A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain

Abstract

Background Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. Methods A phase I study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC, strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. Results 12 subjects received the challenge virus; 6 with 0.5 mL of 6.5 x 103 PFU/mL (low-dose group) and 6 with 0.5 mL of 6.5 x 104 PFU/mL (mid-dose group). All except one in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5 to 9 days) and mean time of viremia was 6.8 days (range 3 to 9 days). Mean peak for all subjects was 1.6 x 107 GE/mL (range 4.6 x 103 to 5 x 107 GE/mL). There were no serious adverse events or long-term safety signals noted. Conclusions We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing.

Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections

“…Limited data are available on how closely these experimental primary DENV infections mimic the immunological subtleties and complexities of natural primary DENV infection. The majority of DHIMs appear to recapitulate the basic clinical features associated with mild natural primary DENV infection, including rash, myalgia, headache, and fever, as well as the crude virologic/serologic features of infection such as peripheral viremia/RNAemia and DENV-specific seroconversion [12,13]. However, no study to date has attempted to directly compare/contrast the molecular signatures associated with either natural or experimental primary DENV infection with any degree of cellular and/or temporal resolution.…”

“…To close this significant knowledge gap, we utilized high-throughput single-cell RNA sequencing (scRNAseq) technology to assess the longitudinal transcriptional profile associated with both experimental and natural primary DENV-1 infection with single-cell resolution. This study utilized samples collected as part WRAIR/SUNY phase one open label DENV-1 human challenge study performed in Syracuse, NY [12], as well as samples collected from children enrolled in a hospital-based acute dengue study in Bangkok, Thailand [14]. Unfractionated PBMC from 8 time points (days 0, 2, 4, 6, 8, 10, 14/15 and 28) from 3 individuals enrolled in the experimental primary DENV-1 infection study were analyzed, as well as 3 time points (acute 1, acute 2, day 180) from two individuals experiencing a natural primary DENV-1 infection.…”

Temporally integrated single cell RNA sequencing analysis of controlled and natural primary human DENV-1 infections

“…The primary objective of this study was to determine the kinetic transcriptional signature associated with experimental DENV-1 infection and to determine how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection. To this end, three subjects from the SUNY/WRAIR DENV-1 DHIM study were selected for analysis ( Figure 1A) (10). All subjects included in this study received 3.25 x 10 3 PFU of the 45AZ5 DENV-1 challenge virus strain following extensive pre-screening to ensure an absence of preexisting DENV immunity.…”

“…Limited data are available on how closely these controlled DENV infections mimic the immunological subtleties and complexities of natural primary DENV infection. The majority of DHIMs appear to recapitulate the basic clinical features associated with mild natural primary DENV infection, including rash, myalgia, headache, and fever, as well as the crude virologic/serologic features of infection such as peripheral viremia/RNAemia and DENV-specific seroconversion (10,11).…”

“…To close this significant knowledge gap, we utilized high-throughput single-cell RNA sequencing (scRNAseq) technology to assess the longitudinal transcriptional profile associated with both controlled and wild-type primary DENV-1 infection with single-cell resolution. This study utilized samples collected as part WRAIR/SUNY phase one open label DENV-1 human challenge study performed in Syracuse, NY (10), as well as samples collected from children enrolled in a hospital-based acute dengue study in Bangkok, Thailand (12). Unfractionated PBMC from 8 time points (days 0, 2, 4, 6, 8, 10, 14/15 and 28) from 3 individuals enrolled in the DHIM study were analyzed, as well as 3 time points (acute 1, acute 2, day 180) from two individuals experiencing a natural primary DENV-1 infection.…”