PERTUSSIS PROTECTION -CURRENT SCHEDULES IN

EUROPE – HOW MANY DOSES THROUGHOUT LIFE?

PERTUSSIS PROTECTION -CURRENT SCHEDULES IN

EUROPE – HOW MANY DOSES THROUGHOUT LIFE?

Susanna EspositoPediatric Highly Intensive Care Unit, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale

Maggiore Policlinico, Milan, Italy

AgendaAgenda

� Global burden of pertussis

� Burden of pertussis in infants, adolescents and adults

� Reservoir of Bordetella pertussis and disease transmission

� Pertussis prevention strategies

� Conclusions

Pertussis ‒ The Global ProblemPertussis ‒ The Global Problem

� Remains endemic worldwide� Estimated 20 ‒50 million cases and 300 000 deaths each year 1-3

� Major public health problem, even in countries with sustained high vaccination coverage 4

� Incidences (2/100,000) in Japan to 124/100,000 in S witzerland) 1,5

� Vaccination has reduced the global burden of pertus sis by over 90% compared to the pre-vaccine era 6

� However, major pertussis epidemics have been reporte d over the last decades in many countries, including Europ e, Japan, North and South America, Australia and New Zealand 1‒11

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

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

25000001

98

0

19

90

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

Number of cases WHO/UNICEF estimate

Nu

mb

er

of

case

s

Va

ccin

ati

on

co

ve

rag

e (

%)

(3 p

rim

ary

DT

P d

ose

s)

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

100

80

60

40

20

01990 1995 2000 2005 2012*

Year

< 1 y

< 1‒6 y

< 7‒10 y

< 11‒19 y20+ y

Inci

denc

e ra

te (

per

100,

000)

Reported Pertussis Incidence by Age Group: 1990 ‒2012*Reported Pertussis Incidence by Age Group: 1990 ‒2012*

*2012 data are provided

CDC data in presentation by J Liang: Tdap Vaccine Recommendations for Pregnant Women. Current Issues in Immunization NetConference. 21 Mar 2013. Available at: http://198.246.98.21/vaccines/ed/ciinc/downloads/2013-03-21/Liang-tdap-2013-03-21.pdf (Accessed April 2013)

21%

18%

26%12% 3%

1%

19%

Reported Pertussis Cases by Age Group – US2010‒2011

Reported Pertussis Cases by Age Group – US2010‒2011

1. CDC. Data on file (2010 Final Pertussis Surveillance Report), Nov 2011. 2. MKT24380 and CDC. Data on file (2011 Final Pertussis Surveillance Report), Oct 2012.MKT26067.

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

Pertussis Morbidity and Mortality in InfantsPertussis Morbidity and Mortality in Infants

� Highest incidence of morbidity and mortality consis tently in infants< 6 months of age who are too young to have complet ed their primary immunization series� Of the estimated 300 000 deaths yearly worldwide, m ost are in young infants;

90% in developing countries with case-fatality rate s 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 p opulation 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

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

Complications of Pertussis in Children ≤ 4 Years of Age in the US, 1997 ‒2000Complications of Pertussis in Children ≤ 4 Years of Age in the US, 1997 ‒2000

Age Hospitalization Pneumonia Seizures Encephalopathy DeathNo. 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

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

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

Transmission cycle of pertussis

between adults and infants1,2

Pertussis vaccination in the

first year of life

Pertussis booster vaccination during

childhood

If no pertussis booster vaccination: protection wanes

over time

Non-vaccinated or partly vaccinated infants: susceptible

Adults and adolescents can serve as reservoirs of pertussis infection

cycleThe

of infection

Household members are often the source of pertussis in young infants (in 76–83% of cases)3

New parents are the source of disease transmission in >50% of infant pertussis cases4

1. Wirsing von König CH, et al. Lancet ID 2002;2:744–50. 2. Finger et al. In: Barron S, ed. Barron's Medical Microbiology 1996; 3. Wendelboe et al. Pediatr Infect Dis J 2007; 26:

