InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Immunology and Microbiology » "Vaccines", book edited by Farhat Afrin, Hassan Hemeg and Hani Ozbak, ISBN 978-953-51-3476-3, Print ISBN 978-953-51-3475-6, Published: September 6, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 8

Immunization against Pertussis: An Almost Solved Problem or a Headache in Public Health

By Waldely de Oliveira Dias, Ana Fabíola R.O. Prestes, Priscila S. Cunegundes, Eliane P. Silva and Isaias Raw
DOI: 10.5772/intechopen.69283

Article top

Immunization against Pertussis: An Almost Solved Problem or a Headache in Public Health

Waldely de Oliveira Dias, Ana Fabíola R.O. Prestes, Priscila S. Cunegundes, Eliane P. Silva and Isaias Raw
Show details


Whooping cough or pertussis is a serious infectious disease of the human respiratory tract, caused by Gram-negative bacteria Bordetella pertussis and Bordetella parapertussisHU. The current pertussis vaccines may consist of dead cells of B. pertussis (whole cell pertussis vaccines—wPs) or purified antigens from the bacterium (acellular pertussis vaccines—aPs). The aPs are less reactogenic and have been widely used in developed countries for more than two decades, but their high cost of production makes them prohibitive for developing countries, and the accelerated rate of epidemic outbreaks has led to the hypothesis that aPs are less effective than the wP ones. Considering cost-effectiveness, some authors have pointed out questions about the possibility of reintroduction of wP vaccines into the primary doses of pertussis vaccination. The Butantan Institute in São Paulo, Brazil, developed a wP vaccine with low endotoxicity (Plow) obtained by chemical extraction of the lipooligosaccharide (LOS) fraction from the outer membrane of the bacterial cell, showing to be less reactogenic and equally immunogenic and protective as the traditional wP vaccine. The Plow may possibly be introduced into the vaccination schedule for immunization of adolescents and young adults in Brazil, an important epidemiological contribution to reducing the circulation of B. pertussis.

Keywords: pertussis, Bordetella pertussis, whole cell pertussis vaccine, acellular pertussis vaccine, resurgence of pertussis

1. Introduction

Pertussis or whooping cough is an acute and serious infectious disease of the respiratory tract, directly transmitted from human to human through respiratory aerosols [1]. The World Health Organization (WHO) estimates the annual incidence of 16 million cases of pertussis, with 195,000 deaths per year, one of the main causes of mortality for vaccine-preventable diseases in children less than five years [2, 3]. The main causative agent is the Gram-negative bacterium Bordetella pertussis, but although Bordetella parapertussisHU leads to a milder disease [4, 5], it has also been associated with more severe episodes, such as pneumonia and bronchopneumonia in children, with possible lethal consequences [67]. The disease is exclusively human, with characteristics that differentiate it from other respiratory diseases [8, 9] and was widely disseminated in pre-vaccine era, mainly affecting children from 1 to 9 years of age. [10]. There is evidence that B. pertussis and B. parapertussisHU were adapted to restricted niches of hosts, which possibly allowed a more effective infection [1114]. Pertussis toxin (PT), considered the main virulence factor of B. pertussis, is not produced by B. parapertussis, where the PT gene is transcriptionally silent [515], which could be a reason for the frequently milder symptoms following infection by B. parapertussis [4, 5, 16, 17].

The classical manifestations of pertussis are divided into three phases: catarrhal, paroxysmal, and convalescent [18], and are particularly serious in unprotected newborns and young infants (<1 year old), with bacteria disseminating into the lungs causing necrotizing bronchiolitis, intra-alveolar hemorrhage, and fibrinous edema. In the most severe cases, there is usually intense lymphocytosis, correlated with pulmonary hypertension, respiratory failure, and death [19]. Older children, adolescents, and adults can also be affected [20], and although in these age groups the clinical manifestations may vary from the classic symptoms to moderate or even absent cough [21], high rates of the bacteria have been found in this population [9], who act as reservoirs and can transmit the infection to at-risk groups, such as neonates and infants [22].

2. Pertussis vaccines: an almost solved problem?

The initial attempts to develop a vaccine against B. pertussis occurred in a completely empirical way, after the culture of this bacterium in the laboratory by Jules Bordet and Octave Gengou, of the Pasteur Institute in Brussels in 1906 [23]. The first effective pertussis vaccine was developed in the 1930s by Pearl Kendrick and Grace Eldering using killed whole B. pertussis cells [24]. The introduction of such whole cell pertussis vaccines (wPs) in the late 1940s, right after combined with the diphtheria and tetanus toxoids for the formulation of the triple bacterial vaccine (DTP) [25], greatly reduced the incidence of the disease [9], leading to its almost eradication in the early 1970s [10]. However, although effective, wPs were associated with undesirable side effects, which led to a decrease in the acceptance of these vaccines and the rapid increase of pertussis incidence in several countries [26, 27]. In Great Britain, by 1977, the vaccination coverage rate for pertussis fell from 77 to 33%, and up to 9%, in some districts [28]. In Japan, the government suspended pertussis vaccination in February 1975, due to widespread publicity of two deaths in children, allegedly related to the vaccine, leading to a whopping cough peak two years later, accounting for 13,000 reported cases and 40 deaths [29, 30]. The reactogenicity of wPs was extensively evaluated in DTP, and the pertussis component proved to be mainly responsible for the toxicity of these combined vaccines. Summarizing the findings from these analyses, some authors report a prospective study conducted in Los Angeles from January 1978 to December 1979 in children of 0–6 years old, involving 15,752 doses of DTP and 784 doses of DT. The children were evaluated for local and systemic reactions occurring within 48 hours of immunization. Overall, all local and systemic reactions were significantly more frequent in children who had taken DTP vaccine than DT. At the site of application, redness, swelling, and pain occurred in 37.4, 40.7, and 50.9%, respectively, in those receiving DTP, but only 7.6, 7.6, and 9.9%, respectively, in those who received DT. The percentage of these reactions in DTP vaccinated increased from the first to the fifth dose [9].

