Pertussis is still a worldwide problem: every year there are almost 20-50 million cases and 300.000 deaths. The incidence is increasing especially between adults and adolescents, with consequences on infants. For this reason, the increasing of a vaccination strategy for adolescent and adult is needed... To learn more, please visit www.waidid.org.

1. THE IMPORTANCE OF PERTUSSIS
BOOSTER VACCINE DOSES
THROUGHOUT LIFE
Susanna Esposito
Pediatric Clinic, University of Perugia
Perugia, Italy

2. Agenda
 Global burden of pertussis
 Impact of pertussis in infants, adolescents and adults
 Reservoir of Bordetella pertussis and disease
transmission
 Conclusions

3. Pertussis ‒ The Global Problem
 Remains endemic worldwide
 Estimated 20‒50 million cases and 300 000 deaths each year1-3
 Major public health problem, even in countries with
sustained high vaccination coverage4
 Incidences (2/100,000) in Japan to 124/100,000 in Switzerland)1,5
 Vaccination has reduced the global burden of pertussis by
over 90% compared to the pre-vaccine era6
 However, major pertussis epidemics have been reported over
the last decades in many countries, including Europe, Japan,
North and South America, Australia and New Zealand1‒11
1. Celentano LP, et al. PIDJ 2005;24:761–5. 2. Crowcroft NS, Pebody RG. Lancet 2006;367:1926–36. 3. WHO. WHO-recommended surveillance standard of pertussis.
Available at: http://www.who.int/immunization_monitoring/diseases/pertussis_surveillance/en/ (last accessed April 2013). 4. Tan T, et al. PIDJv2005;24:S10–18. 5. Sato Y &
Sato H. Biologicals 1999;27:61‒69; 6. Wkly Epidemiol Rec 2010;85:385‒400. 7 Sato H, Sato Y. Clin Infect Dis 1999;28(suppl 2):S124–30. 8. Kamiya H, et al. EID
2012;18:1166‒1169. 9. Hozbor D, et al. J Infect 2009;59:225–31. 10. Hellenbrand W, et al. BMC Infect Dis 2009;9:22. 11. Grant CG & Reid S. NZ Med J 2010;123:46 ‒61

4. Global incidence of pertussis is decreasing as vaccination
coverage increases
0
10
20
30
40
50
60
70
80
90
0
500000
1000000
1500000
2000000
2500000
1980
1990
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Number of cases WHO/UNICEF estimate
Numberofcases
Vaccinationcoverage(%)
(3primaryDTPdoses)
WHO IVB 2010 http://whqlibdoc.who.int/hq/2010/WHO_IVB_2010_eng.pdf (accessed July 2011)
1980:
• almost 2 million reported cases
• low (~20%) vaccination coverage
2009:
• 106K reported cases
• high (~80%) vaccination coverage
Number of reported cases

6. Pertussis Morbidity and Mortality in Infants
 Highest incidence of morbidity and mortality consistently in infants
< 6 months of age who are too young to have completed their primary
immunization series
 Of the estimated 300 000 deaths yearly worldwide, most are in young infants;
90% in developing countries with case-fatality rates estimated to be as high
as 4% of infants < 12 months of age
 Highest complications and hospitalization rate (70%)
 Annually since 1990, 93‒100% of pertussis-related deaths in the US have
occurred in < 4 months of age
 The number of deaths being reported in the infant population has been
steadily rising since the 1980s
Broder et al. MMWR 2006; 55(RR03); 1-34. Celentano LP, et al. Pediatr Infect Dis J 2005;24:761–5. Crowcroft NS, Pebody RG. Lancet 2006;367:1926–36. WHO. WHO-
recommended surveillance standard of pertussis. Available at: http://www.who.int/immunization_monitoring/diseases/pertussis_surveillance/en/ (Accessed April 2013).
California Department of Public Health, Immunization Branch. Available at: http://www.immunizeca.org/wp-content/uploads/2011/01/CDPH_Pertussis_Pertussis_task_force_1-
11-2011.pdf (Accessed May 2013). MMWR 2002;51:73‒76. MMWR 2002;51:616-619. Vitek CR, et al. Pediatr Infect Dis J 2003;22:628‒634

7. Age (years)
Region 0–4 5–14 15–59 ≥60 Total
African Region 83,586 0 135 27 83,748
Region of the Americas 2,356 0 1 3 2,360
Eastern Mediterranean
Region
18,904 0 0 2 18,906
European Region 121 0 2 3 126
South-East Asia Region 89,385 0 0 0 89,385
Western Pacific Region 580 0 1 8 589
World 194,931 0 139 43 195,113
WHO Global Health Observatory Data Repository http://apps.who.int/ghodata/?vid=10015 (accessed July 2011)
The greatest number of pertussis deaths
occur in infants and young children
Estimated pertussis deaths per region and age-group in 2008
The highest pertussis mortality is in infants/young children

