Clinical formulation development of Plasmodium falciparum malaria vaccine candidates based on Pfs48/45, Pfs230, and PfCSP

• Published in: Vaccine 2024-03, Vol.42 (8), p.1980-1992
• Main Authors: Plieskatt, Jordan, Bang, Peter, Wood, Grith Krøyer, Naghizadeh, Mohammad, Singh, Susheel K., Jore, Matthijs M., Theisen, Michael
• Format: Article
• Language: English
• Subjects: Adjuvants; Aluminum; Aluminum Hydroxide; Animals; Antibodies; Antibodies, Protozoan; Antigens; Antigens, Protozoan; Clinical trials; Disease transmission; Drug development; Drug dosages; Drug Product; Formulation; Malaria; Malaria Vaccines - adverse effects; Malaria, Falciparum - prevention & control; Manufacture; Mosquitoes; Plasmodium falciparum; Proteins; Protozoan Proteins; Rabbits; Room temperature; Saponins; Stability analysis; Toxicity; Toxicology; Vaccine; Vaccines; Vector-borne diseases
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2024.02.043

•A dual adjuvant system was developed for the R0.6C and ProC6C malaria vaccines.•R0.6C and ProC6C vaccines were manufactured under cGMP.•The drug products and adjuvants were stable for pharmacy handling at 4 °C and 25 °C.•Repeated dose toxicity studies showed the drug products were safe, immunogenic and functional.•Long-term stability studies support stability over planned clinical trials. Two malaria transmission-blocking vaccine (TBV) candidates, R0.6C and ProC6C, have completed preclinical development including the selection of adjuvants, Alhydrogel® with or without the saponin based adjuvant Matrix-M™. Here, we report on the final drug product (formulation) design of R0.6C and ProC6C and evaluate their safety and biochemical stability in preparation for preclinical and clinical pharmacy handling. The point-of-injection stability studies demonstrated that both the R0.6C and ProC6C antigens are stable on Alhydrogel in the presence or absence of Matrix-M for up to 24 h at room temperature. As this is the first study to combine Alhydrogel and Matrix-M for clinical use, we also evaluated their potential interactions. Matrix-M adsorbs to Alhydrogel, while not displacing the > 95 % adsorbed protein. The R0.6C and ProC6C formulations were found to be safe and well tolerated in repeated dose toxicity studies in rabbits generating high levels of functional antibodies that blocked infection of mosquitoes. Further, the R0.6C and ProC6C drug products were found to be stable for minimally 24 months when stored at 2–8 °C, with studies ongoing through 36 months. Together, this data demonstrates the safety and suitability of the L. lactis expression system as well as supports the clinical testing of the R0.6C and ProC6C malaria vaccine candidates in First-In-Human clinical trials.