden in 1979 and, despite persistent epidemic disease with both morbidity and mortality, immunization was not reintroduced. The efficacy of whole cell pertussis vaccines has also been demonstrated in numerous household contact studies. Efficacy varies by case definition: The most recent US data indicate efficacies between 59% and 97%, depending upon the case definition [32]. In Germany, the efficacy of the whole cell vaccine (produced by Behringwerke, Marburg, Germany) was calculated to be 97.6% (95% confidence interval, 93.1-99.7) by Schmitt et al. [33]. Epidemiology In the prevaccine era and in populations where immunization is not done, pertussis is an epidemic disease with cycles every 2-5 years [1-3]. Fine and Clarkson [34] noted that this cycle did not change, despite a reduction in total cases by immunization. This indicates that immunization controls disease but does not control the prevalence of the organism in the population. From September 1986 to February 1989, my group studied cough illnesses in UCLA students [11]. We found that 26% of those with an illness of 6 days had B. pertussis infections, but none were recognized by their physicians. Since we demonstrated B. pertussis throughout the 2.5-year period, we suggested that B. pertussis infections are endemic in adults and cause the epidemic cycles that predominantly involve unvaccinated children. Since there has been effective routine immunization in the US for > 30 years, these cases in UCLA students occurred in previously vaccinated persons. The prevailing opinion is that vaccine immunity is relatively short-lived, whereas immunity following infection is lifelong. Studies by UCLA researchers suggest this opinion is wrong. Knowing that IgA antibodies to pertussis antigens (PT, FHA, and pertactin) usually result from infection and not vaccination, their prevalence in young German and American men ofsimilar ages was studied [35]. In Germany, routine childhood immunization was not done during the 1970s and 1980s and pertussis was epidemic. To our surprise, the rate and mean values of IgA antibodies in the two populations were similar, suggesting similar adult infection rates. In another study in Germany, B. pertussis infections were common in adults (133/100,000 population) and often occurred in those with a history of childhood pertussis [16]. These data indicate that in populations in which pertussis is controlled by immunization and in populations in which pertussis is epidemic, endemic disease occurs in adults. This endemic disease is responsible for the cyclic disease observed in unvaccinated children. Summary and Conclusions Whole cell pertussis vaccines have been highly successful in controlling epidemic pertussis. Their use, however, has not curtailed the circulation of B. pertussis in the population. In addition, whole cell pertussis vaccines are safe but cause considerable short-term discomfort. In the near future, if the circulation of B. pertussis and pertussis disease is to be controlled, programs involving booster immunizations of older children and adults will be needed. Adult booster immunizations with present whole cell vaccines are not a practical consideration because of reactogenicity. However, endotoxin-free acellular pertussis vaccines should be acceptable for adult use. Immunization programs that include older children and adults may enable the control ofb. pertussis circulation as well as pertussis disease. References 1. Cherry JD, Brunell PA, Golden GS, Darzon DT. Report of the task force on pertussis and pertussis immunization--1988. Pediatrics 1988; 81(suppl):939-84. 2. Cherry JD. The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. CUff Probl Pediatr 1984; 14:1-78. 3. Hodder SL, Mortimer EA Jr. Epidemiology of pertussis and reactions to pertussis vaccine. Epidemiol Rev 1992; 14:243-67. 4. Strebel P, Wharton M, Cochi S. Impact of pertussis vaccination on the burden of acute respiratory illness (ARI) among children in developing countries [abstracts]. In: Program of 122nd annual meeting and exhibition of the American Public Health Association (Washington, DC), 1994:318. 5. Holmes WHo Whooping cough or pertussis. In: Holmes WH, ed. Bacillary and rickettsial infections: acute and chronic, black death to white plague. New York: Macmillan, 1940:395-414. 6. Linnemann CC Jr. Host-parasite interactions in pertussis. In: Manclark CR, Hill JC, eds. International Symposium on Pertussis. Washington, DC: Government Printing Office, US Department ofhealth, Education and Welfare (NIH) 79-1830, 1979:3-18. 7. Bordet J, Gengou U. Le microbe de la coqueluche. Ann Inst Pasteur 1906; 20:48-68. 8. Cherry JD, Baraff LJ, Hewlett E. The past, present, and future of pertussis-the role of adults in epidemiology and future control. West J Med 1989; 150:319-28. 9. Heininger U, Stehr K, Schmitt-Grohe S, et al. Clinical characteristics of illness caused by Bordetella parapertussis compared with illness caused by Bordetella pertussis. Pediatr Infect Dis J 1994; 13:306-9. 10. Heininger U, Cherry JD, Eckhardt T, Lorenz C, Christenson P, Stehr K. Clinical and laboratory diagnosis of pertussis in the regions of a large vaccine efficacy trial in Germany. Pediatr Infect Dis J 1993; 12:504-9. 11. Mink C, Cherry JD, Christenson P, et al. A search for Bordetella pertussis infection in university students. Clin Infect Dis 1992; 14:464-71. 12. Schlapfer G, Cherry JD, Heininger U, et al. Polymerase chain reaction identification of Bordetella pertussis infections in vaccinees and family members in a pertussis vaccine efficacy trial in Germany. Pediatr Infect Dis 1995; 14:209-14. 13. Weiss AA, Hewlett EL. Virulence factors of Bordetella pertussis. Annu Rev Microbiol 1986;40:661-86. 14. Pittman M. Pertussis toxin: the cause of harmful effects and prolonged immunity of whooping cough. A hypothesis. Rev Infect Dis 1979; 1: 401-12. 15. Heininger U, Stehr K, Cherry JD. Serious pertussis overlooked in infants. Eur J Pediatr 1992; 151:342-3. 16. Schmitt-Grohe S, Cherry JD, Heininger U, Oberall M, Pineda E, Stehr K. Pertussis in German adults. Clin Infect Dis 1995;21:860-6.

