Vaccine Profile

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Epaxal: a virosomal vaccine to

prevent hepatitis A infection
Expert Rev. Vaccines 7(8), 11411150 (2008)

Patrick A Bovier
Department of Community and
Primary Care Medicine, Geneva
University Hospitals, Switzerland
Tel.: +41 223 729 610
Fax: +41 223 729 626
patrick.bovier@post.harvard.edu

Over the last few decades, different types of inactivated hepatitis A virus (HAV) vaccines have
been developed: several aluminum-adjuvanted vaccines and an aluminum-free, virosomeformulated vaccine. Both types of vaccines are whole-virus preparations that are produced by
growth of HAV strains in human diploid cell cultures and are subsequently inactivated with
formaldehyde. This review summarizes all published papers on a virosome-formulated vaccine,
Epaxal, based on formalin inactivated HAV (strain RG-SB) adsorbed to the surface of special
liposomes (virosomes), that replace aluminum hydroxide as the adjuvant principle. A single
injection of virosomal HAV vaccine is well tolerated and highly immunogenic, with 8897% of
seroprotection 2 weeks after a first dose. HAV virosomal vaccine can be administered
concomitantly with other vaccines, without inducing antigenic competition. Direct comparison
with aluminum-adsorbed vaccine has shown that the immunogenicity was similar, but fewer
local reactions were reported with Epaxal. Recent studies in children have demonstrated that
Epaxal Junior is also an excellent HAV vaccine for mass vaccination programs.
Keywords : hepatitis A hepatitis A vaccine virosome

Hepatitis A vaccines have been available for

approximately 15 years [1] . Following their
introduction, they were primarily targeted to
individuals at increased risk for hepatitis A,
particularly international travelers, long-term
expatriates, and military personnel [2] . While
this strategy efficiently prevented hepatitis A in
these groups, it had little impact on the overall
incidence of hepatitisA virus (HAV) infections
in most countries.
Humans are the only natural hosts of HAV,
which is a picornavirus first visualized by electron microscopy in 1973. HAV consists of one
ssRNA molecule associated with capsid proteins,
forming a roughly cubic or icosahedric structure
of 2732-nm diameter. In the environment, the
virus can remain stable for several months; it is
resistant to low pH and moderate temperatures
(-2070C) and is inactivated by high temperature (85C for 1min or higher), formalin and
chlorine. Only one serotype of HAV has been
demonstrated by neutralization assays.
The incubation period lasts approximately
28 days (range: 1550 days) following the
ingestion of contaminated food or water or close
contact with an infected host [3] . Transmission
can also occur through blood or blood products
of donors who were in their viremic phase. The
illness has an abrupt onset of fever, malaise,
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10.1586/14760584.7.8.1141

anorexia, nausea, abdominal discomfort, dark

urine and jaundice, and resolves in general
within 2months. The likelihood of symptomatic illness is directly related to age. In children younger than 6years, most infections are
asymptomatic, whereas in older children and
adults, infections are usually clinically apparent, with jaundice occurring in more than
70% of patients. Up to 15% of adults can suffer from prolonged or relapsing illness for up to
6 months. HAV infection can cause fulminant
hepatitis and even death (100 estimated deaths
in the USA per year), which is more frequent
in people with underlying chronic liver disease
(e.g., alcohol related, hepatitis C or chronic
hepatitis B) [46] .
The prevalence of hepatitis A antibodies in the
population or its endemicity depends on different patterns of transmission [68] . Countries of
high endemicity (most countries with developing economies) have a high environmental virus
load and poor hygiene conditions, resulting in a
high infection rate early in childhood, which is
generally asymptomatic (seroprevalence 90%).
Countries with moderate or intermediate endemicity (4050%) are characterized by a lower
infection rate early in childhood and most infections affect late childhood and young adults and
are, generally, clinically apparent, as adults are

