The worldwide impact of The worldwide impact of

hepatitis B vaccination:hepatitis B vaccination:

A historical overviewA historical overview

Prof. Alessandro ZanettiDepartment of Public Health – Microbiology – Virology

Università degli Studi di Milano, Milan, Italy

Hepatitis B: the burden

�2 billion people have been globally

infected with HBV

�Over 350 million chronically infected

�An estimated 500,000-700,000 people die each

year

�4.5 million new HB cases/year (of whom a quarter progress to CLD)

Source: WHO

Types of Hepatitis B vaccines

I generationI generation plasma derived (1981)

II generationII generation yeast-derived (1986)rec-DNA

III generationIII generation - Combined vaccines (HA + HB; hexavalents)

- preS1-S2 vaccines

- novel adjuvanted vaccines

VaccinationVaccination againstagainst

HepatitisHepatitis BB

•Strategies for vaccination initially targeted to groups at increased risk.

•Failure of such policies led WHO to

recommend that all countries should introduce universal infant or adolescent (or both) hepatitis B vaccination into their national

immunisation programmes by 1997.

177 (82%) 177 (82%) countriescountries havehave introducedintroduced HepBHepB vaccine vaccine in in theirtheir nationalnational infantinfant immunizationimmunization scheduleschedule

Source: WHO

Hepatitis B vaccination: immunogenicity

•Several hundred million vaccinations have been administered worldwide with an outstanding record of safety and efficacy.

•Seroprotection rates to anti-HBs are close to 100% in healthy children and ~95% in healthy adults.

• Immunocompromised individuals, the

elderly, the obese and heavy smokers may have suboptimal responses.

•Rapid protection (i.e. HCWs exposed to HBV) can be achieved through the adoption of an accelerated schedule (0, 1, 2 and 12 m).

Hepatitis B vaccination:long-term immunogenicity (1)

�Vaccine-induced antibodies are long-lasting (at least 15-20 years).

�Anti-HBs duration is related to the antibody

peak level achieved after primary vaccination.

�Antibody declines over time, but clinically

significant breakthrough infections are rare.

Hepatitis B vaccination:long-term immunogenicity (2)

• Vaccinees who have lost antibodies over time, usually show a rapid anamnestic

response when boosted.

• Immunological memory for HBsAg can outlast the antibody detection thus

providing long-term protection.

Hepatitis B vaccination: to boost or not to boost?

•Routine administration of booster doses are not necessary to sustain long-term protection.

•Such conclusions are based on data collected during the past 15-20 years of vaccination.

HBV HBV vaccinationvaccination: :

SafetySafety profileprofile (1)(1)

� Vaccination is well-tolerated.

� Local side effects are generally mild and confined to symptoms at the site of injection (i.e. erythema, swalling, induration).

� Systemic reactions (i.e. fatigue, nausea, headache, fever) are uncommon.

� Contraindications: known hypersensitivity to any component of the vaccine or a history of anaphylaxis to a previous dose.

Hepatitis B vaccination: Safety profile (2)

�In 1998 case reports from France raised

concern that HB vaccination may lead to

new cases or relapses of MS or other demyelinating diseases such as G-B.

�In 2008, the same findings were put forward (Mykaeloff Y, Neurology 2009).

�However, no clear causality link has been established, and WHO stated that there were no reason to change current vaccination policy.

0

5

10

15

20

1984 2004

HBsAg

anti-HBc

Impact of Impact of HepatitisHepatitis B mass B mass vaccinationvaccinationinin hyperendemichyperendemic areasareas:: TaiwanTaiwan

July 1984: mass vaccination of newbornsJuly 1984: mass vaccination of newborns

HBsAg prevalence in indivi-duals <20 yrs (Chang, 2004)

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1981-86 1990-94 2004

Annual average incidence(x 105)of HCC among children6-14 yrs (Chang, 1997 and 2004)

9.8%

20.6%

0.6%

2.9%

0.7 x 105

0.36 x 105

0.15

0.19 person/yrs

age groups:6-9 yrs

10-14 yrs15-19 yrs

Impact of Impact of HepatitisHepatitis B mass B mass vaccinationvaccinationinin hyperendemichyperendemic areasareas:: TaiwanTaiwan

July 1984: mass vaccination of newbornsJuly 1984: mass vaccination of newborns

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1981-86 1990-94 2004

Annual average incidence (x 105)of HCC amongchildren 6-14 yrs (Chang, 1997 and 2004)

0.7 x 105

0.36 x 105

0.15

0.19 person/yrs

Hepatitis B vaccine:

the first vaccine

against a major

human cancer

Hepatitis B vaccine:

the first vaccine

against a major

human cancer

age groups:6-9 yrs

10-14 yrs15-19 yrs

Impact of Impact of HepatitisHepatitis B mass B mass vaccinationvaccinationin in hyperendemichyperendemic areasareas:: the Gambiathe Gambia

