Rationale and need for

vaccination against

Hepatitis A
Conflict of Interest: Tonight’s activity is sponsored by HAVSHIELD (Inactivated HepA Vaccine) by
Abbott Vaccines (India)
Disclaimer
• Thank you for sparing your precious time.
• Almost all the slides are prepared by me after thoroughly reading
relevant literature to present an unbiased overview
• We all know the basics (etiology, pathogenesis, clinical
features,management, etc.) of the disease, hence, I will discuss only
those things that I found interesting
• I will not be discussing LIVE ATTENUATED HEP-A VACCINE!
Today’s discussion

•Why we need a •Which vaccine

vaccine against to use
HepA - Disease
burden
Resources
• WHO position paper on Hepatitis A vaccines – October 2022
• A single blind randomized phase 3 study to evaluate safety and
immunogenicity of inactivated hepatitis A vaccine in 1-15 years-old
healthy hepatitis A vaccine-naïve children. Subhash Thuluva,
Ramesh Matur, Kishore TSA, Subba Reddy GV. Vaccine, Volume 39,
Issue 49
Burden Statement
Background
• Hepatitis A virus (HAV) causes inflammatory liver disease that may
progress to fulminant liver failure
• Transmission:
• faecal/oral route
• direct contact with an infectious person
• Incidence of infection correlates with socioeconomic indicators
• decreasing with increasing income/access to clean water/adequate sanitation
Pathogen
• Shed in faeces as non-enveloped virions
• Gets a membrane derived from the host cells while in blood circulation
• Only one serotype. Several genotypes and subgenotypes
• Subgenotypes - used for investigating
• origin of outbreaks
• define routes of transmission
• Resistant to low pH and heat (60ºC for 60 min) as well as to freezing
• Inactivated when exposed to 81 ºC or more for 10 minutes.
• The virus can persist in soil for a prolonged period of time.
• Fecal shedding can last up to 6 months or longer.
Disease
• Incubation period of acute hepatitis A is usually 14–28 (up to 50) days
• Symptoms: malaise, fatigue, anorexia, vomiting, abdominal
discomfort, diarrhoea, fever, headaches, arthralgia, myalgia.
• Elevated liver enzymes, dark urine, clay-coloured stools, jaundice
• Resolves completely in >99% of the cases
• Relapse reported in 3–20% of clinical cases
• Does not cause chronic liver disease
• Immunity to the disease is assumed to persist for life
• Mortality in patients hospitalized with icteric hepatitis A varies with
age
• 0.23% for those less than 30 years of age
• 1.8% to 2.1% for those more than 49 years
• Fulminant hepatitis assoc. with high mortality
• Immunosuppressed patients
• patients with chronic liver disease
• Pregnancy
• increased risk of preterm labour
• gestational complications, such as birth of small-for-gestational-age infants.
Diagnosis
• IgM anti-HAV: detectable in both symptomatic & asymptomatic
• appear within 5–10 days of symptom onset, or during early transaminitis
• persist for about 4 months (range 1–14 months).
• IgG anti-HAV: rise later and then persist for a long period of time, i.e.
for years after infection, or even life-long.
• HAV RNA: detected in body fluids & faeces days before transminitis
• Viremia can persist for several months
Epidemiology
• levels of endemicity - based on IgG anti-HAV antibodies seroprevalence
• high (≥90% by age 10 years)
• intermediate (<90% by age 10 years but ≥50% by age 15 years)
• low (<50% by age 15 years but ≥50% by age 30 years)
• very low (<50% by age 30 years).
• Seroprevalence by age
• provides a measurement of the susceptibility of each age group to new HAV
infections
• is useful to understand the concept of transition, i.e. shifting of risk of infection to
older age groups that have not been infected in childhood, and are at a higher
risk of symptomatic and/or severe disease than younger age groups.
• Global burden of disease (GBD) data 2019
• 159 million acute HAV infections
• 39000 deaths
• 2.3 million disability-adjusted life years
• 66% of acute hepatitis A cases, and 97% of hepatitis A deaths occurred in
low- and lower-middle-income countries
• South-East Asia Region
• 42 million cases
• 24000 deaths (60% of the total deaths due to HAV worldwide)
• Highest mortality in South-East Asia and Eastern Mediterranean regions (12
deaths per 1 million population per year)
Indian situation
• HAV was shown to be associated with up to 50% of all cases of
fulminant hepatic failure in children and a significant indication for
liver transplantation
(Bendre SV et al. Fulminant hepatic failure: etiology, viral markers and
outcome. Indian Pediatr. 1999;36(11):1107–12)
Vaccines
• Antibody threshold for protection from HAV infection in humans: 10
to 33 mIU/ml
• More recent international practice uses either 10 or 20 mIU/ml as the
seroprotection threshold
• No absolute cut-off level for protection has been defined
Inactivated vaccines
• Licensed for use in persons aged ≥12 months (reduce the potential of
interference of the vaccine with pre-existing maternal antibodies)
• Vaccination schedule: 2 doses administered intramuscularly.
• The interdose interval: commonly 6–12 months
• can be extended to 18–36 months
• Doses do not need to be repeated if the interdose interval exceeds
that recommended.
Interchangeability of Inactivated HAV
• Inactivated hepatitis A vaccines produced by different manufacturers
are interchangeable, as are the combinations that contain inactivated
hepatitis A vaccine

