Vaccination in Progress

Progress in Vaccination

Universal hepatitis A

vaccination: potential

introduction in all countries

Paolo Bonanni

Paolo Bonanni

Department of Public Health &

Department of Public Health &

Epidemiology, University of Florence,

Epidemiology, University of Florence,

Italy

Italy

Hepatitis A

Hepatitis A

Perception:

Perception:

Not a serious infection?

Not a serious infection?

“

“

The good news is that you’ve

The good news is that you’ve

got hepatitis A”

got hepatitis A”

Misunderstanding:

Misunderstanding:

Based on lack of

Based on lack of

chronicity

chronicity

Truth:

Truth:

Most common viral hepatitis

Most common viral hepatitis

infection

infection

Substantial morbidity

Substantial morbidity

Significant mortality

Significant mortality

Geographical distribution of

Geographical distribution of

hepatitis A viral infection

hepatitis A viral infection

Geographical distribution of

Geographical distribution of

hepatitis A viral infection

hepatitis A viral infection

Prevalence of

Prevalence of

anti-hepatitis A

anti-hepatitis A

(anti-HAV)

(anti-HAV)

antibodies

antibodies

High

High

Intermediate

Intermediate

Low

Low

Very low

Very low

Hepatitis A: epidemiology in

Europe

HAV

endemicity

Region (by

epidemiological

pattern)

Reported

incidences

(per 100,000)

Average age

at infection

(years)

Predominant route

of transmission

Intermediate Eastern Europe

Southern Europe

Part of Western

Europe

<50

5–24

Person-to-person

Outbreak

Low

Part of Western

Europe

5–15

5–40

Person-to-person

Outbreak

Very low

Northern Europe

<5

>20

Exposure abroad

Outbreak

Epidemiological shift in

Epidemiological shift in

seroprevalence of anti-

seroprevalence of anti-

HAV

HAV

Age (years)

Age (years)

S

e

ro

p

re

v

a

le

n

c

e

S

e

ro

p

re

v

a

le

n

c

e

o

f

a

n

ti

-H

A

V

(

%

)

o

f

a

n

ti

-H

A

V

(

%

)

Improvement in

Improvement in

hygiene

hygiene

0

0

20

20

40

40

60

60

80

80

100

100

10 20 30 40

10 20 30 40

50

50

Van Damme P et al. 1994.

Prevalence of anti-HAV in sera

Prevalence of anti-HAV in sera

collected from different age

collected from different age

groups in Northern Italy (1958–

groups in Northern Italy (1958–

1988)

1988)

0

20

40

60

80

100

1–5

6–15 16–30 31–40 41–50 >50

Age (years)

A

n

ti

-H

A

V

p

re

va

le

n

ce

(

%

)

1958
1977
1988

Hepatitis A in Poland

Hepatitis A in Poland

0

10

20

30

40

50

60

70

80

90

100

1 - 5y 6 -

10y.

11 -

15y.

16 -

20

21 -

25

26 -

30

31 -

35

36 -

40

Age (years)

A

n

ti

-H

A

V

p

re

va

le

n

ce

(

%

)

1979
1997

Cianciara J. Vaccine 2000;18:S68–S70.

Cianciara J. Vaccine 2000;18:S68–S70.

Shift

Shift

Symptomatic HAV infection

Symptomatic HAV infection

by age

by age

0

10

20

30

40

50

60

70

80

90

1

2

3

4

5+

Age (years)

S

ym

p

to

m

at

ic

c

as

es

(

%

)

Changing epidemiology of

Changing epidemiology of

hepatitis A

hepatitis A

Consequences:

Consequences:



childhood infections become very rare

childhood infections become very rare



pool of non-immune children,

pool of non-immune children,

adolescents and young adults develops

adolescents and young adults develops

– facilitates outbreaks of disease

– facilitates outbreaks of disease



exposure and infection occur later in

exposure and infection occur later in

life, resulting in more severe disease

life, resulting in more severe disease

Hepatitis A: only a travellers’

Hepatitis A: only a travellers’

disease?

disease?



Changes in exposure:

Changes in exposure:

–

‘

‘

dining-out’ society

dining-out’ society

–

preference for exotic food, fast food, etc.

preference for exotic food, fast food, etc.