293–9; 4. Gerbie, Tan. Obstet Gynecol 2009; 113: 399–401

Pertussis Transmission to Young InfantsPertussis 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%

Pertussis prevention strategies throughout life

0 3months

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

Pertussis vaccination

�Pertussis vaccines, available as whole-cell or acellular formulations, are an

important component of vaccination schedules worldwide

WHO. Wkly Epidemiol Rec 2010;85:385-400. CDC. MMWR Morb Mortal Wkly Rep 2011;60:13-5Please refer to local prescribing information for the relevant product or contact GSK in your country for information on GSK products

DTPw /DTPaPrimary vaccination

2, 3, 4 months

3, 4, 5 months

2, 4, 6 months

6, 10, 14 weeks

-------------------------Two-dose schedules in

some countries3 and 5 months

dTpaAdditional booster

Preschool

Adolescent

Adult

DTPw /DTPaBooster

16, 18, 24 months

-------------------------

Booster for children who received the two-dose

primary11–13 months

High vaccine response rates against pertussis antigens

with DTPa-HBV-IPV/Hib (2 + 1 schedule)

GSK, GlaxoSmithKline Biologicals

1. Avdicová et al. Eur J Pediatr 2002; 161: 581–7; 2. Gabutti et al. Scand J Infect Dis 2004; 36: 585–92; 3. Results summary for Study 217744/060. [Accessed 31 Aug 2011]

http://download.gsk-clinicalstudyregister.com/files/2194.pdf;

4. Kilpi et al. Hum Vaccine 2009; 5: 18–25; 5. Van Der Meeren et al. Vaccine 2012; Feb 18. [Epub ahead of print]

• Pooled analysis of four studies (N=626)

• Infants received DTPa-HBV-IPV/Hib (GSK) in a 2 + 1 schedule (3, 5, 11/12 months)1–4

*Vaccine response rate for pertussis antigens defined as the appearance of antibodies in initially seronegative subjects (concentration <5 EL.U/ml), or at

least maintenance of pre-vaccination antibody concentrations in initially seropositive subjects; 1 month post-dose 2 and 1 month post-booster dose

Va

ccin

e r

esp

on

se r

ate

s (%

)*

for

pe

rtu

ssis

an

tig

en

s5

100

80

60

40

20

0

PT FHA PRN

Po

st-d

ose

2

Po

st-b

oo

ste

r

Po

st-d

ose

2

Po

st-d

ose

2

Po

st-b

oo

ste

r

Po

st-b

oo

ste

r

Figure adapted from Van Der Meeren et al. Vaccine 2012; Feb 18. [Epub ahead of print]

A vaccine response against pertussis antigens was observed in >97.7%

of subjects across the four studies5

Booster vaccination with dTpa-IPV was as immunogenic

as DTPa-IPV in children (5–6 years) in Italy

� Open, randomised study:

– N=303 children, primed in a 2+1 schedule of DTPa (GSK)

– One dose of dTpa-IPV (GSK) or DTPa-IPV (Sanofi Pasteur), both co-administered with MMRV (GSK)

Reduced-antigen content dTpa-IPV

GSK

N=139

Primary DTP-IPV

Sanofi Pasteur

N=146

GSK, GlaxoSmithKline Biologicals

Ferrera et al. Hum Vaccin Immunother 2012; 8 [Epub ahead of print]

*Booster response: 4-fold increase in antibody concentration (D, T, polio); ≥20 El.U/mL

in initially seronegative subjects, 4-fold increase in subjects with pre-vaccination

antibody concentrations ≥5 El.U/mL to <20 El.U/mL, ≥2-fold increase in subjects with

pre-vaccination antibody concentrations ≥20 El.U/mL (PT, FHA, PRN); ^There is no PRN

antigen in the DTPa-IPV vaccine

Bo

ost

er

resp

on

se r

ate

re

spo

nse

rate

* (

%)

wit

h 9

5%

CI

Ambro/FreeDigitalPhotos.net

Booster vaccination with dTpa induced a comparable

immune response to other licensed vaccines in

adolescents (13–17 years) in the UK: pertussis antigens

GSK, GlaxoSmithKline Biologicals

Southern et al. Vaccine 2005; 23: 3829−35

An

tib

od

y G

MT

(E

l.U

/mL)