Bovier PA et al. Interchangeability and tolerability of a virosomal and an

aluminum-adsorbed hepatitis A vaccine. Vaccine.2005;23(19):2424–9.
Ekwall E et al. Interchangeability of Hepatitis A boosters, Avaxim and
Vaqta, in healthy adults following a primary dose of the combined
typhoid/Hepatitis A vaccine Viatim. Vaccine. 2006;24(20):4450–7.
• Hepatitis A vaccines can be administered simultaneously
• DTP/Hib/OPV/IPV/MMR/HepB/Cholera/JE/Rabies/Yellow fever/
Varicella/PCV/Typhoid (oral and intramuscular)
• Detectable antibodies are estimated to persist for as long as
• 60 years for the 2-dose schedules
• 30 years with single-dose schedules
Live attenuated
• Two live attenuated hepatitis A vaccines
• based either on the viral H2 or the LA 1 strain
• licensed in China since 1992 for subcutaneous administration in
children aged ≥18 months
• also available in India (H2 strain) and a few other countries.
• There is some evidence that administering live attenuated hepatitis A
vaccines simultaneously with other routine immunization vaccines,
including with DTP and MMR, is safe and immunogenic; however
studies are limited
Which vaccine to use?
 H E PAT I T I S A VA C C I N E

Features of Hepatitis A Vaccine

Cultured in human Slightly milky-

embryo lung diploid Each 0.5 ml pediatric dose
contains 250 units Pre-filled syringe white suspension
cell Preservative-free
inactivated HAV antigen – format
TZ84 strain

Stratified precipitate
Followed by: may form, which can
harvestation, be dispersed by
purification, shaking
inactivation by
formaldehyde, and
aluminium adsorbtion

No clumps shall be
found on shaking

*As per product HAV: Hepatitis A virus

Proprietary andinformation
confidential — do not distribute
20
H E PAT I T I S A VA C C I N E

Importance of PRESERVATIVE-FREE VACCINE

1 2 34

Thimerosal, a Due to the concern The AAP and Preservative-free

mercury-based of potential health USPHS established vaccines will
compound, has damage by ethyl the goal of reducing increase public
been widely used as mercury contained or eliminating confidence and
a vaccine in thimerosal, it is thimerosal in compliance to
preservative. no longer used in pediatric vaccines immunization
most vaccines. in July 1999. practice.

Jiang WP, Chen JT, Wang X, et al. Immunogenicity and safety of three consecutive lots of a new preservative-free inactivated AAP: American Academy of Pediatrics;
Proprietary
hepatitis and confidential
A vaccine (Healive): — do not distribute
a double-blind, randomized and controlled trial. Vaccine. 2008;26(18):2297–2301. USPHS: United States Public Health
Service 21
 VA C C I N E ST U DY

Indian Study on Immunogenicity and Safety of 2 dose

Inactivated Hep A vaccine in 1–15-year-olds
Study centers: 8 Study centers located across India
Study period: 29 May 2019 to 3rd August 2020

