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Citation: Huang, X.; Lu, J.; Liao, M.;
Huang, Y.; Wu, T.; Xia, N. Progress
and Challenges to Hepatitis E Vaccine
Development and Deployment.
Vaccines 2024,12, 719. https://
doi.org/10.3390/vaccines12070719
Academic Editor: Bingqian Qu
Received: 11 May 2024
Revised: 24 June 2024
Accepted: 25 June 2024
Published: 28 June 2024
Copyright: © 2024 by the authors.
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Review
Progress and Challenges to Hepatitis E Vaccine Development
and Deployment
Xingcheng Huang 1,2 , Jiaoxi Lu 1,2, Mengjun Liao 1,2, Yue Huang 1,2, Ting Wu 1 ,2 ,* and Ningshao Xia 1,2, *
1State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory,
School of Public Health, Xiamen University, Xiamen 361000, China; 32620221150913@stu.xmu.edu.cn (X.H.);
jiaoxi@stu.xmu.edu.cn (J.L.); liaomengjun@stu.xmu.edu.cn (M.L.); huangyuesph@xmu.edu.cn (Y.H.)
2
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics
and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education
Integration in Vaccine Research, The Research Unit of Frontier Technology of Structural Vaccinology of
Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361000, China
*Correspondence: wuting@xmu.edu.cn (T.W.); nsxia@xmu.edu.cn (N.X.)
Abstract: Hepatitis E is a significant cause of acute hepatitis, contributing to high morbidity and
mortality rates, and capable of causing large epidemics through fecal–oral transmission. Currently,
no specific treatment for hepatitis E has been approved. Given the notably high mortality rate among
HEV-infected pregnant women and individuals with underlying chronic liver disease, concerted
efforts have been made to develop effective vaccines. The only licensed hepatitis E vaccine worldwide,
the HEV 239 (Hecolin) vaccine, has been demonstrated to be safe and efficacious in Phase III clinical
trials, in which the efficacy of three doses of HEV 239 remained at 86.6% (95% confidence interval (CI):
73.0–94.1) at the end of 10 years follow-up. In this review, the progress and challenges for hepatitis E
vaccines are summarized.
Keywords: hepatitis E; HEV; vaccine; clinical trial; outbreaks; progress
1. Introduction
Hepatitis E virus (HEV) is a major infective cause of acute hepatitis, causing an es-
timated 3.3 million cases annually [
1
]. As members of the genus Paslahepevirus, the HEV
strains commonly implicated in human infections are HEV-1, HEV-2, HEV-3, and HEV-4,
all of which belong to the subfamily Orthohepevirinae [
2
]. HEV-7 and HEV-8, first detected
in camels, have been demonstrated to cross-transmit to non-human primates, with one
report of HEV-7 infection in humans [
3
,
4
]. Recently, a rat hepatitis E virus (Rocahepevirus
ratti) has been recognized as an emerging genotype, which may establish persistent infec-
tions in immunocompromised individuals or even immunocompetent individuals [
5
]. An
epidemiological study in Hong Kong found that HEV-C1 infections constitute 8% of all
genotyped hepatitis E cases [6].
Serological studies have estimated that one-third of the global population has been in-
fected with HEV [
7
]. HEV-1 and HEV-2 primarily infect humans, with outbreaks frequently
occurring in hyperendemic regions, such as Asia, Africa, and the Middle East. HEV-1 and
HEV-2 outbreaks are often catalyzed by the accidental contamination of water sources with
feces following heavy rainfall or flooding [
8
]. On the contrary, HEV-3 and HEV-4, primarily
found in developed countries, are associated with foodborne infection or direct contact
with animal reservoirs, specifically domestic pigs and wild boars [
9
]. More specifically,
prevalent HEV genotypes have shifted following local economic development. In China,
improvements in community hygiene since 2000 have led to a shift in the predominant
genotype from HEV-1 to HEV-4 [10].
Although typically resulting in self-limiting acute viral hepatitis, HEV-related infec-
tions pose a significant public health challenge, particularly in low-income countries. Both
Vaccines 2024,12, 719. https://doi.org/10.3390/vaccines12070719 https://www.mdpi.com/journal/vaccines
Vaccines 2024,12, 719 2 of 11
symptomatic infection and seroprevalence rates increase significantly with age [
11
,
12
].
