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.
