15 research outputs found
Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine.
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
Local and systemic effect of transfection-reagent formulated DNA vectors on equine melanoma
Background Equine melanoma has a high incidence in grey horses. Xenogenic DNA
vaccination may represent a promising therapeutic approach against equine
melanoma as it successfully induced an immunological response in other species
suffering from melanoma and in healthy horses. In a clinical study, twenty-
seven, grey, melanoma-bearing, horses were assigned to three groups (n = 9)
and vaccinated on days 1, 22, and 78 with DNA vectors encoding for equine (eq)
IL-12 and IL-18 alone or in combination with either human glycoprotein (hgp)
100 or human tyrosinase (htyr). Horses were vaccinated intramuscularly, and
one selected melanoma was locally treated by intradermal peritumoral
injection. Prior to each injection and on day 120, the sizes of up to nine
melanoma lesions per horse were measured by caliper and ultrasound. Specific
serum antibodies against hgp100 and htyr were measured using cell based flow-
cytometric assays. An Analysis of Variance (ANOVA) for repeated measurements
was performed to identify statistically significant influences on the relative
tumor volume. For post-hoc testing a Tukey-Kramer Multiple-Comparison Test was
performed to compare the relative volumes on the different examination days.
An ANOVA for repeated measurements was performed to analyse changes in body
temperature over time. A one-way ANOVA was used to evaluate differences in
body temperature between the groups. A p–value < 0.05 was considered
significant for all statistical tests applied. Results In all groups, the
relative tumor volume decreased significantly to 79.1 ± 26.91% by day 120 (p <
0.0001, Tukey-Kramer Multiple-Comparison Test). Affiliation to treatment
group, local treatment and examination modality had no significant influence
on the results (ANOVA for repeated measurements). Neither a cellular nor a
humoral immune response directed against htyr or hgp100 was detected. Horses
had an increased body temperature on the day after vaccination. Conclusions
This is the first clinical report on a systemic effect against equine melanoma
following treatment with DNA vectors encoding eqIL12 and eqIL18 and formulated
with a transfection reagent. Addition of DNA vectors encoding hgp100
respectively htyr did not potentiate this effect
Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent
Background Deoxyribonucleic acid (DNA) vaccines are used for experimental
immunotherapy of equine melanoma. The injection of complexed linear DNA
encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a
clinical study including 27 grey horses. To date, the detailed mechanism of
the anti-tumour effect of this treatment is unknown. Results In the present
study, the clinical and cellular responses of 24 healthy horses were monitored
over 72 h after simultaneous intradermal and intramuscular application of
equine IL-12/IL-18 DNA (complexed with a transfection reagent) or comparative
substances (transfection reagent only, nonsense DNA, nonsense DNA depleted of
CG). Although the strongest effect was observed in horses treated with
expressing DNA, horses in all groups treated with DNA showed systemic
responses. In these horses treated with DNA, rectal temperatures were elevated
after treatment and serum amyloid A increased. Total leukocyte and neutrophil
counts increased, while lymphocyte numbers decreased. The secretion of tumour
necrosis factor alpha (TNFα) and interferon gamma (IFNγ) from peripheral
mononuclear blood cells ex vivo increased after treatments with DNA, while
IL-10 secretion decreased. Horses treated with DNA had significantly higher
myeloid cell numbers and chemokine (C-X-C motif) ligand (CXCL)-10 expression
in skin samples at the intradermal injection sites compared to horses treated
with transfection reagent only, suggesting an inflammatory response to DNA
treatment. In horses treated with expressing DNA, however, local CXCL-10
expression was highest and immunohistochemistry revealed more intradermal
IL-12-positive cells when compared to the other treatment groups. In contrast
to non-grey horses, grey horses showed fewer effects of DNA treatments on
blood lymphocyte counts, TNFα secretion and myeloid cell infiltration in the
dermis. Conclusion Treatment with complexed linear DNA constructs induced an
inflammatory response independent of the coding sequence and of CG motif
content. Expressing IL-12/IL-18 DNA locally induces expression of the
downstream mediator CXCL-10. The grey horses included appeared to display an
attenuated immune response to DNA treatment, although grey horses bearing
melanoma responded to this treatment with moderate tumour remission in a
preceding study. Whether the different immunological reactivity compared to
other horses may contributes to the melanoma susceptibility of grey horses
remains to be elucidated
Testing the Efficacy of a Multi-Component DNA-Prime/DNA-Boost Vaccine against Trypanosoma cruzi Infection in Dogs
Immunization of dogs with DNA-prime/DNA-boost vaccine (TcVac1) enhanced the
Trypanosoma cruzi-specific type 1 antibody and
CD8+ T cell responses that resulted in an early control of
acute parasitemia and a moderate decline in pathological symptoms during chronic
phase. Further improvement of vaccine-induced immunity would be required to
achieve clinical and epidemiological benefits and prevent transmission of
parasites from vaccinated/infected dogs to triatomines
Invasive Group B Streptococcus Disease With Recurrence and in Multiples: Towards a Better Understanding of GBS Late-Onset Sepsis.
Group B Streptococcus (GBS) is a common intestinal colonizer during the neonatal period, but also may cause late-onset sepsis or meningitis in up to 0.5% of otherwise healthy colonized infants after day 3 of life. Transmission routes and risk factors of this late-onset form of invasive GBS disease (iGBS) are not fully understood. Cases of iGBS with recurrence (n=25) and those occurring in parallel in twins/triplets (n=32) from the UK and Ireland (national surveillance study 2014/15) and from Germany and Switzerland (retrospective case collection) were analyzed to unravel shared (in affected multiples) or fixed (in recurrent disease) risk factors for GBS disease. The risk of iGBS among infants from multiple births was high (17%), if one infant had already developed GBS disease. The interval of onset of iGBS between siblings was 4.5 days and in recurrent cases 12.5 days. Disturbances of the individual microbiome, including persistence of infectious foci are suggested e.g. by high usage of perinatal antibiotics in mothers of affected multiples, and by the association of an increased risk of recurrence with a short term of antibiotics [aOR 4.2 (1.3-14.2), P=0.02]. Identical GBS serotypes in both recurrent infections and concurrently infected multiples might indicate a failed microbiome integration of GBS strains that are generally regarded as commensals in healthy infants. The dynamics of recurrent GBS infections or concurrent infections in multiples suggest individual patterns of exposure and fluctuations in host immunity, causing failure of natural niche occupation
Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine
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