Primary Objective Secondary Objective

To evaluate the immunogenicity of: To evaluate the safety of:

 two 0.5 mL IM doses of preservative-free  two 0.5 mL IM doses of preservative-

inactivated Hep A vaccine, free inactivated Hep A vaccine,

 6 months apart,  6 months apart,

 administered to 1–15-year-old Hep A  administered to 1–15-year-old healthy

vaccine-naïve children Indian Hep A vaccine-naïve children

 in comparison with GSK Vaccine  in comparison with GSK Vaccine

Subhash Thuluva, Ramesh Matur, Kishore TSA, Subba Reddy GV,

A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-naïve children,
Hep A: Hepatitis A; IM: Intramuscular
Proprietary and confidential — do not distribute
Vaccine, Volume 39, Issue 49,
22
• This was a
• single-blind/ Multicenter/ Parallel
• Randomized/ active-control
• two-arm
• Phase 3
• comparative study to evaluate safety and immunogenicity of
inactivated HAV vaccine in HAV vaccine-naïve children in India
• The total duration of the study was 210 days that included a total of 4
visits
 VA C C I N E ST U DY O U TCO M E M EA S U R ES

Criteria for Evaluation

Proportionof
Proportion ofsubjects
subjectswith
with
Proportion of subjects, 30 days solicitedadverse
adversereactions
reactionsduring:
during:
after 2nd dose achieving: solicited
•• first
first60
60minutes
minutesofofpost-vaccination
post-vaccination
• Seroconversion (seropositive) observationperiod
observation periodand
andfor
for
(≥20 mIU/mL) with anti-HAV •• subsequent
subsequent77consecutive
consecutivedays
days(Day
(Day
IgG from baseline. 0–6)thereafter,
0–6) thereafter,captured
capturedthrough
through
• ≥4-fold increase in anti-HAV subjectdiary.
subject diary.
antibodies from baseline
• ≥2-fold increase in anti-HAV
Immunogenicity Proportion of subjects with
antibody concentration among
unsolicited local and systemic AEs
seroconverted (≥20 mIU/mL) at
during the total post-vaccination
baseline. Safety follow-up period till Day 210.

Geometric mean concentration SAEs reported during the total post-

(GMC) at: vaccination follow-up period till Day
• Baseline 210.
• Day 210 (30 days after 2nd dose).
AEs: Adverse events; Anti-HAV IgG:
Data on file Matur,confidential
Subhash Proprietary
Thuluva, Ramesh and —Reddy
Kishore TSA, Subba do not
GV, distribute Immunonoglobulin G against Hepatitis A
A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-naïve virus; SAEs: Serious adverse events. 24
children,
Vaccine, Volume 39, Issue 49,
 VA C C I N E ST U DY M E T H O D O LO GY

• Two 0.5 mL IM doses, 6 months apart administered to each subject, in both the arms.
• Blood sample (3.5 mL) collected twice, once at screening and again on Day 210 (4wks
after 2nd dose).

520 subjects
equally randomized

Test vaccine (N=260) GSK vaccine (N=260)

1–7 yr. old (n=130) 8–15 yr. old (n=130) 1–7 yr. old (n=130) 8–15 yr. old (n=130)
(completed 117) (completed 116) (completed 114) (completed 120)
Proprietary and confidential — do not distribute
Subhash Thuluva, Ramesh Matur, Kishore TSA, Subba Reddy GV, IM: Intramuscular
A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-naïve children,
Vaccine, Volume 39, Issue 49,
26
Test Test Test
 VA C C I N E ST U DY R ES U LT S

Non-Inferiority Criteria met by test vaccine to GSK

Vaccine®
100% seroconversion was achieved in both groups.
Summary of seroconversion rates for anti-HAV IgG antibody concentration

1–7 year (N=231) 8–15 Year (N=236) Overall (N=467)

Anti-HAV IgG antibody GSK
concentration Test-Hep A GSK vaccine Test-Hep A GSK Vaccine Test-Hep A
vaccine(N=2
(N=117) (N=114) (N=116) (N=120) (N=233)
34)
Pre Vaccination (Day 0) 
Seroconverted 32 29 68 62 100 91
(≥20 mIU/mL) (27.35%) (25.44%) (58.62%) (51.67%) (42.92%) (38.89%)

Post Vaccination (Day 210)  

Seroconverted 117 114 116 120 233 234

(≥20 mIU/mL) (100.00%) (100.00%) (100.00%) (100.00%) (100.00%) (100.00%)

Data on
Subhash Thuluva, fileMatur, Kishore TSA, Subba Reddy GV,
Proprietary and confidential — do not distribute
Ramesh Anti-HAV IgG: Immunoglobulin G
A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-naïve children,
Vaccine, Volume 39, Issue 49, antibody to Hepatitis A virus. 28
Test Test
Test
VA C C I N E ST U DY R ES U LT S
Increase in Concentration of Titers by Preservative-Free
Hep A Vaccine
Good increase in concentration of titers was elicited even in population with >20
mIU/mL baseline titers by the Preservative-Free Hep A Vaccine.

