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Hepatitis B Immunization : Choosing the Most Effective Schedule

Dr Gaurav Gupta, MD

Charak Clinics, Mohali.

MAAP, MIAP

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Conflict of Interest

• Received grants from various vaccine manufacturers including

• - Sanofi Pasteur• - GSK• - Abbott• - Wyeth etc.

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Scope• The hepatitis burden- Worldwide & India• Hepatitis B – disease profile• What is an ideal vaccination schedule?• Why is 0, 1 & 6 the most effective?

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Global Burden—Hepatitis B Virus Infection

• 2 billion people infected with HBV• > 350 million have chronic HBV infection

• >40 million in India

• 600,000 HBV-related deaths• 93% of deaths were the result of chronic infection • 88% of the world's population live in areas where the

prevalence of chronic HBV infection is high (>8% HBsAg +) or moderate (2-7% HBsAg +)

Scaling up Global Access to Hepatitis B Vaccination. WHO July 2009

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Leading Causes of Infectious DiseaseDeaths Worldwide

DiseaseLower respiratory tract infectionsDiarrheal diseasesHIV/AIDSTuberculosisHepatitis virusesHepatitis B virusHepatitis C virusMalaria PertussisNeonatal tetanusMeasles

Est. Deaths per Year~4.2 million~2.2 million~2.0 million~1.5 million~1 million ~620,000

~366,000* ~900,000~295,000~213,000~197,000

Source: WHO, UNICEF, Perz et al, J Hepatology, 2006

6Dr. Gaurav Gupta, Charak Care Clinics, Mohali

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Geographic distribution of chronic hepatitis B virus (HBV) infection — worldwide, 2006*

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Three distinct levels of Hepatitis B endemicity Hepatitis B seroprevalence (Hadler& Margolis)

Endemicity Area HBsAG Seroprevalence

Infected Adults Regions Transmission

High >8% >70%

Asia (except Japan and India), Africa, most of

Middle East, the Amazon basin of south America, most pacific

Island groups and Maoris

•Vertical•Horizontal

Almost all infections are acquired in infancy or

early chidlhood, and few adults remain

susceptible to infection

Intermediate 2% - 8% 20% - 50%

India, part of the Middle East, Western Asia,

Japan, Eastern & Southern Europe, and most south & Central

America

Mixed and transmission occurs in

all age groups but predominant period of transmission probably occurs among young children, adolescents

and young adults.

Low <2% <20%

USA, Canada, Western Europe, Australia and

New Zealand

Primarily among adults

Nevertheless, transmission during the

perinatal period and during childhood

provides a significant contribution to the HBV

carrier burden

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Risk of acquiring HBV from a needlestick

Source-HBs Ag positive, HBe Ag negative—1-6%

Source-HBs Ag positive, HBe Ag positive---22-40%

HCV-3-10%, HIV-0.2-0.5%

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THE BEST PREVENTIVE METHOD IS

VACCINATION

Vertical Transmission Hepatitis B

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HBV Vaccination – Fast Facts

1. Plasma derived vaccines – 1982

2. Yeast derived vaccines – 1986

3. First Mass immunization program – Taiwan 1984

4. Most commonly used vaccination – more than 1 billion doses

given

5. First vaccination to prevent cancer

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Success of Hepatitis B vaccine

• The vaccine has an outstanding record of safety and

effectiveness.

• Vaccination has excellent effectiveness - reduced the rate of

chronic infection to less than 1% from 8-15 %

• In 2009, 177 countries included the hepatitis B vaccine into

their national schedule major increase compared with 31

countries in 1992, when WHO passed a resolution

recommending global vaccination against hepatitis B

Dr. Gaurav Gupta, Charak Care Clinics, Mohali

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Questions needed to be asked regarding Ideal Schedule for Hep B vaccine?

1. Has it been used for extensive period of time?2. Does it protect the highest “at risk” population?3. Are there enough evidence regarding its effectiveness?4. Are other countries using the same in their National Schedules?5. Can it be piggy-backed on to the National Schedule in our Country?

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Hepatitis B immunization

Birth dose and interval between the doses are extremely important :

• not only for the robustness of the immune response, but

• as well for the prevention of vertical and horizontal transmission and

• the long term protection post-vaccination.

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Importance of vaccination schedule at 0-1-6 mo/o vs 2-4-6 mo/o.