JlD 1996; 174 (Suppl 3) Pertussis and the Classical Vaccine S263 17. Madsen T. Vaccination against whooping cough. JAMA 1933; 101: 187~8. 18. Lapin JH. Whooping cough. Springfield, IL: CC Thomas, 1943. 19. Kendrick PL, Eldering G, Dixon MK, Misner J. Mouse protection tests in the study of pertussis vaccines. Am J Public Health 1947;37:803 10. 20. DHSS Joint Committee on Vaccination and Immunization. Whooping cough vaccination: review ofthe evidence on whooping cough vaccination. London: Her Majesty's Stationery Office, 1977. 21. Cherry JD. Strategies for pediatric vaccines: conventional and molecular approaches in strategies for pediatric vaccines. Report of the 104th Ross Conference on Pediatric Research. Columbus, OH: Ross Products Division, Abbott Laboratories, 1994:218-22. 22. Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981; 68:650-60. 23. Baraff LJ, Manc1ark CR, Cherry JD, Christenson P, Marcy SM. Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain. Pediatr Infect Dis J 1989; 8: 502-7. 24. Blumberg DA, Lews K, Mink C, Christenson P, Chatfield P, Cherry JD. Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hyporesponsive episodes, high fevers, and persistent crying. Pediatrics 1993;91:1158-65. 25. Alderslade R, Bellman M, Rawson N, Ross EM, Miller DL. The National Childhood Encephalopathy Study. In: Whooping cough: reports from the Committee and Safety of Medicine and the Joint Committee on Vaccination and Immunization. London: DHSS, 1981:70-154. 26. Shields WD, Nielson C, Buch D, et ai. Relationship ofpertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. J Pediatr 1988; 113:801-5. 27. Griffin MR, Ray WS, Mortimer EA, Fenichel GM, Schaffner W. Risk of seizures and encephalopathy after immunization with the diphtheriatetanus-pertussis vaccine. JAMA 1990;263:1641-5. 28. Walker AM, Jick H, Parera DR, Knauss TA, Thompson RS. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatrics 1988; 81:345-9. 29. Gale JL, Thapa PB, Wassilak SG, Bobo JK, Mendelman PM, Foy HM. Risk ofserious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine. A population-based case-control study. JAMA 1994;271:37-41. 30. Cherry JD. "Pertussis vaccine encephalopathy": it is time to recognize it as the myth that it is [editorial]. JAMA 1990;263:1679-80. 31. Bellman MH, Ross EM, Miller DL. Infantile spasms and pertussis immunization. Lancet 1983; 1:1031-3. 32. Onorato 1M, Wassilak SG, Meade BD. Efficacy of whole-cell pertussis vaccine in preschool children in the United States. JAMA 1992;20: 2745-9. 33. Schmitt HJ, Schuind A, Knuf M, et ai. Acellular pertussis vaccines: the rationale for an efficacy trial in Germany. J Infect Dis 1996;174(suppl 3):S291-4. 34. Fine PEM, Clarkson JA. The recurrence of whooping cough: possible implications for assessment of vaccine efficacy. Lancet 1982; 1:666-9. 35. Cherry JD, Beer T, Chartrand SA, et ai. Comparison of antibody values to Bordetella pertussis antigens in young German and American men. Clin Infect Dis 1995; 20: 1271-4.