Poster Presentation 16th Lorne Infection and Immunity 2026

Looped or exposed? Structural strategies for multi-antigen display in malaria virus-like particles (132000)

Anne Nguyen 1 , Daniel Luque Buzo 2 , Michael Johnson 1 , Jake Baum 1
  1. School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
  2. Electron Microscopy Unit, University of New South Wales, Sydney, NSW, Australia

Background:

Malaria led to an estimated 263 million cases and 597,000 deaths globally in 2023. Despite the approval of the first two malaria vaccines, RTS,S and R21—both based on a virus-like particle (VLP) platform targeting the circumsporozoite protein (CSP)—there remains no fully efficacious or durable vaccine. The parasite’s complex two-host lifecycle and multiple developmental stages present major challenges for single-antigen or single-stage strategies, underscoring the need for multi-stage vaccine platforms capable of inducing broad, long-lasting protection.

 

Methods:

We have designed and produced a panel of multi-valent VLPs based on a woodchuck hepatitis B core (WHBcAg) scaffold using both tandem-core and split-core engineering strategies. These constructs enable the presentation of the CSP NANP15 repeat on the VLP surface in four configurations:

  1. Tandem-core with NANP on one monomer,
  2. Tandem-core with NANP on both monomers,
  3. Split-core with NANP on one monomer, and
  4. Split-core with NANP on both monomers.

VLPs were purified by ultracentrifugation and assessed for assembly, stability, and morphology using biochemical, biophysical, and transmission electron microscopy (TEM) and cryo-electron microscopy (cryo-EM) analyses.

 

Results:

All four constructs successfully assembled into intact VLPs, with TEM confirming well-formed capsids. Immunisation studies in mice are scheduled to commence shortly to evaluate anti-CSP IgG responses across the four structural variants. These experiments will determine which configuration elicits the strongest antibody response and provide insights into how structural design influences immunogenicity.

 

Conclusions and Future Directions:

This work establishes a systematic framework for evaluating tandem-core and split-core VLP technologies as modular vaccine platforms. While this initial panel focuses on the CSP antigen from the sporozoite stage, future work will extend this approach to incorporate additional antigens from blood- and transmission-stage parasites. Together, these efforts aim to advance the rational design of HBcAg-based multi-antigen nanoparticles as next-generation multi-stage malaria vaccines capable of achieving durable and comprehensive protection.