A Phase I/II Study of the Safety, Immunogenicity, and Efficacy of Sm-TSP-2/Alhydrogel® With or Without AP 10-701 for Intestinal Schistosomiasis in Healthy Ugandan Adults

The study will recruit up to 290 healthy adult males and non-pregnant females into a two-part clinical trial of a vaccine to protect against schistosomiasis caused by infection with S. mansoni. Two formulations of the Sm-TSP-2 vaccine will be tested: one using Alhydrogel® only, and one using Alhydrogel® plus AP 10-701, each at 3 different doses of antigen: 10mcg, 30mcg, and 100mcg.
The first part of the study will be a Phase I dose-escalation safety and immunogenicity study followed by a Phase IIb trial in which a larger number of adults will be enrolled to assess the impact of the vaccine on infection with S. mansoni. The impact of the vaccine on infection with S. haematobium will also be assessed although this will be exploratory given that potential cross-protection against this species is only hypothetical at this point.

开始日期2019-10-07

申办/合作机构

Baylor College of Medicine

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100 项与 Sm-TSP-2 相关的临床结果

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100 项与 Sm-TSP-2 相关的转化医学

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100 项与 Sm-TSP-2 相关的专利（医药）

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项与 Sm-TSP-2 相关的文献（医药）

2021-11-01·The Lancet Microbe

Immunomics-guided discovery of serum and urine antibodies for diagnosing urogenital schistosomiasis: a biomarker identification study

Article

作者: Cai, Pengfei ; McManus, Donald P ; Doolan, Denise L ; Amoah, Abena S ; van Dam, Govert ; Field, Matt A ; Ali, Said M ; Kabole, Fatma ; Mekonnen, Gebeyaw G ; Felgner, Philip L ; Hokke, Cornelis H ; Becker, Luke ; Knopp, Stefanie ; Bottazzi, Maria Elena ; Mduluza, Takafira ; Mutapi, Francisca ; Jasinskas, Al ; Proietti, Carla ; Laha, Thewarach ; Rollinson, David ; Adegnika, Akim A ; Oeuvray, Claude ; Loukas, Alex ; Nakajima, Rie ; Tedla, Bemnet A ; Greco, Beatrice ; Sotillo, Javier ; Chaiyadet, Sujittra ; Pearson, Mark S ; Corstjens, Paul L A M

BACKGROUNDSensitive diagnostics are needed for effective management and surveillance of schistosomiasis so that current transmission interruption goals set by WHO can be achieved. We aimed to screen the Schistosoma haematobium secretome to find antibody biomarkers of schistosome infection, validate their diagnostic performance in samples from endemic populations, and evaluate their utility as point of care immunochromatographic tests (POC-ICTs) to diagnose urogenital schistosomiasis in the field.METHODSWe did a biomarker identification study, in which we constructed a proteome array containing 992 validated and predicted proteins from S haematobium and screened it with serum and urine antibodies from endemic populations in Gabon, Tanzania, and Zimbabwe. Arrayed antigens that were IgG-reactive and a select group of antigens from the worm extracellular vesicle proteome, predicted to be diagnostically informative, were then evaluated by ELISA using the same samples used to probe arrays, and samples from individuals residing in a low-endemicity setting (ie, Pemba and Unguja islands, Zanzibar, Tanzania). The two most sensitive and specific antigens were incorporated into POC-ICTs to assess their ability to diagnose S haematobium infection from serum in a field-deployable format.FINDINGSFrom array probing, in individuals who were infected, 208 antigens were the targets of significantly elevated IgG responses in serum and 45 antigens were the targets of significantly elevated IgG responses in urine. Of the five proteins that were validated by ELISA, Sh-TSP-2 (area under the curve [AUC]_serum=0·98 [95% CI 0·95-1·00]; AUC_urine=0·96 [0·93-0·99]), and MS3_01370 (AUC_serum=0·93 [0·89-0·97]; AUC_urine=0·81 [0·72-0·89]) displayed the highest overall diagnostic performance in each biofluid and exceeded that of S haematobium-soluble egg antigen in urine (AUC=0·79 [0·69-0·90]). When incorporated into separate POC-ICTs, Sh-TSP-2 showed absolute specificity and a sensitivity of 75% and MS3_01370 showed absolute specificity and a sensitivity of 89%.INTERPRETATIONWe identified numerous biomarkers of urogenital schistosomiasis that could form the basis of novel antibody diagnostics for this disease. Two of these antigens, Sh-TSP-2 and MS3_01370, could be used as sensitive, specific, and field-deployable diagnostics to support schistosomiasis control and elimination initiatives, with particular focus on post-elimination surveillance.FUNDINGAustralian Trade and Investment Commission and Merck Global Health Institute.