–

how strict are our hygienic measures?

how strict are our hygienic measures?

–

young children are sent to daycare more frequently (at an

young children are sent to daycare more frequently (at an

earlier age)

earlier age)



I

I

f we are not travelling to hepatitis A, hepatitis A is

f we are not travelling to hepatitis A, hepatitis A is

travelling to us!

travelling to us!

–

changing migration patterns

changing migration patterns

–

increasing number of people on the move

increasing number of people on the move

Outbreak of hepatitis A in a

Outbreak of hepatitis A in a

canteen in Genoa, Italy, 1993

canteen in Genoa, Italy, 1993

Epidemiological investigation

Epidemiological investigation

Total no. of anti-HAV-negative employees = 468

Total no. of anti-HAV-negative employees = 468

(37% of all workers)

(37% of all workers)

Attack rate = 11.1%

Attack rate = 11.1%

Total no. of cases = 56

Total no. of cases = 56

Primary cases = 52

Primary cases = 52

Secondary cases = 4

Secondary cases = 4

Asymptomatic = 1

Asymptomatic = 1

Symptomatic = 51

Symptomatic = 51

0

200

400

600

800

1000

1200

1400

1600

1800

J an Mar May J ul Sep Nov J an Mar May J ul Sep Nov

Notified cases of hepatitis A

Notified cases of hepatitis A

in Puglia, Italy, 1996–97

in Puglia, Italy, 1996–97

1996:
5673 cases
138.8/100,000

1997:
5389 cases
131.8/100,0
00

Hepatitis A in Puglia, Italy,

Hepatitis A in Puglia, Italy,

1996–1997

1996–1997

Distribution of cases by age group

Distribution of cases by age group

0%

5%

10%

15%

20%

25%

30%

0-4 5-9 10-1415-1920-2425-2930-3435-64 >65 ns

1996
1997

Hepatitis A in Puglia, Italy,

Hepatitis A in Puglia, Italy,

1996

1996

Epidemiological investigation

Epidemiological investigation

Case control study I (January–April):

Case control study I (January–April):



Raw seafood

Raw seafood

OR: 31.8

OR: 31.8

(95% CI: 12.1–

(95% CI: 12.1–

118)

118)



Contact

Contact

OR: n.c.

OR: n.c.

(95% CI: 2.5–

(95% CI: 2.5–

infinity)

infinity)

Case control study II (August):

Case control study II (August):



Raw seafood

Raw seafood

OR: 12.7

OR: 12.7

(95% CI: 7.8–20.9)

(95% CI: 7.8–20.9)



Contact

Contact

OR: 1.6

OR: 1.6

(95% CI: 0.3–9.8)

(95% CI: 0.3–9.8)

Main costs incurred during the HAV

Main costs incurred during the HAV

outbreak in Puglia, Italy, 1996

outbreak in Puglia, Italy, 1996

Total sample

Total sample

165,506 (100)

165,506 (100)

665,350 (100)

665,350 (100)

1,037,871 (100)

1,037,871 (100)

(n=250)

(n=250)

Average per

Average per

662

662

2,661

2,661

4152

4152

individual

individual

Total for 5889

Total for 5889

3,898,661

3,898,661

15,672,969

15,672,969

24,448,094

24,448,094

cases in Puglia

cases in Puglia

Indirect costs

Indirect costs

1,096,303 (28.1)

1,096,303 (28.1)

5,972,291

5,972,291

(24.4)

(24.4)

Item

Item

Cost in $US (% of total)

Cost in $US (% of total)

Individual patient

Individual patient

NHS

NHS

Society

Society

Lucioni C et al. Pharmacoeconomics 1998;13:257–66.

Lucioni C et al. Pharmacoeconomics 1998;13:257–66.

Importation of hepatitis A

Importation of hepatitis A

Situation in Austria, Belgium and The

Situation in Austria, Belgium and The

Netherlands:

Netherlands:



immigrants residing in these countries return

immigrants residing in these countries return

annually to their country of origin

annually to their country of origin



their children, born in countries with low

their children, born in countries with low

endemicity, contract HAV while on holiday in

endemicity, contract HAV while on holiday in

parents’ home country

parents’ home country



these children cause secondary infections on

these children cause secondary infections on

return to their country of birth

return to their country of birth

The Netherlands: hepatitis A

notifications 1993–1998

van Gorkum J et al

van Gorkum J et al

.

