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Safety Analysis of Leishmania Vaccine Used in a Randomized Canine Vaccine/Immunotherapy Trial.

ABSTRACT: In Leishmania infantum-endemic countries, controlling infection within dogs, the domestic reservoir, is critical to public health. There is a need for safe vaccines that prevent canine progression with disease and transmission to others. Protective vaccination against Leishmania requires mounting a strong, inflammatory, Type 1 response. Three commercially available canine vaccines on the global veterinary market use saponin or inflammatory antigen components (Letifend) as a strong pro-inflammatory adjuvant. There is very little information detailing safety of saponin as an adjuvant in field trials. Safety analyses for the use of vaccine as an immunotherapeutic in asymptomatically infected animals are completely lacking. Leishmania infantum, the causative agent of canine leishmaniasis, is enzootic within U.S. hunting hounds. We assessed the safety of LeishTec^® after use in dogs from two different clinical states: 1) without clinical signs and tested negative on polymerase chain reaction and serology or 2) without clinical signs and positive for at least one Leishmania diagnostic test. Vaccine safety was assessed after all three vaccinations to quantify the number and severity of adverse events. Vaccinated animals had an adverse event rate of 3.09%, whereas placebo animals had 0.68%. Receiving vaccine was correlated with the occurrence of mild, site-specific, reactions. Occurrence of severe adverse events was not associated with having received vaccine. Infected, asymptomatic animals did not have a higher rate of adverse events. Use of vaccination is, therefore, likely to be safe in infected, asymptomatic animals.

SUBMITTER: Toepp A

PROVIDER: S-EPMC5953386 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Safety Analysis of Leishmania Vaccine Used in a Randomized Canine Vaccine/Immunotherapy Trial.

Toepp Angela A Larson Mandy M Grinnage-Pulley Tara T Bennett Carolyne C Anderson Michael M Parrish Molly M Fowler Hailie H Wilson Geneva G Gibson-Corely Katherine K Gharpure Radhika R Cotter Caitlin C Petersen Christine C

The American journal of tropical medicine and hygiene 20180301 5

In Leishmania infantum-endemic countries, controlling infection within dogs, the domestic reservoir, is critical to public health. There is a need for safe vaccines that prevent canine progression with disease and transmission to others. Protective vaccination against Leishmania requires mounting a strong, inflammatory, Type 1 response. Three commercially available canine vaccines on the global veterinary market use saponin or inflammatory antigen components (Letifend) as a strong ...[more]

PMID: 29512486

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Project description:BackgroundA recombinant cysteine proteinase from Leishmania (Leishmania) infantum chagasi (rLdccys1) was previously shown to induce protective immune responses against murine and canine visceral leishmaniasis. These findings encouraged us to use rLdccys1 in the immunotherapy of naturally infected dogs from Teresina, Piauí, a region of high incidence of visceral leishmaniasis in Brazil.Methodology/principal findingsThirty naturally infected mongrel dogs displaying clinical signs of visceral leishmaniasis were randomly divided in three groups: one group received three doses of rLdccys1 in combination with the adjuvant Propionibacterium acnes at one month interval between each dose; a second group received three doses of P. acnes alone; a third group received saline. The main findings were: 1) dogs that received rLdccys1 with P. acnes did not display increase of the following clinical signs: weight loss, alopecia, onychogryphosis, cachexia, anorexia, apathy, skin lesions, hyperkeratosis, ocular secretion, and enlarged lymph nodes; they also exhibited a significant reduction in the spleen parasite load in comparison to the control dogs; 2) rLdccys1-treated dogs exhibited a significant delayed type cutaneous hypersensitivity elicited by the recombinant antigen, as well as high IgG2 serum titers and low IgG1 serum titers; sera from rLdccys1-treated dogs also contained high IFN-? and low IL-10 concentrations; 3) control dogs exhibited all of the clinical signs of visceral leishmaniasis and had low serum IgG2 and IFN-? levels and high concentrations of IgG1 and IL-10; 4) all of the dogs treated with rLdccys1 were alive 12 months after treatment, whereas dogs which received either saline or P. acnes alone died within 3 to 7 months.Conclusions/significanceThese findings illustrate the potential use of rLdccys1 as an additional tool for the immunotherapy of canine visceral leishmaniasis and support further studies designed to improve the efficacy of this recombinant antigen for the treatment of this neglected disease.

