Hepatitis A is an under rated infectious disease in children , with high morbidity and a major cause of fulminant hepatitis in children.There has been a longstanding debate between the LIVE VACCINE FOR HEPATITIS A AND THE KILLED INACTIVATED VACCINE FOR HEPATITIS A. Recent CDC guidelines and INDIAN ACADEMY OF PEDIATRICS GUIDELINES and recent references were studied before making these slides. Hope you find these useful.

2. Common misconceptions
• Hepatitis A is a self limiting disease and is not
serious.
• India is classified as “ high endemic zone” for
Hepatitis A
• Most children get natural infection and
acquire natural immunity
• Vaccination is not mandatory for Hepatitis A

3. What we should know
• Hepatitis A- disease burden
• How is it different from other Vaccine
Preventable Diseases ?
• Shift in endemicity and therefore a pressing
need for long term protection

4. Historical map of Hep A Prevalance 2012- India shown
as high endemic ( red) zone
• World wide incidence > 1.4 million cases yr
• Fulminant hepatic failure is an uncommon
complication, occurring in only 0.14-0.35%
of hospitalized cases. 2
• Fulminant hepatitis is rare, but associated
with high mortality 3
• In Hundreds the number looks small ;
however in actual population it becomes
significant
• In northern European countries 20% of
cases of fulminant viral hepatitis is due to
hepatitis A.2
• Acute hepatitis / Fulminant Hepatic
Failure - severity increases with age
1) http://www.who.int/mediacentre/factsheets/fs328/en/
2) Vaccine. 1992;10 Suppl 1:S21-3
3)WHO position paper 2012

5. Increasing Burden of
Hepatitis A in Adolescents
and Adults and the Need for
Long-Term Protection:
A Review from the Indian
Subcontinent
Agrawal A,. Infect Dis Ther
8,483–497(2019).
• Number of reported
hepatitis outbreaks (N =
291), by state — India,
2011–2013
https://www.cdc.gov/mmw
r/preview/mmwrhtml/mm
6428a3.htm

6. HAV : Hepatitis A Virus; AVH : Acute viral hepatitis; ALF: Acute liver failure;
ACLF: Acute-on chronic liver failure
1.Rakesh PS et al. Indian J Med res. 2017;146(3):426-9;
2. Sood V et al. Indian Pediatr 2019; 56:741-744;
3. Poddar U et al. Arch Dis Child 2002; 87:54-56;
4. Lemon SM et al. J Hepatol 2018; 68:167-184;
Case Fatality Rate (age dependent)3 : 0.1 – 5.4%
• Hospitalization 41 – 83% 1,2
• Days in Hospital 7.61
• Work day loss 20 – 1801
• Cost to one person~25k1
HAV Infection accounted for :
• AVH (Hepatitis A): 48 – 76%2,3
• ALF : 46.5 – 51%2,3
• ACLF : 14.6 – 17%2,3

7. Facts
• Hepatitis A is the most common cause of
Fulminant Hepatic Failure in children (ALF)
Ujjal Poddar Indian Pediatr 2019;56: 731-732
• CDC 2015 –
80 % fatality reported in cases of ALF
The severity and risk of death with ALF
increases with age

8. How Hepatitis A is different from
other VPD’s
• Increasing mortality risk over the years
noted, whereas it has decreased for other
VPD’s- why?
• Number of cases of Hepatitis A are increasing
every year.
Sood, et al. Indian PediatricsVOLUME 56__SEPTEMBER 15, 2019
W.H.O. Position paper Hepatitis A , 2012
Lancet Volume 388, ISSUE 10049, P1030-1031, September 10, 2016

9. Shift in endemicity of Hepatitis A in India
Sood, et al. Indian Pediatrics VOLUME 56__SEPTEMBER 15, 2019

10. Declining Hepatitis A exposure in Indian children
1. Arankalee V et al. J Viral Hepat. 2019 Jun;26(6):757-760 2. Chitambar SD et al. Southeast Asian J Trop Med Public Health. 1999
Jun;30(2):273-6;
2. 3. Arankalle V et al. Vaccine: Development and Therapy, 2014, 4: 7-13