The global consequence of the refusal to accept the wP vaccines resulted in the development of the first acellular pertussis vaccine (aP), the Japanese vaccine of Sato et al. [31], containing purified antigens from the bacterium. As there was an ongoing pertussis epidemic at that time, DTaP vaccines were very rapidly developed in Japan and immediately incorporated into their vaccine calendar in 1981 [32, 33]. In the late 1990s, the wPs were gradually replaced by aPs in many developed countries [34]. Current aP vaccines contain 1–5 purified pertussis proteins: inactivated PT, filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae 2 and 3 [35].

Nowadays, DTP vaccines are available in various formulations, containing whole cell (wP) or acellular (aP) pertussis component combined with diphtheria toxoid (D/d) and tetanus toxoid (T) to produce either full-strength— diphtheria/tetanus/wP (DTwP) or aP (DTaP) vaccines—or reduced antigen-content (Tdap) vaccines, which are used for primary (DTwP or DTaP) or booster (Tdap) immunization. Whole cell pertussis vaccines are not indicated for individuals over seven years of age, and WHO only recommends formulations with lower concentrations of diphtheria toxoid and pertussis (Tdap and Td) in order to reduce their reactogenicity [36, 37]. More recently, DTP is presented as the basis for combined vaccines containing additional antigens added alone or in combinations, such as Haemophilus influenzae type b (Hib), hepatitis B, and inactivated poliovirus [3843], allowing the administration of multiple vaccine antigens in a single injection, leading to the induction of simultaneous immunity for multiple diseases [44, 45]. These combined vaccines were approved by the World Health Organization’s Expanded Program on Immunization (EPI) [4648], which substantially reduced the number of injections required in the childhood vaccine schedule. Clinical studies using the DTPa-HBV-IPV/Hib hexavalent vaccine have shown that it is safe and effective [45, 49], and the incidence of local and systemic adverse reactions was comparable to those observed after administration of single vaccines or other DTaP-based vaccines [5053], always less reactogenic than the combinations using whole cell pertussis vaccine (DTPw) [52].

3. Pertussis resurgence: a multifactorial problem

The preliminary clinical trials comparing DTaP with DTwP in the 1990s suggested comparable efficacy and immunogenicity [5458]. However, more recent data have shown that the disease is not adequately controlled and outbreaks have occurred, even in countries with extensive vaccine coverage [5961]. The reasons for the apparent ineffectiveness of current vaccines and vaccination programs in the control of infection and transmission are unclear, but there are likely to be a number of factors contributing to the short-lived immunity after vaccination [6264]. DTaP vaccines were licensed and recommended as a booster in the USA in 1992 and introduced as primary immunization in newborns in 1997. Currently, even with 95% vaccine coverage in newborns and use of booster dose in adolescents, pertussis is the least immunopreventable disease, with the highest incidence rates already reported in the post-vaccination era [65]. Possible reasons for the resurgence of pertussis include a reduction in vaccine efficacy, with rapid waning immunity, improvement in the epidemiological surveillance and diagnostic methods, and genetic changes in the pathogen [66].

DTaP vaccination induces excellent, but not durable, immune response [6769]. The higher antigenic load of the wPs may explain the epidemiological evidence that supports the longer lasting protection induced by these vaccines, in relation to the aPs. Potentially protective antigens may be absent or may be in insufficient quantity in the aP formulations, or may exhibit poor cross-match with antigens present in the circulating bacterial strains [70]. The immunity conferred by DTaP drops every year after the fifth dose, so that 5 years after the last dose the probability of a child vaccinated with this vaccine to acquire the disease is four to fifteen times greater than that after the initial doses [63, 64, 71, 72], and 80% of these children are no longer protected at the time of Tdap booster [73]. The efficacy conferred by Tdap was 75.3% in a pertussis outbreak in Wisconsin in 2012, falling after 2 years to 34.5% [74].

Differences between wP and aP vaccines, related to its antigenic load and presentation of antigens to antigen presenting cells, lead to a different balance of Th1/Th2/Th17 response. The role of Th1 and Th17 cells has been demonstrated in the protective immunity induced by B. pertussis infection or immunization with wP, and on the other hand, immunization with an aP vaccine administered with alum as adjuvant induced Th2 and Th17 cells, but poor Th1 response [75]. The multiple virulence factors of B. pertussis, many of them efficiently maintained in the wP vaccines, presuppose a better stimulation of innate immunity, leading to the generation of effective Th1/Th17-skewed adaptive immunity [76].

The probability of contracting the disease of humans primed with DTwP is lower than those primed with DTaP [62, 63, 68, 69]. Adolescents vaccinated with three doses of DTaP were 3.3 times more likely to contract pertussis than children vaccinated only with DTwP [46, 62]. These data were recently confirmed in baboons, an animal model that reproduces the characteristics of human infection [7779]. Baboons immunized with DTaP and challenged with a clinical isolate of B. pertussis are heavily colonized and do not control the infection until 4–5 weeks, transmitting the bacteria to naive animals. Those vaccinated with DTwP are colonized, but without leukocytosis, and control the infection in 2–3 weeks, faster than those not previously vaccinated [78].

There is evidence that circulating strains of B. pertussis are evolving to evade the vaccine-conferred immunity [80]. In fact, pertactin-deficient B. pertussis strains were identified in 85% of the isolates obtained from eight US states between 2011 and 2013 [81]. These samples emerged rapidly and did not express the PRN contained in the DTaP vaccine, and suggesting selective advantage, individuals previously vaccinated against pertussis had higher chance of infection with the PRN-deficient strains than with the strain expressing that protein [8285]. Besides that, an increase in the incidence of vaccine alleles of B. pertussis could also suggest an evolutionary epitope-mediated vaccine pressure [8689], contributing to the reemergence of pertussis in humans, and in this sense, it is also not clear how the B. parapertussis can answer to the selective pressure exerted by large-scale vaccination against B. pertussis.