.

Ned Tijdschr Geneeskd 1998;142:1919–23.

Ned Tijdschr Geneeskd 1998;142:1919–23.

180

160

140

120

100

80

60

40

20

0

1993

1994

1995

1996

1997

1998

N

u

m

b

e

r

o

f

n

o

ti

fi

e

d

c

a

s

e

s

Year

Turkey and Morocco

Other foreign countries

The Netherlands

Unknown origin

Migration and population

Migration and population

mobility

mobility

bridges geo–biological

bridges geo–biological

boundaries

boundaries



People move rapidly between prevalence gaps

People move rapidly between prevalence gaps



This translates into a rapid mobility of risk of

This translates into a rapid mobility of risk of

disease acquisition

disease acquisition

–

need for appropriate preventive

need for appropriate preventive

interventions

interventions



risk-group vaccination policy

risk-group vaccination policy



vaccination of young children from

vaccination of young children from

ethnic

ethnic

minorities

minorities

Norway: hepatitis A

Norway: hepatitis A

notifications 1994–1998

notifications 1994–1998

0

100

200

300

400

500

600

1994

1995

1996

1997

1998

TOTAL
IV drug users
IV drug contacts
Other

Long-lasting protection

Long-lasting protection

Benefits

Benefits



Immunity maintained

Immunity maintained

–

at individual level

at individual level

–

throughout population

throughout population



Longer duration of protection against

Longer duration of protection against

infection

infection

–

associated morbidity and mortality

associated morbidity and mortality

reduced

reduced

–

viral transmission reduced

viral transmission reduced



Costs of booster programmes reduced

Costs of booster programmes reduced

–

lower costs:

lower costs:

–

direct

– indirect

Persistence of protection from

Persistence of protection from

hepatitis A vaccines

hepatitis A vaccines

Long-term follow-up data: p

Long-term follow-up data: p

ublished results

ublished results



Adults

Adults

–

hardly any subjects lose their antibodies

hardly any subjects lose their antibodies

–

follow-up for 8 years after first dose

follow-up for 8 years after first dose

–

estimated persistence: 10–20 years and

estimated persistence: 10–20 years and

more

more



Children

Children

–

few data currently reported

few data currently reported

–

hardly any subjects lose their antibodies

hardly any subjects lose their antibodies

–

follow-up for 5 years after first dose

follow-up for 5 years after first dose

–

estimated persistence: 14–25 years

estimated persistence: 14–25 years

Vancouver (Canada):

Vancouver (Canada):

outbreak in

outbreak in bi/homosexual

men

men



Sept ‘97–April ‘98: 163 cases

Sept ‘97–April ‘98: 163 cases



89% male

89% male



55% of all cases bi/homosexual men

55% of all cases bi/homosexual men



15% food-service workers

15% food-service workers



One death (hepatitis C co-infection)

One death (hepatitis C co-infection)

Vancouver:

Vancouver:

outbreak

outbreak

response

response



Hepatitis A vaccination of

Hepatitis A vaccination of

bi/homosexual men (one dose)

bi/homosexual men (one dose)



10,000 doses provided (50% coverage)

10,000 doses provided (50% coverage)



Begun late December 1997

Begun late December 1997



Available at clinics, physicians’ offices

Available at clinics, physicians’ offices



Extensively promoted

Extensively promoted

Evaluation of vaccination

Evaluation of vaccination

campaign in

campaign in bi/homosexual

men



92% had heard about the programme

92% had heard about the programme



59% had heard and were vaccinated

59% had heard and were vaccinated



33% had heard but were not vaccinated

33% had heard but were not vaccinated



33% couldn’t be bothered

33% couldn’t be bothered



21% didn’t perceive self-risk

21% didn’t perceive self-risk



21% previously immunised

21% previously immunised



16% had hepatitis A

16% had hepatitis A



Multiple hepatitis A outbreaks

Multiple hepatitis A outbreaks



Vaccination campaigns curtailed

Vaccination campaigns curtailed

outbreaks

outbreaks



Costly, short-term benefit

Costly, short-term benefit



Proposed solution: universal

Proposed solution: universal

childhood vaccination

childhood vaccination

Vancouver (Canada):

summary of results of a

vaccination strategy for high-

risk groups

Hepatitis A – reported cases

Hepatitis A – reported cases

(per 100,000 population)