Acute HEV infection in pregnant women may result in fulminant hepatic failure, an ex-
plosive disease with a mortality rate of up to 30% [
13
]. Additionally, vertical transmission
from the mother to the child during gestation is clear [
14
–
16
]. Of note, individuals who
are immunocompromised or have undergone solid organ transplants may have difficulty
in clearing hepatitis E virus if infected with HEV-3 or HEV-4. This susceptibility can lead
to progressive liver fibrosis and even liver failure [
17
,
18
]. In patients with pre-existing
chronic liver disease (CLD), HEV infection is a potential trigger of acute-on-chronic liver
failure, which accelerates disease progression and increases the mortality rates in these
patients [19,20].
To date, specific drugs approved for the treatment of HEV infection are
limited [21,22]
.
The primary strategy against hepatitis E focuses on prevention. The development of inacti-
vated or live attenuated virus vaccines has been challenged by the inefficient replication
of HEV in cell cultures [
23
], so the recombinant HEV vaccines were considered a promis-
ing strategy. The only commercialized HEV vaccine is a recombinant vaccine, HEV 239
(Hecolin, Xiamen Innovax Biotech, Xiamen, China), which was licensed in China in 2012
and, subsequently, in Pakistan in 2020.
2. Clinical Progress
HEV has single-stranded RNA consisting of three overlapping open reading frames
(ORF1–3) in its 7.5 kb genome. Recently, a novel ORF-4 has been identified solely in HEV-
1 [
24
]. The capsid protein encoded by ORF2, consisting of 660 amino acids, is crucial for
binding to host cells and eliciting neutralizing antibodies. Consequently, it has been ranked
as a candidate target site for recombinant HEV vaccine development [
25
]. Currently, four re-
combinant hepatitis E vaccines have reached the clinical stage (Table 1). The first candidate
vaccine, rHEV, was a 56-kDa baculovirus-expressed virus-like particle (VLP) developed by
GlaxoSmithKline (GSK, Brentford, United Kingdom) and the National Institutes of Health
(NIH, Bethesda, MD, USA). The safety and efficacy of rHEV were successfully evaluated
in Phase II trials in Nepal from 2000 to 2004 [
26
]. Unfortunately, no further progress has
been reported on the development of this vaccine. Another hepatitis E vaccine, HEV 239, is
a 26-kDa recombinant polypeptide that corresponds to 368–606 aa of the capsid protein
from a HEV-1 strain. Being licensed for use in individuals aged >16 years, HEV 239 is
available as a three-dose schedule (0, 1, and 6 months), with each dose containing 30
µ
g of
the antigen. More recently, HEV P179 (Changchun institute of Biological Products Co., Ltd,
Changchun, China) has been developed based on the 439–617 aa of capsid protein from
a HEV-4 strain. The safety of HEV P179 has been evaluated in a Phase I clinical trial in
Jiangsu Province, China [
27
]. The fourth recombinant hepatitis E vaccine, developed by
Zydus Lifesciences Ltd. (Ahmedabad, India), is currently undergoing a Phase II clinical
trial in India [28].
Table 1. Hepatitis E vaccines under clinical evaluation.
Vaccine Manufacturer Antigen Express
System Dose Efficacy Development
Status Ref
HEV 239
(Hecolin) Xiamen Innovax
Biotech HEV-1 ORF2
(aa 368–606) Escherichia coli 0, 1, 6 m
100% (95% CI *,
72.1–100.0) Licensed,
Phase IV [29–31]
rHEV GlaxoSmithKline HEV-1 ORF2
(aa 112–607) Baculovirus 0, 1, 6 m 95.5% (95% CI
*, 85.6–98.6) Phase II [26]
Lipo-NE-P Zydus Lifesciences
Limited
HEV-1 ORF2
(aa 458–607) Escherichia coli 0, 1, 6 m - Phase II [28]
HEV P179
Changchun institute
of biological products
Co., Ltd
HEV-4 ORF2
(aa 439–617) Escherichia coli 0, 1, 6 m - Phase Ib [27]
* CI, 95% confidence interval.
