Hepatitis B Vaccine revisited - Ideal Schedule & recommendations

Presented in SAVE Sanofi Aventis program for Pediatricians from Western India in Goa in May 2012

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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 Disease
Deaths Worldwide
Disease
Lower respiratory tract infections
Diarrheal diseases
HIV/AIDS
Tuberculosis
Hepatitis viruses
Hepatitis B virus
Hepatitis C virus
Malaria
Pertussis
Neonatal tetanus
Measles
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

6. 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 1
Hep.B at 0-1-6
Group 2
Hep.B at 2-4-6
Anti-HBs ³ 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 ³ 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
84.3941.7
0
1000
2000
3000
4000
5000
6000
7000
After 1st dose After 2nd dose After 3rd dose
GMT (mIU/ml)
GMT (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
transmissi
on (Yes/
No)



HBsAg+
Mothers
%



HBeAg
+
mother
s
%HBsA
g+



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 1
st
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 monitoring
Available 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 2
nd
and 3
rd
doses
If the gap is less, then a 4
th
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 3
rd
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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