11. Lesser endemicity means -
Higher age at first exposure to Hepatitis A
• Because of more severe infection later in life,
there is a need for long term protection
A comprehensive literature review of all the
studies since 2005
Infect Dis Ther 8, 483–497 (2019).
https://doi.org/10.1007/s40121-019-00270-9

12. Reality check -True or False
• Health workers are at increased risk for acquiring
Hep A through occupational exposure
• Hepatitis A can spread via infected needles in
people who inject drugs
• MSM have high risk for acquiring Hep A
• HAV infection may increase HIV replication
• People with chronic liver disease are at high risk
for acquiring Hep A infection.

13. Reality check -True or False
• Health workers are at increased risk for acquiring
Hep A through occupational exposure (F)
• Hepatitis A can spread via infected needles in
people who inject drugs (T)
• MSM have high risk for acquiring Hep A (T)
• HAV infection may increase HIV replication( T)
• People with chronic liver disease are at high risk
for acquiring Hep A infection.(F)
US Department of Health and Human Services/Centers for Disease Control and
Prevention MMWR / July 3, 2020 / Vol. 69 / No. 5

14. Which one to choose ?
WHO position paper on hepatitis A vaccines:
June 2012—
Both inactivated and live attenuated
hepatitis A vaccines are highly immunogenic
and immunization will generate long-lasting,
possibly life-long, protection
against hepatitis A in children as well as in
adults.
WHO position paper on hepatitis A vaccines: June 2012—
Recommendations. Vaccine (2012),
http://dx.doi.org/10.1016/j.vaccine.2012.10.102

15. CRUX OF INACTIVATED HAV STUDIES ON LONG TERM IMMUNOGENICITY
Infect Dis Ther 2020
https://doi.org/10.1007/s40121-020-00311-8

16. Hepatitis A Vaccine – Live Attenuated
H2 strain

17. Single dose of live H2 strain HAV vaccines , a 20 yrs experience
in China
• Shown remarkable safety, immunogenicity, and long-term
protection
In China, a decrease in HAV incidence was reported from
359.7/100,000 (1992) to 17.7/100,000 (2009), which is
approximately a 93% decrease from 1992 to 2009
• Mao JS, Chai SA, Xie RY, Chen NL, Jiang Q, Zhu XZ, et
al. Further evaluation of the safety and protective efficacy of live attenuated hepatitis A vaccine
(H2-strain) in humans. Vaccine. 1997;15:944-7.
• Zhuang FC, Qian W, Mao ZA, Gong YP, Jiang Q, Jiang LM, et al. Persistent efficacy of live
attenuated hepatitis A vaccine (H2-strain) after a mass vaccination program. Chin Med J
(Engl). 2005;118:1851-6.
• HUMAN VACCINES & IMMUNOTHERAPEUTICS ,2016, VOL. 12, NO. 12, 3160–3165
http://dx.doi.org/10.1080/21645515.2016.1216286

18. Live Attenuated H2 strain HAV vaccine highlighting
points
Simulate natural
infection
Produce a complex
immune response
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 =
106.5 TCID50
Same dose for adults ,
children

19. Most cited Prominent Indian Study of LIVE Hepatitis
A vaccine immunogenity

20. After 10 yrs 106 out of 108 subjects
had seroconversion (98 %)

21. Unicentric study (10 years)
Evaluation of Immunogenicity and Tolerability of a Live attenuated Hepatitis A
vaccine in Indian children
111.1
66.6
100.4
0
50
100
150
2004 2007 2010 2014
GMT(mIU/mL)
*
* GMT of 2004 not presented as anti HAV titres
>100mIU/mL were not quantified in 2004Bhave S. et al. J. Ind. Ped. 2015;52:687-690
95.8 92.3
77.7
87.6
0
25
50
75
100
2004 2007 2010 2014
Seroprotection(%)
Seroprotection Rate
Geometric Mean Titers
10 year
*
 Study Design: Single centre, non-randomized, open, confirmatory trial (2004-2014)
 Children 12months to 12 years received a single dose of Hepatitis.
 121/143 evaluated at 10 years
 115 have completed 12 year
Good seroprotection rate and GMT at end of 10 yrs