2008 Expert Reviews Ltd

ISSN 1476-0584

1141

Vaccine Profile

Bovier

more likely to have clinical manifestations. These countries can

potentially have large outbreaks, owing to the high environmental virus load and a high proportion of susceptible individuals.
Countries with low endemicity (most countries with established
economies) have a very low incidence rate in childhood and most
adults have no hepatitis A antibody. As socioeconomic and living conditions improve, emerging countries tend to move from
a high endemicity to a moderate or low endemicity pattern, thus
increasing the burden of HAV infection on adults. This transition
is often described as an epidemiological shift. Many countries of
South America and Eastern Asia, including China, have seen this
change in the last 1020 years, whereas most countries of Central
America, Africa and Indian subcontinent remain characterized
by a high endemicity.
To decrease the reservoir of nonimmune individuals and the
circulation of HAV in the community [9] , several countries have
implemented vaccination programs of children, which resulted
in a dramatic change of the epidemiology of epidemic jaundice [1015] . Unlike viral disease that have airborne transmission
(e.g.,measles, mumps, rubella or varicella) and that require very
high vaccination coverage to interrupt transmission (>9095%),
lower levels of vaccination coverages against HAV (5070%)
resulted in a strong decline in rates observed not only in vaccinated toddlers and children, but also in nonvaccinated children
and adults, suggesting a strong herd-immunity effect [10,11] .
In countries of low endemicity, current recommendations for
the use of hepatitis A vaccine still include specific risk groups,
such as travelers, who travel to areas from low to high endemicity,
individuals with occupational exposures (e.g., laboratory personnel involved with HAV) or at risk behaviors (e.g.,homosexually
active men or intravenous drug users). In countries of intermediate
endemicity, universal immunization of children against HAV is
recommended as a supplement to health education and improved
sanitation [10,11,16,17] . In the USA, universal immunization is now
recommended for children aged 1223 months [18] .

Serum anti-HAV IgM antibodies are generally detectable 13weeks after infection and
increase rapidly over the following 48weeks
before declining to undetectable levels, usually within 6months [3] . Anti-HAV IgG are
also detectable early in the course of the infection and continue to rise over several months,
conferring life-long immunity. Before the
availability of specific vaccines, the administration of anti-HAV immunoglobulin from
human serum was the only prophylactic
option, if given within 2weeks of exposure.
One prophylactic dose of 0.05ml/kg provides
protection for 46months [18,19] .
Since 1979, it has been possible to cultivate and serially grow HAV in cell culture,
leading to the development of several HAV
1142

Epaxal

Epaxal uses virosomes as adjuvant instead of aluminium salts.

Developed during the late 1980s, virosomes are spherical vesicles that are made up of phospholipids, lecithin (phosphatidyl
choline) and cephalin (phosphatidylethanolamine), of approximately 150 nm in diameter. In addition, the fusion active
influenza glycoprotein hemagglutinin and the neuraminidase
are intercalated into the phospholipid bilayer (Figure 1) [2226] .
Formalin-inactivated and purified HAV virions (24 IU/0.5
ml formerly 500radioimmunoassay units/0.5ml) grown on
MRC-5 human diploid cell culture are then adsorbed to the
virosome surface. This structure provides intrinsic adjuvant
properties to the virosome, owing to fusion active glycoprotein
facilitating the delivery of the HAV antigen to immunocompetent cells. Indeed, hemagglutinin enables the virosome to
attach to a macrophage (Figure2) . It has been demonstrated that
virosomes are able to elicit both cell-mediated and humoral
immune responses [27,28] .
B

A
HAV

Neuraminidase

~150 nm

Passive & active immunization

against hepatitis A

vaccines over the last decades: Havrix (GlaxoSmithKline), Vaqta

(Merck Serono), Avaxim (Sanofi Pasteur) and Epaxal (Berna
Biotech). To produce each vaccine, cell cultured-adapted virus is
propagated in human fibroblasts, purified from cell lysates and
inactivated with formalin. For Havrix, Vaqta and Avaxim, inactivated HAV are adsorbed to an aluminum hydroxide adjuvant
, whereas virosomes are used for Epaxal. Adsorption to aluminum salts was the only approved adjuvant method for inactivated
vaccines since the 1920s and was used for the first HAV vaccine
licensed in 1992 [20] . Aluminum salt-based adjuvants induce protection against an associated antigen through a depot effect and a
local inflammatory response.
A live-attenuated HAV vaccine has been developed and is
licensed in China [21] and some Asian countries. This article will
summarize the main results of all the papers published on the
virosomal vaccine Epaxal until 2007.