Summary of anti-HAV IgG antibody concentration in terms of Fold Rise – PP Population

1–7 year (N=231) 8–15 Year (N=236) Overall (N=467)
Anti-HAV IgG antibody
concentration Test-Hep A GSK Vaccine Test-Hep A GSK Vaccine Test-Hep A GSK Vaccine
N1 (%) (N=117) (N=114) (N=116) (N=120) (N=233) (N=234)

107 98
≥2-Fold increase in all subjects 103 (90.35%) 100 (86.21%) 207 (88.84%) 201 (85.90%)
(91.45%) (81.67%)

94 76 79 176
≥4-Fold increase in all subjects 100 (85.47%) 173 (73.93%)
(82.46%) (65.52%) (65.83%) (75.54%)
Subhash Thuluva, Ramesh Matur, Kishore TSA, Subba Reddy GV,
A single
Data onblind
Proprietaryfilerandomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-
naïve children, and confidential — do not distribute
Vaccine, Volume 39, Issue 49,
30
Test Test Test
 VA C C I N E ST U DY R ES U LT S

GMC Evaluation
GMCs in Test Hep A vaccine groups were significantly higher when compared with
GSK Vaccine®.

Summary of geometric mean concentration for anti-HAV IgG antibody concentration - PP Population

1–7 year (N=231) 8–15 year (N=236) Overall (N=467)

Anti-HAV IgG
antibody
concentration Test Hep A GSK vaccine Test Hep A GSK vaccine Test Hep A GSK vaccine
(N=117) (N=114) (N=116) (N=120) (N=233) (N=234)

Pre Vaccination (Day 0)

GMC 44.60 33.25 761.05 356.90 183.11 112.29

Post Vaccination (Day 210)

GMC 27792.89 12534.60 58155.36 25848.58 40139.65 18167.84

Subhash Data on file Matur, Kishore TSA, Subba Reddy GV,
Proprietary and confidential — do not distribute
Thuluva, Ramesh
A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-
Anti-HAV IgG: Immunoglobulin G antibody to
naïve children, Hepatitis A virus; GMCs: Geometric mean 32
Vaccine, Volume 39, Issue 49, concentrations.
Test Test Test
VA C C I N E ST U DY R ES U LT S
Better Safety with the Preservative-free Test Hep A
Vaccine
Better safety was reported with the Preservative-Free Test Hep A vaccine.

Summary of subjects with any AEs – Safety population

Category 1–7 year (N=260) 8–15 Year (N=260) Overall (N=520)

N1 (%) GSK Vaccine GSK Vaccine GSK Vaccine

Test-Hep A Test-Hep A Test-Hep A
(N=130) (N=130) (N=260)
(N=130) (N=130) (N=260)

Any AE 17 (13.08%) 17 (13.08%) 11 (8.46%) 14 (10.77%) 28 (10.77%) 31 (11.92%)

Subhash Thuluva, Ramesh Matur, Kishore TSA, Subba Reddy GV,

A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-
naïve children,
Vaccine, Volume 39, Issue 49,
Data on file and confidential — do not distribute
Proprietary AEs: Adverse events
34
 VA C C I N E ST U DY R ES U LT S
Better Safety with the Preservative-free Test Hep A
Vaccine

Data on fileMatur, Kishore TSA, Subba Reddy GV,

Proprietary and confidential — do not distribute
Subhash Thuluva, Ramesh
A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-
naïve children, 35
Vaccine, Volume 39, Issue 49,
 VA C C I N E ST U DY R ES U LT S
Better Safety with the Preservative-free Test Hep A
Vaccine

Subhash Data on file Matur, Kishore TSA, Subba Reddy GV,

Proprietary and confidential — do not distribute
Thuluva, Ramesh
A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15  years-old healthy hepatitis A vaccine-
naïve children, 36
Vaccine, Volume 39, Issue 49,
Thank you for your time