Vaccines 2024,12, 719 3 of 11
3. Hepatitis E Vaccine Efficacy and Safety in Clinical Trials
Both rHEV and HEV 239 vaccines have demonstrated efficacy and safety in published
clinical studies (Table 2). In the Phase I clinical trials of rHEV, 88 healthy volunteers aged
18–50 years received three doses at 0, 1, and 6 months, and 22 volunteers were administered
doses at 1, 5, 20, and 40
µ
g for dose escalation. All of the formulations showed high
immunogenicity with good tolerability, with the 20
µ
g formulations being selected for
subsequent development [
12
]. In a double-blind, placebo-controlled Phase II trial, 2000 anti-
HEV-negative healthy male adults were randomly assigned to receive three doses of 20
µ
g
of the rHEV vaccine or placebo. During the 2-year follow-up period post-vaccination,
hepatitis E occurred in 66 of the 896 individuals (7.4%) in the placebo group compared
to 3 of the 898 individuals (0.3%) in the vaccine group, indicating a vaccine efficacy of
95.5% (95% confidence interval (CI), 85.6–98.6) [
26
]. Despite these promising outcomes,
GSK unexpectedly discontinued the development of the rHEV vaccine [32].
The HEV 239 vaccine, co-developed by Xiamen Innovax Biotech and Xiamen Univer-
sity, is the most extensively studied vaccine, and has been demonstrated to be safe and
effective in individuals >16 years of age. HEV 239 has been comprehensively evaluated
through Phase I to Phase IV clinical trials in China. Additionally, in October 2017, a Phase IV
clinical trial was conducted to evaluate its effectiveness and safety among childbearing
women in Bangladesh [
33
]. Another randomized Phase I clinical trial was conducted in the
U.S. in 25 participants aged 18 to 45 years to evaluate the safety and immunogenicity [34].
For emergency use, the first vaccination campaign using Hecolin was conducted in 2022
during an outbreak in an internally displaced persons (IDP) camp in South Sudan, covering
more than 40,000 people, including pregnant women [35].
In the Phase I clinical trial, 44 healthy volunteers aged 21–55 years were enrolled to
receive 20
µ
g of the HEV 239 vaccine at month 0 and 1, with a follow-up extending to
60 days after the initial dose. The results showed that the safety of the vaccine was good,
and no abnormal changes were observed in the blood biochemical markers. No serious
adverse events (SAE) related to the vaccine were reported during the follow-up period [
36
].
The Phase II clinical trial was separated as Phase IIa and Phase IIb, with an 18-month
follow-up period [
37
]. In the dose-scheduling component, 457 healthy adults were ran-
domly assigned to three groups, which were vaccinated with two or three doses of 20
µ
g
of the HEV 239 vaccine at 0, 1, and 6 months or 0 and 1 months, respectively, and three
doses of the commercial hepatitis B vaccine at 0, 1, and 6 months as a control. In the
dose-escalation component, 155 healthy adults were randomized in four groups, with
each group receiving the HEV 239 vaccine at 0, 1, and 6 months in doses of 10, 20, 30,
and 40
µ
g. The vaccine was well tolerated, and no statistically significant difference in
the localized adverse reactions between the two-dose and three-dose regimens were re-
ported (p> 0.05). The rates of systemic adverse reactions and SAE were comparable to
those of the control group (p> 0.05). Both the three-dose group and the two-dose group
showed a high rate of anti-HEV IgG seroconversion (100% vs. 98%). Notably, a higher
geometric mean concentration (GMC) of anti-HEV IgG was observed in the three-dose
group compared to the two-dose group (15.9 vs. 8.6 WHO units (Wu)/mL, p< 0.05) [
37
].
The dose escalation component revealed the IgG titers increased progressively with the
increasing dosage from 10 to 40
µ
g. The adverse event rates remained consistent across
the four dosage groups, indicating the vaccine was well tolerated and immunogenic at
all dosage levels. Additionally, the incidence of subclinical HEV infection (indicated by
spontaneous seroconversion or a >3-fold increase in anti-HEV IgG level) was significantly
reduced following the second and third doses of the vaccine, suggesting its protection
against new infections. After completing the Phase II clinical trial, a 0-, 1-, and 6-month
schedule using a 30 µg formulation was selected for the Phase III clinical trial.