8. Complications of Pertussis in Children
 4 Years of Age in the US, 1997‒2000
Age Hospitalization Pneumonia Seizures Encephalopathy Death
No. with
Pertussis
< 6 M 4,543 847 103 15 56 7,203
6‒11 M 301 92 7 1 1 1,073
1‒4 Y 324 168 36 3 1 3,137
CDC. MMWR 2002;51(4):73‒76

9. Department of Health Sciences
University of Florence
Risk factor for death
- Lack of pertussis vaccination,
- premature birth,
- low birth weight,
- younger age
- higher peak leukocytosis
- Early antibiotic treatment
WBC> 70 400/μl was particularly predictive,
especially if birth weight was low
a rapid increase in pulse and respiratory
rates was associated with death risk
 while leukocytosis may just be a
marker of Ptx activity, Ptx inhibition of
inhibitory G protein signaling affecting
heart and lung function may be the
proximate cause of death.
Risk factors associated with infant deaths from
pertussis: a case-control study
Winter K. Clin Infect Dis 2015;61:1099–1106.

10. Preterm and LBW infants are at increased risk of infection and
hospitalisation from vaccine preventable diseases1
Disease Increase in risk for preterm infants
Invasive
pneumococcal
disease
Rotavirus
gastroenteritis
Influenza
Pertussis
2x hospitalisation in preterm vs full term infants2
infection in very preterm (<32 weeks) infants4
9x
severe disease in preterms6
hospitalisation in LBW/VLBW infants1,5
2.6x
2.5x
severe disease with a history of prematurity3
5x
1. Gagneur A et al. Hum Vaccin Immunother 2015;11:2556–2563; 2. Riise OR et al. Pediatr Infect Dis 2017;36:e151–e156; 3. Marshall H et al. Pediatr Infect Dis 2015;34:339–345; 4. Shinefield H et al. Pediatr Infect Dis J 2002;21:182–186;
5. Newman R et al. Pediatrics 1999;103:E3; 6. Garcia M et al. Epidemiol Infect 2015;143:2939–2949 1
0

11. Pertussis is shifting to older children and adults: Europe 1998–
2007
Adapted from Zepp et al. Lancet Infect Dis 2011:11;557–70 (Derived from EUVAC NET data: http://www.euvac.net/graphics/euvac/pdf/pertussis1.pdf and
http://www.euvac.net/graphics/euvac/pdf/pertussis2.pdf)
<1 year 1–4 years 5–9 years 10–14 years ≥15 years
42% in ≥15 year olds
1998
1999
2000
2001
2002
2003–2007
0% 20% 40% 60% 80% 100%
~15% in ≥15 year olds

12. Age group
Clinical
characteristic
Adolescents (%)
(10‒19 years)
Adults (%)
( 20 years)
Paroxysms 82–100 74–100
Whoop 30–67 8–82
Apnea 19–86 29–92
Cyanosis 6–15 0–12
Vomiting 45–71 10.5–70
Hospitalization 1.4–7.5 3.5–5.7
Clinical Symptoms of Pertussis in Adolescents and
Adults
1.Aoyama T, et al. AJDC 1992;146:163‒166; 2. Farizo KM, et al. Clin Infect Dis1992; 14:708‒719; 3. Postels-Multani S, et al. Infection1995;23:139‒142; 4. Schmitt-Grohé, et al.
Clin Infect Dis 1995;21:860‒866; 5. Trollfors B & Rabo E. Br Med J Clin Res Ed 1981;283:696‒697.; 6. Yih WK, et al. J Infect Dis 2000;182:1409‒1416; 7. DeSerres G, et al. J
Infect Dis 2000;182:174‒179

13. Pertussis Transmission to Young Infants
 Prospective international multicenter study
of laboratory confirmed pertussis cases in
≤ 6 M and their household and non-
household contacts – France, Germany,
US, Canada
 95 index cases and 404 contacts – source
case was identified for 61.5% of index
cases
 mean age of the infant index case was
2.9 M (35 - < 2 mos; 38 - 2 to 3 mos; 22 - 4 to 6
mos)
Wendelboe AM, et al. Pediatr Infect Dis J 2007;26:293-299
Source cases
Parents
55%
Siblings - 16%
Aunts/
Uncles - 10%
Friends/
Cousins - 10%
Grandparents - 6%
Part-time
caregivers
2%

