Phase 1 study identifies well-tolerated dengue challenge strain
Researchers identified a dengue challenge strain that was well tolerated and “resulted in an uncomplicated dengue illness.” They said it could be suitable for dengue human infection models aimed at testing vaccines and therapeutics.
“Dengue is a global health problem, and the development of an effective dengue vaccine that protects against all four serotypes is a high priority,” Timothy P. Endy MD, MPH, professor and chair in the department of microbiology and immunology at SUNY Upstate Medical University, told Healio.
A partially effective vaccine against dengue is potentially dangerous, putting patients infected with one of the four serotypes at risk for more serious disease if they are infected with another.
“The most recent licensed vaccine, Dengvaxia by Sanofi Pasteur, has been shown to be not effective in subjects who have never been exposed to dengue virus, with the greatest efficacy in those with previous dengue infection,” Endy said.
“Also, this vaccine had less effective protection against dengue virus serotypes 1 and 2,” he said, adding that a second vaccine, by Takeda, has similar difficulties in that published preliminary results showed a high level of efficacy against serotypes 1 and 2, but less so with 3 and 4.
The FDA approved Dengvaxia for children in May 2019, but recommendations for its use are still pending.
“The difficulty in dengue vaccine development is the complexity of making an effective vaccine against all four serotypes in one formulation, the lack of a biomarker that denotes protection and the lack of [an] animal model that translates to human effectiveness,” Endy explained. “Controlled human infection models (CHIMS) have been used successfully to develop vaccines against malaria, influenza, enteric pathogens and [there are] discussions to use the same for Zika and COVID-19. This CHIM for dengue virus called the dengue human infection model will be a human model in which to test vaccines and therapeutics as [an] early milestone development marker to measure potential effectiveness of an intervention prior to [a] larger and more costly phase 3 efficacy study.”
In a phase 1 study, Endy and colleagues enrolled 12 healthy adult volunteers to test a challenge virus, DENV-1-LVHC, strain 45AZ5. According to the study, they used a dose-escalating design to determine the safety of the challenge virus and evaluated participants extensively for 28 days and then to 6 months. Among the 12 participants, six received a low dose and six received a larger dose.
Endy explained that volunteers experienced mild dengue fever and the challenge virus resulted in an incubation time, viremia duration, peak viremia and clinical symptoms similar to wild-type dengue virus.
According to the study, all but one participant in the low-dose group developed detectable viremia. Overall, the average incubation period was 5.9 days and mean time of viremia was 6.8 days. The researchers noted that there were no serious adverse events.
“DENV-1-LVHC challenge in human volunteers was safe, resulted in an uncomplicated dengue illness and shows promise as a dengue human infection model in which to test dengue vaccines and therapeutics,” Endy concluded.