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

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.

Sequential Chemoimmunotherapy of Experimental Visceral Leishmaniasis Using a Single Low Dose of Liposomal Amphotericin B and a Novel DNA Vaccine Candidate

“…Lack of efficacy with administration as monotherapy was also observed in repeated-dose studies, which demonstrated good tolerability of LEISHDNAVAX in L. donovani-infected mice (19). Infection inocula and parasite burdens at the end of treatment were similar in this study and the tolerability study (19). Combined treatment approaches are an increasingly attractive treatment option for VL and aim to increase efficacy and to reduce treatment durations and the risk of the emergence of drug resistance (9,20,21).…”

“…LEISHDNAVAX did not show significant antileishmanial efficacy when administered as monotherapy at the highest dose used in prophylactic studies (7); it demonstrated efficacy only when coadministered with liposomal amphotericin B. Lack of efficacy with administration as monotherapy was also observed in repeated-dose studies, which demonstrated good tolerability of LEISHDNAVAX in L. donovani-infected mice (19). Infection inocula and parasite burdens at the end of treatment were similar in this study and the tolerability study (19).…”

DNA vaccine against visceral leishmaniasis: a promising approach for prevention and control

“…The efficacy was further supported by a surge in IFN‐γ and TNF‐α levels along with extreme down‐regulation of IL‐4 and IL‐10 levels . Further, this novel DNA vaccine candidate against leishmaniasis was reported to be safe and well tolerated in both naive‐ and Leishmania‐ infected mice . It can further be evaluated for human clinical trials.…”

DNA and RNA Vaccines: Current Status, Quality Requirements and Specific Aspects of Preclinical Studies

“…Технология мини-кольцевых ДНК активно используется в разработке новых методов лечения неинфекционных заболеваний, но для профилактики инфекционных заболеваний не получила широкого развития. В настоящее время ведется разработка только одной перспективной вакцины для профилактики и лечения лейшманиоза -LEISHDNAVAX [18].…”

“…Следовательно, возможно использование данных ранее проведенных исследований. В случае изменения вектора, системы доставки, способа введения или любых других модификаций, влияющих на поглощение клеткой и/или биораспределение, необходимо проводить новые исследования 18 .…”