14. Pertussis incidence and mortality is underestimated and
underreported
Pertussis burden is likely to be underestimated due to:1
1. Lima et al. The Burden of Pertussis in the Asia-Pacific Region. ESPID 2010;
2. Cherry Pediatr Infect Dis J 2006;25:361–2; 3. Stefanoff et al. ESPID 2011 abstract
Low disease
awareness
Limited facilities
for laboratory
analysis
No common
case-definition
Lack of surveillance
data
Few reliable
reporting systems
In general the actual incidence of pertussis could be 40–160-fold higher than
official figures2,3

15. Diagnosis of Pertussis: time sequence
Cough 3 weeks 4 weeks
culture and PCR
PCR and
serologic
tests
serologic tests

16. The development of less reactogenic Pa vaccines replaced Pw products in most
developed countries to address concerns about Pw-associated adverse events1
Acellular pertussis vaccines contain selected components of B. pertussis that play an
important role in the pathogenesis of the disease1
– These vaccines contain a limited number of B. pertussis proteins; some contain one
pertussis component, whereas some contain as many as five1
Acellular pertussis vaccines
Acceptance
by parents
and
physicians
Improved
compliance
with
vaccination
programmes
Increased
vaccination
coverage
Better
disease
control
DTPa, diphtheria-tetanus-acellular pertussis; DTPw, diphtheria-tetanus-whole-cell pertussis
1. Poolman & Hallander. Expert Rev Vaccines 2007; 6: 47–56

17. 0
50,000
100,000
150,000
200,000
250,000
300,000
Numberofcases
Year
CDC, National DiseasesSurveillance System Reported Pertussis
Cases: 1922‒2012*
0
10,000
20,000
30,000
40,000
1990 1995 2000 2005 2010
Tdap
DTaP
*2012 data are provisional
SOURCE: CDC, National Diseases Surveillance System (NNDSS) and Supplemental Pertusssis Surveillance System and 1922-1949, passive reports to the Public Health
Service. NNDSS, National Notifiable Diseases Surveillance System. http://www.cdc.gov/pertussis/surv-reporting.html (last accessed May 2013)
1922 1930 1940 1950 1960 1970 1980 1990 2000 2012
DTP

18. Vaccination with DTPa has been effective at
reducing pertussis disease as observed by impact
data in Sweden
In Sweden, the impact of the pertussis vaccination programme was regained by
DTPa vaccination
1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Cases,per100000
0
50
100
150
200
250
300
350
DTPw DTPa
Year
DTPw, diphtheria-tetanus-whole-cell pertussis
Rohani et al. Science 2010; 330: 982–5 (Figure reproduced with permission)

19. Pertussis vaccines have been shown to be efficacious in a
number of trials against WHO-defined typical pertussis
0
10
20
30
40
50
60
70
80
90
100
Absolutevaccineefficacy;%,95%CI
Stockholm
1986
Stockholm
1992
Italy
1992
G’burg
1991
Senegal
1990
Erlangen
1991
Mainz
1992
Munich
1993
2
w
w
w
w
5–11 m, then
8–12 weeks
later
2,4,6 m 2,4,6 m 2,4,6 m 3,4,5 m
3,5,7 &
17 m
3,5,7 &
15-24 m
X acP – n-component acellular pertussis vaccine
w wcP – whole-cell Pertussis vaccine
Vaccination schedule
Household
contact
study
Randomised controlled trials
1
w w
1
4
2
2
2
3 3
3
4
Minimum observed mean efficacy of
3-component vaccines
Open-label, non-
randomised trial
3,5
&
12 m
Partially randomised
trialsa
GSK formulation
DTPa vaccines have similar efficacy and effectiveness following infant
vaccination as compared with that of DTPw, with fewer side effects1
aRandomised for relative risk of DTPa vs DTP
CI, confidence interval; DTP, diptheria-tetanus-pertussis; DTPa, diptheria-tetanus-acellular pertussis; G’Burg, Gothenburg; M, months
Edwards & Decker, In: Vaccines. 2008: 467–517

20. Department of Health Sciences
University of Florence
Pertactin-negative Bordetella pertussis
strains: evidence for a possible selective
advantage.
2- to 4-fold greater odds of having PRN– B.
pertussis when fully vaccinated according to
schedule
vaccinated persons have greater susceptibility to
PRN– strains compared with PRN+ strains.
Martin SW. Clin Infect Dis 2015;60:223-227.
87% of 2012 isolates included in our
analysis were pertactin-deficient

21. Department of Health Sciences
University of Florence
Loconsole D. Pediatr Infect Dis J. 2017 Sep 21. [Epub ahead of print]
Resurgence of Pertussis and Emergence of the
Ptxp3 Toxin Promoter Allele in South Italy.
The hypervirulent strain was also found in vaccinated
people. This suggests bacterial adaptation to the vaccine
and raises questions about acellular vaccine effectiveness
Of the 661 cases recorded in 2006-2015, 80.3% required hospitalization;
of these, 45.4% were aged <1 year. Of the 80 sequenced samples, the
allelic profile ptxA1-ptxP3-prn2 was detected in 74.

