Assessment of novel adjuvanted virus-like particle vaccine candidates against Plasmodium falciparum malaria

Thesis

Malaria remains a major global health burden, with an estimated 263 million cases and 597 000 deaths reported in 2023, primarily affecting children under five and pregnant women in sub-Saharan Africa. Virus-like particle (VLP) vaccines have emerged as promising interventions, with RTS,S and R21 now in use. However, RTS,S has demonstrated <40% efficacy, while R21 has achieved <80% in recent trials, underscoring the need for improved vaccine strategies.

This thesis presents preclinical studies aimed at enhancing the immunogenicity and efficacy of R21/Matrix M malaria vaccine. Three key approaches were explored: (1) the development of bivalent VLP vaccine candidates incorporating the NANP repeat region of the circumsporozoite protein (CSP) alongside the full-length sporozoite microneme protein essential for cell traversal-1 (SPECT-1) antigen of Plasmodium falciparum (Pf), (2) the assessment of R21 variants modified by the inclusion of cleavage and/or junctional epitopes and the removal of the CSP C-terminal region, and (3) the role of adjuvant selection in shaping vaccine-induced immune responses.

A subset of the bivalent vaccine candidates was successfully produced and tested in murine models using a prime-boost regimen (3-week interval). Three weeks post-boost, mice were challenged with transgenic Plasmodium berghei parasites expressing both PfSPECT-1 and PfCSP. Among the tested candidates, one showed immune responses and protection levels comparable to those induced by R21. The comparable efficacy of the bivalent candidate to R21 firmly supports the feasibility of multivalent VLP vaccines which could be designed as a multi-stage or multi-strain malaria vaccine.

Matrix-M was used as the primary adjuvant in the first two approaches. For the third, SMNP and LMQ were tested to determine their ability to enhance IgG response and improve efficacy. SMNP, in particular, showed promising results as it elicited immune response and protection comparable to that of Matrix-M, indicating its potential as a viable alternative adjuvant. A dose-sparing study was also conducted as part of this strategy to evaluate the potential of Matrix-M and SMNP to elicit strong immune responses at reduced antigen doses. Matrix-M, in particular, maintained robust immunogenicity and provided partial protection at a low antigen dose (0.1 µg). This finding is especially relevant for real-world application in endemic regions, where vaccine supply limitations and manufacturing capacity are significant barriers to malaria vaccine coverage.

Authors: Turan, G

• DOI: 10.5287/ora-ryyv6k6mz
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Matrix-M; adjuvants; virus-like particles; LMQ; VLPs; plasmodium falciparum; malaria; SPECT-1 Vaccines; SMNP; CSP
• Subjects: Intracellular pathogens; Plasmodium; Parasite vaccines; Malaria vaccine; Malaria--Prevention