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

Abstract

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.

A two-dose viral-vectored Plasmodium vivax multistage vaccine confers durable protection and transmission-blockade in a pre-clinical study

“…This process has been hampered by the lack of a continuous culture system for blood-stages, restricted availability of ideal animal models to study parasite biology, and the lack of funding support ( 8 ). Our recent progress in the development of the m8Δ/AAV1-based P. falciparum multistage vaccine has enabled us to use it for P. vivax vaccines ( 17 ). In the present study, the newly developed m8Δ/AAV1-based P. vivax vaccine successfully provided 100% protection in a “humanized” rodent malaria parasite model and 95% field-relevant TB efficacy as demonstrated by a DMFA of P. vivax isolates from infected patients from the Brazilian Amazon.…”

“…For prime immunization, 1 × 10 7 plaque-forming units (PFU) of m8Δ-Pv(P7.5-s25-CSP-VK210/247) were administered by tail scarification ( 29 ) as priming, and 1 × 10 10 viral genomes of AAV1-Pv(s25-CSP-VK210/247) were intramuscularly administered 6 weeks after priming. Negative control animals were injected with PBS or m8Δ-prime and AAV1-boost after a 6-week interval ( 17 ).…”

“…We recently developed a vaccine platform using viral vectors, including a highly attenuated strain of vaccinia virus, LC16m8Δ (m8Δ)–a genetically stable variant of the efficacious Japanese smallpox vaccine LC16m8, and adeno-associated virus (AAV), commonly utilized in gene therapy for humans. The multistage vaccine for P. falciparum , incorporating genes for the circumsporozoite protein PfCSP and ookinete protein Pfs25, fused into a single protein, induced sterile protection and halted transmission, maintaining prolonged robust immune responses and protective efficacy ( 17 ).…”