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. 2015 Aug;22(8):628-35.
doi: 10.1038/gt.2015.35. Epub 2015 Apr 30.

Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine

Affiliations

Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine

O Riede et al. Gene Ther. 2015 Aug.

Abstract

The leishmaniases are a complex of vector-borne diseases caused by protozoan parasites of the genus Leishmania. LEISHDNAVAX is a multi-antigen, T-cell epitope-enriched DNA vaccine candidate against human leishmaniasis. The vaccine candidate has been proven immunogenic and showed prophylactic efficacy in preclinical studies. Here, we describe the safety testing of LEISHDNAVAX in naive mice and rats, complemented by the demonstration of tolerability in Leishmania-infected mice. Biodistribution and persistence were examined following single and repeated intradermal (i.d.) administration to rats. DNA vectors were distributed systemically but did not accumulate upon repeated injections. Although vector DNA was cleared from most other tissues within 60 days after the last injection, it persisted in skin at the site of injection and in draining lymph nodes. Evaluation of single-dose and repeated-dose toxicity of the vaccine candidate after i.d. administration to naive, non-infected mice did not reveal any safety concerns. LEISHDNAVAX was also well tolerated in Leishmania-infected mice. Taken together, our results substantiate a favorable safety profile of LEISHDNAVAX in both naive and infected animals and thus, support the initiation of clinical trials for both preventive and therapeutic applications of the vaccine.

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Figures

Figure 1
Figure 1
Biodistribution and persistence of LEISHDNAVAX following single and multiple i.d. injections. Groups of 10 Wistar rats (5 male, 5 female) were injected once (a) or four times in weekly intervals (b–d) with 120 μg LEISHDNAVAX. Tissue samples were taken and processed 24 h (a and b), 14 days (c) or 60 days (d) after the last injection. Vector copy numbers were determined by qPCR. Single animal data and geometric mean values are given in log scale. Dotted lines indicate lower the limit of quantification LLOQ. Lnn ax: axillary lymph nodes; Lnn ing: inguinal lymph nodes; Lnn mes mesenteric lymph nodes; M. femoris: quadriceps muscle of thigh.
Figure 2
Figure 2
Immunogenicity of ascending LEISHDNAVAX doses in mice. Groups of 10 BALB/c mice (5 male, 5 female) were immunized i.d. at the tail base five times in weekly intervals with either PBS or LEISHDNAVAX (10, 50 or 100 μg per dose). Fourteen days after the last immunization LEISHDNAVAX-specific antibodies (total IgG) in sera were quantified by ELISA using plates coated with a mixture of recombinant LEISHDNAVAX antigens. ***P⩽0.001 (Student's t-test); n.s.: not significant.
Figure 3
Figure 3
Parasite burden in BALB/c and C57BL/6 mice following administration of single and repeated doses of LEISHDNAVAX and PBS. Parasite burden expressed in Leishman-Donovan Units (LDU) is shown for BALB/c mice in spleens (a) and livers (b) (n=8–9 mice per group) and for C57BL/6 mice in spleens (c) and livers (d) (n=4–8 mice per group). Mice were infected on day 0, treated once (day 7), twice (day 7 and 14) or three times (day 7, 14 and 21), respectively, with 100 μg LEISHDNAVAX per dose or PBS. Parasite burden was determined 7 days after the last treatment and in addition, for two groups of C57BL/6 mice receiving either three LEISHDNAVAX or PBS injections, 29 days after the third treatment (day 50 post infection). White bars represent PBS-treated groups and dark gray bars LEISHDNAVAX-treated groups, error bars indicate s.e.m. Differences between groups were statistically not significant based on a one-way ANOVA followed by Bonferroni's multiple comparison's test, which compared groups that had received the same number of injections of PBS or LEISHDNAVAX (P>0.05).

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