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Available online 21 July 2011
Keywords:
Dengue vaccines
Dengue
Dengue virus
a b s t r a c t
Dengue represents a major public health problem of growing global importance. In the absence of specic dengue therapeutics, strategies for disease control have increasingly focused on the development
of dengue vaccines. While a licensed dengue vaccine is not yet available, several vaccine candidates
are currently being evaluated in clinical trials and are described in detail in accompanying articles. In
addition, there are a large variety of candidates in preclinical development, which are based on diverse
technologies, ensuring a continued inux of innovation into the development pipeline. Potentially, some
of the current preclinical candidates may become next generation dengue vaccines with superior product proles. This review provides an overview of the various technological approaches to dengue vaccine
development and specically focuses on candidates in preclinical development.
2011 World Health Organization.. Published by Elsevier Ltd. All rights reserved.
1. Introduction
Dengue is a mosquito-borne avivirus disease that has spread
to most tropical and many subtropical areas and creates a significant burden of disease and economic costs in endemic countries
[14]. As specic dengue therapeutics are not available and disease
prevention is limited to vector control measures, the development
of a dengue vaccine would represent a major advance in the control
of the disease (reviewed in [5]). While no licensed dengue vaccine
currently exists, vaccine development has progressed considerably
in recent years. Several candidates are currently undergoing either
clinical evaluation or preclinical development. These have been
reviewed recently [69].
This review focuses on dengue vaccine candidates in preclinical development. It is based on published and unpublished data
presented by vaccine developers and researchers at the WHO/IVI
Informal Consultation on Next Generation Dengue Vaccines and
Diagnostics (12 November 2010, Atlanta). Additional preclinical
candidates from the published literature are included in the review
to illustrate the wide range of strategies applied to dengue vaccine
development. The rst part of the review presents an overview
Disclaimer: Two of the authors (JH, JS) are staff members of the World Health
Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the
World Health Organization.
Corresponding author. Tel.: +41 22 791 4531; fax: +41 22 791 4860.
E-mail address: hombachj@who.int (J. Hombach).
0264-410X/$ see front matter 2011 World Health Organization.. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2011.07.017
less clear (reviewed in [9,11,12]). Further research is needed to better dene and validate immune correlates of protection for vaccine
development [11].
Another challenge for vaccine development is the potentially
detrimental role of immune enhancement in dengue pathogenesis [5]. Severe disease is most commonly observed in secondary,
heterologous DENV infections. Antibody-dependent enhancement
(ADE) of infection has been proposed as the primary mechanism
of dengue immunopathogenesis [13,14]. In vitro studies suggest
that the capacity of DENV antibodies to contribute to neutralization or enhancement of infection is determined by multiple factors,
including antibody specicity, antibody afnity, antibody titre and
epitope accessibility (reviewed in [15,16]).
The potential risk of immune enhancement of infection and disease underscores the importance of developing dengue vaccines
which produce balanced, long-lasting immunity to all four DENV
serotypes. A tetravalent vaccine eliciting protective, neutralizing
antibody responses against all serotypes should address theoretical
concerns about vaccine-induced ADE. However, vaccine-induced
ADE might again become problematic as antibody titres wane postvaccination.
DEN virions are composed of a lipid envelope modied by the
insertion of envelope (E) proteins and premembrane/membrane
(prM/M) proteins (depending on the maturation state [17]), surrounding a nucleocapsid composed of capsid (C) proteins and the
viral RNA genome (reviewed in [18]). Human antibodies raised
against the DEN virion are mostly targeted at the E and prM
proteins [19]. Research to determine the most suitable target epitopes for vaccines is ongoing, and while considerable progress
has been made in the characterization of the humoral immune
response to DENV, important knowledge gaps still exist. There
is evidence suggesting that anti-E antibodies have higher typespecic neutralization capacity and lower ADE potential than
anti-prM antibodies. Moreover, most potent DENV neutralizing
antibodies identied so far recognize epitopes in domain III of
the E protein (EDIII) which is involved in binding of DENV to
cell receptors [1927]. The conundrum of the human antibody
response to DENV infection is that most antibodies are specic for
domain II of the E protein (EDII) [19], which contains a variety of
serotype and avivirus cross-reactive epitopes. The contribution of
the human antibody bias to EDII to sensitization for ADE has not
been determined. Because of its antigenic nature, EDIII is considered an antigenic target of particular relevance for dengue vaccine
development. New vaccine strategies may have to be developed
to enhance the human anti-EDIII response. Antibodies directed
against the C protein and against non-structural proteins, such as
NS1, have also been detected in DENV-infected individuals, but
their role in dengue immunity or immunopathogenesis remains
unclear [9].