2021-08-01·Vaccine: X

Potency testing for a recombinant protein vaccine early in clinical development: Lessons from the Schistosoma mansoni Tetraspanin 2 vaccine

Article

作者: Keegan, Brian ; Scholte, Larissa ; Bottazzi, Maria Elena ; Li, Guangzhao ; Hotez, Peter ; Diemert, David ; Bethony, Jeffrey ; Hoeweler, Lara ; Peng, Jin

INTRODUCTIONAs a primary stability-indicating parameter, potency should be strategically evaluated during each phase of vaccine development. Herein, we present potency testing during the early clinical development of the Schistosoma mansoni (Sm) Tetraspanin-2 vaccine formulated on Alhydrogel (Sm-TSP-2/Al). As Sm-TSP-2/Al does not induce sterilizing immunity against its target pathogen (Sm) in animal models, potency is measured by "serological substitution", a method that can add significant variation to the potency metric, especially when used in a compliance (or 'single data point') approach.METHODSPotency data were analyzed using the compliance approach to determine if two clinical lots of Sm-TSP-2/Al retained potency over 84 and 36 months post-release, respectively. These same data were also analyzed by: i) least-squares regression with a joinpoint regression analysis; ii) control charting of stability slopes; and iii) bootstrap modeling. Nested-regression and bootstrapping were used to compare the potency of the first (#11-69F-003) and second (#1975) clinical lots of Sm-TSP-2/Al.RESULTSDespite significant variability in the immune assay, both clinical lots of Sm-TSP-2/Al remained potent for 84 and 36 months, respectively, in all four statistical approaches. The first lot of Sm-TSP-2/Al showed a gain in potency starting at 36 months post-release as captured by joinpoint regression. The two clinical lots of Sm-TSP-2/Al had comparable long-term potency.CONCLUSIONWhile a compliance approach can monitor the long-term stability of Sm-TSP-2/Al, it risks putting this critical stability-indicating parameter out of specification with each time point tested due to statistical multiplicity. Alternative statistical methods, such as joinpoint regression or bootstrapping, do not have this limitation and offer even more precise estimations of potency, with the added benefit of also providing predictive analytics. Nested regression and bootstrapping were shown to be a viable alternatives for lot-to-lot comparisons of the stability of Sm-TSP-2/Al. Instructions for implementing both these potency testing approaches are provided.

2020-08-01·International Journal for Parasitology2区 · 医学

Uptake of Schistosoma mansoni extracellular vesicles by human endothelial and monocytic cell lines and impact on vascular endothelial cell gene expression

2区 · 医学

Article

作者: Becker, Luke ; Cooper, Martha ; Sotillo, Javier ; Loukas, Alex ; Pearson, Mark S ; Chaiyadet, Sujittra ; Laha, Thewarach ; Wise, Ingrid ; Doolan, Denise L ; Kifle, Desalegn Woldeyohannes ; Waardenberg, Ashley J

The ability of the parasitic blood fluke Schistosoma mansoni and other parasitic helminths to manipulate host biology is well recognised, but the mechanisms that underpin these phenomena are not well understood. An emerging paradigm is that helminths transfer their biological cargo to host cells by secretion of extracellular vesicles (EVs). Herein, we show that two populations of S. mansoni secreted EVs - exosome-like vesicles (ELVs) and microvesicles (MVs) - are actively internalised in two distinct human cell lines that reflect the resident cell types encountered by the parasite in vivo: human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes. RNA-sequencing of HUVECs co-cultured with S. mansoni ELVs compared with untreated HUVECs revealed differential expression of genes associated with intravascular parasitism, including vascular endothelial contraction, coagulation, arachidonic acid metabolism and immune cell trafficking and signalling. Finally, we show that antibodies raised against recombinant tetraspanin (TSP) proteins from the surface of S. mansoni EVs significantly blocked EV uptake by both HUVECs and THP-1 monocytes whereas pre-immunisation antibodies did not. To our knowledge, this is the first evidence demonstrating the internalisation of secreted EVs from any helminth into vascular endothelial cells, providing novel insight into the potential mechanisms underlying host-schistosome interactions. The ability of anti-TSP antibodies to block vesicle uptake by host target cells further supports the potential of TSPs as promising antigens for an anti-fluke vaccine. It also suggests a potential mechanism whereby the current candidate human schistosomiasis vaccine, Sm-TSP-2, exerts its protective effect in animal models.

100 项与 Sm-TSP-2 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
曼氏血吸虫病	临床2期	乌干达	Baylor College of Medicine	2019-10-07
血吸虫病	临床1期	-	QIMR Berghofer Medical Research Institute	-
血吸虫病	临床1期	-	Albert B. Sabin Vaccine Institute, Inc.	-