583. Evaluation of a pDNA-Based Anthrax Vaccine and Immune Correlates of Protection in Mice and Non-Human Primates
Authors: Peggy Lalor, Vanessa Whitlow, C. Richard Lyons, Julie Lovechik, Mark R. Perry, Jane Morrow, Peter Hobart, Holly Horton, Larry Smith, David Kaslow, Alain Rolland
Journal: Molecular Therapy (2006)

VCL-AB01 is a bivalent plasmid DNA (pDNA)-based anthrax vaccine candidate (composed of pDNA encoding detoxified Protective Antigen (PA) and Lethal Factor (LF) formulated with a cationic lipid system) currently in a Phase 1 trial. The immunogenicity and protective efficacy of this investigational vaccine were evaluated in lethal B. anthracis spore challenge mouse and NHP models. DBA/2 mice received VCL-AB01 intramuscularly (100 μg; 15/sex/group) on Days 7 and 14 (accelerated regimen) or Days 0 and 14 (standard regimen). A third group received Anthrax Vaccine Adsorbed (AVA; Bioport; 50 μL subcutaneously) on Days 0 and 14. Only 10 mice/sex of the 15/sex/group were challenged intratracheally on Day 35 (lethal dose; 1.3 X 106 Sterne strain spores). Sera collected on Days 0, 28 (unchallenged group only) and 50 were evaluated for toxin neutralization activity (TNA). By Day 28, VCL-AB01- vaccinated mice had lower TNA [geometric mean titers (GMT) of 76 and 106 ED50 for accelerated and standard regimens, respectively] than AVA-vaccinated mice (GMT=396 ED50). Four of the 10 animals vaccinated with VCL-AB01 on the accelerated regimen and 2/10 vaccinated on the standard regimen had no detectable TNA, yet both challenged cohorts were highly protected (85% and 95%), with comparable survival to the AVA-vaccinated cohort (90%) and demonstrated significantly (p<0.0001; Kruskal-Wallis Test) increased TNA post challenge compared to non-challenged cohorts at Day 50. Cynomolgus macaques (2/sex/group) received either VCL-AB01 (0.6 mg/mL) or 1.0 mL of PBS intramuscularly on Days 0, 14 and 28. Animals received a lethal challenge (AMES strain spores; Mean = 486 LD50) at 10 weeks and monitored for survival. Sera collected on Days 0, 28, 42 and 70 (just prior to challenge) and 3 weeks post- challenge were evaluated for TNA and serum antibodies. At 10 weeks, just prior to challenge, sera samples were negative for TNA. PA- and LF-specific antibodies were variable, ranging from 21-58 μg/mL and from 2-390 μg/mL, respectively. Despite low antibody titers and absence of TNA, 75% of VCL-AB01 vaccinated animals survived challenge. Survival was associated with an exponential rise in titers observed by 3 weeks post challenge (4748–8231 μg/mL PA-specific antibodies; 3045–12948 μg/mL LF-specific antibodies; TNA = 11,296–23,676 ED50). All control animals died 3-8 days post-challenge. Collectively, these results show that surviving animals with low or absent pre-challenge neutralizing antibodies and/or low PA- and LF-specific antibody titers were able to mount a rapid protective immunological response of a very high magnitude to the lethal spore challenge. These results indicate that: 1) vaccination with pDNA elicits a potent B-cell priming response that can be activated to full effector function extremely rapidly in the face of exposure to B. anthracis; 2) serum antibody and TNA titers are not optimal predictors of protection; and 3) other measures predictive of pDNA vaccine efficacy are needed. Presenting author is employee of Vical Incorporated, manufacturer of the investigational vaccine.