Hemagglutinin

Liposomal membrane
lecithin
cephalin

Figure 1. Representation of a virosome with HAV. (A) HAV virus adsorbed on its
surface and (B) electron microscopy of a virosomal preparation.
HAV: Hepatitis A virus.

Expert Rev. Vaccines 7(8), (2008)

Epaxal : a virosomal vaccine to prevent hepatitis A infection

To date, approximately 40 clinical studies have demonstrated the

efficacy and safety of Epaxal in several countries, involving over
6800subjects (>1500 children) and 1000 controls. Epaxal is currently licensed in over 40 countries worldwide in 0.5ml prefilled
syringes for intramuscular injection. Since spring 2000, Epaxal
has been produced without thiomersal and does not contain any
other preservative. A pediatric presentation with half the dose
(Epaxal Junior, 12 IU/0.25ml) has also been developed and is
currently under registration.
Immunogenicity

Vaccine Profile

In a study on antibody kinetics involving 30 volunteers, 100%

of 12subjects tested had specific neutralizing antibodies 10 days
after the first dose of Epaxal [34] ; neutralizing antibodies are necessary to inhibit the virus activity and confer long-term immune
protection against HAV infection. Such antigenic response after
a single dose makes this vaccine an excellent candidate to be used
when rapid protection is needed (e.g., travel in an area of high
endemicity and postexposure prophylaxis). Epaxal has also been
used in a small hospital outbreak in Thailand to interrupt the
spread of HAV infection [35] . The index case had been infected
during his clinical duties as a radiology student. Two classmates
developed symptoms 2 weeks later. Of the 58 remaining students,
26 were seronegative at this time and were vaccinated. No further
HAV case occurred after immunization with Epaxal.

In clinical studies with HAV vaccines, a level of 20 mIU/ml of

anti-HAV antibodies as measured by ELISA is considered as
the lower limit that confer seroprotection; this cut-off is generally used to compute seroconversion rate. Lower limits, such as
10mIU/ml, have also been used [18] .
Clinical efficacy
The immunogenicity of Epaxal has been reported in several The clinical efficacy of Epaxal has been demonstrated in a plapublished studies (Table 1) . Adults under 50 years of age displayed cebo-controlled trial in Nicaragua involving 274 children aged
seroprotection rates of 8897% at 2weeks after a first injection and 1.56years [36] . Nicaragua is a country of high endemicity where
of 98100% at 4weeks. A second dose administered 12months infection occurs in early childhood; approximately 40% of chillater boosts the immune response with a 2030-fold increase in dren are seropositive for HAV at 2years of age and 85% at 5years.
the geometric mean concentrations (GMCs) of HAV antibodies, A total of 979children were screened. Among the seronegative
conferring 100% of seroprotection. A similar response was also seen children that participated in the trial, anti-HAV IgM antibodies
in the volunteers who were seronegative after 12months, strongly were detected in 31volunteers of the control group and in 10volsuggesting an anamnestic response, rather than a failure of HAV unteers in the vaccine group; all HAV infections among vaccine
immunization (Bovier P, Unpublished Data) .
Lower seroconversion rates were found in a
single study with 15 adults aged 6073years
Inactivated HAV virion
[29] . Lower immune response has also been
Antigen presentation
reported by other authors for other hepatitis
A vaccines in older subjects [30] .
Macrophage
In infants and children, seroprotection
1
was achieved for 93100% 4 weeks after
HA-mediated endocytosis
the first dose and for 100% after the second dose. In infants below 1 year of age, a
6
small interference due to maternal antibod2
Acidification
of
vacuole
ies was found [31] , as anti-HAV titers were
lower after the second dose than for infants
4
enrolled without maternal antibodies. This
5
has also been shown for other hepatitisA
Fusion and formation
vaccines [32] .
of antigen-MHC II complex
Proteolysis
3
As travelers often need several immuniMembrane fusion
zations prior to their departure, antigenic
MHC II-containing vacuole
competition may occur when multiple vaccines are used simultaneously, in particular when live-attenuated vaccines, such as
Figure 2. Mechanism of action of hepatitis A virosomal vaccine. After
yellow fever vaccine, are used. The immuintramuscular injection, formalin-inactivated HAV adsorbed on the surface of a virosome
are taken up by immunocompetent cells (e.g., macrophage) via influenza HA-mediated
nogenicity of the virosomal HAV vaccine
endocytosis (1). Exposure to the low pH (~5) of the cell endosome (2) causes
administered simultaneously with a yelconformational changes in HA, resulting in fusion (3) of the virosome and endosome
low fever vaccine was tested in an open
membranes. Within the endosome, the virus antigen is proteolysed (4) to antigenic
prospective trial with two parallel groups
peptides. Thereafter, the antigen-containing endosomes join (5) with vacuoles
and no difference was found [33] .
containing MHC II molecules. The resulting MHC IIantigen complex is transported to
the surface of the cell (6)where it initiates either a specific humoral response and/or a
Since HAV vaccines are often used for
cellular immune response.
travelers who seek advice a few weeks before
HA: Hemagglutin; HAV: Hepatitis A vius.
their departure, rapid protection is needed.
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1143