In 2007–2009, a randomized, double-blind, controlled Phase III clinical trial of the
HEV 239 vaccine was conducted in 11 rural townships in Dongtai city in Eastern China. To
evaluate the efficacy of the vaccine, a symptom-based active hepatitis surveillance system
including 205 sentinels was established, which comprised virtually all of the village clinics,
Vaccines 2024,12, 719 4 of 11
the township hospitals, and public and private clinics, covering all of the residents in the
11 rural townships [29].
A total of 112,604 healthy subjects aged 16 to 65 years old were enrolled, stratified by
age and sex, and randomly assigned to the vaccine and control groups. The vaccine group
was administered 30
µ
g of HEV 239, while the control group received 5
µ
g of the hepatitis
B vaccine, both following to a 0-, 1-, and 6-month schedule. The results indicated that
52% of the subjects were anti-HEV IgG negative at the baseline, and 99.9% of the negative
subjects seroconverted after receiving three doses of the HEV 239 vaccine. Most of the
adverse reactions were mild, with the incidence of serious adverse events (SAEs) being
similar in the vaccine and control groups (p> 0.05). No SAEs were related to vaccination.
The trial was successful in achieving its primary aim, which was to prevent symptomatic
HEV infection. The vaccine showed a 100% efficacy rate (95% CI: 72.1–100) in those who
received three doses of the HEV 239 vaccine according to the protocol, which included
hepatitis E cases occurring during 12 months from the 31st day after the third dose. Overall,
23 cases of hepatitis E occurred between the first immunization and month 19, including
1 in the vaccine group and 22 in the control group, resulting in a protection rate of 95.5%
(95% CI: 66.3–99.4). Among these cases, 13 cases were successfully genotyped, revealing
12 with HEV-4 and 1 with HEV-1, highlighting the cross-protective efficacy of the HEV
239 vaccine.
The initial study ended on month 19. All of the participants remained blinded, and
the follow-up extended to month 55. During this extended period, 37 new cases were
confirmed. Among the participants who received three doses, a total of 48 cases occurred
from month 7 to month 55, including 3 cases in the vaccine group and 45 cases in the control
group, demonstrating a protective efficacy of 93.3% (95% CI: 78.6–97.9). For those who
received at least one dose, 60 cases occurred from the first dose through to month 55, with
7 cases in the vaccine group and 53 cases in the placebo group, resulting in an efficacy rate
of 86.8% (95% CI: 71.0–91.9) [30].
Based on these findings, a 10-year follow-up study of HEV 239 was conducted to
assess the long-term efficacy [
31
]. In addition to the participants from the Phase III clinical
trial, an additional 178,236 residents of the study region, who were within the age range
of the study participants but did not participate in the Phase III trial, were included as an
external control group. Over the 10-year period, 415 cases of hepatitis E were identified,
including 13 cases (0.2 per 10,000 person-years) in the vaccine group, 77 cases (1.4 per
10,000 person-years) in the placebo group, and 325 cases (1.8 per 10,000 person-years)
in the external control group. Among the participants who received at least one dose
and were followed from the onset of the initial study, the 10-year efficacy rate was 83.1%
(95% CI: 69.4–91.4) when compared to the placebo group and 88.0% (95% CI: 79.1–93.7)
in comparison with the external control group. Furthermore, 70% of the subjects who
received three dose and were seronegative at the baseline maintained detectable levels
of anti-HEV IgG antibodies in the 8.5-year period. The success of these clinical trials for
the HEV 239 vaccine has stimulated enthusiasm and optimism in the campaign against
hepatitis E.
More recently, another E. coli-expressed hepatitis E vaccine, p179, has demonstrated its
safety in Phase I clinical trials [
27
]. This study was designed to consist of a dose escalation
scheduling of 20
µ
g, 30
µ
g, and 40
µ
g P179 components, with 30
µ
g of HEV 239 as a control.
A total of 120 eligible participants aged 16–65 years were randomized and vaccinated at
0, 1, and 6 months. All three of the different dosages of the HEV p179 vaccine showed
safety and good tolerance. Similar solicited total and systemic adverse reaction incidence
of the P179 groups and the control group were observed (p> 0.05), as well as the changes
in the blood routine and serum biochemical indexes [
27
]. A Phase II clinical trial of P179
is ongoing. For Lipo-NE-P, developed by Zydus Lifesciences Ltd., no results have been
published on Clinical-Trials.gov or in the academic literature.