22. Number of paediatric pertussis cases by age and
vaccination status: California, 2010
0
200
400
600
800
1000
1200
1400
1600
Cases
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
6 doses
5 doses
1-4 doses
0 dose
Age in years
Winter K, et al. J Pediatr. 2012; 161: 1091–6
Figure reproduced with permission from Mosby Inc.

23. 18.7% positivity for Bordetella
pertussis in children 7-17 years
old with chronic cough
Principi N et al., J Med Microbiol 2017

24. 26Infect Immun 2001

25. Department of Health Sciences
University of Florence
100 children
Antibody responses to pertussis toxoid
were undetectable in 49% of children at
the 5 year follow up visit,
responses were predicted to be
undetectable in 69% (95% CI 45–88%) of
children by the time of their teenage
booster at 13–14 years of age.
Vorsey M. Vaccine 2016;34:4221-8
The predicted persistence and kinetics of antibody
decline 9 years after pre-school booster vaccination in
UK children.

26. Pertussis prevention strategies throughout life
0 3
months
Adolescents AdultsChildren
Waning
immunity1
Vaccine induced
protection1
Limited natural
immunity1
Transmission2,3
Elderly
1. Adapted from Wendelboe et al. Pediatr Infect Dis J 2005: 24; S58–S61; 2. Sawyer, Chair ACIP Pertussis Vaccine WG, Oct 24, 2012; 3. CDC. MMWR 2011; 60: 13–15;
4. Tan & Gerbie, Obstetrics Gynecol 2013; 122: 370–3; 5. CDC. MMWR 2011; 60: 1117–23; 6. CDC. MMWR 2012; 61; 66–72; 7. CDC. MMWR 2013; 62: 66–72;
8. Healy et al. Clin Infect Dis 2011; 52: 157–62

27. Department of Health Sciences
University of Florence
Underimmunization drives community outbreaks of
pertussis.
Long SS. J Pediatr 2017;183:3. Robinson SG. J Pediatr 2017;183:159-63
hypothesized that
during a widespread
pertussis outbreak in
Oregon in 2012,
spread of infection
between communities
was driven by social
networks of people
less likely to
immunize their
children. They further
posited that if this
hypothesis was
correct, cases of
pertussis among the
underimmunized
would be expected to
cluster in the early
stages of an outbreak.
Results showed that unimmunized and underimmunized cases
had calendar onset of disease 41 days earlier than fully or
mostly immunized cases
351 pertussis cases in children 2 months - 10 years
childhood cases of pertussis can be proxies or signals
for pertussis disease within the social networks in which
children or their families are located

28. Department of Health Sciences
University of Florence
all adolescents and adults receive the Tdap
vaccine to replace the scheduled tetanus and
diphtheria toxoids vaccine (Td) booster
all people who have or anticipate having
close contact with infants <12 months of age
receive a single dose of Tdap,
all immediately postpartum women who have
not previously received a Tdap vaccine
receive a dose prior to leaving the hospital.
Recommendations have now been
expanded to routinely immunize all
adults 65 years of age and older
with a single dose of Tdap;
administer a booster dose of Tdap
with each pregnancy, regardless
of interval between pregnancies,
ideally after the 20th week of
gestation.

29. Pertussis incidence, British Columbia
0
20
40
60
80
100
120
140
160
2003 2006
15–19 year olds
10–14 year olds
Pertussisincidence
(casesper100,000))
-84%
-84%
Greenberg et al, Pediatr Infect Dis J 2009; 28: 521–8

30. dTpa elicited a robust increase in pertussis
antibodies when administered as a decennial booster
Australia1 Finland2
1. Booy et al. Vaccine 2011; 29: 45–50
2. Mertsola et al. Clin Infect Dis 2010; 51: 656−62 *Data are presented for group originally vaccinated with dTpa
Seropositivity
threshold
(5 El.U/mL)
 In both studies, the decennial booster was generally well tolerated
AntibodyGMCs(El.U/mL)(log)
with95%CIs*
Ambro/FreeDigitalP
hotos.net