Vaccine Profile

Bovier

Table 1. Summary of selected studies addressing the immunogenicity of the Epaxal vaccine.
Author

Country

Loutan
(1994)

Switzerland 104

Poovorawan Thailand
(1995)

Patients Mean age

(n)
(range)

79

Ref.
Dose Seroprotection Seroprotection Seroprotection Long(ml) 2weeks after 1month after 1month after term
follow-up
first dose (%)* first dose (%)* second dose
(%)*

24 years

0.5

(1735 years)

0.5

89

99

100

Yes

[57]
[54]

100

[42]

Holzer
(1996)

Switzerland 201

30 years

0.5

91

98

100

Ambrosch
(1997)

Austria

111

22 years

0.5

97

99

100

Yes

[55]

Bovier
(1999)

Switzerland 105

24 years

0.5

88

100

100

Yes

[33]

Usonis
(2003)

Lithuania

30
30

(67 months)
(57 years)

0.5

100
100

100
100

[31]

Ambrosch
(2004)

Austria

30

(1845 years)

0.5

100

100

[34]

Riedemann
(2004)

Chile

20
80

(1216 months) 0.5

(517 years)

94
99

100
100

[56]

Bovier
(2005)

Switzerland 58

23 years

0.5

100

100

Pancharoen
(2005)

Thailand

(812 years)
(812 years)

0.1#
0.25

100
100

100
100

[40]

DAcremont Switzerland 59
(2006)
31

(1745 years)
(5075 years)

0.5

100
65

100
97

[29]

Dagan
(2007)

Israel

105
109

(1215 months) 0.25

(1215 months) 0.25

93
94

100**
100**

Yes
Yes

[39]

Van der
Wielen
(2007)

Belgium

123
123

9 years
(116 years)

98
98

100**
100**

Yes
Yes

[41]

33
55

96

96

0.25
0.5

Yes

[43]

20 mIU/ml.
Ongoing long-term follow studies.

10 mIU/ml.

Based on 23 volunteers.
#
Intradermally administered.
**
Second dose administered after 6 months.

With coadministration of diphtheriatetanuspertussispoliomyelitisHaemophilus influenzae type b, measlesmumpsrubella and oral polio vaccine.
*

recipients occurred within 6weeks. Protective efficacy in primary

and intent-to-treat analyses was low and not significant during
the first 6weeks. After 6weeks, the protective efficacy of Epaxal
was 100%, similar to other licensed vaccines, despite the use of
different end points (school absence [37] and clinically apparent
hepatitis A [38]).
Use of lower dose inchildren

Several studies have been conducted in children aged 116years,

demonstrating that lower doses could be used (Table 1) [3941] .
In two recent published trials, Epaxal has been compared with
an aluminum-adjuvanted vaccine. In both trials, the administration of the lower dose of Epaxal (pediatric presentation,
Epaxal Junior) resulted in higher GMCs 4weeks after vaccination when compared with the aluminum-adjuvanted vaccine.
1144

Seroconversion rates were also higher [39,41] . After the second dose,
the GMCs increased sharply, conferring 100% seroprotection for
bothvaccines.
Safety