Vaccines 2024,12, 719 5 of 11
4. Hepatitis E Vaccination with Two-Dose Schedule and Accelerated Schedule
In hepatitis E epidemic settings, such as IDP camps in South Sudan, where formalized
infrastructure and coordinated humanitarian response are not effective in controlling trans-
mission, vaccination against hepatitis E could be important in confining the outbreak [
35
].
The routine hepatitis E vaccination schedule comprises doses at 0, 1, and 6 months, however,
the frequent movements of people for better living conditions in the IDP camps make it
challenging to provide timely protection for them. Thus, shorter immunization schedules
will be necessary. In the Phase III study of HEV 239, 15 days after the second dose and
before the third dose, five cases occurred in the control group, while there were no cases in
the vaccine group, resulting a 100% (95% CI: 9.1–100) protection rate in 4.5 months with
the two-dose regimen [
30
]. Up to month 120 in the extension study, the two-dose regimen
demonstrated an 89.9% (95% CI: 43.4–99.7) efficacy rate vs. the external control group [
31
].
Among the participants who were seronegative before vaccination, the two-dose regimen
with a one-month interval showed comparable seropositive rates (100% vs. 100%) at month
7 (6 months after the second dose) compared with those who received the three-dose at
month 13 (7 months after the third dose), but a lower GMC of anti-HEV IgG [2.06 Wu/mL
(95% CI: 1.68–2.51) vs. 4.09 Wu/mL (95% CI: 3.81–4.39)] [
30
]. Similar results were observed
in a Phase I study in U.S. seronegative adults, in which the GMCs at 28 days after dose 2
and dose 3 were 6.16 Wu/mL (95% CI: 4.40–8.63) and 11.50 Wu/mL (95% CI: 7.90–16.75),
respectively [
34
]. Additionally, a randomized, controlled trial conducted in Bangladesh
evaluated the immunogenicity and safety of a two-dose schedule of HEV 239 administered
at a one-month interval. In this study, 100 individuals aged 16–39 years were randomized
to receive either two doses of the HEV 239 or the HBV vaccine, following a 0- and 1-month
schedule, with follow-up extending to 23 months after the last dose. All of the seronegative
participants in the HEV 239 group seroconverted at month 2, maintained a 98% positivity
rate at 24 months, and exhibited elevated HEV IgG antibody levels compared to the HBV
vaccine group (p< 0.001), with geometric mean titers of 20.2 vs. 0.09 Wu/mL at month 2
and 1.6 vs. 0.11 Wu/mL at month 24 [38].
In addition to the two-dose data, an accelerated three-dose schedule was also evalu-
ated. Z. Chen et al. conducted a Phase IV trial to assess the safety and immunogenicity of
an accelerated HEV 239 schedule at 0, 7, and 21 days. The study randomized 126 anti-HEV
seronegative adults to receive either the accelerated schedule or the routine schedule. The
results indicated that all of the participants in both the accelerated and the routine groups
were seropositive at 1 month after the three doses (57/57 and 63/63, respectively), with no
significant differences in the GMC of anti-HEV IgG being noted between the two groups
(8.51 vs. 9.67 Wu/mL). The incidence rates of solicited adverse reactions were comparable
(32.26% vs. 30.16%, p= 0.800). These findings suggest that the immunogenicity of the
accelerated 0-, 7- and 21-day schedule in adults is non-inferior to that of the routine regimen
in adults [39].
5. Hepatitis E Vaccine in Elderly People
Epidemiological studies have identified that the highest incidence and mortality rates
of hepatitis E occur in adults over the age of 60. To evaluate the safety and immunogenicity
of HEV 239 in the elderly population (aged > 65 years), an open-label, controlled study
was conducted [
40
]. A total of 200 elderly people aged > 65 years and 201 adults aged
18–65 years received HEV 239, according to the routine schedules. At month 7, 96.7% of
the elderly people and 98.9% of the adults aged 18–65 years seroconverted. The GMCs of
anti-HEV IgG were 5.36 Wu/mL (95% CI: 3.88–7.41) and 10.84 Wu/mL (95% CI: 9.42–12.47)
in the baseline seronegative elderly people and the adults aged 18–65 years, respectively.
The HEV 239 was well tolerated among the elderly, with 40% reporting adverse events,
which is comparable to the 42.3% reported in the 18–65 age group. No vaccine-related SAEs
were reported.