Although highly effective in reducing the incidence of pertussis infections, the acellular pertussis vaccines have little or no efficacy against B. parapertussis [17, 90, 91]. Some authors have postulated that vaccination with aPs can interfere with the “clearance” of B. parapertussis, facilitating the adaptive performance of this pathogen, which could lead to the emergence of more susceptible hosts to B. parapertussis infection [92]. Accordingly, a gradual increase in the prevalence of B. parapertussis has been observed as a result of epidemiological pertussis immunization with vaccines that are less protective against B. parapertussis than the natural infection with B. pertussis [93]. Similar to the serum specificity observed in other infectious diseases, pertussis vaccines may have led to epidemiological pressure, with an increase in the prevalence of B. parapertussis. Since the differential diagnosis would not affect clinical procedures, the vast majority of pertussis studies are not directed to the identification of B. parapertussis, which probably has led to unreported cases. However, studies aimed at the differential diagnosis showed that B. parapertussis comprise from 2 to 36% of the cases [94].

In August 2015, the World Health Organization published its position on pertussis vaccines [95], in an attempt to provide substantiated information for immunization and public health programs, in a document that replaces the previous one published in 2010 [35]. The main goal of this position paper was to guide the choice of pertussis vaccines—wP or aP—to the most current strategies to reduce the risk of pertussis in infants and young children. In this document, it was established that the goal to be achieved in all countries is the maintenance of high vaccination coverage (higher than 90%). High levels of safety and protection can be obtained by the wP and the aP vaccines, after the primary series of immunization with three doses, ideally completed by the sixth month of life (Table 1). However, although systemic and local reactions are more commonly associated with wP, the duration of protection conferred by these vaccines is longer [9698]. The pertussis vaccination schedule should maintain protection for at least six years in countries using wP, but the protection may suffer a marked decline before the age of six years when aP is used (Table 1) [95]. Vaccination of pregnant women has been recommended by WHO as the best strategy for disease prevention in infants too young to be vaccinated or with incomplete immunization schedule, and the change from wP to aP in primary immunization should only be considered in countries that are able to maintain a schedule with periodic reinforcement and sustainable maternal immunization. If this is not the case, immunization with wP should be maintained and in national programs using aP, consideration should be given to the introduction of additional booster doses in the case of pertussis reemergence [95]. The production cost of the aP vaccine is considerably higher than that of the wP (difference of more than 5 US$ per dose with PAHO’s revolving fund price), which has a direct implication in health systems, especially in underdeveloped and developing countries.

Balance of benefits and costsAcellular pertussis vaccine (aP)Whole cell pertussis vaccine (wP)
Quality of evidence for benefitsHighly effectiveHighly effective
Intervention effects
  • Primary series reduces the risk of severe pertussis

  • Lower incidence of adverse reactions than with wP vaccine [96, 97]

  • Primary series reduces the risk of severe pertussis

  • Primary series not associated with serious adverse effects

Duration of protection
  • May decline before 6 years

  • At least 6 years

  • Longer than that induced by aP [98]

Resource implications
  • Significantly more expensive than the wP vaccine

  • Significantly less expensive than the aP vaccine

Table 1.

WHO evidences to pertussis vaccines [95].

Considering cost-effectiveness in the implementation of national vaccination programs, some authors have pointed out questions about the possibility of reintroduction of wP vaccines into the primary doses of pertussis vaccination [76, 99, 100], which could again lead to the problems with the reactogenicity of these vaccines.

4. Back to the past: whole cell pertussis vaccine as a new alternative

In Brazil, mandatory notification of all outbreaks began in 1975 when the pertussis entered the list of notifiable diseases. In the early 1980s, more than 40,000 cases were reported per year, with an incidence rate >30/100,000 inhabitants. With the introduction of the DTP vaccine in the Brazilian scheme of childhood vaccination in 1983, this number fell sharply [101]. In 2002, the first three doses of the DTwP were replaced by the tetravalent vaccine DTwP + H. influenzae type B (DTwP-Hib), that in 2012 was replaced by the pentavalent DTwP + H. influenzae type B + hepatitis B (DTwP-Hib-HBV). The first three doses of the pentavalent vaccine are administered at 2, 4, and 6 months of age, followed by DTwP booster at 15 and 48 months of age. DTaP vaccine is recommended for children at increased risk of developing or who have developed severe adverse events to the DTwP, and the vaccine is available at the Special Immunobiological Reference Centers. After 2014 the Brazilian National Immunization Program began to offer Tdap to pregnant women [102]. Despite the high vaccination coverage (>95%) since 2011, a significant increase in the number of reported cases of pertussis in Brazil has been observed, with an incidence rate in 2013 of 14,058 confirmed cases/100,000 in infants under one year of age, the majority of cases and deaths in unvaccinated children younger than 4 months old [103].

The Butantan Institute in São Paulo, Brazil, produces DTwP vaccine since 1953. Currently, more than 90% of Brazilian children are vaccinated at the age of 2/4/6 and 15 months life, which are about 250 million doses annually. Over the past 20 years, the Institute has been investigating new pertussis vaccines, less reactogenic and at low cost [104].

Although effective, wP vaccines contain a significant amount of lipooligosaccharide (LOS), an endotoxin of Gram-negative outer membrane that may be involved in the local and systemic adverse vaccine reactions. The introduction of procedures that increase the safety of wP vaccines maintaining its effectiveness remains a very important aspect, especially for developing countries that do not have access to currently available aP vaccines. In this sense, a whole cell pertussis vaccine was developed with low endotoxicity (Plow) obtained by chemical extraction of the LOS fraction from the outer membrane of the bacterial cell [105]. This vaccine was evaluated as DTwP vaccine, combined with tetanus and diphtheria toxoids in a Phase I field trial in infants, showing to be less reactogenic and equally immunogenic and protective as the traditional DTP vaccine [106].

