METHODS: All reported DENV protein sequence data for each serotype was retrieved from the NCBI Entrez Protein (nr) Database (txid: 12637). The downloaded sequences were then separated according to the individual serotype proteins by use of BLASTp search, and subsequently removed for duplicates and co-aligned across the serotypes. Shannon's entropy and mutual information (MI) analyses, by use of AVANA, were performed to measure the diversity within and between the serotype proteins to identify HCSS nonamers. The sequences were evaluated for the presence of promiscuous T-cell epitopes by use of NetCTLpan 1.1 and NetMHCIIpan 3.2 server for human leukocyte antigen (HLA) class I and class II supertypes, respectively. The predicted epitopes were matched to reported epitopes in the Immune Epitope Database.
RESULTS: A total of 2321 nonamers met the HCSS selection criteria of entropy 0.8. Concatenating these resulted in a total of 337 HCSS sequences. DENV4 had the most number of HCSS nonamers; NS5, NS3 and E proteins had among the highest, with none in the C and only one in prM. The HCSS sequences were immune-relevant; 87 HCSS sequences were both reported T-cell epitopes/ligands in human and predicted epitopes, supporting the accuracy of the predictions. A number of the HCSS clustered as immunological hotspots and exhibited putative promiscuity beyond a single HLA supertype. The HCSS sequences represented, on average, ~ 40% of the proteome length for each serotype; more than double of pan-DENV sequences (conserved across the four serotypes), and thus offer a larger choice of sequences for vaccine target selection. HCSS sequences of a given serotype showed significant amino acid difference to all the variants of the other serotypes, supporting the notion of serotype-specificity.
CONCLUSION: This work provides a catalogue of HCSS sequences in the DENV proteome, as candidates for vaccine target selection. The methodology described herein provides a framework for similar application to other pathogens.
METHODOLOGY: We collected data of patients with ICH diagnosed via a plain computed tomography of the brain (CT brain) with thrombocytopenia and positive Dengue virus type 1 nonstructural protein (NS1) antigen test or positive dengue serology IgM from January 2014 till June 2015 at our center. Nine patients were included and all 20 other remaining patients reported in literature so far are discussed.
DISCUSSION: We found that all patients in our center requiring neurosurgical intervention died. Another interesting observation is that detection of Dengue IgG usually meant more severe ICH and poorer outcomes. From our series, platelet levels did not seem to influence the outcome.
CONCLUSION: We recommend that for early detection of ICH, Dengue IgG should be routinely screened and a high index of suspicion be maintained. Future research should be focused on determining predictors of ICH in patients with dengue fever so that preventive steps can be taken as mortality is high and no treatment seems beneficial at the moment once severe ICH occurs.
METHODS: We employ a dynamic Markov model of the effects of vector control on dengue in both vectors and humans over a 15-year period, in six countries: Brazil, Columbia, Malaysia, Mexico, the Philippines, and Thailand. We evaluate the cost (direct medical costs and control programme costs) and cost-effectiveness of sustained vector control, outbreak response and/or medical case management, in the presence of a (hypothetical) highly targeted and low cost immunization strategy using a (non-hypothetical) medium-efficacy vaccine.
RESULTS: Sustained vector control using existing technologies would cost little more than outbreak response, given the associated costs of medical case management. If sustained use of existing or upcoming technologies (of similar price) reduce vector populations by 70-90%, the cost per disability-adjusted life year averted is 2013 US$ 679-1331 (best estimates) relative to no intervention. Sustained vector control could be highly cost-effective even with less effective technologies (50-70% reduction in vector populations) and in the presence of a highly targeted and low cost immunization strategy using a medium-efficacy vaccine.
DISCUSSION: Economic evaluation of the first-ever dengue vaccine is ongoing. However, even under very optimistic assumptions about a highly targeted and low cost immunization strategy, our results suggest that sustained vector control will continue to play an important role in mitigating the impact of environmental change and urbanization on human health. If additional benefits for the control of other Aedes borne diseases, such as Chikungunya, yellow fever and Zika fever are taken into account, the investment case is even stronger. High-burden endemic countries should proceed to map populations to be covered by sustained vector control.
METHODS: This study evaluated the cost effectiveness and impact of dengue vaccination in Malaysia from both provider and societal perspectives using a dynamic transmission mathematical model. The model incorporated sensitivity analyses, Malaysia-specific data, evidence from recent phase III studies and pooled efficacy and long-term safety data to refine the estimates from previous published studies. Unit costs were valued in $US, year 2013 values.
RESULTS: Six vaccination programmes employing a three-dose schedule were identified as the most likely programmes to be implemented. In all programmes, vaccination produced positive benefits expressed as reductions in dengue cases, dengue-related deaths, life-years lost, disability-adjusted life-years and dengue treatment costs. Instead of incremental cost-effectiveness ratios (ICERs), we evaluated the cost effectiveness of the programmes by calculating the threshold prices for a highly cost-effective strategy [ICER <1 × gross domestic product (GDP) per capita] and a cost-effective strategy (ICER between 1 and 3 × GDP per capita). We found that vaccination may be cost effective up to a price of $US32.39 for programme 6 (highly cost effective up to $US14.15) and up to a price of $US100.59 for programme 1 (highly cost effective up to $US47.96) from the provider perspective. The cost-effectiveness analysis is sensitive to under-reporting, vaccine protection duration and model time horizon.
CONCLUSION: Routine vaccination for a population aged 13 years with a catch-up cohort aged 14-30 years in targeted hotspot areas appears to be the best-value strategy among those investigated. Dengue vaccination is a potentially good investment if the purchaser can negotiate a price at or below the cost-effective threshold price.