Schistosoma Mansoni Antigen Sm-p80: Prophylactic Efficacy using TLR4 Agonist Vaccine Adjuvant Glucopyranosyl Lipid A-Alum in Murine and Non-Human Primate Models

4区 · 医学

Article

作者: Ahmad, Gul ; Siddiqui, Arif J ; Siddiqui, Afzal A ; Le, Loc ; Kim, Eunjee ; Molehin, Adebayo J ; Torben, Workineh ; Zhang, Weidong ; Carter, Darrick ; Lazarus, Samra

Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading candidate for a schistosomiasis vaccine. The prophylactic and antifecundity efficacy of Sm-p80 has been tested in three animal models (mouse, hamster and baboon) using a multitude of vaccine formulations and approaches. In our continual effort to enhance the vaccine efficacy, in this study, we have utilized the adjuvant, synthetic hexa-acylated lipid A derivative, glucopyranosyl lipid A (GLA) formulated in aluminum (GLA-Alum) with recombinant Sm-p80. The rSm-p80+GLA-Alum immunization regimen provided 33.33%–53.13% reduction in worm burden in the mouse model and 38% worm burden reduction in vaccinated baboons. Robust Sm-p80-specific immunoglobulin (Ig)G, IgG1, IgG2a and IgM responses were observed in all immunized animals. The rSm-p80+GLA-Alum coadministration induced a mix of T-helper (Th) cells (Th1, Th2 and Th17) responses as determined via the release of interleukin (IL)-2, IL-4, IL-18, IL-21, IL-22 and interferon-γ.

2018-08-01·Annals of the New York Academy of Sciences2区 · 综合性期刊

Sm‐p80‐based vaccine trial in baboons: efficacy when mimicking natural conditions of chronic disease, praziquantel therapy, immunization, and Schistosoma mansoni re‐encounter

2区 · 综合性期刊

Article

作者: Zhang, Weidong ; Siddiqui, Afzal A. ; Carey, David ; Molehin, Adebayo J. ; Torben, Workineh ; Kottapalli, Pratibha ; Redman, Whitni K. ; Kim, Eunjee ; Rojo, Juan U. ; Siddiqui, Arif J. ; Hunter, Derick ; Ahmad, Gul ; Kottapalli, Kameswara R. ; van Dam, Govert J. ; Sudduth, Justin ; Freeborn, Jasmin ; Corstjens, Paul L.A.M. ; Papin, James F. ; Ganapathy, Pramodh K. ; Wettashinghe, Ruwanthi ; Sennoune, Souad R.

AbstractSm‐p80‐based vaccine efficacy for Schistosoma mansoni was evaluated in a baboon model of infection and disease. The study was designed to replicate a human vaccine implementation scenario for endemic regions in which vaccine would be administered following drug treatment of infected individuals. In our study, the Sm‐p80‐based vaccine reduced principal pathology producing hepatic egg burdens by 38.0% and egg load in small and large intestines by 72.2% and 49.4%, respectively, in baboons. Notably, hatching rates of eggs recovered from liver and small and large intestine of vaccinated animals were significantly reduced, by 60.4%, 48.6%, and 82.3%, respectively. Observed reduction in egg maturation/hatching rates was supported by immunofluorescence and confocal microscopy showing unique differences in Sm‐p80 expression in worms of both sexes and matured eggs. Vaccinated baboons had a 64.5% reduction in urine schistosome circulating anodic antigen, a parameter that reflects worm numbers/health status in infected hosts. Preliminary analyses of RNA sequencing revealed unique genes and canonical pathways associated with establishment of chronic disease, praziquantel‐mediated parasite killing, and Sm‐p80‐mediated protection in vaccinated baboons. Overall, our study demonstrated efficacy of the Sm‐p80 vaccine and provides insight into some of the epistatic interactions associated with protection.

2018-08-01·Annals of the New York Academy of Sciences2区 · 综合性期刊

Sm‐p80‐based schistosomiasis vaccine: double‐blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission‐blocking efficacy

2区 · 综合性期刊

Article

作者: Lazarus, Samra ; Rojo, Juan U. ; May, Jordan ; Reed, Steven G. ; Kottapalli, Pratibha ; Ganapathy, Pramodh K. ; Papin, James F. ; Zhang, Weidong ; Redman, Whitni K. ; Siddiqui, Arif J. ; Carey, David ; Siddiqui, Afzal A. ; Sennoune, Souad R. ; Bergthold, Jenn D. ; Kim, Eunjee ; Torben, Workineh ; Sudduth, Justin ; Freeborn, Jasmin ; Le, Loc ; Karmakar, Souvik ; Molehin, Adebayo J. ; Carter, Darrick ; Gray, Sean A. ; Kottapalli, Kameswara R. ; Marks, Florian ; Wolf, Roman F. ; Mayer, Bryan T. ; Ahmad, Gul ; Nguyen, Catherine ; Damian, Raymond T.

AbstractSchistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double‐blind studies of an Sm‐p80‐based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg‐induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology‐producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg‐load by 89.95%. A 35‐fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail‐infective stage (miracidia), demonstrates the parasite transmission‐blocking potential of the vaccine. Substantially higher Sm‐p80 expression in female worms and Sm‐p80‐specific antibodies in vaccinated baboons appear to play an important role in vaccine‐mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine‐induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm‐p80‐based vaccine for schistosomiasis.

100 项与 Sm-p80-VR1020 相关的药物交易

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