Safety data about reactogenicity have also been collected in several

studies. The most frequent local manifestations are essentially
pain, redness and induration at the site of injection. Direct comparison of the virosomal vaccine with the aluminum-adsorbed
vaccine has shown that the aluminum-adsorbed vaccine (given
as two separate primary injections [Havrix 720 ]) [42] or a single
primary injection (Havrix 1440 ) [43] induces a similar antigenic
response, but considerably more local reactions than the virosomal vaccine (Table 2) . In general, this difference is observed after
the administration of the first dose of the HAV vaccine and not
Expert Rev. Vaccines 7(8), (2008)

Vaccine Profile

Epaxal : a virosomal vaccine to prevent hepatitis A infection

Table 2. Local adverse events after the first and second dose of virosomal (Epaxal, 0.5 ml) and
aluminumadjuvanted hepatitis A vaccines in adults.
Author

Total

Number of volunteers (%)

Pain/soreness

Induration

Redness

Ref.

Swelling

1 AE

Just etal.

Virosomal

40

10 (25)

2 (5)

0 (0)

10 (25)

[58]

Aluminum-adjuvanted

7 (88)

2 (25)

0 (0)

7 (88)

[58]

201

25 (12)

14 (7)

95

60 (63)

16 (17)

147

38 (26)

21 (14)

13 (9)

47 (32)

[42]

24 (36)

9 (13)

7 (11)

28 (42)

[42]

58

14 (24)

3 (5)

2 (3)

1 (2)

17 (29)

[43]

59

38 (64)

5 (9)

0 (0)

0 (0)

38 (64)

[43]

49

13 (27)

3 (6)

14 (29)

[43]

Aluminum-adjuvanted second dose 47

20 (43)

4 (9)

20 (43)

[43]

Holzer etal.
Virosomal first dose
Aluminum-adjuvanted first dose

Virosomal second dose

Aluminum-adjuvanted seconddose # 67

5 (3)*
9 (10)

34 (17)

[42]

63 (66)

[42]

Bovier etal.
Virosomal first dose
Aluminum-adjuvanted first dose
Virosomal second dose

Clarke etal.**
Virosomal

338

71 (21)

16 (5)

12 (4)

79 (23)

[44]

Aluminum-adjuvanted

75

42 (56)

6 (8)

4 (5)

43 (57)

[44]

Volunteers aged 20 years who received a first dose of hepatitis A virus (HAV) vaccine.
Experimental vaccines with 1000 radioimmunoassay units of HAV antigen, not commercially available.

p < 0.05, Fishers exact test.

Volunteers received two injections of Havrix 720 at separate sites.

#
Volunteers recieved one dose of Havris 720.
**
Volunteers aged 16 years who received a first or a second dose of HAV vaccine.

Volunteers received one dose of Havrix 1440 .

AE: Adverse event.
*

thereafter. In a postmarketing safety study involving 413subjects in the UK and comparing the administration of Epaxal and
Havrix, local sides effects appeared to be 2.5-times less frequent
for Epaxal recipients, especially for pain (21 vs 56%) that was less
intense and resolved more quickly (3 days of pain: 9 vs 23%) [44] .
The reduced rate of local adverse reactions has been attributed to
the biodegradable nature of virosomal constituents [26] .
Systemic reactions most frequently reported by volunteers are
headache and malaise (Table3) , without significant difference when
compared with an aluminum-adjuvanted vaccine. A postmarketing surveillance has been ongoing since 1994 and did not reveal
any unexpected side effects (approximately one adverse vaccinerelated event per 100,000 doses). Similar results have been found
in children aged 116 years, who also report reduced local reactions with Epaxal and Epaxal Junior (Table4) [41] compared with
an aluminum-adjuvanted HAV vaccine.
Interchangeability

As several vaccines have been licensed, the interchangeability of

the virosomal vaccine with aluminum-adsorbed HAV vaccines is
of great practical importance to both healthcare workers and vaccine recipients. This has been carefully studied in a prospective
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randomized crossover study with 111 volunteers, who were first

randomly assigned to receive Epaxal or Havrix as a first dose,
and rerandomized 12months later to receive Epaxal or Havrix
as a second dose. No significant difference was found in term of
imunogenicity, indicating that the virosomal and the aluminumadsorbed HAV vaccine were interchangeable for primary or booster
vaccination [43] . Another open, noncomparative, single-center study
demonstrated that the virosomal vaccine can be used successfully
to boost HAV immunity following primary vaccination with an
aluminum-adsorbed vaccine [45] .
Response to a delayed booster dose

