Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor.

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.

Case-area targeted interventions (CATI) for reactive dengue control: Modelling effectiveness of vector control and prophylactic drugs in Singapore.

BACKGROUND: Targeting interventions to areas that have recently experienced cases of disease is one strategy to contain outbreaks of infectious disease. Such case-area targeted interventions (CATI) have become an increasingly popular approach for dengue control but there is little evidence to suggest how precisely targeted or how recent cases need to be, to mount an effective response. The growing interest in the development of prophylactic and therapeutic drugs for dengue has also given new relevance for CATI strategies to interrupt transmission or deliver early treatment. METHODS/PRINCIPAL FINDINGS: Here we develop a patch-based mathematical model of spatial dengue spread and fit it to spatiotemporal datasets from Singapore. Simulations from this model suggest CATI strategies could be effective, particularly if used in lower density areas. To maximise effectiveness, increasing the size of the radius around an index case should be prioritised even if it results in delays in the intervention being applied. This is partially because large intervention radii ensure individuals receive multiple and regular rounds of drug dosing or vector control, and thus boost overall coverage. Given equivalent efficacy, CATIs using prophylactic drugs are predicted to be more effective than adult mosquito-killing vector control methods and may even offer the possibility of interrupting individual chains of transmission if rapidly deployed. CATI strategies quickly lose their effectiveness if baseline transmission increases or case detection rates fall. CONCLUSIONS/SIGNIFICANCE: These results suggest CATI strategies can play an important role in dengue control but are likely to be most relevant for low transmission areas where high coverage of other non-reactive interventions already exists. Controlled field trials are needed to assess the field efficacy and practical constraints of large operational CATI strategies.

CpG motifs as adjuvant in DNA vaccination against Chlamydophila psittaci in turkeys.

Plasmid DNA (pcDNA1::MOMP) expressing the major outer membrane protein (MOMP) of an avian Chlamydophila psittaci serovar D strain and recombinant MOMP (rMOMP) with or without the immunomodulating CpG oligonucleotides (CpG ON) were tested for their ability to elicit an immune response and to induce protection in turkeys against homologous challenge. Two CpG ON were chosen for in vivo application based on their in vitro capacity to stimulate the production of nitric oxide (NO) in chicken macrophages and their in vitro capacity to induce turkey lymphocyte proliferation. Priming and boosting of turkeys with pcDNA1::MOMP was able to prevent severe clinical signs and bacterial replication in a turkey model of C. psittaci infection. rMOMP boosting induced high antibody titers, but these did not correlate with the level of protection. Although the CpG ON induced a significant in vitro response, the presence of the CpG ON as an adjuvant generated no significant effect on the immune response or on the protective capacity of the tested vaccination methods.