22. The 2nd most cited Indian Study on
Live HAV vaccine immunogenicity
A prospective, multicentric, open labeled hospital based study was conducted at
the four metropolitan cities of India, namely Delhi, Mumbai, Kolkata and Chennai
from April 2007 to February 2008 amongst
505 subjects.
After 6 weeks 95% seroconversion
After 6 months 98 % seroconversion
The titres were well above the seroprotective limit of antibody level of
20 milli IU /ml .
Faridi MM, Shah N, Ghosh TK, Sankaranarayanan VS, Arankalle V, Aggarwal A, Sathiyasekaran M, Bhattacharya N, Vasanthi T,
Chatterjee S, Choudhury J, Mitra M. Immunogenicity and safety of live attenuated hepatitis A vaccine: a multicentric study.
Indian Pediatr. 2009 Jan;46(1):29-34. PMID: 19179715.

23. Multi centric Study (5 years)
Immunogenicity & Safety of Live attenuated Hepatitis A Vaccine :
• Study Design: Multi centric, non-comparative, non-randomized, open,
confirmatory trial - New Delhi, Mumbai, Chennai, Kolkata (2008-13)
• 343/505 Children, 18 – 60 months age followed up for 5 years – single dose
• Now 9 years completed
Mitra et al. Hum. Vacc. Immunotherap. 2015; 11(5): 1147-1152 5 year
0
20
40
60
80
100
120
140
160
6weeks
6months
1year
2year
3year
5year
GMT…
95% 97.90% 98.30% 96.15% 97.80% 97.30%
0%
20%
40%
60%
80%
100%
6 Wks 6 mos 1 yr 2 yr 3 yr 5 yr
Seroprotection at 5 yrs
6 weeks=65
6 months=138.1
1 year=135.2
2 year=124.6
3 year=137.6
5 year=127.1
Good seroprotection rate (97.30%) and GMT (127.1) at end of 5 yrs

24. Immune memory at 17-years of follow-up of a single dose of
live attenuated hepatitis A vaccine
Ying Chen a,1, - Immune memory at 17-years of follow-up of a single dose of live attenuated hepatitis A vaccine (Vaccine – 2017)
 Objectives: To assess the duration and characteristics of immunity conferred by the widely
used HAV vaccine.
 Study Cohort & Study Design:
• 3,515 HAV susceptible children aged 1–12 years (mean age 5.4 years) were enrolled
between 1996 and 1999 and assigned randomly to either receive a single dose of the HA
vaccine or to serve as controls.
• In this present study, recipients of HAV vaccine without either natural infection or vaccine
booster were selected as participants.
• A challenge dose of HAV vaccine was administered to each participant immediately after
collection of a blood sample. A second blood sample was obtained two weeks after the
booster.

25. Crux of the post 17 year challenge dose study
As per WHO guidelines, required level for sero protection against Hep A is 20 m IU/ML
For any vaccine or post infection , antibody titres / GMT will start falling after some
period
Aim behind doing the study was after long duration, what is the actual clinical
effectiveness of the Live vaccine in real time scenario and to see what if GMT titers
are below recommended levels
Anti HAV negative - Subject who were having GMT below required level of 20 m
IU/mL after 17yrs
Anti HAV positive - Subject who were having GMT level above required level
of20 m IU/mL after 17 yrs

