Malaria immunisation beyond subunit vaccines: Current progress

Subunit vaccines against malaria target the circumsporozoite protein, and two vaccines are currently licensed: RTS,S/AS01 and R21/Matrix-M. However, their limitation is that they provide protection only against Plasmodium falciparum. Prof. Miguel Prudêncio (University of Lisbon, Portugal) reviewed additional vaccine strategies aiming to extend protection beyond P. falciparum [1].

An alternative to subunit vaccines is whole-sporozoite vaccination. “As the name indicates, these vaccines rely on the sporozoite itself. This has been achieved for P. falciparum by attenuating this parasite, but the same approach is not feasible for P. vivax”, said Prof. Prudêncio. One such candidate is PbVac, which uses genetically modified P. berghei, a parasite not pathogenic to humans. In a phase 1/2 trial, PbCac showed acceptable safety and tolerability, with a 95% reduction in P. falciparum parasite density, dose-dependent cross-species cellular immune responses, and functional antibody production [2].

Based on this concept, the PbviVac platform was developed, using P. berghei genetically modified to express P. vivax proteins in addition to the circumsporozoite protein, and demonstrated immunogenicity in non-human primates. Further refinements include PbviVacTRAP, incorporating the thrombospondin adhesion protein (TRAP), which plays a role in salivary gland invasion, sporozoite motility, and host-cell interaction but normally elicits limited immunogenicity. In preclinical studies, PbviVacTRAP induced  antibodies against both the circumsporozoite and TRAP proteins, along with robust cellular responses against TRAP. Another candidate vaccine, PbviVacPvs25, expresses the Pvs25 protein,  essential for parasite survival and epithelial penetration. In mouse models, PbviVacPvs25 triggered antibodies targeting both circumsporozoite and Pvs25 proteins [1].

“In summary, PbVac established proof-of-concept for whole-sporozoite vaccination against malaria using P. falciparum as the target and clinically validated this approach,” said Prof. Prudêncio. “For P. vivax, we now have three constructs at different stages of their development.”

1. Prudêncio M. Recent advances in malaria vaccination: Innovations & impact. 6^th ESCMID Vaccines, 10–13 September 2025, Lisbon, Portugal.
2. Reuling IJ, et al. Sci Transl Med. 2020;12(544):eaay2578.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 18 September 202521 October 2025