Vaccines 2024,12, 719 6 of 11
6. Hepatitis E Vaccine in Pregnant Women
HEV infection poses a high maternal morbidity and mortality for pregnant women
during hepatitis E outbreaks. Previous studies on HEV vaccines and maternal outcomes are
still limited. In the Phase III trial of HEV 239, 37 subjects in the vaccine group and 31 subjects
in the placebo group became pregnant and were inadvertently vaccinated. Wu et al. [
41
]
compared the pregnancies in the HEV 239 and placebo groups with matched non-pregnant
women for adverse events and pregnancy outcomes in a preliminary post hoc analysis. Only
one pregnant person receiving HEV 239 reported mild local pain, and the rate of adverse
events for both the HEV 239 and the placebo groups were similar to those of the matched
non-pregnant women. Elective abortions were reported by 51.3% in the vaccine group and
45.2% in the placebo group, and the remaining pregnancies were delivered vaginally or
via C-section, with no spontaneous abortions or infant malformations. Subsequently, a
double-blinded, cluster-randomized Phase IV trial was conducted in Bangladesh in 2017,
in which about 20,000 women aged 16–39 years were randomly allocated in a 1:1 ratio to
receive either the HEV 239 or the hepatitis B vaccine. The primary outcome was a confirmed
HEV infection in the pregnant women; moreover, the safety and immunogenicity of the
vaccine were evaluated as well. The participants who became pregnant during the 2-year
follow-up period were visited every 2 weeks to collect the pregnancy outcomes and were
monitored for clinical hepatitis [
33
]. The study finished in 2022, but the findings have not
yet been disclosed.
In 2023, Guohua et al. [
42
] conducted a safety post hoc analysis on data from the
Phase III clinical trial of human papillomavirus (HPV) type 16/18 vaccine (Cecolin), which
provided more robust safety evidence. A total 7372 healthy women aged 18–45 years old
were randomly assigned to receive three doses of the control vaccine Hecolin (n= 3683)
or the test vaccine Cecolin (n= 3689) at 0, 1, and 6 months. Finally, 140 pregnant women
experienced 143 pregnancy events following the vaccination. The incidences of adverse
reactions were 31.8% in Hecolin recipients compared to 35.1% in those receiving Cecolin
(p= 0.6782). In the analysis of the impact of vaccine exposure for pregnancy on adverse
pregnancy outcomes and pregnancy complications, proximal exposure was defined as
vaccination during pregnancy or the onset of pregnancy within 90 days post any dose,
and pregnancy beyond 90 days after vaccination was distal exposure. Compared with
HPV vaccination, no significantly increased risk of abnormal fetal loss (OR = 0.80, 95% CI:
0.38–1.70) or neonatal abnormalities (OR = 2.46, 95% CI: 0.74–8.18) were observed in the
women with proximal exposure to HEV vaccination, as did distal exposure. This post
hoc analysis suggested no increased risk from the HEV vaccination in pregnant women
compared to the HPV vaccination [42].
Although the current evidence does not support the use of hepatitis E vaccination
in routine immunization for pregnant women, the World Health Organization (WHO)
issued statements in 2021 to recommend the vaccination of pregnant women against
hepatitis E during outbreaks [
43
]. In 2022, a vaccination campaign against hepatitis E
was implemented in the Bentiu internally displaced persons camp in South Sudan [
35
].
Approximately 40,000 (86%) residents of the Bentiu IDP camp aged 16–40 years, including
pregnant women, received at least one dose of the HEV 239 vaccine. In the shelter survey,
91 (7.6%) of the 1195 individuals reported new symptoms within 72 h following the
vaccination. Of these, women experienced new symptoms more frequently than men
(73 (10%) vs. 18 (3.7%),
p< 0.001
). Among 118 pregnant women identified with a known
HEV 239 vaccination, 1 reported abdominal cramps, which resolved two hours following
the onset of the symptoms. To establish the safety and immunogenicity of Hecolin during
pregnancy, the International Vaccine Institute (IVI) plans to initiate a Phase II, randomized,
observer-blind, controlled clinical trial to evaluate the safety and immunogenicity of HEV
239 in pregnant women in Pakistan in 2024 [44].
