Phase I clinical evaluation of rDEN4Delta30-200,201: a live attenuated dengue 4 vaccine candidate designed for decreased hepatotoxicity

Abstract

The rDEN4Delta30-200,201 is a live attenuated DENV-4 vaccine candidate specifically designed to further attenuate the rDEN4Delta30 parent virus. In the present study, 28 healthy adult volunteers were randomized to receive either 10(5) plaque-forming unit (PFU) of vaccine (20) or placebo (8) as a single subcutaneous injection. Volunteers were evaluated for safety every other day for 16 days. Serum neutralizing antibody titer against DEN4 was determined at study day 28, 42, and 180. The vaccine infected all vaccinees and was well tolerated without inducing alanine aminotransferase (ALT) elevations. Although virus was not recovered from the serum of any vaccinee, moderate levels of neutralizing antibody were induced in all volunteers. Thus the restricted replication of rDEN4Delta30-200,201 previously documented in animal models was confirmed in humans. The rDEN4Delta30-200,201 is a promising candidate and can be considered for inclusion in a tetravalent dengue virus (DENV) vaccine.

Figure 1

Frequency of selected clinical signs from volunteers receiving 10⁵ plaque-forming unit (PFU) of rDEN4Δ30-200,201 vaccine candidate, 10⁵ PFU of rDEN4Δ30 vaccine candidate, or placebo. The frequency of viremia, rash, and serum alanine aminotransferase (ALT) elevation were significantly lower among recipients of the rDEN4Δ30-200,201 vaccine compared with recipients of the rDEN4Δ30 vaccine (*, P = 0.0001; **, P = 0.02; ***, P = 0.05).

Figure 2

Direct comparison of the PRNT₆₀ at day 42 of volunteers vaccinated with rDEN4Δ30-200,201 or rDEN4Δ30. Vaccinees in each trial received 10⁵ plaque-forming unit (PFU) of vaccine as a single subcutaneous dose. Day 42 serum samples collected from vaccinees enrolled in this rDEN4Δ30-200,201 clinical trial and day 42 serum samples retained from vaccinees enrolled in the previous rDEN4Δ30 clinical trial were evaluated in the same PRNT assay. The geometric mean titer is shown and standard deviation levels are indicated.