Periodic Reporting for period 1 - WORMVACS2.0 (Innovations for vaccines against helminth infections)
Reporting period: 2023-09-01 to 2025-02-28
Infections with parasitic worms (helminths) continue to cause a massive global health burden with more than a billion people infected. Yet, effective vaccines to enable control and elimination of helminth infections do not exist. Main reasons for this are that helminth vaccine target discovery approaches are not well-developed, protective immune responses against helminths are not well-understood, specific production platforms to produce effective helminth vaccines are not available. Hence, a strategy for evidence-based selection and development of pre-clinical and clinical vaccine candidates is lacking.
The overall ambition of WORMVACS2.0 is to establish an effective pipeline to support helminth vaccine development and ultimately the control and elimination of some of the world’s most devastating and persistent Neglected Tropical Diseases (NTDs) caused by parasitic worms. We aim to achieve this through an innovative program based on controlled human infection models, novel platforms for vaccine antigen production, experimental animal models, and improved vaccine target discovery methods applying state-of-the-art immunological profiling to identify correlates and signatures of protection. WORMVACS2.0 focusses on schistosome and hookworm infections, two of the most important helminth infections in terms of impact on global human health.
Our specific objectives are:
· Fill critical gaps in our knowledge of immunity against helminths. We use biospecimens and data derived from unique controlled human infection models with Necator americanus (intestinal nematode, hookworm) and Schistosoma mansoni (trematode, blood fluke), that were or will be carried out in in both non-endemic and endemic areas.
· Establish a pipeline of evidence-based vaccine discovery and development. WORMVACS2.0 utilises clinical, immunological and parasitological data, and innovative production platforms to allow rapid selection, production, and engineering of a diverse portfolio of helminth vaccine antigens for pre-clinical and clinical testing.
· Optimise the efficacy of existing vaccine candidates for S. mansoni and N. americanus infections.
WORMVACS2.0 will contribute to expected work programme outcomes:
· Use of increased knowledge of immunity to helminth infection, to develop vaccines with improved efficacy.
· Participation of manufacturers applying innovative and sustainable technologies for producing next generation effective vaccines against infections of global importance.
· A diversified portfolio of hookworm and schistosome vaccine candidates that will go across current technological and knowledge barriers. The resulting portfolio will support policy makers and funders to make informed decisions for vaccine development with increased success rates.
· Innovative and improved design of preclinical/clinical studies, aimed to shorten vaccine development time through implementation of innovative production platforms and the use of controlled human infection and challenge models.
The overall ambition of WORMVACS2.0 is to establish an effective pipeline to support helminth vaccine development and ultimately the control and elimination of some of the world’s most devastating and persistent Neglected Tropical Diseases (NTDs) caused by parasitic worms. We aim to achieve this through an innovative program based on controlled human infection models, novel platforms for vaccine antigen production, experimental animal models, and improved vaccine target discovery methods applying state-of-the-art immunological profiling to identify correlates and signatures of protection. WORMVACS2.0 focusses on schistosome and hookworm infections, two of the most important helminth infections in terms of impact on global human health.
Our specific objectives are:
· Fill critical gaps in our knowledge of immunity against helminths. We use biospecimens and data derived from unique controlled human infection models with Necator americanus (intestinal nematode, hookworm) and Schistosoma mansoni (trematode, blood fluke), that were or will be carried out in in both non-endemic and endemic areas.
· Establish a pipeline of evidence-based vaccine discovery and development. WORMVACS2.0 utilises clinical, immunological and parasitological data, and innovative production platforms to allow rapid selection, production, and engineering of a diverse portfolio of helminth vaccine antigens for pre-clinical and clinical testing.
· Optimise the efficacy of existing vaccine candidates for S. mansoni and N. americanus infections.
WORMVACS2.0 will contribute to expected work programme outcomes:
· Use of increased knowledge of immunity to helminth infection, to develop vaccines with improved efficacy.
· Participation of manufacturers applying innovative and sustainable technologies for producing next generation effective vaccines against infections of global importance.
· A diversified portfolio of hookworm and schistosome vaccine candidates that will go across current technological and knowledge barriers. The resulting portfolio will support policy makers and funders to make informed decisions for vaccine development with increased success rates.
· Innovative and improved design of preclinical/clinical studies, aimed to shorten vaccine development time through implementation of innovative production platforms and the use of controlled human infection and challenge models.
Regarding the objective to fill critical gaps in knowledge of human immunology, focus has so far been on studying samples from the controlled human schistosome infections (single and repeated exposures to male cercariae; the COHSI and reCOHSI trials), and from controlled human hookworm infections (single and repeated exposures to L3 larvae; the ITCHHI trial). Evaluation of the schistosome trials indicated that no protection against challenge occurs after repeated exposure in this model, but clinical tolerance is observed. To create an in-depth understanding of the immune responses in primary and repeated schistosome infections we recorded antibody profiles against a diverse panel of antigens printed on microarrays. To determine the immune cell signatures, we applied SITE-Seq (single cell sequencing and surface proteome analysis) CyTOF (mass cytometry). While integrated analysis of these data is ongoing, we have selected already a set of schistosome antigens and reCOHSI samples for further testing with respect to antibody affinity, receptor binding, glycosylation etc., as parameters that will support the selection procedure. In contrast to reCOHSI, the ITCHHI hookworm study does indicate a protective effect in the intervention group (reduced egg burden after vaccination with drug-attenuated parasites) and for the latter study the antibody profiles against a diverse panel of antigens printed on microarrays have been recorded and are being analysed for association with protection.
