1. Hepatitis A – An Indian perspective
Dr Shrish Bhatnagar

2. Dedication
JNMC
SGPGIMS
Late Dr S K BHATNAGAR

3. Hepatitis A An Overview

4. Hepatitis A: Characteristics and Needs
Asymptomatic/Acute Hepatitis/ FHF
No chronicity, No carriers, No M-F trans
Severity related to age
All unexposed susceptible
Life long immunity

5. Average loss of 30 working days (adults)
Consequences
Average loss of 30 working days (adults)
Ref: Mortality: Wilner IR et al, An intern Med 1998, 128:111-4

6. Consequences
Co-infections in Acute Hepatitis: A + E A+TYPHOID A+FALCIPARUM B/C +A WILSON’S + A
Unusual manifestations: Age 18 months – 144 months (ref: Pune ‘98 – ’99) Ascites, Edema, Firm hepatomegaly, SGPT < 500 Pleural Effusion, Cholecystitis, Rashes, Delayed recovery 6 wks – 6 months

7. Reality check HAV : 51% Unknown HAV 23% 34% Others 17% HAV+HBV HBV
FHF - Etiology (n=36) KEM Hospital, Pune (96-97)
HAV : 51%
Unknown
HAV
23%
34%
Others
17%
HAV+HBV
HBV
HAV+HEV 6% 9%
11%

8. So what about Vaccination Programme?
More about Hepatitis A
Diagnostic difficulties
FHF - commonest cause
Morbidity high in older children and adults
So what about Vaccination Programme?

9. Ref: Weekly epidemiological record 2000
WHO position paper
Highly endemic countries – large scale immunization efforts not recommended
Low endemicity – immunization of high risk populations
Intermediate endemicity – Significant health burden and Vaccination programs
Ref: Weekly epidemiological record 2000

10. Indian scenario

11. HAV Epidemiological Study (Indian Population)
Seroprevalence study of Hepatitis A virus antibody in Indian children (2011 – 2012)
Centres: Kolkata, Pune, Delhi & Chennai
Population: 928 Children
Age group: 18 months to 10 years age
Arankelle V, Mitra M et al, Changing epidemiology of HAV in Indian children.. A Poster presentation at CIDSCON, 2013

12. Highlights
HAV seroprevalence significantly increased with age in all SECs (p< for all) except upper SEC (p-0.124)
Statistically significant association was observed between HAV seroprevalence and educational background (p )
Source of drinking water also showed an association with HAV seroprevalence
Fewer subjects from a household with private toilet within the house (33.1%) were seropositive as compared with those using open field for defecation (75%)

13. Conclusion
This shift in age in the epidemiology of HAV infection over a period of time has clearly shown an increase in the number of non-immune subjects in the pediatric age group. This difference in the number of HAV seropositive cases over age clearly demonstrates a shift in epidemiology
Transition in the rate of endemicity from lower age group to higher age group has led to an increased incidence of disease morbidity and mortality which is otherwise high in endemic zones that are relatively asymptomatic
Decreased seroprevalence of HAV in all age segments of the study population demands effective vaccination schedule as per the recommendation of Indian Academy of Pediatrics Committee on Immunization (IAPCOI), 2011 and WHO for routine vaccination either by live attenuated or inactivated hepatitis A vaccine

14. What IAP recommends?? IAP immunization timetable ( 2014)
“additional newer vaccine ”
IAP recommended vaccine for routine useJa
Vaccines under special circumstances
BCG
Hep B
Polio
DTP
Tdap
Hib
Pneumococcal
Rotavirus
MMR
Varicella
Hepatitis A
Typhoid
HPV
Rabies
Influenza
PPSV23 JE
Cholera
Yellow Fever
Meningococcal
IAP Recommended immunization schedule for children aged 0-18 years (with range), 2014.

15. Types of Hepatitis A Vaccines

16. Types of Hepatitis A Vaccines
Inactivated vaccine
First vaccine available in Europe in 1991
Approved in the US in 1995
Given IM - 2 dose series, 6-18 months apart Seroconversion more than 95%
Cannot replicate
Induce neutralizing antibodies (humoral immunity)
Antibody titer diminishes with time
Require booster doses ?
Expensive
Content Adjuvant – aluminum hydroxide
Live attenuated vaccine
Earliest attempts to develop a live attenuated vaccine were made in 1980
H-2 strain HAV vaccine has been licensed for use in China since 1992 (Zhejiang Pukang Co )
Simulate natural infection
Produce a complex immune response
Produce both humoral as well as cellular immunity
H2 strain – licensed for use above age 1 yr
Single dose S / C ( deltoid )
Freeze dried 0.5 ml
Same dose for adults , children
Do not content adjuvant
Storage C
> 130 million Children vaccinated ‘successfully’

17. Live Attenuated Vaccine Safety and Efficacy
HA live vaccine safety Zhang S. Zhonghua Yi Xue Za Zhi 1990 Dec;70(12):682-4, 48
HA Live Vaccine :Immunogenecity (single dose)Seroconversion = >20mIU/ml
Cheng NL. Zhonghua Yi Xue Za Zhi 1992 Oct;72(10):581-3, 638
3089 candidates(4-27 years) in 3 batches
No local or systemic reactions during 42 day follow up
Serum enzymes remained within normal range
11451 healthy persons in 3 batches
Overall seroconversion rate: 92.9%
Quick antibody response: weeks