Vaccines 2024,12, 719 7 of 11
7. Hepatitis E Vaccine in Patients with CLD
Hepatitis E infection poses a significant risk to individuals with pre-existing liver dis-
eases, usually triggering acute-on-chronic liver failure and increasing mortality rates among
these patients [
20
,
21
]. In an extended analysis of the HEV 239 Phase III clinical trial, 406 sub-
jects in the vaccine group and 424 in the placebo group were hepatitis B surface antigen
(HBsAg)-positive. After a routine vaccination schedule, both HBsAg-negative and HBsAg-
positive individuals exhibited comparable levels of anti-HEV-IgG antibodies (19.32 vs.
19.00 Wu/mL). The solicited adverse event rates were similar between HBsAg-negative
and HBsAg-positive individuals in the vaccine group (13.61% vs. 11.58%,
p> 0.05) [45]
.
Furthermore, a subsequent Phase IV clinical study was conducted to evaluate the immuno-
genicity and safety of HEV 239 in chronic hepatitis B (CHB) patients in China [
46
]. The
findings confirmed that the hepatitis E vaccine was safe and well tolerated among CHB
patients, with no significant clinical changes observed in the liver function indicators. At
month 1 after the routine schedule, the seroconversion rates were >97% in both the CHB
and the control groups. Additionally, the GMC of anti-HEV IgG was non-inferior in the
CHB group, with a ratio of 69% (95% CI: 55–85) compared to the control group.
Table 2. Clinical studies of the HEV 239 vaccine.
NCT Number Study Start Primary Objectives Enrollment Vaccination
Schedule Phases Country Status Ref
ACTRN12607000368437 January 2005
Safety and
immunogenicity,
exploration of dose and
schedule
457 for dose-
scheduling; 155
for dose
escalation
0,1,6mor0,6
mII China Completed [37]
NCT01014845 August 2007 Efficacy and safety in
healthy adults 112,604, 16–65 y 0, 1, 6 m III China Completed [29–31]
NCT02417597 April 2015 Efficacy and safety in
elderly people >65 years
400 for >65 y;
201 for 18–65 y 0, 1, 6 m IV China Completed [40]
NCT02584543 October 2015
Safety and
immunogenicity of
coadministration with the
HBV vaccine
602, ≥18 y 0, 1, 6 m IV China Completed [47]
NCT02964910 August 2016 Efficacy and safety in
people with chronic HBV 475, ≥30 y 0, 1, 6 m IV China Completed [46]
NCT03168412 May 2017
Immunogenicity and
safety of an accelerated
vaccination schedule
126, ≥18 y 0, 7, 21 d or 0, 1,
6 m IV China Completed [39]
NCT02759991 October 2017
Immunogenicity and
safety of a two-dose
schedule
100, 16–39 y 0, 1 m II Bangladesh Completed [38]
NCT02759991 October 2017
Effectiveness and safety in
women of childbearing
age in Bangladesh
19,460, 16–39 y 0, 1, 6 m IV Bangladesh Completed -
NCT03827395 April 2019
Safety and
immunogenicity in U.S.
adults
25, 18–45 y 0, 1, 6 m I USA Completed [34]
NCT06306196 April 2024
Immunogenicity and
safety of Hecolin in
HIV-positive/negative
adults and in children
410, 18–45 y;
175, 12–17 y;
175, 6–11 y;
100, 2–5 y
0, 1, 6 m IIb South Africa Active, not
recruiting -
NCT05808166 June 2024
Safety and
immunogenicity in
pregnant Pakistani
women
2358, 16–45 y 0, 1, 6 m II Pakistan Active, not
recruiting -
8. Challenges in Hepatitis E Vaccine Development
Hepatitis E is widely recognized as the most common cause of acute viral hepatitis
globally. During 2010–2020, 12 independent outbreaks occurred in different countries,
resulting in more than 30,000 symptomatic cases [
48
]. A promising hepatitis E vaccine
has been first licensed in China and was recommended to prevent outbreaks of hepatitis
E and mitigate the consequences for high-risk populations in the current WHO position
Vaccines 2024,12, 719 8 of 11
paper [
43
]. However, the absence of WHO pre-qualification and limited immediate avail-
ability of Hecolin complicate its deployment for both political and practical reasons. To
facilitate access to the vaccine in low-income countries, the Global Alliance for Vaccines and
Immunization (GAVI) has included the HEV vaccine in its 2024 investment strategy [49].