(lo

g)

wit

h 9

5%

CI

dTpaGSKN=68

dTpa Sanofi Pasteur

N=74

dTpa-IPVSanofi Pasteur

N=75

dTSanofi Pasteur

N=71

PT

FHA

PRN

• Randomised single-blind study conducted in the UK (N=323)

• Primed with ≥4 doses of DT-containing vaccine (3+1) with ≥8 years since the last dose

• Head-to-head comparison, subjects received a single dose of one of four vaccines: dTpa (GSK),

dTpa (Sanofi Pasteur), dTpa-IPV (Sanofi Pasteur ), dT (Sanofi Pasteur MSD)

Ambro/FreeDigitalPhotos.net

Reactogenicity of dTpa compared to other licensed

vaccines in adolescents (13–17 years) in the UK

Pain/tenderness SwellingRedness

^‡

†

†dTpa (GSK) vs dT (p=0.265)‡dTpa (Sanofi Pasteur) vs dT (p=0.098)

^dTpa-IPV vs dT (p=0.001)Southern et al. Vaccine 2005; 23: 3829−35

dT (Sanofi Pasteur)

dTpa (Sanofi Pasteur)

Reduced antigen content dTpa (GSK)

dTpa-IPV (Sanofi Pasteur)

Inci

denc

e (%

)

Local symptom

comparable

Adolescent and Adult Groups for whom CDC Strongly Recommends Tdap Vaccine

Adolescent and Adult Groups for whom CDC Strongly Recommends Tdap Vaccine

� ALL Adolescents beginning at 11–12 years of age – No minimal interval between last Td and Tdap vaccine 1,2 – (78.2% immunized) 3

� ALL Adults especially those who are Close Key Conta cts of Infants < 12 months of age 4 – including persons ≥ 65 years of age1,5 – (13% immunized) 6

� Healthcare workers who have direct patient contact i n any hospital or clinic setting 2 – (27% immunized) 6

� Wound Care – Any adolescent or adult who gets a sever e cut or burn and needs protection against tetanus infection 5

� Tdap should be used in place of Td if person has not had a previous dose of Tdap 4

1. MMWR 2011;60(1):13‒15. 2. AAP & CDC. Pediatrics 2011;128:809-812. 3. MMWR 2012;61(34):671‒677. 4. Kretsinger K, et al. MMWR 2006;55(RR17):1–33; 5. MMWR 2012;61(25):468‒470. 6. CDC. Press Briefing Transcript. Telebriefing on US Adult Vaccination rates. Tues Jan 29, 2013. www.cdc.gov/media/releases/2013/t0129_adult_vacc_rates.html (Accessed May 2013)

Adolescent and Adult Groups for Whom CDC Strongly Recommends Tdap Vaccine

Adolescent and Adult Groups for Whom CDC Strongly Recommends Tdap Vaccine

� Pregnant women (after 20 weeks gestation) who have n ot previously received a dose of Tdap should receive a dose1 –(2.8% immunized) 1

� Newest recommendation: dose of Tdap should be given d uring each pregnancy between 27 weeks and 36 weeks regard less of the interval since the last pregnancy 1

� Postpartum administration of Tdap as soon as possible after delivery and before hospital discharge remains a vi able optionfor those women who did not receive the vaccine dur ing pregnancy and have never received a dose of Tdap vac cine in the past 1,2

� Postpartum administration of Tdap is ONLY a one time dose 1,2

1. MMWR 2013;62;7:131‒135; 2. Kretsinger K, et al. MMWR 2006;55(RR17):1–3

Pertussis Incidence, British ColumbiaPertussis Incidence, British Columbia

0

20

40

60

80

100

120

140

160

2003 2006

15–19 year olds10–14 year olds

84% reduction in 10 ‒14 year olds

Tdap 5 begun in 14–16 year olds, 2004

Greenberg DP, et al. Pediatr Infect Dis J 2009;28(6):521–8

Reduction in 10 ‒14 year olds shows evidence of herd immunity

Per

tuss

isin

cide

nce

(cas

es p

er 1

00,0

00)