Response to a delayed booster dose was also studied, as travelers

may not always come back to complete their primary course in due
time (12months). A study demonstrated that a booster dose of
the virosome vaccine was still highly immunogenic in 97 subjects
primed with a single dose of this vaccine [46] . The interval between
the first and the second doses ranged from 18 to 54 months and
8591% had still protective titers (10 mIU/ml). All volunteers
displayed an excellent immune response with a sharp increase in
specific antibodies. There was no correlation between the interval
in months between the two doses and the immune response after
1145

Vaccine Profile

Bovier

Table 3. Systemic adverse events after the first and second dose of virosomal (Epaxal, 0.5 ml) and
aluminum-adjuvanted hepatitis A vaccines in adults.
Author

Total

Number of volunteers (%)

Headache

Malaise

Nausea

Anorexia

Ref.
1 AE

Holzer etal.

Virosomal first dose

201

41 (20)

23 (11)

17 (9)

[42]

Aluminum-adjuvanted first dose

95

14 (15)

17 (18)

9 (10)

[42]

Virosomal second dose

147

18 (12)

6 (4)

5 (3)

[42]

7 (11)

5 (8)

3 (5)

[42]

58

12 (21)

7 (12)

3 (5)

3 (5)

31 (53)

[43]

59

15 (25)

10 (17)

7 (12)

2 (3)

38 (64)

[43]

49

9 (18)

7 (14)

0 (0)

2 (4)

15 (31)

[43]

4 (9)

6 (13)

4 (9)

2 (4)

10 (21)

[43]

Aluminum-adjuvanted second dose 67

Bovier etal.

Virosomal first dose

Aluminum-adjuvanted first dose
Virosomal second dose

Aluminum-adjuvanted second dose 47

Clarke etal.

Virosomal

338

3 (1)

4 (1)

26 (8)

[44]

Aluminum-adjuvanted

75

2 (3)

4 (5)

8 (11)

[44]

Solicited systemic adverse events reported by volunteers in the 4 days following immunization with a hepatitis A virus (HAV) vaccine (standardized questionnaire).
Volunteers received two injections of Havrix 720 at separate sites.
Volunteers received one dose of Havris 720.

Volunteers received one dose of Havrix 1440 .

#
Unsolicited systemic adverse events reported by volunteers aged 16 years who received a first or a second dose of HAV vaccine.
AE: Adverse event.
*

the second dose. A recent study has shown that this interval could
be extended to 811 years after a first dose of the HAV virosome
vaccine [47] .
Duration of protection & booster schedule

The long-term protection induced after immunization with the

virosome vaccine was studied among adult volunteers enrolled
in four different clinical trials. Lower 95% confidence interval (CI) limits and seroconversion rate were calculated using a
linear mixed model to estimate the persistence of serum antibodies over time. To assess the robustness of the mathematical
model, several sensitivity analyses were performed. Based on
190volunteers having at least two valid assessments of titers
from year 3 onward, the median duration of protection was
55.5 years, with a lower limit of the 95% CI of 48.7 years
[48] . Duration below 25.3years was predicted for only 5% of
the subjects. The use of a more conservative threshold, higher
yearly decline rate and exclusion of volunteers with increasing
titers over time did not affect these results. The International
Consensus Group on HAV Immunity reviewed published and
unpublished literature on the existing HAV vaccines and came
to the conclusion that there is currently no evidence to support
an additional booster after a full primary course of vaccinations against HAV [49] . This recommendation is valid for all
currently licensed vaccines. T-cell-mediated response is thought
to play an important role and may persist even when antibody
concentrations have declined.
1146

Similar results have been found in infants and children, irrespective of maternal antibodies. The 5-year seroporotection of children involved in the Nicaragua field trial [36] has been tested and
all still had seroprotective antibody levels (Christian Herzog, Berna
Biotech, Pers. Comm.) . Similar follow-up studies are ongoing with
recent trials in which the pediatric dose (Epaxal Junior 0.25ml)
has been used [39,41] .
Expert commentary