26. Immune memory at 17-years of follow-up of a
single dose of live attenuated hepatitis A vaccine
Ying Chen a,1, - Immune memory at 17-years of follow-up of a single dose of live attenuated hepatitis A vaccine (Vaccine – 2017)
28 fold increase in GMC's in anti-HAV positive group
The level of anti-HAV serumIgG in anti-HAV
positive group before and after the boost
2000
1500
1000
500
0
Anti-HAVserumIgGtiter(mIU/mL)
1832
65
Anti-HAV Positive
83 fold increase in GMC's in anti-HAV positive group
800
600
400
200
0
Anti-HAVserumIgGtiter(mIU/mL)
663
8
Anti-HAV Negative
The level of anti-HAV serumIgG in anti-HAV
negative group before and after the boost

27. Immune memory at 17-years of follow-up of a
single dose of live attenuated hepatitis A vaccine
• The GMCs increased from 67.6 mIU/mL to 1832.1
mIU/mL in the anti-HAV positive group and from 8
mIU/mL to 661.3 mIU/mL in the negative groups.
( In anti-HAV positive group ~28 fold increase in
GMC’s; In anti-HAV negative group ~83 fold
increase in GMC’s )
• Although the antibody titer in the anti-HAV
negative group was significantly lower than that in
anti-HAV positive group pre-challenge, there was
no significant difference in antibody titer between
the two groups post-challenge

28. Immune memory at 17-years of follow-up of a
single dose of live attenuated hepatitis A vaccine
• Single dose of the live attenuated HA vaccine showed good B cell and T
cell immune memory and likely provides long-term protection.
• It is encouraging to note that when encountering the antigen again,
antigen-specific memory B and T cells are capable of mobilizing rapid
responses, which is demonstrated by the ability to promptly mount an
anamnestic antibody response to a booster dose and the secretion of
specific cytokines.
• There was a significant increase in the secretion of IFN by CD3+ T cell in
vivo was measured after a booster. Furthermore, the IFN secretion from
CD3+ - CD8+ subset was remarkably higher than that from CD3+CD4+
subset, which satisfied the characteristic of live attenuated vaccine to
mediate a cellular based response.
Ying Chen et al, - Immune memory at 17-years of follow-up of a single dose of live attenuated
hepatitis A vaccine (Vaccine – 2017)

29. Immune memory at 17-years of
follow-up of a single dose of live
attenuated hepatitis A vaccine
CONCLUSION-
The study clearly shows that even after 17
years, subjects who were below required
level of GMC; also produced more than
required GMC level once they get exposed to
infection

30. Lack of published Indian studies with
killed/ inactivated Hepatitis A vaccine
Concerns have been raised over the following disadvantages
of killed/ inactivated Hep A vaccine in Indian scenario
- 2 times the cost of a live single dose Hep A vaccine
- Ease of administration better with S.C. Live vaccine, less pain
- Compliance for 2nd dose is an issue with killed/ inactivated
vaccine
- Robust cell mediated immunity better documented in Indian
studies on Live Hep A vaccine.
No Indian studies on long term efficacy or immunogenicity
of killed / inactivated Hep A vaccine.
Chetan Trivedi et al.
Pediatric Infectious Disease, Volume 1 Issue 4 (October–December 2019)

31. Prior 2 dose schedule of Live attenuated
Hep A Vac revised to SINGLE DOSE BY IAP

32. Hepatitis A vaccine Recommendations
Recommendation WHO (2012) IAP ACVIP(2016)
Age 12 months 12 months
Live Hep. A vaccine Single dose Single dose
Killed Hep A vaccine Two doses
2nd dose ; 6-12 months (up
to 18 months) apart
Two doses
2nd dose ; 6-18 months apart
Since 2016,Indian Academy of Paediatrics (IAP) also recommends for Live Hep A vaccine as
a single dose or 2 dose schedule of killed Vaccine
HUMAN VACCINES & IMMUNOTHERAPEUTICS 2016, VOL. 12, NO. 12, 3160–3165
WHO position paper 2012 and IAP 2016,

