NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults

Abstract

The investigational vaccine, NDV-3, contains the N-terminal portion of the Candida albicans agglutinin-like sequence 3 protein (Als3p) formulated with an aluminum hydroxide adjuvant in phosphate-buffered saline. Preclinical studies demonstrated that the Als3p vaccine antigen protects mice from oropharyngeal, vaginal and intravenous challenge with C. albicans and other selected species of Candida as well as both intravenous challenge and skin and soft tissue infection with Staphylococcus aureus. The objectives of this first-in-human Phase I clinical trial were to evaluate the safety, tolerability and immunogenicity of NDV-3 at two different antigen levels compared to a saline placebo. Forty healthy, adult subjects were randomized to receive one dose of NDV-3 containing either 30 or 300 μg of Als3p, or placebo. NDV-3 at both dose levels was safe and generally well-tolerated. Anti-Als3p total IgG and IgA1 levels for both doses reached peak levels by day 14 post vaccination, with 100% seroconversion of all vaccinated subjects. On average, NDV-3 stimulated peripheral blood mononuclear cell (PBMC) production of both IFN-γ and IL-17A, which peaked at day 7 for subjects receiving the 300 μg dose and at day 28 for those receiving the 30 μg dose. Six months after receiving the first dose of NDV-3, nineteen subjects received a second dose of NDV-3 identical to their first dose to evaluate memory B- and T-cell immune responses. The second dose resulted in a significant boost of IgG and IgA1 titers in >70% of subjects, with the biggest impact in those receiving the 30 μg dose. A memory T-cell response was also noted for IFN-γ in almost all subjects and for IL-17A in the majority of subjects. These data support the continued investigation of NDV-3 as a vaccine candidate against Candida and S. aureus infections.

Conflict of interest statement

Conflict of Interest

C.S.S., A.S.I., S.G.F., Y.F., M.R.Y., J.E.E. and J.P.H. own equity in NovaDigm Therapeutics, Inc., which is developing vaccine technologies.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Plasma Anti-Als3 Total IgG and IgA1 Titers through Day 270 post vaccination

Plasma was collected from all subjects at several time points and analyzed for anti-Als3 total IgG and IgA1 titers using indirect ELISA (see “Methods”). Geomean anti-Als3p IgG (panel A) and IgA1 (panel B) values and standard deviations of the geomean are shown, though the latter are generally within the bounds of the symbol at each time point.

Figure 2. Fold-Rise Increases in Plasma Anti-Als3p Total IgG and IgA1 through Day 270 post vaccination

The fold-rise in antibody titer is calculated for each subject as the ratio of the antibody titer at each time point post vaccination to the pre vaccination titer (day 0). For a given group and time point, the fold-rise is calculated as the geomean of the fold-rise values for all individuals in the group for total IgG (panel A) and IgA1 (panel B). Geomean values and standard deviations of the geomean are shown for each group and time point. The dashed line represents a 4-fold rise in antibody titer.

Figure 3. Als3-stimulated IFN-γ and IL-17A production by PBMCs for all subjects receiving the 30 μg dose through Day 270 post vaccination

PBMCs were collected from all subjects at several time points and were analyzed for Als3-specific stimulation of IFN-γ (panel A) or IL-17A (panel B) production using ELISpot assay (see “Methods”). Values less than 2 are plotted as a cloud at the bottom of the stack so that all subjects are represented on the figure. The definition of a responder in either assay is an ELISpot result that is a ≥ 25 SFU per 106 cells difference in Als3 peptide-stimulated cultures minus unstimulated cultures (dashed line). The median value ( ) for each data set is shown.

Figure 4. Als3-stimulated IFN-γ and IL-17A production by PBMCs for all subjects receiving the 300 μg dose through Day 270 post vaccination

PBMCs were collected from all subjects at several time points and were analyzed for Als3-specific stimulation of IFN-γ (panel A) or IL-17A (panel B) production using ELISpot assay (see “Methods”). Values less than 2 are plotted as a cloud at the bottom of the stack so that all subjects are represented on the figure. The definition of a responder in either assay is an ELISpot result that is a ≥ 25 SFU per 106 cells difference in Als3 peptide-stimulated cultures minus unstimulated cultures (dashed line). The median value ( ) for each data set is shown.

Figure 5. Percentage of Subjects Responding with IFN-γ and IL-17A producing PBMCs through Day 270 post vaccination

The plotted results represent the percentage of individuals in a given group and time point that had a valid IFN-γ (panel A) or IL-17A (panel B) ELISpot response that exceeded the specified cutoff (≥25 SFU per 106 cells difference in Als3 peptide-stimulated cultures minus unstimulated cultures).