In a report published on March 21, 2024 in EMBO Molecular Medicine (A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion) investigators at Seattle Children's Research Institute and Sanaria Inc. describe the development of a whole malaria parasite vaccine strain that infects the liver, develops to the late liver stage, and then gets completely stuck and cannot burst out of the liver to cause symptomatic blood infection. The creation of this strain called LARC2 (Late liver-stage Arresting, Replication Competent) was accomplished by deletion of only two parasite genes out of the approximately 5,000 in the Plasmodium falciparum (Pf) parasite genome, This incapacitated parasite strain will be the sole immunogen in Sanaria's third generation vaccine, Sanaria® PfSPZ LARC2 Vaccine. The study was led by Dr. Debashree Goswami and Dr. Hardik Patel working in the laboratory of Dr. Stefan Kappe at Seattle Children's Research Institute and a team at Sanaria led by Dr. B. Kim Lee Sim.
Mosquitoes inoculate malaria parasites called sporozoites (SPZ), which rapidly infect liver cells within which each individual parasite can multiply to produce up to 50,000 parasites over 6-7 days. This first phase of infection goes completely unnoticed and doesn't cause any symptoms. When the parasites burst out of the liver they infect tens of thousands of red blood cells, causing deadly malaria disease. The Kappe team, in collaboration with Dr. Ashley Vaughan at Seattle Children's Research Institute, constructed the LARC2 strain by deleting two critical genes without which the parasites multiply in the liver almost to maturity but then disintegrate, which prevents new parasites from getting into the blood stream. In this way, LARC2 parasites stimulate a very strong immune response in the liver, which protects against future malaria infections. By assessing aseptic, purified, cryopreserved PfSPZ-LARC2 produced at Sanaria in humanized mice with human liver cells and human red blood cells, the study team was able to show that the mature, late liver stages of the malaria parasite life cycle were completely compromised.
"These weakened parasite strains can check in but they can't check out," says Kappe, who is also a professor in the Department of Pediatrics at the University of Washington.
Sanaria founder and CEO, Stephen L. Hoffman, MD said, "Sanaria's PfSPZ-LARC2 Vaccine has the potential to save millions of lives and eliminate malaria from defined geographic areas when administered in mass vaccination programs. We are planning to assess PfSPZ-LARC2 Vaccine in clinical trials in 2024 in the US, Germany, and Burkina Faso. Previous generations of PfSPZ vaccines either do not meet WHO requirements for 90% protection against infection or have potential for breakthrough infections into the blood stream. We are therefore eagerly anticipating taking this novel, genetically engineered vaccine strain into clinical studies."
To protect against and eliminate malaria the WHO has recognized the need for vaccines that prevent human blood-stage infection in individuals that have >90% vaccine efficacy for at least 12 months against infection with naturally transmitted Plasmodium falciparum malaria, which is responsible for >98% of the 625,000 deaths from malaria. Only Sanaria's P. falciparum sporozoite vaccines have achieved >90% vaccine efficacy against controlled human malaria infections and shown sustained protection without boosting against natural transmission in Africa. PfSPZ-LARC2 parasites are predicted to induce strong cellular immune responses in the liver that will be highly protective against infection. In their publication the study team demonstrated that LARC2 vaccination completely protects against infection in mouse models of malaria.
It took us nearly 20 years to get to the PfSPZ-LARC2 Vaccine. Finding the right genes that, when removed from the parasite genome, stop the parasite right when it wants to get out of the liver, was an enormous task. Our results provide a clear indication that safe, complete developmental attenuation of malaria parasites is possible and we are excited to see the outcome of the first clinical trials with this vaccine."
Dr. Stefan Kappe at Seattle Children's Research Institute
"We are enthusiastic about the potential for PfSPZ-LARC2 Vaccine to prevent malaria in travelers to endemic regions, and in pregnant women and children in areas with malaria, and eventually to eliminate malaria from entire regions," said Professor Peter Kremsner, Director of the Institute for Tropical Medicine, University of Tübingen in Germany, and President of the Centre de Recherches Médicales de Lambaréné (CERMEL) in Gabon.
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