33. Sandeep 4 yrs male, brought with
fever, vomiting, pain abdomen
• Vomitings 3 to 4 per day-NB/NP since 10 days
• Fever started 10 days back , low grade
undocumented, intermittant, responding to
paracetamol. Lasted 3 days
• Lack of appetite since 10 days
• Dull aching abdominal pain, intermittant, mild
• No history of high coloured urine/ acholic stools
• No yellow discoloration of sclera
• No malena/ hemetemesis/rash/ joint pains
• No diarrhoea or constipation

34. • Immunized as per UIP schedule
• Travelled to native village 6 weeks back
• Belongs to middle class family
• No h/o tranfusion or surgery
• Anthropometry normal for age
• Vitals stable
• No pallor, icterus, clubbing, edema
• No signs of dehydration
• Conscious cooperative
• Per abdomen – soft non tender, no
hepatomegaly

35. Doctor what has happened to Sandeep?
• DD?
• Will you consider infectious hepatitis in such a
child , especially when there is NO ICTERUS on
day 10 of lack of appetite, pain abdomen,
vomitings?
and NO HEPATOMEGALY?

36. High index of suspicion needed for diagnosis
In children under 6yrs of age with Hepatitis A
infection-
70% HAV infected kids are asymptomatic
In those who are symptomatic,
Icterus is uncommon .
Lednar WM, Lemon SM, Kirkpatrick JW, Redfield RR, Fields ML, Kelley
Am J Epidemiol 1985;122:226–33. https://
doi.org/10.1093/oxfordjournals.aje.a114093
Hadler SC, Webster HM, Erben JJ, Swanson JE, Maynard JE.
N Engl J Med 1980;302:1222–7. https://doi.org/10.1056/
NEJM198005293022203

37. Labs
• Raised AST, ALT 1684 I.U. and 1865 I.U. resp.
• TSB 2 gm% with 0.5 gm% Indirect Fraction
• Coagulogram Normal
• Hemogram ,PBF, RBS, SERFT normal
• Widal and Blood cultures awaited.
• Urine RE- Normal & negative for BS/BP
• Stool Re – Normal
• USG abdomen – Leads nowhere as usual-
Please correlate clinically is the bottomline.
• IgM HAV POSITIVE

38. Sandeep followed up at regular intervals
• Followed up for ---------------- days/ months
• Are relapses known?
• Is chronicity known ?
• On what day of the symptoms the IgM HAV is
expected to be positive?
• How long do IgM antibodies to HAV last?
Glikson M, Galun E, Oren R, Tur-Kaspa R, Shouval D. Relapsing hepatitis
A. Review of 14 cases and literature survey. Medicine (Baltimore)
1992;71:14–23. https://doi.org/10.1097/00005792-199201000-00002
Koff RS. Clinical manifestations and diagnosis of hepatitis A virus
infection. Vaccine 1992;10(Suppl 1):S15–7. https://doi.
org/10.1016/0264-410X(92)90533-P

39. Sandeep followed up at regular intervals
• Followed up for ---------------- 2months to 6 months
• Are relapses known? YES-10- 15 % have prolonged or
relapsing course
• Is chronicity known ? No
• On what day of the symptoms the IgM HAV is expected
to be positive? Day 5 onwards
• How long do IgM antibodies to HAV last? 6 months and
upto 1 yr in a few pts.
Glikson M, Galun E, Oren R, Tur-Kaspa R, Shouval D. Relapsing hepatitis A.
Review of 14 cases and literature survey. Medicine (Baltimore)
1992;71:14–23. https://doi.org/10.1097/00005792-199201000-00002
Koff RS. Clinical manifestations and diagnosis of hepatitis A virus infection.
Vaccine 1992;10(Suppl 1):S15–7. https://doi. org/10.1016/0264-
410X(92)90533-P

