Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study

• DOI: 10.3389/fimmu.2022.1005476
• Publication Date: 2022-09-29T14:56:33Z
• Authors: Mitsuhiro Iyori; Andrew M. Blagbor...; Tetsushi Mizuno; Yu-ichi Abe; Mio Nagaoka; Naoto Hori; Iroha Yamagoshi; Dari F. Da; William F. Gregory; Ammar A. Hasyim; Yutaro Yamamoto; Akihiko Sakamoto; Kunitaka Yoshida; Hiroaki Mizukami; Hisatoshi Shida; Shigeto Yoshida
• Keywords: 0301 basic medicine; plasmodium falciparum; PfCSP; Immunology; malaria; Protozoan Proteins; Antibodies, Protozoan; LC16m8Δ; adeno-associated virus (AAV); RC581-607; Dependovirus; 3. Good health; Antimalarials; Disease Models, Animal; Mice; 03 medical and health sciences; Pfs25; vaccine; Malaria Vaccines; Animals; Humans; Immunologic diseases. Allergy; Malaria, Falciparum

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of Plasmodium falciparum that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy. The genes encoding P. falciparum circumsporozoite protein (PfCSP) and the ookinete protein P25 (Pfs25) are expressed as a Pfs25–PfCSP fusion protein, and the heterologous m8Δ-prime/AAV-boost immunization regimen in mice provided both 100% protection against PfCSP-transgenic P. berghei sporozoites and up to 100% transmission blocking efficacy, as determined by a direct membrane feeding assay using parasites from P. falciparum-positive, naturally-infected donors from endemic settings. Remarkably, the persistence of vaccine-induced immune responses were over 7 months and additionally provided complete protection against repeated parasite challenge in a murine model. We propose that application of the m8Δ/AAV malaria multistage vaccine platform has the potential to contribute to the landmark goals of the malaria vaccine technology roadmap, to achieve life-long sterile protection and high-level transmission blocking efficacy.