Many developed countries using acellular pertussis vaccines in infancy have introduced a booster dose for adolescents [107], preventing the carrier state, an attempt to block the spread of the disease to infants not immunized or with incomplete immunization schedule. Due to its low reactogenicity, the Plow vaccine may possibly be introduced into the vaccination schedule for immunization of adolescents and young adults in Brazil, an important epidemiological contribution to reducing the circulation of B. pertussis.

Preliminary studies in our laboratory have shown that the Plow is able to protect mice against B. parapertussis (unpublished data), suggesting an important role in the control of this pathogen, which has not been reached by vaccination with acellular pertussis vaccines [17, 90, 91, 108, 109].

The cost to produce the Plow vaccine is the same as the conventional whole cell pertussis vaccine, which makes its use feasible in developing countries, such as Brazil [89, 110], as an alternative for use in different strategies for the control of pertussis resurgence, including vaccination of adolescents and adults, due to their lower reactogenicity.


This work was funded by the Brazilian National Bank for Economic and Social Development (BNDES), National Council for Scientific and Technological Development (CNPq), and Butantan Foundation.


1 - de Greeff SC, Mooi FR, Westerhof A, Verbakel JM, Peeters MF, Heuvelman CJ, Notermans DW, Elvers LH, Schellekens JF, de Melker HE. Pertussis disease burden in the household: How to protect young infants. Clinical Infectious Diseases. 2010;50(10):1339–1345. DOI: 10.1086/652281
2 - Centers for Disease Control and Prevention. Pertussis. (Whooping Cough). 2016. Available from: [Accessed: March 28, 2017]
3 - Provisional 2015 Reports of Notifiable Diseases, January 8, 2016/64(52). Center for Disease Control and Prevention. Available from: [Accessed: March 28, 2017]
4 - Mastrantonio P, Stefanelli P, Giuliano M, Herrera Rojas Y, Ciofi degli Atti M, Anemona A, Tozzi AE. Bordetella parapertussis infection in children: Epidemiology, clinical symptoms, and molecular characteristics of isolates. Journal of Clinical Microbiology. 1998;36(4):999–1002
5 - Bergfors E, Trollfors B, Taranger J, Lagergard T, Sundh V, Zackrisson G. Parapertussis and pertussis: Differences and similarities in incidence, clinical course, and antibody responses. International Journal of Infectious Diseases. 1999;3:140–146. DOI: 10.1016/S1201-9712(99)90035-8
6 - Bjornstad ON, Harvill ET. Evolution and emergence of Bordetella in humans. Trends in Microbiology. 2005;13:355–359. DOI: 10.1016/j.tim.2005.06.007
7 - Preston A, Parkhill J, Maskell DJ. The Bordetellae: Lessons from genomics. Nature Reviews Microbiology. 2004;2:379–390. DOI: 10.1038/nrmicro886
8 - Cherry JD, Heininger U. Pertussis and other Bordetella infections. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan S, editors. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2009. pp. 1683–1706
9 - Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clinical Microbiology Reviews. 2005;18:326–382. DOI: 10.1128/CMR.18.2.326-382.2005
10 - Centers for Disease Control and Prevention. Pertussis. In: Atkinson W, Wolfe S, Hamborsky J, editors. Epidemiology and Prevention of Vaccine-Preventable Diseases. 12th ed., second printing. Washington DC: Public Health Foundation; 2012. pp. 215–232
11 - Parkhill J, Sebaihia M, Preston A, et al. Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica. Nature Genetics. 2003;35:32–40. DOI: 10.1038/ng1227
12 - Cummings CA, Brinig MM, Lepp PW, van de Pas S, Relman DA. Bordetella species are distinguished by patterns of substantial gene loss and host adaptation. Journal of Bacteriology. 2004;186:1484–1492. DOI: 10.1128/JB.186.5.1484-1492.2004
13 - Li LJ, Dougan G, Novotny P, Charles IG. P.70 pertactin, an outer-membrane protein from Bordetella parapertussis: Cloning, nucleotide sequence and surface expression in Escherichia coli. Molecular Microbiology. 1991;5:409–417. DOI: 10.1111/j.1365-2958.1991.tb02123.x
14 - Blom J, Hansen GA, Poulsen FM. Morphology of cells and hemagglutinogens of Bordetella species: Resolution of substructural units in fimbriae of Bordetella pertussis. Infection and Immunity. 1983;42:308–317
15 - Arico B, Rappuoli R. Bordetella parapertussis and Bordetella bronchiseptica contain transcriptionally silent pertussis toxin genes. Journal of Bacteriology. 1987;169:2847–2853. DOI: 10.1128/jb.169.6.2847-2853.1987
16 - Heininger U, Stehr K, Schmitt-Grohé S, Lorenz C, Rost R, Christenson PD, Uberall M, Cherry JD. Clinical characteristics of illness caused by Bordetella parapertussis compared with illness caused by Bordetella pertussis. Pediatric Infectious Disease Journal. 1994;13(4):306–309. DOI: 10.1097/00006454-199404000-00011
17 - Liese JG, Renner C, Stojanov S, Belohradsky BH. Clinical and epidemiological picture of B pertussis and B parapertussis infections after introduction of acellular pertussis vaccines. Archives of Disease in Childhood. 2003;88:684–687. DOI: 10.1136/adc.88.8.684