For the objective of establishing a pipeline of evidence-based vaccine discovery and development we have designed a strategy for integration of diverse in vitro and in vivo data. The integrated analysis is supported by the FAIR data warehouse and dashboard that we have created, which includes all existing and future WORMVACS2.0 data. Prioritisation of candidate antigens is based on antibody reactivity and function, and association with protective responses to challenge infection in the human infection models, or to an endemic Ugandan S. mansoni infection cohort that contains groups susceptible and resistant to natural reinfection. Selected vaccine candidate antigens are being produced in up to three innovative platforms, mRNA, outer membrane vesicles (OMV), and plants (N. benthamiana/tobacco) to allow comparative testing in rodent models. So far, based on IgM and IgG reactivity in samples from the COHSI, reCOHSI and ITCHHI studies, combined with previous experimental data by consortium partners and systematic review of literature, we made a first shortlist of candidate vaccine antigens. An initial set of conventional recombinant antigens from both parasite species and matching human sera derived from the infection models has been used to set up assays for testing antibody functionality, now ready for further exploration. The 12 schistosome and 8 hookworm targets shortlisted, including the Smp80 and NaGST1 benchmark antigens, are being produced in the above platforms. Platform development is ongoing by genetic engineering of E. coli strains to optimise OMV production and by expanding the glycoengineering toolkit applicable to tobacco plants for tailored glycoprotein production. Benchmark antigens are ready to be tested in rodent models. Licenses and protocols have been finalised.
The objective of improving the efficacy of yet suboptimal exisintg vaccine candidates is pursued by exploring the innovative platforms for production of benchmark antigens Smp80 and NaGST1. WORMVACS2.0 aims to extend pre-clinical (mRNA, OMV, N. benthamiana in rodent models, year 2-4) and clinical (mRNA in human, year 4-5) data for benchmark antigens as well as other candidates (a.o. SmTSP2, NaAPR1 and SmCathB1). We aim to conduct an early clinical evaluation of the most advanced candidate for S. mansoni as novel, efficacious mRNA vaccine.
For the objective of establishing a pipeline of evidence-based vaccine discovery and development we have designed a strategy for integration of diverse in vitro and in vivo data. The integrated analysis is supported by the FAIR data warehouse and dashboard that we have created, which includes all existing and future WORMVACS2.0 data. Prioritisation of candidate antigens is based on antibody reactivity and function, and association with protective responses to challenge infection in the human infection models, or to an endemic Ugandan S. mansoni infection cohort that contains groups susceptible and resistant to natural reinfection. Selected vaccine candidate antigens are being produced in up to three innovative platforms, mRNA, outer membrane vesicles (OMV), and plants (N. benthamiana/tobacco) to allow comparative testing in rodent models. So far, based on IgM and IgG reactivity in samples from the COHSI, reCOHSI and ITCHHI studies, combined with previous experimental data by consortium partners and systematic review of literature, we made a first shortlist of candidate vaccine antigens. An initial set of conventional recombinant antigens from both parasite species and matching human sera derived from the infection models has been used to set up assays for testing antibody functionality, now ready for further exploration. The 12 schistosome and 8 hookworm targets shortlisted, including the Smp80 and NaGST1 benchmark antigens, are being produced in the above platforms. Platform development is ongoing by genetic engineering of E. coli strains to optimise OMV production and by expanding the glycoengineering toolkit applicable to tobacco plants for tailored glycoprotein production. Benchmark antigens are ready to be tested in rodent models. Licenses and protocols have been finalised.
The objective of improving the efficacy of yet suboptimal exisintg vaccine candidates is pursued by exploring the innovative platforms for production of benchmark antigens Smp80 and NaGST1. WORMVACS2.0 aims to extend pre-clinical (mRNA, OMV, N. benthamiana in rodent models, year 2-4) and clinical (mRNA in human, year 4-5) data for benchmark antigens as well as other candidates (a.o. SmTSP2, NaAPR1 and SmCathB1). We aim to conduct an early clinical evaluation of the most advanced candidate for S. mansoni as novel, efficacious mRNA vaccine.
In month 1-18 of the project (M1-18) we have been generating essential data and exploring technologies for the selection, production and testing of schistosome and hookworm vaccine candidates. Once favorable pre-clinical data has been obtained, key needs will be identified to ensure further progress to clinical development and implementation, in particular focusing on access to funding and market, regulatory framework and international context.