After nearly 15years of use, Epaxal has been shown to be an efficient vaccine and has been used in many countries to provide protection for travelers visiting destinations of high HAV endemicity.
The use of Epaxal in this case has been made simple because
a single dose confers a rapid protection prior to departure and
because the second dose can be safely administered several years
later to confer a long-lasting protection. Furthermore, its excellent
local tolerance is a real advantage when several immunizations
are needed prior to departure, especially among individuals who
fear injections and needles. Most of the time, the injection of the
virosomal vaccine is described as painless by the patients (personal
experience in a travel clinic).
The most recent studies performed in children have also
shown that Epaxal is a potent HAV vaccine for countries that
have decided to promote universal mass-immunization programs against HAV. Owing to its excellent local tolerance,
the virosomal vaccine can be easily used concomitantly with
traditional vaccines, such as recently shown for pentavalent
Expert Rev. Vaccines 7(8), (2008)

Epaxal : a virosomal vaccine to prevent hepatitis A infection

(diphtheriatetanuspertussispoliomyelitisHaemophilus influenzae typeb) and measlesmumpsrubella vaccines [39] . In these

studies, half of the adult dosing was sufficient to confer an excellent protection for children, which will hopefully make Epaxal
Junior very competitive on the market.
These excellent characteristics should help to promote the use of
such an innovative vaccine and foster further research for new vaccine
delivery systems that are immunogenic and well tolerated.
Five-year view

Several questions remain unanswered regarding the future use of

HAV vaccine and of Epaxal. First, the exact duration of protection after two doses remains uncertain. Current estimates rely on
mathematical models, which tend to underestimate the persistence of humoral immunity and that do not take into account the
probable persistence of cellular immunity. Follow-up studies of
previously vaccinated volunteers are ongoing to measure anti-HAV
antibodies 15 and 20 years after immunization. This information
will help to confirm whether predicted estimates were accurate.

Vaccine Profile

Beside follow-up studies of volunteers initially enrolled in clinical

studies, surveillance of HAV cases is also needed to ensure that
breakthroughs do not occur over time among previously vaccinated
individuals. As for adults, the exact duration of protection after
two doses of the Epaxal 0.25ml in children is still uncertain. The
ongoing follow-up studies among children will be very important
to decide whether an additional dose will be necessary.
Second, not much is known about the exact maximal interval
that can be recommended between two doses of the virosomal
HAV vaccine, for people who did not complete their primary
course as recommended (two doses at 612months interval). As
time goes by, further studies will help us to decide whether the
generally accepted rule in the world of vaccinology (every dose
counts) is also true for HAV virosome vaccine.
Finally, will the use of virosomes as antigen delivery systems
continue to be developed for other antigens? Virosomal vaccines
containing multiple antigens had been initially presented when
the virosomes were first used as adjuvant [50] . However, since
these promising results, no further research has been conducted,

Table 4. Local adverse events after the first and second dose of a virosomal (Epaxal, 0.5 ml or Epaxal
Junior, 0.25 ml) and an aluminum-adjuvanted hepatitis A vaccine (Havrix Junior, 0.5 ml) in children.
Author

Total

Number of volunteers (%)

Pain

Induration

Redness

Swelling

Ref.
1 local AE Fever
38.5

Usonis etal.
Virosomal (0.5 ml) first dose

60

2 (3)

1 (2)

0 (0)

3 (<1)

2 (3)

[31]

Virosomal (0.5 ml) second dose

55

7 (13)

4 (7)

1 (2)

3 (<1)

0 (0)

[31]

Mayorga Prez etal.