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

An

tib

od

y G

MC

s (E

l.U

/mL)

(lo

g)

wit

h 9

5%

CIs

*

Ambro/FreeDigitalPhotos.net

Adolescent and Adult Pertussis Vaccine Recommendations in Europe

Adolescent and Adult Pertussis Vaccine Recommendations in Europe

EUVAC.NET. Pertussis vaccination overview in European countries. Available at: http://www.euvac.net/graphics/euvac/vaccination/pertussis.html (Last accessed April 2013)

Country Pertussis containing vaccineAustria Tdap 13 years, Tdap 18-20 years, Tdap every 10 years u ntil 60 years, then

every 5 years

Belgium Tdap 14-16 years, cocoon

Finland Tdap 14-15 years

France DTaP-IPV 11-13 years or if missed catch up Tdap-IPV 16-18 years, Tdap-IPV once in adulthood, HCW, CCW, cocoon

Germany Tdap or Tdap-IPV 9-17 years, Tdap once in adulthood, HCW, CCW, cocoon

Greece Tdap 11-12 years, if missed Tdap once in adulthood

Ireland Tdap 11-14 years

Italy Tdap 11-12 years

Luxembourg Tdap-IPV 15-16 years, then every 10 years

Norway Tdap in adults every 10 years until 60 years

Sweden Tdap 14-16 years

Switzerland Tdap 11-15 years, Tdap 25-29 years, cocoon

� Adults are an important source of infection for infants,

particularly family members1

� dTpa vaccination in adults can boost immunogenicity, even in

adults with no previous vaccination for many years2

• Double-blind, randomised, controlled trial in 460 adults

≥40 years of age with no diphtheria or tetanus vaccination for

20 years or unknown vaccination history2

• ≥96.4% seropositivity/seroprotection observed for all antigens

after 3 doses of dTpa or dTpa-IPV (GSK) 2

1. Zepp et al. Lancet Infect Dis 2011: 11; 557–70; 2. Theeten et al. Curr Med Res Opin 2007; 23: 2729–39

Immunogenicity in adults can be boosted with dTpa even in

a catch-up setting

Cost-effectiveness of Adult Pertussis VaccinationCost-effectiveness of Adult Pertussis Vaccination

� A German model has suggested that an adult pertussi svaccination program would be cost effective� A one-time adult vaccination strategy would prevent 498,000 cases� A decennial adult vaccination strategy would preven t 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

Antepartum and Cocooning Programs

Major objective � Protect young infants, who are too young to be immu nized, from getting

pertussis disease 1‒4

Rationale � Targeted Tdap immunization of all potential adolesce nt and adult contacts

of infants 1,2

Vaccination strategies close contacts of the infant� Pregnant women between 27 and 36 weeks gestation wi th each

pregnancy and postpartum mothers 1,3,4

� Family members and relatives 1,2,4

� Babysitters, nannies, daycare providers� Other close contacts 4

1. Forsyth KD, et al. Vaccine 2007;25:2634–42. 2. Coudeville L, et al. PLoS ONE 2009;4(7):e6284. 3. Healy CM, et al. Vaccine 2009;27(41):5599–5602. 4. Gerbie MV and Tan TQ. Obstet Gynecol 2009;113(2pt1):399–401

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 withcocooning recommendation

Country withoutcocooning recommendation

ConclusionsConclusions

� Pertussis remains a major public health problem esp ecially in adolescents and adults where the incidence of disea se is increasing and causing a substantial disease burden

� Most infants are infected by an adolescent or adult contact

� Development of improved surveillance systems and re cognition of adolescent and adult pertussis disease is needed

� In order to control spread of disease, vaccine stra tegies focused on increasing vaccination rates in the adolescent and adult populations are critical

� Cocooning is an increasingly common method to prote ct infants from disease

� Educational interventions are required for HCW and patients to increase awareness of adolescent and adult pertussis disease and importance of Tdap vaccination