(per 100,000 population)

USA, 1991

USA, 1991

8.0–11.9

>11.9

4.0–7.9

0.0–3.9

‘

‘

The diverse patterns of hepatitis A

The diverse patterns of hepatitis A

epidemiology in the United States:

epidemiology in the United States:

implications for vaccination

implications for vaccination

strategies’

strategies’

“

“

A significant reduction of hepatitis A

A significant reduction of hepatitis A

incidence at the national level could

incidence at the national level could

most probably follow a routine

most probably follow a routine

childhood vaccination strategy,

childhood vaccination strategy,

rather than a selective risk group

rather than a selective risk group

vaccination strategy.”

vaccination strategy.”

Bell BP et al. J Infect Dis 1998;178:1579–84.

ACIP – Prevention of Hepatitis A Through

Active or Passive Immunization

MMWR 1999;48:RR-12.

States, areas and communities where the average

States, areas and communities where the average

annual hepatitis A rate during 1987–1997 was at least

annual hepatitis A rate during 1987–1997 was at least

twice the national average (

twice the national average (





20/100,000)

20/100,000)

Children should be routinely vaccinated

Children should be routinely vaccinated

States, areas and communities where the average annual

States, areas and communities where the average annual

hepatitis A rate during 1987–1997 was higher than the

hepatitis A rate during 1987–1997 was higher than the

national average (but less than twice as high) (

national average (but less than twice as high) (





10/100,000)

10/100,000)

Children should be considered for routine vaccination

Children should be considered for routine vaccination

States with average annual hepatitis A incidence <10/100,000

States with average annual hepatitis A incidence <10/100,000

Vaccination of risk groups

Vaccination of risk groups

Cost-effectiveness of childhood

Cost-effectiveness of childhood

hepatitis A vaccination in the

hepatitis A vaccination in the

USA

USA

Immunisation of single birth cohort in 11

Immunisation of single birth cohort in 11

states with highest rates

states with highest rates

Benefits:

Benefits:





lifetime risk of symptomatic

lifetime risk of symptomatic

infections

infections

from 4.4% to 0.6%

from 4.4% to 0.6%

Prevents 4,175 hospitalisations

Prevents 4,175 hospitalisations

Saves 90 lives (3,934 life-years)

Saves 90 lives (3,934 life-years)

Saves $24.4 million in medical

Saves $24.4 million in medical

treatment

treatment

Costs:

Costs:

$51.2 million

$51.2 million

Cost-effectiveness: $12,780/year of life saved

Cost-effectiveness: $12,780/year of life saved

(YOLS)

(YOLS)

Jacobs RJ et al. Arch Pediatr Med
2000;154:763–70.



Catalonia, Spain, 1998

Catalonia, Spain, 1998

–

intermediate incidence: 5(50)/100,000

intermediate incidence: 5(50)/100,000

–

shift in the age of peak incidence

shift in the age of peak incidence

–

vaccination of 12-year-olds (A+B)

vaccination of 12-year-olds (A+B)



Israel, 1999

Israel, 1999

–

intermediate incidence: >30/100,000

intermediate incidence: >30/100,000

–

shift in the age of peak incidence

shift in the age of peak incidence

–

vaccination of children aged >1 year

vaccination of children aged >1 year



Puglia, Italy, 1997

Puglia, Italy, 1997

–

large food-borne outbreaks

large food-borne outbreaks

–

shift in the age of peak incidence

shift in the age of peak incidence

–

vaccination of 12-year-olds (A+B) and children aged

vaccination of 12-year-olds (A+B) and children aged

>1 year

>1 year

Recent introduction of universal

hepatitis A vaccination

Combined hepatitis A+B vaccine (Twinrix™,

Combined hepatitis A+B vaccine (Twinrix™,

adult dose) immunogenicity data: 0–6

adult dose) immunogenicity data: 0–6

schedule

schedule

(age 1–11 years) (n=197)

(age 1–11 years) (n=197)

Van der Wielen M et al. Pediatr Infect Dis J 2000;19:848–53.

