The MultiViVax project has successfully established a blood-stage CHMI with P. vivax. Initially a pilot study was conducted whereby P. vivax sporozoites were delivered by mosquito bite to two healthy, malaria-naive adults. Blood was taken from both successfully infected volunteers and frozen down for future use in CHMI studies to assess vaccine efficacy and reinfection studies. A study, conducted in Q1 2019, assessed the optimum dose of the banked parasite inoculum required to successfully carry out CHMI trials. The optimised dose was subsequently administered to volunteers who had been vaccinated with the blood-stage vaccine. A total of 8 volunteers completed vaccinations with ChAd63 and MVA PvDBP_RII. Vaccinations caused predominantly mild to moderate, expected side effects with no safety concerns. Antibody responses following the final vaccination were relatively low. There was no significant efficacy seen on blood-stage malaria challenge conducted at 2-4 weeks following the final vaccination.
The first study of repeat homologous blood-stage P. vivax CHMI and commenced in January 2019. Five phases of the study were completed, followed by a final phase involving heterologous CHMI with P. falciparum. A total of 19 participants completed primary P. vivax CHMI, 12 completed secondary CHMI and 2 completed tertiary CHMI. No serious or unexpected safety concerns have been identified. Upon repeat P. vivax CHMI, symptoms and laboratory abnormalities occurred less frequently and were of milder severity compared to primary CHMI. Parasite growth, however, was similar between primary and repeat CHMI with no evidence of development of anti-parasitic immunity upon repeat homologous CHMI. Further work is underway to try and further characterise this phenomenon of clinical immunity following repeat homologous CHMI in humans. Samples collected during the CHMI re-infection trials will be used for parasite RNAseq and immuno-screening analysis. In preparation for these assays, a P.vivax protein expression library was developed. A number of proteins have been successfully produced and selected for immuno-screening.
The leading P. vivax transmission-blocking antigen has been evaluated preclinically in the form of two different vaccine candidates. The leading preclinical candidate has undergone cGMP manufacture during 2019/2020 in preparation for Phase I clinical testing. Volunteers were vaccinated with different doses of the vaccine in Matrix-M adjuvant. Safety and immunogenicity data from this study is available. As part of this trial, the functional impact of antibodies induced by vaccination will be assessed using a direct membrane feeding assay. Several transgenic P.falciparum line were also generated but these were not suitable to establish and qualify an SMFA to test vaccine induced antibodies.
Transgenic P. knowlesi parasites have been edited to replace endogenous PkDBP and replace this with PvDBP. These parasites have been used to validate GIA methodology for P.knowlesi. The serum samples from the blood-stage vaccine clinical trial were tested for GIA and published here:
https://pubmed.ncbi.nlm.nih.gov/35664997/(si apre in una nuova finestra).