18. Live Attenuated Vaccine Safety and Efficacy
HA Live Vaccine : Protective Efficacy(single dose)
Mao JS et al. Vaccine, 1997, 15(9):
Long Term Epidemiological Effects (10 yrs, single dose)
Zhuang F, et al. Zhonghua Liu Xing Bing Xue Za Zhi 2001 Jun;22(3):188-90
4 year study at 11 primary schools starting
1991
Vaccinated Controls
Cumulative
person yrs
Cases of HA Nil
Decrease in hepatitis A incidence rate in 1-15 year olds : 97% and 98%
Decrease in hepatitis A incidence rate in whole population: 95% and 90%
Seroconversion 80% ( 10 yrs)

19. HA Live vaccine Sustain Immunogenicity
Years after Inoculation
Ran. Sub. No.
Seroconversion (%)
GMT
Abbott EIA mIU/ml
2 Months
220
98.6
287
1 Year
219
93.6
226
6 Years
108
83.3
173
10 Years 86
80.2
145
15 years 96
81.3
128
Mao et al, Vaccine, (1997)
Zuang et al, Zhongua Liu Xing Bing Xue Za Zhi (2001)
Zuang et al, Chines Med. J (2005)
Zhonghua Liu Xing Bing Xue Za Zhi Dec;31(12):

20. Live HA vaccine Single dose or Booster??
Korea, Shanghai, Hebie & Beijing
Single dose
Double dose
SP%
GMT
2 Mths. 95
131 -
1 year 80 81 85
107
3 years 75
100
924
8 years 72 89 98
262
Protection in both 100%
Xuan Yi Wang et al, Vaccine (2007)

21. Live HA vaccine Single dose or Booster??
14 single dose vaccines had HAVAB ( IgG) > 10,000
‘Amnestic response’
Probably natural infection = booster effect
T cell dependant memory ( long term)
Observations do not support need for booster in present scenario
Xuan Yi Wang et al, Vaccine (2007)
Korea, Shanghai, Hebie

22. Live HA vaccine Single dose or Booster??
As per the International Consensus Group on Hepatitis A Virus Immunity* Data have shown that after a full primary vaccination course, protective antibody amounts persist beyond 10 years in healthy individuals, and underlying immune memory provides protection far beyond the duration of anti-HAV antibodies. The group concluded that there is no evidence to lend support to HAV booster vaccination after a full primary vaccination course in a healthy individual. However, further investigations are needed before deciding if boosters can be omitted in special patient-groups. “ ”

23. HA vaccine Inactivated vs Live
Shanghai, Korea (117 children 3-11 yrs)
IgG subclasses studied – similar effects
Cell mediated immunity – not studied
Inactivated
Live
SP%
GMT
1 mos. 44 22 31 20
7 mos. (2 doses)
100
2615
1306
24 mos.
654
217
Xuan Yi Wang et al, Vaccine (2004)

24. HA vaccine Inactivated vs Live
In case of live vaccine decline in antibody titre is slower as against inactivated vaccine – Vaccine 1998
Inactivated vaccine (2 doses)
Inactivated vaccine GMT after 5 yrs
Live attn vaccine GMT after 15 years (128 mIU/ml)
Live attn vaccine

25. Comparing Live vs Inactivated
INACTIVATED VACCINES
Licensed for use > 1 year
Seroprotection > 95%
Minimal adverse effects
Two dose schedule, IM
Aqueous formulation
LIVE VACCINE (H2 strain )
Licensed for use > 1 year
Seroprotection > 95%
Minimal adverse effects
Single dose schedule, SC
Same dose for children and adults
Freeze dried

26. Indian Data

27. First study outside China
Evaluation of Immunogenicity and Tolerability
of a Live attenuated Hepatitis A vaccine
in Indian children
Department of Pediatrics, KEM Hospital, Pune.
Single centre, non-comparative, non-randomized,
open, confirmatory trial
Study : August to December Bhave, Bavdekar, Madan, Jha, Bhure, Pandit Indian. Pediatr (2006)

28. RESULTS – Immunogenicity (Seroprotection – IgG levels > 20 mIU/ml )
Seroconversion : 98.15

29. HA Live Vaccine Indian Experience
An Open label evaluation of Immunogenicity and Safety of Biovac-A Freeze Dried, Live Attenuated Hepatitis-A Vaccine in healthy children (2012)
Kolkata & Pune
140 Children – 12 years age
Single dose wks Sero protection % GMT (mlU/ml) ± 28.08
Minimal side effects
The post vaccination median titre (IQR) for total anti-HAV antibodies was 64.0 ( ) mIU/mL (Kolkata 70.7 [ ] mIU/mL, Pune [ ] mIU/mL)

30. WHO Position paper 2012

31. Change in IAP recommendation

32. HA Live Vaccine Conclusion
Live attenuated H2 strain Hepatitis A vaccine was highly immunogenic and safe in Indian children
A single dose of live attenuated Hepatitis A vaccine produced an excellent seroconversion and had a good tolerability profile

33. Thank You