1986: universal infant vaccination

0

1

2

3

4

5

6

7

8

9

10

pre-vaccine post-vaccine

HBsAg Childhoodprevalence

(Whittle, 1995; Viviani, 1999)

10%

0.6%

1986 2003

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

2

1997 2003

Impact of Impact of HepatitisHepatitis B mass B mass vaccinationvaccination in in hyperendemichyperendemic areasareas

MalaysiaMalaysia• 1990: universal infantvaccination

Hawaii• 1991: universal infantvaccination

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

1990 2004

Incidence (x 105) of acute HepB in

children and adults:

HBsAg HBsAg prevalenceprevalencein in childrenchildren(7(7--12 12 yrsyrs) )

declineddeclined toto::1.6%

0.3%

4.5 x 104.5 x 1055

0 x 100 x 1055

Impact of Hepatitis B mass Impact of Hepatitis B mass vaccination in hypervaccination in hyper--endemic endemic

areas areas AlaskaAlaska

��1981: 1981: universaluniversal vaccinationvaccination of of childrenchildren

��SharpSharp declinedecline incidenceincidence of acute of acute hepatitishepatitis B (B (nextnext toto zero).zero).

��Trend Trend towardstowards decreasingdecreasing incidenceincidenceof HCC in of HCC in subjectssubjects <30 <30 yearsyears of of ageage..

Mc Mahon B, VHPB, Sevilla 2004.

Hepatitis B vaccination in ItalyHepatitis B vaccination in Italy

(Strategies) (Strategies)

1983 1983 19911991

Selectivevaccination

• Universal vaccination• Screening of pregnantwomen• Vaccination of high riskgroups

MorbidityMorbidity rate (x 10rate (x 1055 inhabitantsinhabitants) of ) of hepatitishepatitisB in B in ItalyItaly, , accordingaccording toto ageage (1990(1990--2009)2009)

0

2

4

6

8

10

12

14

16

18

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

0-14

15-2425 +

Total

Cases/1

00.0

00

Age group:

Vaccination

SEIEVA

Incidence x 105 in 2009:

0-14 aa 0.0115-24 aa 0.5

>24 aa 1.3

Total 1

Impact of hepatitis B vaccination in Afragola a highlyendemic area of Southern Italy

(Da Villa et al, 2007)

0

2

4

6

8

10

12

14

16

6-14yrs

15-20yrs

>25-58yrs

Total

1978

2006

Age-specific prevalence of HBsAg

0

10

20

30

40

50

60

70

80

6-14yrs

15-20yrs

>25-58yrs

Total

1978

2006

Age-specific prevalence of anti-HBc

13.4%

0.91%

66.9%

7.6%

Impact of HBV Impact of HBV vaccinationvaccinationin in ItalyItaly

•A generation of children and youngpeople (30 age cohorts) is emergingwith pratically no markers of HBV infection.

1981 1990 2001 2009

Prevalence of anti-HBc in

individuals aged<30 years

16.8%

5.8%

<1%

Incidence rates of acute hepatitis B and hepatitis Delta

SEIEVA 1990-2006

0

10

20

30

40

50

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

HDV

HBV

Cases/1

,000

,000

World wide impact of hepatitis B accination

�Italy’s programme of vaccination has resulted in substantial progress towards the prevention and control of hepatitis B.

�Our findings compare well with data reported elsewhere (e.g. Taiwan, the Gambia, Alaska) where the impact of vaccination in terms of reduction in incidence, in carrier rate, and in HBV-related mortality has been impressive.

HBV HBV infectionsinfections in in

vaccinees vaccinees

�Cases of hepatitis B in vaccinated people are very rare and generally confined to those who did not complete the schedule of vaccination properly.

�Breakthrough infections (anti-HBc +, transient ALT ↑) have been occasionally observed in successfully vaccinated people.

HBV HBV escapeescape mutantsmutants

�Breakthrough infections caused by S gene mutants (G145R) have been reported in babies born to HBsAg carrier mothers

(Zanetti, 1988; Carman, 1990)

�Despite concern that these mutants could evade the vaccine-induced immuneresponse and infect vaccinated individuals, at present they do not pose a real public health threat.

G145R

Conclusions (1)

�Safe and effective vaccines have

been available since the early 80’s, offering the opportunity to exert substantial prevention and control of the disease and its long-term severe consequences on a global scale.

�Globally, a remarkable significant progress in implementation of vaccination against HB has been achieved in recent years, but much remains to be done to meet the WHO goal of controlling HB in the community at large.

Conclusions (2)

�At present most of the countries that are not yet covered by vaccination are those economically underprivileged.

�Efforts should be undertaken so as to override social and economic barriers hampering the introduction of HB vaccination in countries with low resources, which are those with the highest endemicity.

�Migration and travels from and to highly endemic countries may increase the risk of exposure to the virus requiring a global strategy to make control and elimination of HBV feasible.