Project description:BackgroundAlthough the killed whole-cell and live attenuated plague vaccine have been licensed, they are rarely used today because of toxicities, limited evidence of efficacy against plague, poor immune persistence required booster immunization every year, and limited commercial availability. This study was a randomized phase 2a clinical trial aimed to evaluating the immunogenicity and safety of a novel subunit plague vaccine.Methods240 healthy adults aged 18-55 y were enrolled and randomly assigned at a ratio of 1:1 to receive 2 doses of 15 or 30 mcg vaccine at a 28-day interval between doses. Blood samples were collected at day 0, 28 and 56. Adverse events were collected during the first 28 d after each vaccination. Serious Adverse Event was observed throughout the study period.Results239 participants received the first dose at day 0 and 238 received the second dose at day 28. Antibodies to envelope antigen faction 1 (F1) and recombinant virulence antigen (rV) were increased at day 28, and boosted significantly at day 56. For anti-F1 antibodies, geometric mean titer (GMT) and geometric mean fold increase (GMFI) were significantly higher in 30 mcg group than in the 15 mcg group(each P1< 0.05 at day 28 and each P1< 0.001 at day 56), with similar seroconversion rate of antibodies between 15 and 30 mcg group at both of the 2 time points. For anti-rV antibodies, seroconversion rate at day 28 in 30 mcg group was higher than that in 15 mcg group. However, GMT and GMFI of anti-rV antibodies were increased to approximately the same levels in the 2 groups. Similar booster immune response was also noticed in both groups at day 56. The injections were well tolerated, with mainly mild or moderate local and systemic adverse reactions (lower than grad 3). The proportion of pain at injection site was higher in 30 mcg group. None of SAEs were reported during 56 d.ConclusionThe plague vaccine comprised of F1 and rV antigens showed good safety and immunogenicity in adults aged 18-55 y old. The data show that the 30 mcg formulation is generally more immunogenic than the 15 mcg formulation, and represents the preferred formulation for further clinical development. It will be important to evaluate the long-term efficacy for appropriate formulations of the plague subunit vaccine.

Project description:ImportanceAn alternative option to maternal vaccination to prevent severe pertussis in infants is vaccination at birth. Data are needed on the immunogenicity and safety of a birth dose of monovalent acellular pertussis (aP) vaccine.ObjectiveTo compare IgG antibody responses to vaccine antigens at 6, 10, 24, and 32 weeks of age between newborn infants receiving the aP vaccine and hepatitis B vaccine (HBV) or HBV alone.Design, setting, and participantsA randomized clinical trial was conducted at 4 sites in Australia (Sydney, Melbourne, Adelaide, and Perth) between June 11, 2010, and March 14, 2013, among 440 healthy term (>36 weeks' gestation) infants aged less than 5 days at recruitment. Statistical analysis was performed from March 1, 2015, to June 2, 2016.InterventionNewborns received HBV and, after stratification by maternal receipt of adult-formulated aP-containing vaccine (tetanus toxoid, reduced diphtheria toxoid, and pertussis antigen content [Tdap]) prior to pregnancy, were block randomized to receive the aP vaccine (without diphtheria or tetanus) within 5 days of birth or not. At 6, 16, and 24 weeks, infants received a hexavalent vaccine with pediatric-formulated diphtheria, tetanus and pertussis antigens (DTaP), Haemophilus influenzae type b (Hib), HBV, and polio vaccine, as well as the 10-valent pneumococcal conjugate vaccine.Main outcomes and measuresDetectable (>5 enzyme-linked immunosorbent assay units per milliliter) and geometric mean concentrations of IgG antibody to pertussis toxin (PT), pertactin, and filamentous hemagglutinin at 6, 10, and 24 weeks stratified by maternal Tdap history, and antibody at 32 weeks to HBV, Hib, polio, diphtheria, tetanus, and pneumococcal serotypes. The primary outcome was detectable IgG to both PT and pertactin at 10 weeks.ResultsA total of 440 infants (207 girls and 233 boys; median gestation, 39.2 weeks) were randomized to receive the aP vaccine plus HBV (n = 221) or HBV only (control group; n = 219). At 10 weeks, 192 of 206 infants who received the aP vaccine (93.2%) had detectable antibodies to both PT and pertactin vs 98 of 193 infants in the control group (50.8%) (P < .001), with the geometric mean concentration for PT IgG 4-fold higher among the group that received the aP vaccine. At age 32 weeks, all infants (n = 181 with sera available for testing) who received the aP vaccine at birth had detectable PT IgG and significantly lower IgG geometric mean concentrations for Hib, hepatitis B, diphtheria, and tetanus antibodies. Local and systemic adverse events were similar between both groups at all time points.Conclusions and relevanceThe monovalent aP vaccine is immunogenic and safe in neonates and, if licensed and available, would be valuable for newborns whose mothers did not receive the Tdap vaccine during pregnancy.Trial registrationhttp://anzctr.org.au Identifier: ACTRN12609000905268.

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Safety Analysis of Leishmania Vaccine Used in a Randomized Canine Vaccine/Immunotherapy Trial.

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Safety Analysis of <i>Leishmania</i> Vaccine Used in a Randomized Canine Vaccine/Immunotherapy Trial.

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