40. 12 Yr old Rashmi has jaundice and her
reports confirm its Hep A
• She has jaundice since 5 days
• Had fever 10 days back lasting 5 days
• Associated anorexia, nausea
• The parents have already visited a physician
before coming to you but are “Unsatisfied”
• They want a double opinion
• They have some queries too
(masoom sawaals)

41. Masoom sawaals
• How many days school leave is needed for her?
• Can the saliva of an infected child be a source of transmission
to other siblings at home?
• The previous doctor advised post exposure prophylaxis by Hep
A vaccine to sibs. Within how many weeks of exposure to the
infected child should the vaccine be given, to be effective.
Rashmi came to you on day 5 of jaundice.
This means how many days of exposure to the sibs ? Within
how many days should we vaccinate Rashmi’s sibs?

43. Clemens R, Safary A, Hepburn A, Roche C, Stanbury WJ, André FE. Clinical experience with an
inactivated hepatitis A vaccine. J Infect Dis 1995;171(Suppl 1):S44–9.
https://doi.org/10.1093/infdis/171. Supplement_1.S44
• How many days school leave is needed for her?
At least 2 weeks after the onset of jaundice ( infectivity period 2 weeks before
and 2 weeks after the onset of symptoms )
• Can the saliva of an infected child be a source of transmission to other siblings
at home? No case reported of such a transmission though theoretical risk
noted.
• Post exposure prophylaxis by Hep A vaccine to sibs within 2 weeks of
exposure to the infected child.
Rashmi came to you on day 5 of jaundice.
This means how many days of exposure to the sibs ? Within how many days
should we vaccinate Rashmi’s sibs?
As early as possible and in such a scenario , the killed Hep A vaccine gives
early protection and is preferred in epidemics for the same reason
After 15 days of inactivated HAV Vaccine, 88 percent seroconverted and after
1 month 95 percent SC.

44. Gaurav 7 months old , lives in U.S.A.
Parents plan a holiday trip in the coming week ,to
African countries which are endemic for Hepatitis A
Choose the best advice for him regarding killed Hep A
vaccination
1) Can not be vaccinated for Hep A at this age
2) Give Immunoglobulin and vaccination both and second dose
as per schedule, after 6 months.
3) Give Immunoglobulin and vaccination both
Repeat 2 dose schedule once child is 1 yr old
4) Vaccination and immunoglobulin can not be given together
for Hepatitis A prevention.Give only immunoglobulin

45. Gaurav 7 months old , lives in U.S.A.
Parents plan a holiday trip in the coming week ,to
African countries which are endemic for Hepatitis A
Choose the best advice for him regarding killed Hep A
vaccination
1) Can not be vaccinated for Hep A at this age
2) Give Immunoglobulin and vaccination both and second dose
as per schedule, after 6 months.
3) Give Immunoglobulin and vaccination both
Repeat 2 dose schedule once child is 1 yr old
4) Vaccination and immunoglobulin can not be given together
for Hepatitis A prevention. Give only immunoglobulin.

46. Take home message
Hepatitis A case mortality increases with age. Fulminant hepatitis is rare, but associated with high mortality
India moved from high to intermediate zone of hepatitis A endemicity because of improved sanitation, hygiene
practices and vaccination
Single dose of live vaccine is adequate in our country which is in endemic zone.
Live Hep A vaccine provides both Humoral & Cell Mediated Immunity.
Though required level of protection is 20 MIU/ml, Live Hep A vaccine provideed GMT 127.1 even at end of 5 years
and 100.4 at the end of 10 years
The only Hepatitis A Vaccine which is backed up with Indian trials- 5 yr multi-centric and 10 yr unicentric trial
respectively
It has advantage of longer protection due to advantage of memory cells. Proved with 17 year booster challenge
test.
Live attenuated Hep A vaccine has advantage of less pain as administration through s/c route