Pre-clinical development of viral vectored transmission-blocking malaria vaccines

Thesis

Malaria transmission-blocking vaccine candidate antigens have been developed to induce antibodies using different delivery systems, mainly protein-in-adjuvant formulations, independently in various laboratories giving varied transmission-blocking activity (TBA). However, only one candidate antigen has been tested in clinical trials. In order to advance the most efficacious target(s) for possible clinical development, a rank order of the leading antigens based on TBA in a head-to-head comparison using a single delivery platform was made. Candidate antigens, AnAPN1, PfsHAP2, Pfs230-C, Pfs25, and Pfs48/45 (with or without N-glycosylation site substitution), were generated as recombinant viral-vectored vaccines using simian adenovirus and modified vaccinia Ankara and administered to mice in a heterologous prime-boost regimen. Vaccine-induced antibody responses were induced to all except PfsHAP2 were maintained up to ten and a half months post-boost. TBA was assessed at the peak response against Plasmodium falciparum NF54 laboratory strain and African field isolates by ex vivo membrane feeding assays in Anopheles stephensi and A. gambiae respectively. Antibodies to three antigens [Pfs230-C, Pfs25 and Pfs48/45+_NGln] had TBA against P. falciparum NF54, and those against Pfs230-C and Pfs25 consistently showed efficacy regardless of the parasite exposure in both mosquito species. Further analysis of antibody responses to these two candidate antigens showed concentration-dependent efficacy against P. falciparum field isolates. In a rabbit study, responses to Pfs230-C, Pfs25 and Pfs48/45+_NGln also showed IgG concentration-dependent efficacy. To assess TBA against AnAPN1, antibody responses to three fragments were tested. TBA was observed only against N-terminal 135 amino acid fragment. Pfs230-C and Pfs25 were generated as fusion vaccines using either a self-cleaving or glycine-proline linker sequence. Comparable antibody responses were induced between the two fusion strategies that had synergistic effects at inhibiting P. falciparum NF54 development in A. stephensi.

Authors: Kapulu, MC

• Publication date: 2014
• DOI: 10.5287/ora-x5rpobvb8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: pre-clinical; transmission-blocking; viral-vectors; immunology; malaria; vaccines
• Subjects: Parasitology; Malaria; Infectious diseases; Medical Sciences; Vaccinology; Disease prevention; Immunology