Dengue vaccine development has been hampered by the lack
of an adequate animal model for the disease [28]. Normal mice
do not display signicant viremia or disease when infected with
human DENV isolates. Intracerebral challenge of mice with certain mouse-adapted DENV strains produces a paralysis phenotype,
and this intracerebral challenge model has been used to evaluate protective efcacy of vaccine candidates in mice. Furthermore,
immunocompromised mouse models have been developed which
show some of the characteristics of human disease and can also be
used as an in vivo system for studying ADE [2931]. However, concerns remain about whether the full spectrum of dengue immunity
and disease can be modeled in this immunocompromised setting.
Humanized mice that lack a murine antibody response but demonstrate some symptoms that re-capitulate human infection are also
being investigated [32,33]. Non-human primates (NHPs) are susceptible to infection by DENV and develop viremia, but do not
show signicant clinical signs of infection. Studies to address pro-
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Table 1
Dengue vaccine candidates in preclinical development.
Technological
approach
Vaccine developer
Details
Development stage
Recombinant subunit
vaccines
IPK/CIGB
Kobe University
CDC
NMRC
Cytos Biotechnology
VaxInnate
ICGEB
NHRI
DNA vaccines
VLP vaccines
Inovio Pharmaceuticals
ICGEB
Kobe University
Virus-vectored vaccines
NMRC
GSK/WRAIR/FIOCRUZ
FIOCRUZ
UNC
UTMB
Themis Bioscience/Institut Pasteur
ICGEB
GenPhar/NMRC
NMRC
NMRC/WRAIR
Abbreviations: CDC: Centers for Disease Control and Prevention, USA; CIGB: Center for Genetic Engineering and Biotechnology, Cuba; FIOCRUZ: Oswaldo Cruz Foundation,
Brazil; GSK: GlaxoSmithKline Biologicals; ICGEB: International Centre for Genetic Engineering and Biotechnology, India; IPK: Pedro Kour Tropical Medicine Institute, Cuba;
NHRI: National Health Research Institutes, Taiwan; NMRC: Naval Medical Research Center, USA; NSTDA: National Science and Technology Development Agency, Thailand;
UNC: University of North Carolina at Chapel Hill, USA; UTMB: University of Texas Medical Branch, USA; WRAIR: Walter Reed Army Institute of Research, USA.
DNA delivery system based on electroporation-enhanced transfection, suitable for both intradermal and intramuscular routes.
Electroporation-based DNA immunization is currently being tested
in phase 1 clinical trials for HIV and inuenza prevention and in
phase 2 clinical trials for hepatitis C, HPV 16/18 and AML/CML cancer therapeutic studies. Immunization of mice with the tetravalent
dengue vaccine candidate, using intramuscular electroporation of
three doses (10 g DNA) at biweekly intervals, resulted in neutralizing antibody titres against all four DENV serotypes. Immunization
of NHPs was also shown to elicit robust tetravalent antibody
responses. Further studies to assess DENV cross-reactive versus
serotype-specic antibody responses are in progress.
Another tetravalent DNA vaccine candidate developed at Kobe
University is composed of a mixture of four plasmid vectors, each
of which expresses the prM and E proteins (prM/E) of one DENV
serotype. Two doses of the tetravalent vaccine (100 g per dose, at
three week intervals) were administered to mice using a needle-
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