18 - American Academy of Pediatrics. Summaries of infectious diseases. In: Pickering LK, Baker J, Kimberlin DW, Long SS, editors. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. By: AAP Committee on Infectious Diseases. Elk Grove Village, IL; 2012. pp. 553–566
19 - Paddock CD, Sanden GN, Cherry JD, Gal AA, Langston C, Tatti KM, Wu KH, Goldsmith CS, Greer PW, Montague JL, Eliason MT, Holman RC, Guarner J, Shieh WJ, Zaki SR. Pathology and pathogenesis of fatal Bordetella pertussis infection in infants. Clinical Infectious Diseases. 2008;47(3):328–338. DOI: 10.1086/589753
20 - Nennig ME, Shinefield HR, Edwards KM, Black SB, Fireman BH. Prevalence and incidence of adult pertussis in an urban-population. Journal of the American Medical Association. 1996;275:1672–1674. DOI: 10.1001/jama.1996.03530450062034
21 - Ward JI, Cherry JD, Chang SJ, Partridge S, Keitel W, Edwards K, Lee M, Treanor J, Greenberg DP, Barenkamp S, Bernstein DI, Edelman R, APERT Study Group. Bordetella pertussis infections in vaccinated and unvaccinated adolescents and adults, as assessed in a national prospective randomized acellular pertussis vaccine trial. Clinical Infectious Diseases. 2006;43(2):151–157. DOI: 10.1086/504803
22 - Lavine J, Broutin H, Harvill ET, Bjornstad ON. Imperfect vaccine-induced immunity and whooping cough transmission to infants. Vaccine. 2010;29:11–16. DOI: 10.1016/j.vaccine.2010.10.029
23 - Bordet J, Gengou O. Le microbe de la coqueluche. Annales de l’Institut Pasteur. 1906;2:731–741
24 - Kendrick P, Eldering GA. A study in active immunization against pertussis. With statistical analyses of the data by AJ BOROWSKI. American Journal of Epidemiology. 1939;29:133–153. DOI: 10.1093/oxfordjournals.aje.a118485
25 - McIntyre P. Vaccination strategies for the prevention of neonatal pertussis. Expert Review of Vaccines. 2004;34:375–378. DOI: 10.1586/14760584.3.4.375
26 - Centers for Disease Control. International notes pertussis – England and Wales. Morbidity and Mortality Weekly Report. 1982;31(47): 629–640
27 - Baker JP. The pertussis vaccine controversy in Great Britain, 1974–1986. Vaccine. 2003;21:4003–4010. DOI: 10.1016/S0264-410X(03)00302-5
28 - Swansea Research Unit of the Royal College of General Practitioners. Effect of a low pertussis vaccination uptake on a large community. British Medical Journal. 1981;282(6268):23–26. DOI: 10.1136/bmj.282.6257.23
29 - Kanai K. Japan’s experience in pertussis epidemiology and vaccination in the past thirty years. Japanese Journal of Medical Science and Biology. 1980;33:107–143. DOI: 10.7883/yoken1952.33.107
30 - Kimura M, Kuno-Sakai H. Pertussis vaccines in Japan—a clue toward understanding Japanese attitude to vaccines. Journal of Tropical Pediatrics. 1991;37:45–47. DOI: 10.1093/tropej/37.1.45
31 - Sato Y, Kimura M, Fukumi H. Development of a pertussis component vaccine in Japan. Lancet. 1984;1:122–126. DOI:.10.1016/S0140-6736(84)90061-8
32 - Kimura M, Kuno-Sakai H. Pertussis vaccines in Japan. Acta Paediatrica Japonica. 1988;30:143–153. DOI: 10.1111/j.1442-200X.1988.tb02512.x
33 - Noble GR, Bernier RH, Esber EC, Hardegree MC, Hinman AR, Klein D, Saah AJ. Acellular and whole-cell pertussis vaccines in Japan. Report of a visit by US scientists. Journal of the American Medical Association. 1987;257:1351–1356. DOI: 10.1001/jama.1987.03390100089032
34 - Preston A, Maskell DJ. A new era of research into Bordetella pertussis pathogenesis. Journal of Infection. 2002;44:13–16. DOI: 10.1053/jinf.2001.0933
35 - World Health Organization. Pertussis vaccines: WHO position paper. Weekly Epidemiological Record. 2010;85:385–400
36 - WHO. DTP Vaccine Rates Information Sheet. May 2014. Available from: [Accessed: March 28, 2017]
37 - WHO Report. Pertussis vaccines: WHO position paper, August 2015—Recommendations. Vaccine. 2016;34:1423–1425. DOI: 10.1016/j.vaccine.2015.10.136
38 - Committee on Infectious Diseases, American Academy of Pediatrics. Prevention of poliomyelitis: Recommendations for use of only inactivated poliovirus vaccine for routine immunization. Pediatrics. 1999;104:1404–1406
39 - Van Damme P. Hepatitis B: Vaccination programmes in Europe – An update. Vaccine. 2001;19:2375–2379. DOI: 10.1016/S0264-410X(00)00457-6
40 - Zepp F, Schuind A, Meyer C, S¨anger R, Kaufhold A, Willems P. Safety and reactogenicity of a novel DTPa-HBV-IPV combined vaccine given along with commercial Hib vaccines in comparison with separate concomitant administration of DTPa, Hib, and OPV vaccines in infants. Pediatrics. 2002;109:1–8
41 - Gylca R, Gylca V, Benes O, Melnic A, Chicu V, Weisbecker C, Willems P, Kaufhold A. A new DTPa-HBV-IPV vaccine co-administered with Hib, compared to a commercially available DTPw-IPV/Hib vaccine co-administered with HBV, given at 6, 10 and 14 weeks following HBV at birth. Vaccine. 2000;19:825–833. DOI: 10.1016/S0264-410X(00)00231-0
42 - Decker MD, Edwards KM, Steinhoff MC, Rennels MB, Pichichero ME, Englund JA, Anderson EL, Deloria MA, Reed GF. Comparison of 13 acellular pertussis vaccines: Adverse reactions. Pediatrics. 1995;96:557–566