31. Cost-effectiveness of Adult Pertussis Vaccination
 A German model has suggested that an adult pertussis
vaccination program would be cost effective
 A one-time adult vaccination strategy would prevent 498,000 cases
 A decennial adult vaccination strategy would prevent 1 million
cases
 The programs would cost
 €366 million and €687 million, respectively
 €160 and €200 per case prevented, respectively
Lee GM, et al. Vaccine 2008;26(29–30):3673–9

32. Countries with cocooning recommendations
1. Australian Immunisation Handbook 9th edition 2008; Part 2.3.2, available from: http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-
specialgroups (accessed June 2011); 2. Kinkhoest (pertussis) – vaccinatie. Available from: http://www.zorg-en-gezondheid.be/Ziektes/Vaccinaties/Vaccins-A-Z/Kinkhoest-
%28pertussis%29---vaccinatie/ (accessed June 2011; 3. Haut conseil de la santé publique. Bulletin Épidémiologique Hebdomadaire 2009;16–17:46–76; 4.
Impfempfehlungen der Ständigen Impfkommission am Robert Koch-Institut/Stand: Juli 2010. Epidem Bull 2010;30:279–98; 5. New Zealand Ministry of Health
Immunisation Handbook 2011; Ch 6; 6. CDC. MMWR 2011;60:13–5; 7. http://www.cdc.gov/vaccines/recs/provisional/default.htm (accessed August 2011); 8. WHO
vaccination schedule, available from: http://apps.who.int/immunization_monitoring/en/globalsummary /ScheduleSelect.cfm (accessed June 2011)
Country with
cocooning
recommendatio
n
Country without
cocooning
recommendation

33. Department of Health Sciences
University of Florence
Hasala,2008  the results of neonatal
vaccination with DTaP vaccine in 50 infants
between 2 to 14 days of age. The
administration of an additional dose at birth
was safe and well tolerated, but was
associated with lower geometric mean
antibody concentration for toxin and pertactin
fimbrae, diphtheria
efficacia del vaccino della
vaccinati alla nascita [n: 45]
età anti-PT anti-FHA anti-PRN
3 mesi 8.7 4.3 13.0
5 mesi 41.2 29.4 70.6
6 mesi 60.9 39.5 82.6
12 mesi 87.5 42.5 85.0
Belloni C et al. Pediatrics 2003; 111: 1042-1045
pertosse somministrato alla nascita
Vaccination in the neonates

34. VACCINE EFFECTIVENESS ACCORDING TO TRIMESTER OF
PREGNANCY
(Winter et al., Clin Infect Dis 2017)

35. Department of Health Sciences
University of Florence
total of 21 studies were included in this review.
OR 0.47 to 1.50 for preterm birth (less than 37 weeks of gestation)
0.65-1.00 for small for gestational age (birth weight less than the 10th percentile)
0.36-0.85 for stillbirth
0.16-1.00 for neonatal death
0.76-1.20 for low birth weight (less than 2,500 g)
0.20-0.91 for congenital anomalies
All lower 95% confidence intervals (CIs) were less than 1.0.
Of three retrospective studies assessing chorioamnionitis after vaccination, one showed a
small but statistically significant increase.
Safety of Tetanus, Diphtheria, and Pertussis Vaccination
During Pregnancy: A Systematic Review.
McMillan M. Obstetrics & Gynecology 2017; 129:560-73

36. Department of Health Sciences
University of Florence
What determines uptake of pertussis vaccine in
pregnancy? A cross sectional survey in an ethnically
diverse population of pregnant women in London.
Donaldson B. Vaccine 2015;33: 5822–8
Awareness of the programme was 63% (126/200) with actual uptake of the vaccine only
26.0% (52/200).
34.0% (68/200) of women were offered the vaccine at their GP practice, only 24% reported
a meaningful discussion with their GP about it
Feeling uninformed, lack of professional encouragement and uncertainties of risk and
benefit of the vaccine were the greatest barriers to uptake.

38. Conclusions
 Pertussis remains a major public health problem especially in
adolescents and adults where the incidence of disease is increasing and
causing a substantial disease burden
 Most infants are infected by an adolescent or adult contact
 Development of improved surveillance systems and recognition of
adolescent and adult pertussis disease is needed
 In order to control spread of disease, vaccine strategies focused on
increasing vaccination rates in the adolescent and adult populations are
critical
 Educational interventions are required for HCW and patients to increase
awareness of adolescent and adult pertussis disease and importance of
Tdap vaccination

39. ITALIAN VACCINATION SCHEDULE

40. MULTIDISCIPLINARY EDUCATION ON PERTUSSIS IMMUNIZATION
APPEARS A KEY FOR THE SUCCESS