Group 1Hep.B at 0-1-6

Group 2Hep.B at 2-4-6

Anti-HBs 10 mIU/mL 100% [97.2 ; 100]

99.0% [94.3 ; 99.4]

GMTs 3 643 mIU/mL

[502;709]

1 052 mIU/mL

[163;253]

Greenberg D et al.- Ped. Inf. Dis. Journal. 21(8):769-776, August 2002

Results: Anti-HBs Post-dose 3

Post-dose 2 (at 2 months of age): Anti-HBs 10 mIU/mL in 47% of infants of group 1 versus only 9% in group 2

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749.12

23.44 79.70

6375.86

84.3941.70

1000

2000

3000

4000

5000

6000

7000

After 1st dose After 2nd dose After 3rd dose

GMT (mIU/ml)

GM

T (

mIU

/ml)

GMT (mIU/ml) 0,1,2 schedule

GMT (mIU/ml) 0,1,6 schedule

Ab titres (ShanvacB) with 0-1-2 &0-1-6 schedules

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GMT in infant vaccinated against Hepatitis B by different vaccination schedules

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WHO targets hepatitis B control in Western Pacific Region

An universal vaccination program was launched in Taiwan in 1984

HBsAg positive rate in children < 12 y/o :

• Before vaccination program: 9.8%

• After the institution of program,

– 4.8% at 5 years

– 1.3% at 10 years

– 0.7% at 15 years

The annual rate of incidence of childhood HCC decreased from 0.52 to 0.13 per 100 000 children after the vaccination program.

The schedule implemented is birth, 1 and 6 months of age.

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Estimation of annual incidence of HBs Ag chronic carrier due to vertical transmission

What is the «cost» of a delayed schedule?

Universal prevention of vertical transmission (Yes/

No)

HBsAg+ Mothers

%

HBeAg+

mothers

%HBsAg+

Estimated Infected

neonates (%)

Rate per 100 000 Births

per year*

Total Annual incidence of

chronic carriage due

to vertical transm

India (1996) No 4.6 18.0 0.67 605 162 563

Singapore (1998)

Yes 3.4 39.0 0.92 827 474

Bangladesh No 3.5 30.2 0.76 687 25 690

Chauvin P, Ekra D, Plotkin S.- Vaccine. 2002 Jul 26;20(23-24):2848-50

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The Rationale

1st Dose – At birth - Prevents vertical transmission

2nd Dose – Min 4 wk later – Limited number of seroconversion

after 1st dose, hence closely spaced second dose – prevents

immediate horizontal transmission

3rd Dose -- Min 8 weeks after 2nd Dose,

-- Min 16 weeks after 1st Dose,

-- After 24 weeks age,

(ACIP/ AAP recommendations)

Leads to increased antibody titres – Better Long Term protection

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AAP recommendations - hepatitis B, 2012

Dr. Gaurav Gupta, Charak Care Clinics, Mohali

• Administer Monovalent HepB to all newborns before hospital discharge• The second dose should be administered at age of 1 to 2 months• The final dose should be administered no earlier than age 24 weeks

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Comparision of vaccination schedule in different countries throughout world

Country Hepatitis B vaccination schedule

USA birth; 1-2, 6-18 months;

Canada 1st contact; +1, >+2 months;

England birth; 1, 2, 6 months;

Germany 2, 4, 11-14 months;

South Africa 6, 10, 14 weeks;

Australia birth; 2, 4, 6 months; 1, 10-13 years;

India Birth; 6, 10, 14 weeks;

China birth; 1, 6 months;

Ref: WHO. Immunization surveillance, assessment and monitoringAvailable at:http://www.who.int/immunization_monitoring/data/data_subject/en/index.html

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International Schedules

Majority of schedules begin at birth

Many vaccination schedules end at 6 months age or more

Gap of at least 8 weeks between 2nd and 3rd doses

If the gap is less, then a 4th dose given

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Key Points

• The GMTs with 0, 1, and 6 months schedule are upto 10 times higher than 0, 1, and 2 months schedule.

• Infants who achieve higher Anti HBs titers maybe protected better in later years.

• The seroprotection rates are found to be highest when the interval between the second and third dose is longer.

• The classic 0, 1, and 6 months schedule yields a high seroconversion rate and relatively high titers of anti-HBs that will persist for an extended period of time.