43 - Yeh SH, Ward JI, Partridge S, Marcy SM, Lee H, Jing J, et al. Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants. Pediatric Infectious Disease Journal. 2001;20:973–980
44 - Andre FE. Development and clinical application of new polyvalent combined paediatric vaccines. Vaccine. 1999;17:1620–1627. DOI: 10.1016/S0264-410X(98)00426-5
45 - Dodd D. Benefits of combination vaccines: Effective vaccination on a simplified schedule. American Journal of Managed Care. 2003;9(Suppl.):S6-S12
46 - Report of the Global Advisory Group. Expanded Programme on Immunization. Weekly Epidemiological Record. 1992;67:11–15
47 - WHO. Hepatitis B vaccine-making global progress. Expanded Programme on Immunization. WHO Update; 1996
48 - Global Programme for Vaccine and Immunization (GPV). The WHO position paper on Haemophilus influenzae type b conjugate vaccines. Weekly Epidemiological Record. 1998;73:64–68
49 - Capiau C, Poolman J, Hoet B, Bogaerts H, Andre F. Development and clinical testing of multivalent vaccines based on a diphtheria-tetanus acellular pertussis vaccine: Difficulties encountered and lessons learned. Vaccine. 2003;21:2273–2287. DOI: 10.1016/S0264-410X(03)00107-5
50 - Zepp F, Knuf M, Heininger U, Jahn K, Collard A, Habermehl P, et al. Safety, reactogenicity and immunogenicity of a combined hexavalent tetanus, diphtheria, acellular pertussis, hepatitis B, inactivated poliovirus vaccine and Haemophilus influenzae type b conjugate vaccine, for primary immunization of infants. Vaccine. 2004;22:2226–2233. DOI: 10.1016/j.vaccine.2003.11.044
51 - Saenger R, Maechler G, Potreck M, Zepp F, Knuf M, Habermehl P, et al. Booster vaccination with hexavalent DTPa-HBV-IPV/Hib vaccine in the second year of life is as safe as concomitant DTPa-IPV/Hib+HBV administered separately. Vaccine. 2005;23:1135–1143. DOI: 10.1016/j.vaccine.2004.08.030
52 - Cohen R, Schuerman L. Reactogenicity of a new DTPa-HBV-IPV (+ and /Hib) vaccines after primary and booster doses. Presented at: 18th Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID) Noordwijk, The Netherlands, 2000
53 - Infanrix hexaTM. Product Monograph. GlaxoSmithKline; 2016 GlaxoSmithKline Inc. 7333 Mississauga Road Mississauga, Ontario L5N 6L4
54 - Lugauer S, Heininger U, Cherry JD, Stehr K. Long-term clinical effectiveness of an acellular pertussis component vaccine and a whole cell pertussis component vaccine. European Journal of Pediatrics. 2002;161:142–146. DOI: 10.1007/s00431-001-0893-5
55 - Salmaso S, Mastrantonio P, Tozzi AE, Stefanelli P, Anemona A, Ciofi degli Atti ML, Giammanco A, Group SIW. Sustained efficacy during the first 6 years of life of 3-component acellular pertussis vaccines administered in infancy: The Italian experience. Pediatrics. 2001;108:E81. DOI: 10.1542/peds.108.5.e81
56 - Taranger J, Trollfors B, Lagergård T, Lind L, Sundh V, Zackrisson G, Bryla DA, Robbins JB. Unchanged efficacy of a pertussis toxoid vaccine throughout the two years after the third vaccination of infants. Pediatric Infectious Disease Journal. 1997;16(2):180–184. DOI: 10.1097/00006454-199702000-00003
57 - Edwards KM, Decker MD. Pertussis vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 6th ed. Edinburgh, Scotland: Elsevier Saunders; 2013. pp. 447–492
58 - Plotkin SA, Cadoz M. The acellular pertussis vaccine trials: An interpretation. Pediatric Infectious Disease Journal. 1997;16:508–517. DOI: 10.1097/00006454-199705000-00011
59 - Cherry JD. Epidemic pertussis in 2012 – The resurgence of a vaccine preventable disease. New England Journal of Medicine. 2012;367:785–787. DOI: 10.1056/NEJMp1209051
60 - Chiappini E, Stival A, Galli L, de Martino M. Pertussis re-emergence in the post-vaccination era. BMC Infectious Diseases. 2013;13:151. DOI: 10.1186/1471-2334-13-151
61 - Clark TA, Messionier NE, Hadler SC. Pertussis control: Time for something new? Trends in Microbiology. 2012;20:211–213. DOI: 10.1016/j.tim.2012.03.003
62 - Sheridan SL, Ware RS, Grimwood K, Lambert SB. Number and order of whole cell pertussis vaccines in infancy and disease protection. Journal of the American Medical Association. 2012;308:454–456. DOI: 10.1001/jama.2012.6364
63 - Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning protection after fifth dose of acellular pertussis vaccine in children. New England Journal of Medicine. 2012;367:1012–1019. DOI: 10.1056/NEJMoa1200850
64 - Misegades LK, Winter K, Harriman K, Talarico J, Messonnier NE, Clark TA, Martin SW. Association of childhood pertussis with receipt of 5 doses of pertussis vaccine by time since last vaccine dose, California, 2010. Journal of the American Medical Association. 2012;308(20):2126–2132. DOI: 10.1001/jama.2012.14939
65 - Centers for Disease Control and Prevention. Notifiable diseases and mortality tables. Morbidity and Mortality Weekly Report. 2013;62:669–682. Available from: [Accessed: March 28, 2017]
66 - Cherry JD. Pertussis: Challenges today and for the future. PLoS Pathogens. 2013;9(7):e1003418. DOI: 10.1371/journal.ppat.1003418