Virosomal (0.5 ml) first dose

137

19 (14)

7 (5)

[36]

Placebo (0.5 ml) first dose

137

11 (8)

5 (4)

[36]

Dagan etal.
Virosomal (0.25 ml) first dose

105

19 (18)

7 (7)

8 (8)

24 (23)

24 (22)

[39]

Aluminum-adjuvanted first dose

103

13 (13)

7 (7)

8 (8)

19 (18)

14 (13)

[39]

Virosomal (0.25 ml) first dose

123

(12)**

(1)

(1)

2 (2)

[41]

Virosomal (0.5 ml) first dose

123

(14)

(1)

(2)

1 (1)

[41]

Aluminum-adjuvanted first dose

62

(31)

(2)

(2)

0 (0)

[41]

Virosomal (0.25 ml) second dose

123

(17)

(3)

(0)

0 (0)

[41]

Virosomal (0.5 ml) second dose

123

(20)

(3)

(3)

3 (2)

[41]

Aluminum-adjuvanted
seconddose

62

(26)

(2)

(2)

0 (0)

[41]

Van der Wiele etal.#

**

Local adverse events were reported by parent or legal guardian in the 4 days following immunization using a standardized questionnaire.

30 children aged 67 months and 30 volunteers 57 years; the hepititus A virus (HAV) vaccine was administered into the lateral thigh (infants) or into the deltoid
muscle (children).

Children aged 1.56 years; the HAV vaccine or placebo was administered into the deltoid muscle.

Children aged 1215 months; the HAV vaccine was administered into the lateral thigh concomitantly with diphtheriatetanuspertussispoliomyelitisHaemophilus
influenzae typeb, oral polio and measlesmumpsrubellavaccines.
#
Children aged 116 years; the HAV vaccine was administered into the deltoid muscle.
**
p value <0.05, Fishers exact test.

Induration and/or swelling.

AE: Adverse event.

www.expert-reviews.com

1147

Vaccine Profile

Bovier

except for influenza vaccines [51,52] . A virosomal vaccine against

HAV and HBV would also be of great use for both children
andadolescents.
In conclusion, owing to the changing epidemiology of HAV, there
is an increasing demand for HAV vaccines, especially from countries
with emerging economies. The availability of another potent vaccine is therefore welcome and can only stimulate further research
and innovations. Different vaccination strategies may emerge in
the coming years, such as alternative routes of administration
(e.g.,intradermally) or a reduced number of doses (e.g., Argentina
has implemented a strategy in which only a single dose of HAV vaccine is inoculated to 12-month-old children [53]). This context can
only stimulate further research and development in this area.
Acknowledgements

The author thanks Monika Griot-Wenk and Christian Herzog from Berna
Biotech for their comments on the manuscript.

Financial & competing interests disclosure

PA Bovier has received speaker fees from Berna Biotech to present the results
of different clinical studies with the virosomal vaccine hepatitis A vaccine in
the past 10 years: 1997 (Hepatitis A vaccine: current trends, 5th International
Conference on Travel Medicine, Genve, Suisse), 2000 (Clinical experience
with an inactivated virosome formulated hepatitis A vaccine, 10th European
Congress of Clinical Microbiology and Infectious Diseases, Stockholm, Sude),
2003 (Evolution of vaccines against hepatitisA: from the classic adjuvant
to the new adjuvanted vaccines, Symposium on New Technological Platforms
in the Development and Production of Vaccines organised by Berna Biotech,
Edinburgh, Scotland) and 2006 (Advances in travel vaccination: virosomal
hepatitis A vaccine, Northern European Conference on Travel Medicine
2006, Edinburgh, Scotland). The author has no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
The epidemiology of hepatitis A has changed globally over the last decades, because of major socioeconomic improvements in many
countries. This epidemiological shift has increased the risk of clinically apparent hepatitis A infection in adults, not only in developed
but also in emerging countries.
Epaxal is a licensed vaccine against hepatitis A virus infection that uses a new adjuvant technology without aluminum salts called
virosomes. A first dose of Epaxal induces a rapid and specific immune response against hepatitis A infection in seronegative children
and adults, with a duration of protection estimated to exceed 20years after the second dose.
Epaxal is also characterized by a low incidence of soreness at the injection site after the first dose. This is an important feature for
people who fear injection and/or require multiple injections.

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Affiliation

Patrick A Bovier
Department of Community and Primary
Care Medicine, Geneva University
Hospitals, Switzerland
Tel.: +41 223 729 610
Fax: +41 223 729 626
patrick.bovier@post.harvard.edu

Expert Rev. Vaccines 7(8), (2008)