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IAP recommendations

Hep B vaccine may be given in any of the following schedules:(i) Birth, 1 and 6 months(ii) Birth, 6 and 14 weeks(iii) 6, 10 and 14 weeks(iv) Birth, 6 weeks, 6 months(v) Birth, 6 weeks,10 weeks, 14 weeks

The IDEAL schedule is 0 1 6 months.

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0, 1 & 6 months

• Gold standard,

• Protects high risk infants,

• Enough evidence regarding long term efficacy (at least 25

years), and being used by many countries,

• Cannot be easily integrated with the national schedule

IAPCOI – Most widely used, IDEAL, High Antibody Titres

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0, 6 & 14 weeks

•Not enough evidence regarding long term effectiveness

•Protects High risk infants,

•Can be piggy backed to existing EPI

•Slightly lower titres since 3rd dose completed before 24 weeks

- ? Clinical significance

IAPCOI – Recommended for Public Health since protects

against Vertical Transmission, and can be integrated with EPI

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6,10 & 14 weeks

•Does NOT protect against vertical transmission

•Can be piggybacked to EPI,

IAPCOI – Only recommended for missed birth dose

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Birth, 6,10 & 14 weeks

•Protects against vertical transmission

•Can be piggybacked to EPI,

•Increases overall cost of vaccination

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Birth 6 weeks & 6 months

Similar to the classic schedule of 0 1 & 6 months

Can be partially piggybacked to EPI,

IAP recommendation for Office Practice ?

0, 4/6 week, 6 months

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Interesting facts – IAPCOI recommendations

•Catch-up vaccination schedule - 0,1 & 6 months for ALL

children to prevent horizontal transmission.

•For management of infants of HbsAg +ve mothers - the “closely

spaced schedule” should NOT be used.

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Importance of a 6 month visit: pediatricians perspective

• 24 wk (6 mo) visit introduces a potential visit between 14 weeks (DTP3) and 36 weeks (measles) to evaluate child development and monitor progress including

• Major motor skills

• Fine motor skills

• Language

• Vision and hearing

• Social achievements and play

• Evaluation of weaning issues

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FAQ

When should double dose be given?In elderly, immunocompromised and chronic renal failure

patients– 4 doses at 0,1,2 and 12 months, double dose is to be given

Should routine testing of HBs Ab be done after completion of vaccination schedule ?

Only for a small minority of vaccinees including babies of HBsAg +ve mothers, close contacts of HbsAg +ve, health care workers and people with co-morbidities,

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FAQ

What antibody titres signify a response?

Antibody levels more than 10 mIu/ml signify a response

What should be done in Nonresponders?

Non responders should be tested for Hepatitis B carrier status. If negative, repeat the complete vaccination schedule, 50% would respond , rest are permanently susceptible

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FAQ

Is booster dose required ?• Routine boosters are NOT needed in healthy children and

adults• Individuals who respond to the vaccination series and have

levels of 10 mIU/ml after vaccination are protected against hepatitis B disease for life even if the levels drop to below protective levels or are undetectable later. This is due to Immune memory.

• In immunocompromised and those who have CRF, CLD etc. levels should be regularly checked (? Yearly) and booster dose given when the levels fall below protective levels

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FAQ

What the accelerated schedules for HBV vaccine?• 0, 1, 2 & 12 months • 0, 7 days, 21 days and 12 months

What are the recommendations for premature babies?• Some infants born prematurely with low birth weight (<2000 g)

may not respond well to vaccination at birth. However, by one month of chronological age, all premature infants, regardless of initial birth weight or gestational age, are likely to respond adequately.

• Give birth dose, but don’t count it. Start afresh from1 month age

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Longer needle length for Hep-B vaccination of macrosomic neonates

• Use of a longer (1 in.) rather than a standard (5/8 in.) needle used for macrosomic neonates (birthweight over 4000 g) may affect antibody titers

• Fifty nine healthy infants were vaccinated at birth, 1, and 6 months of age with hepatitis B vaccine,

• Macrosomic infants who were immunized with a longer needle achieved significantly higher antibody titers to hepatitis B surface antigen than standard needle length (median, 3890.2 vs 1311.7 mIU/mL)

Ref: Vaccine, Volume 30, (21), 2 May 2012, 3155–58

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