67 - Warfel JM, Edwards KM. Pertussis vaccines and the challenge of inducing durable immunity. Current Opinion in Immunology. 2015;35:48–54. DOI: 10.1016/j.coi.2015.05.008
68 - 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. Clinical Infectious Diseases. 2013;56:1248–1254. DOI: 10.1093/cid/cit046
69 - Liko J, Robison SG, Cieslak PR. Priming with whole-cell versus acellular pertussis vaccine. New England Journal of Medicine. 2013;368:581–582. DOI: 10.1056/NEJMc1212006
70 - Mooi FR, Van Der Maas NA, De Melker HE. Pertussis resurgence: Waning immunity and pathogen adaptation: Two sides of the same coin. Epidemiology and Infection. 2013;13:1–10. DOI: 10.1017/S0950268813000071
71 - Tartof SY, Lewis M, Kenyon C, White K, Osborn A, Liko J, Zell E, Martin S, Messonnier NE, Clark TA, Skoff TH. Waning immunity to pertussis following 5 doses of DTaP. Pediatrics. 2013;131(4):e1047-e1052. DOI: 10.1542/peds.2012-1928
72 - Witt MA, Katz PH, Witt DJ. Unexpectedly limited durability of immunity following acellular pertussis vaccination in preadolescents in a North American outbreak. Clinical Infectious Diseases. 2012;54:1730–1735. DOI: 10.1093/cid/cis287
73 - McGirr A, Fisman DN. Duration of pertussis immunity after DTaP immunization: A meta-analysis. Pediatrics. 2015;135:331–343. DOI: 10.1542/peds.2014-1729
74 - Koepke R, Eickhoff JC, Ayele RA, Petit AB, Schauer SL, Hopfensperger DJ, Conway JH, Davis JP. Estimating the effectiveness of tetanus-diphtheria-acellular pertussis vaccine (Tdap) for preventing pertussis: Evidence of rapidly waning immunity and difference in effectiveness by Tdap brand. Journal of Infectious Diseases. 2014;210:942–953. DOI: 10.1093/infdis/jiu322
75 - Ross PJ, Sutton CE, Higgins S, Allen AC, Walsh K, Misiak A, Lavelle EC, McLoughlin RM, Mills KH. Relative contribution of Th1 and Th17 cells in adaptive immunity to Bordetella pertussis: Towards the rational design of an improved acellular pertussis vaccine. PLoS Pathogens. 2013;9(4):e1003264. DOI: 10.1371/journal.ppat.1003264
76 - Ausiello CM, Cassone A. Acellular pertussis vaccines and pertussis resurgence: Revise or replace? mBio. 2014;5(3):e01339–14. DOI: 10.1128/mBio.01339-14
77 - Warfel JM, Beren J, Kelly VK, Lee G, Merkel TJ. Nonhuman primate model of pertussis. Infection and Immunity. 2012;80:1530–1536. DOI: 10.1128/IAI.06310-11
78 - Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:787–792. DOI: 10.1073/pnas.1314688110
79 - 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 Immunology. 2013;6(4):787–796. DOI: 10.1038/mi.2012.117
80 - Bart MJ, Harris SR, Advani A, Arakawa Y, Bottero D, Bouchez V, Cassiday PK, Chiang CS, Dalby T, Fry NK, et al. Global population structure and evolution of Bordetella pertussis and their relationship with vaccination. mBio. 2014;5(2):e01074–14. DOI: 10.1128/mBio.01074-14
81 - Martin SW, Pawloski L, Williams M, Weening K, DeBolt C, Qin X, Reynolds L, Kenyon C, Giambrone G, Kudish K, Miller L, Selvage D, Lee A, Skoff TH, Kamiya H, Cassiday PK, Tondella ML, Clark TA. Pertactin negative Bordetella pertussis strains: Evidence for a possible selective advantage. Clinical Infectious Diseases. 2015;60(2):223–227. DOI: 10.1093/cid/ciu788
82 - Pawloski LC, Queenan AM, Cassiday PK, Lynch AS, Harrison MJ, Shang W, Williams MM, Bowden KE, Burgos-Rivera B, Qin X, Messonnier N, Tondella ML. Prevalence and molecular characterization of pertactin deficient Bordetella pertussis in the United States. Clinical and Vaccine Immunology. 2014;21(2):119–125. DOI: 10.1128/CVI.00717-13
83 - Queenan AM, Cassiday PK, Evangelista A. Pertactin-negative variants of Bordetella pertussis in the United States. New England Journal of Medicine. 2013;368:583–584. DOI: 10.1056/NEJMc1209369
84 - Hegerle N, Guiso N. Bordetella pertussis and pertactin deficient clinical isolates: Lessons for pertussis vaccines. Expert Review of Vaccines. 2014;13:1135–1146. DOI: 10.1586/14760584.2014.932254
85 - Lam C, Octavia S, Ricafort L, Sintchenko V, Gilbert GL, Wood N, McIntyre P, Marshall H, Guiso N, Keil AD, Lawrence A, Robson J. Rapid increase in pertactin-deficient Bordetella pertussis isolates, Australia. Emerging Infectious Diseases. 2014;20:626–633. DOI: 10.3201/eid2004.131478
86 - Elomaa A, Advani A, Donnelly D, Antila M, Mertsola J, Hallander H, He Q. Strain variation among Bordetella pertussis isolates in Finland, where the whole cell pertussis vaccine has been used for 50 years. Journal of Clinical Microbiology. 2005;43:3681–3687. DOI: 10.1128/JCM.43.8.3681-3687.2005
87 - van Amersfoorth SC, Schouls LM, van der Heide HG, Advani A, Hallander HO, Bondeson K, von König CH, Riffelmann M, Vahrenholz C, Guiso N, Caro V, Njamkepo E, He Q, Mertsola J, Mooi FR. Analysis of Bordetella pertussis populations in European countries with different vaccination policies. Journal of Clinical Microbiology. 2005;43:2837–2843. DOI: 10.1128/JCM.43.6.2837-2843.2005
88 - van Gent M, de Greeff SC, van der Heide HG, Mooi FR. An investigation into the cause of the 1983 whooping cough epidemic in the Netherlands. Vaccine. 2009;27(13):1898–1903. DOI: 10.1016/j.vaccine.2009.01.111
