Safety, Tolerability, and Pharmacokinetics of JNJ-1802, a Pan-serotype Dengue Direct Antiviral Small Molecule, in a Phase 1, Double-Blind, Randomized, Dose-Escalation Study in Healthy Volunteers.

BACKGROUND: Dengue is a growing global health threat with no specific antiviral drugs available for treatment or prophylaxis. This first-in-human, double-blind, randomized, placebo-controlled study aimed to examine the safety, tolerability, and pharmacokinetics of increasing single and multiple oral doses of JNJ-1802, a pan-serotype dengue antiviral small molecule. METHODS: Eligible healthy participants (18-55 years of age) were randomized to receive oral JNJ-1802 in fasted conditions as (1) single doses (50-1200 mg; n = 29) or placebo (n = 10); or (2) once-daily doses (50-560 mg for 10 consecutive days or 400 mg for 31 days; n = 38) or placebo (n = 9). Safety and tolerability were evaluated throughout the study. Plasma and urine samples were collected at predetermined time points to characterize pharmacokinetics. RESULTS: JNJ-1802 was generally safe and well-tolerated. One grade 3 adverse event (depression) was reported but not considered drug-related by the investigator. Two grade 2 events of rash occurred (multiple-dose part) that were considered very likely related to JNJ-1802 by the investigator and resolved. No clinically relevant changes were observed in laboratory tests, electrocardiograms, or vital signs.JNJ-1802 exposure after single or multiple doses increased dose-proportionally from 50 to 150 mg and less than dose-proportionally for higher doses. The terminal elimination half-life was 6.3-9.2 days and the accumulation factor was 4.3-7.3 after 10 days and 14.6 after 31 days with low amounts of unchanged drug in urine (<0.001% of the 400 mg dose). CONCLUSIONS: Pharmacokinetics and safety results of JNJ-1802 support further clinical development for the treatment and prevention of dengue infection.

A phylogenetic study of dengue virus in urban Vietnam shows long-term persistence of endemic strains.

Dengue virus (DENV) causes repeated outbreaks of disease in endemic areas, with patterns of local transmission strongly influenced by seasonality, importation via human movement, immunity, and vector control efforts. An understanding of how each of these interacts to enable endemic transmission (continual circulation of local virus strains) is largely unknown. There are times of the year when no cases are reported, often for extended periods of time, perhaps wrongly implying the successful eradication of a local strain from that area. Individuals who presented at a clinic or hospital in four communes in Nha Trang, Vietnam, were initially tested for DENV antigen presence. Enrolled positive individuals then had their corresponding household members invited to participate, and those who enrolled were tested for DENV. The presence of viral nucleic acid in all samples was confirmed using quantitative polymerase chain reaction, and positive samples were then whole-genome sequenced using an amplicon and target enrichment library preparation techniques and Illumina MiSeq sequencing technology. Generated consensus genome sequences were then analysed using phylogenetic tree reconstruction to categorise sequences into clades with a common ancestor, enabling investigations of both viral clade persistence and introductions. Hypothetical introduction dates were additionally assessed using a molecular clock model that calculated the time to the most recent common ancestor (TMRCA). We obtained 511 DENV whole-genome sequences covering four serotypes and more than ten distinct viral clades. For five of these clades, we had sufficient data to show that the same viral lineage persisted for at least several months. We noted that some clades persisted longer than others during the sampling time, and by comparison with other published sequences from elsewhere in Vietnam and around the world, we saw that at least two different viral lineages were introduced into the population during the study period (April 2017-2019). Next, by inferring the TMRCA from the construction of molecular clock phylogenies, we predicted that two of the viral lineages had been present in the study population for over a decade. We observed five viral lineages co-circulating in Nha Trang from three DENV serotypes, with two likely to have remained as uninterrupted transmission chains for a decade. This suggests clade cryptic persistence in the area, even during periods of low reported incidence.

Evolution of inflammation and immunity in a dengue virus 1 human infection model.

Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics and subtropics. More than 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and more than 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. We observed a robust DENV-specific immunoglobulin A (IgA) antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV virion-specific humoral immunity. RNA sequencing analysis revealed discrete and temporally restricted gene modules that correlated with acute viremia and the induction of adaptive immunity. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

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.

A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly.

BACKGROUND: Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. METHODS: A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45µg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. RESULTS: Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45µg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). CONCLUSIONS: Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45µg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15µg commercial presentation. All treatments were generally safe and well-tolerated.

