Epidemiology and burden of dengue fever in the United States: a systematic review.

BACKGROUND: Dengue is currently a global concern. The range of dengue vectors is expanding with climate change, yet United States of America (USA) studies on dengue epidemiology and burden are limited. This systematic review sought to characterize the epidemiology and disease burden of dengue within the USA. METHODS: Studies evaluating travel-related and endemic dengue in US states and territories were identified and qualitatively summarized. Commentaries and studies on ex-US cases were excluded. MEDLINE, Embase, Cochrane Library, Latin American and Caribbean Center of Health Sciences Information, Centre for Reviews and Dissemination and Clinicaltrials.gov were searched through January 2022. RESULTS: 116 studies were included. In US states, dengue incidence was generally low, with spikes occurring in recent years in 2013-16 (0.17-0.31 cases/100,000) and peaking in 2019 (0.35 cases/100,000). Most cases (94%, n = 7895, 2010-21) were travel related. Dengue was more common in Puerto Rico (cumulative average: 200 cases/100,000, 1980-2015); in 2010-21, 99.9% of cases were locally acquired. There were <50 severe cases in US states (2010-17); fatal cases were even rarer. Severe cases in Puerto Rico peaked in 1998 (n = 173) and 2021 (n = 76). Besides lower income, risk factors in US states included having birds in residence, suggesting unspecified environmental characteristics favourable to dengue vectors. Commonly reported symptoms included fever, headache and rash; median disease duration was 3.5-11 days. Hospitalization rates increased following 2009 World Health Organization disease classification changes (pre-2009: 0-54%; post-2009: 14-75%); median length of stay was 2.7-8 days (Puerto Rico) and 2-3 days (US states). Hospitalization costs/case (2010 USD) were$14 350 (US states),$1764-$5497 (Puerto Rico) and$4207 (US Virgin Islands). In Puerto Rico, average days missed were 0.2-5.3 (work) and 2.5 (school). CONCLUSIONS: Though dengue risk is ongoing, treatments are limited, and dengue's economic burden is high. There is an urgent need for additional preventive and therapeutic interventions.

A phase I randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and immunogenicity of a live-attenuated quadrivalent dengue vaccine in flavivirus-naïve and flavivirus-experienced healthy adults.

Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. V181 is an investigational, live, attenuated, quadrivalent dengue vaccine. In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in baseline flavivirus-naïve (BFN) and flavivirus-experienced (BFE) healthy adults were evaluated in two formulations: TV003 and TV005. TV005 contains a 10-fold higher DENV2 level than TV003. Two-hundred adults were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against the 4 DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. There were no discontinuations due to adverse events (AE) or serious vaccine-related AEs in the study. Most common AEs after TV003 or TV005 were headache, rash, fatigue, and myalgia. Tri- or tetravalent vaccine-viremia was detected in 63.9% and 25.6% of BFN TV003 and TV005 participants, respectively, post-dose 1 (PD1). Tri- or tetravalent dengue VRNT60 seropositivity was demonstrated in 92.6% of BFN TV003, 74.2% of BFN TV005, and 100% of BFE TV003 and TV005 participants PD1. Increases in VRNT60 GMTs were observed after the first vaccination with TV003 and TV005 in both flavivirus subgroups for all dengue serotypes, and minimal increases were measured PD2. GMTs in the TV003 and TV005 BFE and BFN groups remained above the respective baselines and placebo through 1-year PD2. These data support further development of V181 as a single-dose vaccine for the prevention of dengue disease.

Barriers and facilitators to the participation of subjects in clinical trials: An overview of reviews.

BACKGROUND: The demand for clinical trial participants is today one of the highest it has ever been and continues to increase. At the same time, subject recruitment continues to be problematic and the major reason for clinical trial premature terminations. The literature on clinical trial recruitment, which spans several decades and includes hundreds of studies, has an abundance of findings that can be synthesized by way of an overview to provide a well-informed and complete picture of the factors that determine subject participation. OBJECTIVES: An overview of the systematic reviews that report barriers and facilitators to clinical trial participation was conducted. The extracted data were synthesized, and a thematic framework of the factors that affect subject participation in clinical trials was developed. The overview extended across medical subjects and demographics. METHODS: Thirty reviews that complied with the inclusion criteria were included. These reviews covered 753 relevant primary studies and reported 881 barriers and facilitators. The barriers and facilitators were thematically synthesized and a thematic framework of 20 themes was developed. The quality of the included reviews was assessed and reported. MAIN RESULTS: Several opportunities to increase clinical trial participation, by developing interventions and changing the trial design, derived from an analysis of the thematic framework. That analysis also showed that most of the 20 themes operate mainly as a barrier or as a facilitator, and that most have an effect across medical subjects. As to the quality elements assessed, some reviews complied almost fully but most only partially.

Two-year antibody persistence in children vaccinated at 12-15 months with a measles-mumps-rubella virus vaccine without human serum albumin.

One combined measles-mumps-rubella (MMR) vaccine without Human Serum Albumin (HSA) is currently licensed in the USA (M-M-R II; Merck, USA) and another has been developed (Priorix™ [MMR-RIT, GSK, Belgium]). In this follow-up study, children from USA or Puerto Rico, who had received one dose of M-M-R II or MMR-RIT at 12-15 months of age in the primary study (NCT00861744), were followed-up for 2 y post-vaccination. Anti-measles and anti-rubella antibodies were measured using Enzyme-Linked Immunosorbent Assay (ELISA), and anti-mumps antibodies using ELISA and plaque reduction neutralization (PRN) assays. Serious adverse events (SAEs) were recorded during the entire follow-up. The according-to-protocol (ATP) persistence cohort included 752 children (M-M-R II = 186, MMR-RIT = 566), who received primary vaccination at a mean age of 12.3 ( ± 0.67) months. 104 children were revaccinated with MMR-containing vaccines; therefore, serology results for timepoints after revaccination were excluded from the analysis. Seropositivity for measles (Year 1≥ 98.3%; Year 2≥ 99.4%) and rubella (Year 1≥ 98.9%; Year 2 = 100%) remained as high at Year 2 as at Day 42. Similarly, seropositivity for mumps determined by ELISA (Year 1≥ 90.1%; Year 2≥ 94.1%) and PRN assays (Year 1≥ 87.5%; Year 2≥ 91.7%) persisted. Thirty-three SAEs were recorded in 23 children; 2 SAEs (inguinal adenitis and idiopathic thrombocytopenic purpura) and one SAE (febrile convulsion) were considered as potentially related to MMR-RIT and M-M-R II, respectively. This study showed that antibodies against measles, mumps and rubella persisted for up to 2 y post-vaccination with either MMR vaccine in children aged 12-15 months, and that both vaccines were well-tolerated during the follow-up period.