89 - Berbers GA, de Greeff SC, Mooi FR. Improving pertussis vaccination. Human Vaccine. 2009;5:497–503. DOI: 10.4161/hv.8112
90 - Willems RJ, Kamerbeek J, Geuijen CA, Top J, Gielen H, Gaastra W, Mooi FR. The efficacy of a whole cell pertussis vaccine and fimbriae against Bordetella pertussis and Bordetella parapertussis infections in a respiratory mouse model. Vaccine. 1998;16:410–416. DOI: 10.1016/S0264-410X(97)80919-X
91 - David S, van Furth R, Mooi FR. Efficacies of whole cell and acellular pertussis vaccines against Bordetella parapertussis in a mouse model. Vaccine. 2004;22(15):1892–1898. DOI: 10.1016/j.vaccine.2003.11.005
92 - Long GH, Karanikas AT, Harvill ET, Read AF, Hudson PJ. Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis. Proceedings. Biological Sciences. 2010;277(1690):2017–2025. DOI: 10.1098/rspb.2010.0010
93 - Restif O, Wolfe DN, Goebel EM, Bjørnstad ON, Harvill ET. Of mice and men: Asymmetric interactions between Bordetella pathogen species. Parasitology. 2008;135:1517–1529. DOI: 10.1017/S0031182008000279
94 - Watanabe M, Nagai M. Whooping cough due to Bordetella parapertussis: An unresolved problem. Expert Review of Anti-infective Therapy. 2004;2:447–454. DOI: 10.1586/14787210.2.3.447
95 - World Health Organization. Pertussis vaccines: WHO position paper. Weekly Epidemiological Record. 2015;90:433–460. Available from: [Accessed: March 31, 2017]
96 - Jefferson T, Rudin M, DiPietrantonj C. Systematic review of the effects of pertussis vaccines in children. Vaccine. 2003;21:2003–2014. DOI: 10.1016/S0264-410X(02)00770-3
97 - Bar-On ES, Goldberg E, Hellmann S, Leibovici L. Combined DTP-HBV-HIB vaccine versus separately administered DTPHBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD005530. DOI: 0.1002/14651858.CD005530.pub3
98 - Quinn HE, Mcintyre PB. Pertussis epidemiology in Australia over the decade 1995–2005, trends by region and age group. Communicable Diseases Intelligence. 2007;31(2):205–215
99 - Meade BD, Plotkin SA, Locht C. Possible options for new pertussis vaccines. The Journal of Infectious Diseases. 2014;209(S1):S24-S27. DOI: 10.1093/infdis/jit531
100 - Locht C, Mielcarek N. New pertussis vaccination approaches: En route to protect newborns? FEMS Immunology & Medical Microbiology. 2012;66:121–133. DOI: 10.1111/j.1574-695X.2012.00988.x
101 - Torres RSLA, Santos TZ, Torres RAA, Pereira VVG, Fávero LAF, Filho ORM, Penkal ML, Araujo LS. Resurgence of pertussis at the age of vaccination: Clinical, epidemiological, Wand molecular aspects. Jornal de Pediatria (Rio J). 2015;91(4):333–338. DOI: 10.1016/j.jped.2014.09.004
102 - Brazilian Ministry of Health. Informe Técnico para Implantação da Vacina Adsorvida Difteria, Tétano e Coqueluche (Pertussis Acelular) Tipo adulto – dTpa. 2014. Available from:
103 - Guimarães LM, Carneiro ELNC, Carvalho-Costa FA. Increasing incidence of pertussis in Brazil: A retrospective study using surveillance data. BMC Infectious Diseases. 2015;15:442–453. DOI: 10.1186/s12879-015-1222-3
104 - Dias WO, Leite LCC, Horton DSPQ, Sakauchi MA, Kubrusly FS, Furuyama N, Nascimento IP, Quintilio W, Higashi HG, Raw I. New approaches in pertussis vaccines for developing countries. In: Méndez-Vilas A, editor. Communicating Current Research and Educational Topics and Trends in Applied Microbiology. FORMATEX C/ Zurbarán 1, 2º - Oficina 1 06002 Badajoz Spain Vol. 2. 2007.pp. 668–672
105 - Dias WO, van der Ark AAJ, Sakaushi MA, Kubrusly FS, Prestes AFRO, Borges MM, Furuyama N, Horton DSPQ, Quintilio W, Antoniazi M, Kyipers B, van der Zeijst BAM, Raw I. A whole cell pertussis with reduced content of endotoxin. Human Vaccines & Immunotherapeutics. 2013;9(2):339–348. DOI: 10.4161/hv.22847
106 - Zorzeto TQ, Higashi HG, da Silva MTN, Carniel EF, Dias WO, Ramalho VD, Mazzola TN, Lima SCBS, Morcillo AM, Stephano MA, Antonio MARG, Zanolli ML, Raw I, Vilela MMS. Immunogenicity of a whole-cell pertussis vaccine with low lipopolysaccharide content in infants. Clinical and Vaccine Immunology. 2009;16:544–550. DOI: 10.1128/CVI.00339-08
107 - Cornia PB, Hersh AL, Lipsky BA, Newman TB, Gonzales R. Does this coughing adolescent or adult patient have pertussis? Journal of the American Medical Association. 2010;304(8):890–896. DOI: 10.1001/jama.2010.1181
108 - Khelef N, Danve B, Quentin-Millet MJ, Guiso N. Bordetella pertussis and Bordetella parapertussis: Two immunologically distinct species. Infection and Immunity. 1993;61(2):486–490
109 - Stehr K, Cherry JD, Heininger U, Schmitt-Grohé S, Uberall M, Laussucq S, Eckhardt T, Meyer M, Engelhardt R, Christenson P. A comparative efficacy trial in Germany in infants who received either the Lederle/Takeda acellular pertussis component DTP (DTaP) vaccine, the Lederle whole-cell component DTP vaccine, or DT vaccine. Pediatrics. 1998;101(1):1–11
110 - Higashi HG, Luna E, Precioso AR, Vilela M, Kubrusly FS, Dias WO, Raw I. Acellular and “low” pertussis vaccines: Adverse events and the role of mutations. The Revista do Instituto de Medicina Tropical de São Paulo. 2009;51(3):131–134. DOI: 10.1590/S0036-46652009000300002