Article

Dengue vaccine development: a 75% solution?

5824 Edson Lane, Bethesda, MD 20852, USA. Electronic address: .
The Lancet (Impact Factor: 45.22). 09/2012; DOI: 10.1016/S0140-6736(12)61510-4
Source: PubMed
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    ABSTRACT: SUMMARY A dengue vaccine is expected to be available within a few years. Once vaccine is available, policy-makers will need to develop suitable policies to allocate the vaccine. Mathematical models of dengue transmission predict complex temporal patterns in prevalence, driven by seasonal oscillations in mosquito abundance. In particular, vaccine introduction may induce a transient period immediately after vaccine introduction where prevalence can spike higher than in the pre-vaccination period. These spikes in prevalence could lead to doubts about the vaccination programme among the public and even among decision-makers, possibly impeding the vaccination programme. Using simple dengue transmission models, we found that large transient spikes in prevalence are robust phenomena that occur when vaccine coverage and vaccine efficacy are not either both very high or both very low. Despite the presence of transient spikes in prevalence, the models predict that vaccination does always reduce the total number of infections in the 15 years after vaccine introduction. We conclude that policy-makers should prepare for spikes in prevalence after vaccine introduction to mitigate the burden of these spikes and to accurately measure the effectiveness of the vaccine programme.
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    ABSTRACT: Dengue is a global public health concern and this is aggravated by a lack of vaccines or antiviral therapies. Despite the well-known role of CD8(+) T cells in the immunopathogenesis of Dengue virus (DENV), only recent studies have highlighted the importance of this arm of the immune response in protection against the disease. Thus, the majority of DENV vaccine candidates are designed to achieve protective titers of neutralizing antibodies, with less regard for cellular responses. Here, we used a mouse model to investigate CD8(+) T cell and humoral responses to a set of potential DENV vaccines based on recombinant modified vaccinia virus Ankara (rMVA). To enable this study, we identified two CD8(+) T cell epitopes in the DENV-3 E protein in C57BL/6 mice. Using these we found that all the rMVA vaccines elicited DENV-specific CD8(+) T cells that were cytotoxic in vivo and polyfunctional in vitro. Moreover, vaccines expressing the E protein with an intact signal peptide sequence elicited more DENV-specific CD8(+) T cells than those expressing E proteins in the cytoplasm. Significantly, it was these same ER-targeted E protein vaccines that elicited antibody responses. Our results support the further development of rMVA vaccines expressing DENV E proteins and add to the tools available for dengue vaccine development.
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    ABSTRACT: Several dengue vaccines are under development, and some are expected to become available imminently. Concomitant with the anticipated release of these vaccines, vaccine allocation strategies for dengue-endemic countries in Southeast Asia and Latin America are currently under development. We developed a model of dengue transmission that incorporates the age-specific distributions of dengue burden corresponding to those in Thailand and Brazil, respectively, to determine vaccine allocations that minimize the incidence of dengue hemorrhagic fever, taking into account limited availability of vaccine doses in the initial phase of production. We showed that optimal vaccine allocation strategies vary significantly with the demographic burden of dengue hemorrhagic fever. Consequently, the strategy that is optimal for one country may be sub-optimal for another country. More specifically, we showed that, during the first years following introduction of a dengue vaccine, it is optimal to target children for dengue mass vaccination in Thailand, whereas young adults should be targeted in Brazil.
    Journal of Theoretical Biology 10/2013; DOI:10.1016/j.jtbi.2013.10.006 · 2.30 Impact Factor