Periodic Reporting for period 1 - SPARCL (Dissecting early Skin-based immune responses to PARasites in ControLled human infection studies to design novel vaccines)
Berichtszeitraum: 2023-05-01 bis 2025-10-31
Parasitic diseases cause considerable morbidity and mortality in poverty-stricken areas, affecting hundreds of millions of lives globally. Vaccines are urgently needed to alleviate disease and lift the economic consequences. Plasmodium falciparum malaria, Schistosoma mansoni and Necator americanus hookworms are together responsible for the greatest burden of disease. Vaccination with attenuated parasites is a successful strategy in inducing immunity to parasites in animal models. Recently, Roestenberg’s group has shown in proof-of-concept clinical trials that attenuated parasite vaccination in humans results in a high protection rate from challenge with wild type parasites. This unique data indicates a role for the skin as a prime immunological organ. Based on these findings, this project aims to create a next generation of highly immunogenic, adjuvanted whole parasite vaccines, ready for pre-clinical testing. Chemical tools will be developed to load whole parasites with adjuvants. To measure the immunogenicity of the new vaccines, tools need to be developed to measure early skin-based humoral and cellular immune markers which associate with protection. By making use of controlled human infection models, the functionality of antibodies will be assessed with novel molecular imaging tools to quantitatively analyze movement kinematics of parasites in representative 3D environments resembling the human skin. Cellular correlates of protection in skin will be mapped using imaging mass cytometry on freshly obtained skin biopsies from experimentally infected volunteers. In parallel high-dimensional flow cytometry will be used to analyze circulating immune markers. By integrating local and systemic immune profiles, this project takes a comprehensive approach to identify immune responses associated with protection. This high-risk high-gain project aims to break the impasse in the field of parasite vaccine development and open a novel out-of-the-box avenue to advance the vaccine pipeline.
A 3D model has been developed to measure the movement of schistosomes and hookworms. Additionally, the previously developed software SMOOT (sporozoite motility orienting and organizing tool), originally designed to analyze the movement of malaria sporozoites, has been adapted to also analyze the movements of hookworms and schistosomes. This model will be used to test the inhibitory capacity of antibodies, present in serum from volunteers previously enrolled in controlled human infection studies, on the movement of the parasites.
In a recently performed malaria challenge trial, skin biopsies were collected from participants and will soon be used to analyze immune responses.
Circulating immune markers have been analyzed from samples obtained in earlier performed challenge trials. Results from three Schistosomiasis trials and two malaria trials have been published.
A method for adjuvant loading on sporozoites has been developed and two adjuvant candidates have been tested. The adjuvanted sporozoites have shown to be as motile and infective as non-adjuvanted control sporozoites and macrophages exposed to adjuvanted sporozoites showed increased immune activation.
In a recently performed malaria challenge trial, skin biopsies were collected from participants and will soon be used to analyze immune responses.
Circulating immune markers have been analyzed from samples obtained in earlier performed challenge trials. Results from three Schistosomiasis trials and two malaria trials have been published.
A method for adjuvant loading on sporozoites has been developed and two adjuvant candidates have been tested. The adjuvanted sporozoites have shown to be as motile and infective as non-adjuvanted control sporozoites and macrophages exposed to adjuvanted sporozoites showed increased immune activation.