Despite the evidence of heat stability being 2 months at 30–37
◦
C, the package insert
of Hecolin recommends cold-chain storage (2–8
◦
C). Prefilled syringes provide precise
dosing and lower the risk of contamination, but cause more complexities in transportation,
storage, and waste management. Furthermore, for mass vaccination efforts in developing
countries, a multi-dose packaging option would be preferable, while requiring process
changes and further stability studies. A shorter vaccination schedule is desirable in out-
break control situations. The available data have suggested a rapid and strong anti-HEV
antibody response and high protection following a two-dose regimen, which supports its
implementation during outbreaks. However, more robust evidence is needed in order to
confirm its long-term protection.
Hecolin is licensed for individuals who are older than 16 years of age. Nonetheless,
epidemiology studies have reported that more than 18% prevalence of anti-HEV IgG
was found in children under 15 years of age in developing countries [
50
]. A survey
conducted in the Bentiu refugee camp highlighted that, among the 670 suspected cases in
the initial quarter of 2022, 422 (63%) suspected cases were reported in persons younger than
16 years of age, suggesting the urgent demand for vaccination in those individuals [
51
].
There are notable gaps and deficiencies in safety and protective data among high-risk
populations, including pregnant women, individuals with chronic liver disease, and the
immunosuppressed. Although long-term protective effects have been demonstrated by a
ten-year follow-up study, whether a booster dose is necessary remains unclear.
Cross-reactivity among different HEV genotypes infecting humans has been demon-
strated
in vitro
. Therefore, the HEV vaccine is expected to provide cross-genotype protec-
tion against all four genotypes. During the Phase III clinical trials of the HEV 239 vaccine,
sufficient data supported the cross-protection of HEV 239 against HEV-4, but not for HEV-1
or HEV-2. The current research in Bangladesh may provide additional insight into the
effectiveness of HEV 239 against these genotypes. As an RNA virus, HEV mutations are
mainly associated with pathogenesis and susceptibility to antiviral drugs by enhancing
HEV replication and infectivity. Few mutations have been demonstrated to be involved
with viral immune escape [
52
]. On the other hand, the zoonotic potential of emerging
genotypes highlights the importance of cross-genotype protection mediated by the hepatitis
E vaccine. For instance, rat HEV is highly divergent from the subfamily Orthohepevirinae,
sharing only 50–60% genomic identity [
53
]. Further study is needed in order to determine
whether prior vaccine-induced immunity cross-protects against rat HEV.
9. Conclusions
Many efforts and trials have led to the ultimate successful development and clinical
validation of the HEV vaccine. Expanding the coverage of HEV vaccination will be crucial
in reducing the burden of HEV infections. To meet the global outbreak response strategy,
issues related to WHO pre-qualification, age range expansion, the optimization of the immu-
nization schedule under emergency, and vaccine transportation and administration remain
to be addressed. Furthermore, additional clinical trials are required in order to evaluate the
benefits and safety of the HEV vaccine in high-risk populations, particularly in pregnant
women, individuals with underlying chronic liver disease, and children <16 years of age.
Despite these issues, the successful deployment in South Sudan has demonstrated that
contingency vaccination with the hepatitis E vaccine is practicable in complex emergencies,
which may catalyze the use of the HEV vaccine in the future.
Author Contributions: Conceptualization, X.H.; writing—original draft preparation, X.H.; writing—
review and editing, X.H., J.L. and T.W.; bibliography information collection, J.L., M.L. and Y.H. project
administration, T.W. and N.X.; funding acquisition, T.W. and N.X. All authors have read and agreed
to the published version of the manuscript.
Vaccines 2024,12, 719 9 of 11
Funding: We gratefully acknowledge the funding agencies that supported this work. This work was
financially supported by the National Natural Science Foundation of China (Grant No. 81991491), the
CAMS Innovation Fund for Medical Sciences (Grant No. 2019RU022), and the Fundamental Research
Funds for the Central Universities (Grant No. 20720220006).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data sharing is not applicable to this article.
Acknowledgments: We extend our deepest gratitude to the dedicated researchers and developers of
the hepatitis E vaccine for their invaluable contributions to public health. In addition, we thank the
editors and reviewers, who have contributed immensely to improving this publication’s quality.
Conflicts of Interest: The authors declare no conflicts of interest.
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