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Next Generation Dengue Vaccines: a Review of Candidates in Preclinical Developmentଝ Vaccine 29 (2011) 7276–7284 Contents lists available at ScienceDirect Vaccine j ournal homepage: www.elsevier.com/locate/vaccine Next generation dengue vaccines: A review of candidates in preclinical developmentଝ a b c a,∗ Julia Schmitz , John Roehrig , Alan Barrett , Joachim Hombach a Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland b Arboviral Diseases Branch, Centers for Disease Control and Prevention, Fort Collins, CO, USA c Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USA a r t i c l e i n f o a b s t r a c t Article history: Dengue represents a major public health problem of growing global importance. In the absence of spe- Available online 21 July 2011 cific 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 Keywords: are currently being evaluated in clinical trials and are described in detail in accompanying articles. In Dengue vaccines addition, there are a large variety of candidates in preclinical development, which are based on diverse Dengue technologies, ensuring a continued influx of innovation into the development pipeline. Potentially, some Dengue virus of the current preclinical candidates may become next generation dengue vaccines with superior prod- uct profiles. This review provides an overview of the various technological approaches to dengue vaccine development and specifically focuses on candidates in preclinical development. © 2011 World Health Organization.. Published by Elsevier Ltd. All rights reserved. 1. Introduction of dengue immunity, challenges to vaccine development and the various technologies used, while the second part provides a more Dengue is a mosquito-borne flavivirus disease that has spread detailed description of specific vaccine projects in preclinical devel- to most tropical and many subtropical areas and creates a signif- opment. icant burden of disease and economic costs in endemic countries [1–4]. As specific dengue therapeutics are not available and disease 2. Overview of dengue vaccine development prevention is limited to vector control measures, the development of a dengue vaccine would represent a major advance in the control 2.1. Dengue immunity and challenges to vaccine development of the disease (reviewed in [5]). While no licensed dengue vaccine currently exists, vaccine development has progressed considerably The disease dengue is caused by four dengue viruses (DENV), in recent years. Several candidates are currently undergoing either DENV-1 to DENV-4. Due to their serological and genetic relatedness clinical evaluation or preclinical development. These have been they are considered four serotypes of DENV. Multiple DENV can reviewed recently [6–9]. co-circulate in endemic areas (reviewed in [10]). Infection by one This review focuses on dengue vaccine candidates in preclin- serotype confers lasting protection against re-infection by the same ical development. It is based on published and unpublished data serotype, but only transient protection against secondary infec- presented by vaccine developers and researchers at the WHO/IVI tion by one of the three heterologous serotypes (reviewed in [9]). Informal Consultation on Next Generation Dengue Vaccines and Dengue vaccine development efforts therefore aim for a tetrava- Diagnostics (1–2 November 2010, Atlanta). Additional preclinical lent vaccine which simultaneously provides long-term protection candidates from the published literature are included in the review against all DENV serotypes. to illustrate the wide range of strategies applied to dengue vaccine The mechanism of protective immunity against dengue is not development. The first part of the review presents an overview fully understood. There is considerable evidence for a major role of antibody-mediated DENV neutralization in protection against infection and disease [9]. However, it is unclear what quantity of ଝ Disclaimer: Two of the authors (JH, JS) are staff members of the World Health neutralizing antibody is needed for protective immunity, and it is Organization. The authors alone are responsible for the views expressed in this pub- increasingly likely that the contribution of neutralizing antibodies lication and they do not necessarily represent the decisions, policy or views of the to protection will not become known until efficacy trials of candi- World Health Organization. ∗ date vaccines have been completed. In addition, contributions of Corresponding author. Tel.: +41 22 791 4531; fax: +41 22 791 4860. E-mail address: [email protected] (J. Hombach). other immune mechanisms such as cytotoxic T cell responses are 0264-410X/$ – see front matter © 2011 World Health Organization.. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2011.07.017 J. Schmitz et al. / Vaccine 29 (2011) 7276–7284 7277 less clear (reviewed in [9,11,12]). Further research is needed to bet- tective efficacy of vaccine candidates in NHPs therefore measure ter define and validate immune correlates of protection for vaccine prevention or reduction of viremia upon viral challenge [28]. development [11]. Another challenge for vaccine development is the potentially 2.2. Technological approaches to dengue vaccine development detrimental role of immune enhancement in dengue pathogene- sis [5]. Severe disease is most commonly observed in secondary, A wide range of vaccine technologies has been applied to heterologous DENV infections. Antibody-dependent enhancement dengue vaccine development, including live attenuated virus (LAV), (ADE) of infection has been proposed as the primary mechanism purified inactivated virus (PIV), recombinant subunits, virus-like of dengue immunopathogenesis [13,14]. In vitro studies suggest particles (VLPs), and plasmid or viral vectors. Each of these that the capacity of DENV antibodies to contribute to neutraliza- approaches has its advantages and challenges. tion or enhancement of infection is determined by multiple factors, LAV vaccines have been shown to produce robust, lasting including antibody specificity, antibody affinity, antibody titre and and broad immunity, including humoral and cellular immune epitope accessibility (reviewed in [15,16]). responses [34]. In addition, their production cost tends be lower The potential risk of immune enhancement of infection and dis- than for many other vaccine technologies. However, it has often ease underscores the importance of developing dengue vaccines proven difficult to achieve a level of attenuation which opti- which produce balanced, long-lasting immunity to all four DENV mally balances low reactogenicity (e.g. avoidance of clinical dengue serotypes. A tetravalent vaccine eliciting protective, neutralizing symptoms) with sufficiently high immunogenicity. In addition, LAV antibody responses against all serotypes should address theoretical vaccines should replicate well in cell culture in order to facilitate concerns about vaccine-induced ADE. However, vaccine-induced their production, while their transmissibility by mosquitoes should ADE might again become problematic as antibody titres wane post- be prevented or strongly reduced. Attenuation strategies for live vaccination. dengue vaccines include serial cell passage (e.g. in Primary Dog Kid- DEN virions are composed of a lipid envelope modified by the ney cells). The first tetravalent dengue vaccine was produced in this insertion of envelope (E) proteins and premembrane/membrane way [35]. Additionally, introduction of selected mutations or cre- (prM/M) proteins (depending on the maturation state [17]), sur- ation of chimeric viruses by recombinant DNA technology can be rounding a nucleocapsid composed of capsid (C) proteins and the used. Success of these strategies is however often limited by lack viral RNA genome (reviewed in [18]). Human antibodies raised of a detailed understanding of the molecular determinants of vir- against the DEN virion are mostly targeted at the E and prM ulence due to unavailability of animal models, as described above. proteins [19]. Research to determine the most suitable target epi- There are also concerns about the genetic stability of LAV vaccines, topes for vaccines is ongoing, and while considerable progress including the possibility of reversion to a more virulent pheno- has been made in the characterization of the humoral immune type and the theoretical risk of recombination between vaccine response to DENV, important knowledge gaps still exist. There and wild-type viruses. Furthermore, the need to achieve a bal- is evidence suggesting that anti-E antibodies have higher type- anced immune response against all four DENV serotypes presents specific neutralization capacity and lower ADE potential than a particular challenge for multi-component LAV vaccines. Repli- anti-prM antibodies. Moreover, most potent DENV neutralizing cation interference between the different serotypes of DENV in antibodies identified so far recognize epitopes in domain III of tetravalent formulations has been observed, resulting in a reduc- the E protein (EDIII) which is involved in binding of DENV to tion of neutralizing antibodies to some serotypes, when compared cell receptors [19–27]. The conundrum of the human antibody to monovalent formulations. LAV vaccines represent the majority response to DENV infection is that most antibodies are specific for of dengue vaccine candidates in clinical evaluation [36–47], and domain II of
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