Simulation-guided phase 3 trial design to evaluate vaccine effectiveness to prevent Ebola virus disease infection: Statistical considerations, design rationale, and challenges.

Starting in December 2013, West Africa was overwhelmed with the deadliest outbreak of Ebola virus known to date, resulting in more than 27,500 cases and 11,000 deaths. In response to the epidemic, development of a heterologous prime-boost vaccine regimen was accelerated and involved preparation of a phase 3 effectiveness study. While individually randomized controlled trials are widely acknowledged as the gold standard for demonstrating the efficacy of a candidate vaccine, there was considerable debate on the ethical appropriateness of these designs in the context of an epidemic. A suitable phase 3 trial must convincingly ensure unbiased evaluation with sufficient statistical power. In addition, efficient evaluation of a vaccine candidate is required so that an effective vaccine can be immediately disseminated. This manuscript aims to present the statistical and modeling considerations, design rationale and challenges encountered due to the emergent, epidemic setting that led to the selection of a cluster-randomized phase 3 study design under field conditions.

Annual all-cause healthcare costs among influenza patients with and without influenza-related complications: analysis of a United States managed care database.

BACKGROUND: Several studies have reported that patients with influenza have a high risk of developing complications such as secondary infections, exacerbation of cardiovascular conditions and asthma. However, limited data exists on the healthcare cost burden for influenza patients with and without influenza-related complications. OBJECTIVE: We compared healthcare utilization and costs among influenza patients with related complications versus patients without complications. METHODS: In this retrospective database analysis (LifeLink database: 1998-2009) of a US managed care database, we selected patients diagnosed with influenza during influenza seasons and categorized them as complicated or uncomplicated based on the presence or absence of a diagnosis for a related complication in the year following their influenza diagnosis. Multivariable regression analyses were conducted to compare all-cause utilization and costs (adjusted to 2009 US dollars) between the two groups. RESULTS: We identified 54,469 patients of which ~65 % had evidence for at least one complication. Patients with complicated influenza had a 1.5-fold higher rate of inpatient utilization compared with uncomplicated cases (p < 0.001). Significantly higher covariate-adjusted predicted mean annual costs were also observed among complicated influenza patients across all care (p-values <0.001 for all comparisons). CONCLUSION: Healthcare costs were twice as high among influenza patients with complications versus those without, with inpatient and outpatient services being the primary cost drivers. Now with the universal recommendation for seasonal influenza vaccination for all individuals ≥6 months of age, improvement in coverage rates may help reduce the healthcare utilization and costs associated with influenza and associated complications.

The burden of influenza complications in different high-risk groups: a targeted literature review.

OBJECTIVES: The objective was to review the published literature on seasonal influenza to assess the differences between complications and mortality rates for those adults at high risk of influenza complications, including the resource use of those hospitalized with influenza complications. METHODS: A targeted literature review was performed using electronic database keyword searches, specific inclusion criteria, quality rating of the reviewed full-text articles and abstraction of data to present published evidence on the incidence, complication rates and health service use associated with clinical influenza in different adult high-risk groups including those who are aged 65 years and older or those with different chronic underlying medical conditions. RESULTS: Key findings for incidence rates of clinical influenza were that incidence rates are similar among people with chronic cardiovascular or respiratory comorbidity, and may be higher in those with allogeneic stem cell transplants compared to those with autologous transplants. Rates of hospitalization and/or pneumonia or lower respiratory tract infection for those with chronic conditions or those who are immunocompromised are substantially higher than those in people over age 65 but without additional high-risk factors. A person who is hospitalized and has a laboratory-confirmed influenza diagnosis has a probability of intensive care unit admission of between 11.8-28.6% and of death of between 2.9-14.3%. CONCLUSIONS: These findings indicate that although the burden of influenza varied across high-risk groups, it also varied widely across studies within a single high-risk group. A key finding was that those over 65 years of age but without additional high-risk factors had a low risk of influenza complications. A limitation of the review is that most of the studies of hospitalized patients did not present outcomes data separately by high-risk group and only limited data were identified on rates of hospitalization or lower respiratory tract infection for most high-risk groups. Information about influenza complication rates and resource use, including influenza vaccines, chemoprophylaxis and/or treatment strategies for different high-risk groups, is needed to evaluate new interventions.