Timing

(months)

Anti-HAV

(% seropositive)

GMT

(mIU/ml)

Anti-HepB

(% seropositive)

1

99.5

434

30.3

8

2

98.5

293

47.3

11

6

98.0

193

78.2

34

7

100

11,543

98.5

8056

GMT

(mIU/ml)

Combined hepatitis A+B vaccine

Combined hepatitis A+B vaccine

(Twinrix): immunogenicity data

(Twinrix): immunogenicity data

(age 12–15 years) (n=145 in each arm)

Timing

(months)

(%positive)

Anti-

HBs

(%SP)

Anti-

HAV

(%positive)

Anti-

HBs

(%SP)

1

99.3

349

43

14.3

93.2

227

29.1

9.8

2

100

245

38

9.9

99.3

548

85.6

42

6

100

178

68

20.1

99.3

298

98

305.3

7

100

5486.9

97.9

4948.6

100.0

4174

100

5054.3

0–6 schedule: 720/20

0–1–6 schedule: 360/10

Levie J et al. Presented at ESPID Congress, Crete, 19–21

Levie J et al. Presented at ESPID Congress, Crete, 19–21

May 1999.

May 1999.

GMT

(mIU/ml)

GMT

(mIU/ml)

GMT

(mIU/ml)

GMT

(mIU/ml)

Anti-

HAV

Conclusions (1)

Conclusions (1)



The costs of hepatitis A outbreaks are high, both in

The costs of hepatitis A outbreaks are high, both in

terms of suffering and of direct and indirect costs

terms of suffering and of direct and indirect costs



Hepatitis A can no longer be regarded as a purely

Hepatitis A can no longer be regarded as a purely

travel-related infectious disease (less than 20% of

travel-related infectious disease (less than 20% of

notified cases are due to day care contact,

notified cases are due to day care contact,

international travel & homosexual contact)

international travel & homosexual contact)



Exposure to HAV is shifting as well

Exposure to HAV is shifting as well

–

hepatitis A is travelling to us

hepatitis A is travelling to us

–

‘

‘

dining-out’ culture

dining-out’ culture

–

eating habits (raw seafood)

eating habits (raw seafood)



Mobile populations rapidly move between

Mobile populations rapidly move between

prevalence gaps, and their children have a different

prevalence gaps, and their children have a different

probability of disease acquisition

probability of disease acquisition

Conclusions (2)

Conclusions (2)



The HA vaccine has been shown to confer long term

The HA vaccine has been shown to confer long term

persistence of vaccine induced antibodies (at least

persistence of vaccine induced antibodies (at least

25 years)

25 years)



Added value of long term persistence:

Added value of long term persistence:

–

immunity maintained (at population level)

immunity maintained (at population level)

–

reduction of virus transmission

reduction of virus transmission

–

cost reduction for booster programmes

cost reduction for booster programmes



Public health authorities need to make use of their

Public health authorities need to make use of their

exisiting surveillance systems to assess the

exisiting surveillance systems to assess the

desirability and feasibility of introducing a routine

desirability and feasibility of introducing a routine

hepatitis A vaccination programme.

hepatitis A vaccination programme.



This decision should take into account:

This decision should take into account:

–

local epidemiology

local epidemiology

–

economic implications

economic implications

–

conflicting healthcare demands

conflicting healthcare demands

The changing dynamics of Hepatitis A.
The implications for Europe

Sorrento (Italy), 14 June 2000

Symposium speakers:

Pierre Van Damme

University of Antwerp, Belgium

Beth Bell

Centers for Disease Control, Atlanta,

USA

Graham Cooksley Royal Brisbane Hospital, Australia

Brian Gushulak

International Organization for Migration,

Switzerland

Paolo Bonanni

University of Florence, Italy

Cinzia Germinario

University of Bari, Italy

Lluis Salleras

Generalitat of Catalonia, Spain

Patricia Daly

Vancouver/Richmond Health

Board, Canada

Koen Van Herck University of Antwerp, Belgium

Vaccination in Progress

Progress in Vaccination