Bivalent virus-like particles expressing SPECT1 and CSP trigger pre-erythrocytic malaria immunity and protect against transgenic Plasmodium falciparum sporozoite challenge in mice

Journal article

Introduction: The decline in protective antibody titers and efficacy over time of the circumsporozoite protein (CSP)-based RTS,S/AS01 and R21/Matrix-M vaccines highlights the need for improved vaccines. Sporozoite microneme protein essential for cell traversal-1 (SPECT-1) is a conserved Plasmodium falciparum (Pf) antigen that plays a key role in parasite movements while traversing host cells. Targeting SPECT-1 as an addition to the CSP in the same vaccine may enhance immune response and protection. Methods: We engineered a series of recombinant Hepatitis B surface antigen (HBsAg) virus-like particles (VLPs) displaying PfSPECT-1 alone or in combination with NANP repeats and C-terminal region of PfCSP. These monovalent and bivalent VLP vaccine candidates were evaluated alongside R21 in a prime-boost regimen which was followed by challenge with transgenic P. berghei parasite expressing the same P. falciparum antigens. We also assessed the quality of the antibody response following vaccination. Based on the antibody titers and protective efficacy, one bivalent VLP construct was selected for further evaluation with different adjuvant formulations. Results: All bivalent VLPs formed to display antigenic epitopes that were accessible to antigen-specific antibodies. Bivalent VLPs induced IgG responses against both NANP and PfSPECT-1 epitopes, confirming in vivo co-display of the target antigens. One of the bivalent candidates (N4) provided similar efficacy to R21 in formulation with Matrix-M adjuvant in BALB/c mice, whereas addition of PfSPECT-1 significantly reduced efficacy of another candidate (N2). NANP-specific IgG response negatively correlated with blood stage parasite load. When N4 was formulated with LMQ or SMNP adjuvants, measured humoral responses or protective efficacy did not improve. Further investigation is needed to determine whether the immune response persists over time. Discussion: Our findings show that PfSPECT-1 can be effectively incorporated into the HBsAg VLPs and co-displayed with CSP epitopes without impairing immunogenicity. Although protection was evaluated using transgenic P. berghei parasites expressing P. falciparum antigens, the modular HBsAg VLP platform theoretically allows incorporation of antigens from other Plasmodium species such as P. vivax.

Authors: Turan, G; Mukhopadhyay, E; Truby, A; Fedorova, K; Peralta Alvarez, MP

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Frontiers Media
• Journal: Frontiers in Immunology
• Volume: 17
• Pages: 1790309
• Article number: 1790309
• Publication date: 2026-05-14
• Acceptance date: 2026-04-29
• DOI: 10.3389/fimmu.2026.1790309
• EISSN: 1664-3224
• ISSN: 1664-3224
• Language: English
• Keywords: VLP; SMNP; malaria; LMQ; Matrix-M; parasite; NANP; SPECT-1