Malaria is one of the most important diseases in the world, causing hundreds of millions of cases, and approximately 600,000 deaths annually. SIGHTM’s malaria agenda supports malaria elimination & control through strategic planning, and operational support for national and international initiatives including those of Sanaria Inc., a biotechnology company devoted to the development of high efficacy malaria vaccines with a corporate objective of “malaria elimination through vaccination.”
One goal of SIGHTM is to develop increased capacity worldwide, particularly in Africa, for conducting controlled human malaria infections (CHMIs) for assessment of new malaria drugs, vaccines, and diagnostics, and to assess the impact of innate and acquired human responses on malaria infections. SIGHTM is facilitating the application in malaria research of aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (PfSPZ), a product manufactured by Sanaria called PfSPZ Challenge, in the conduct of CHMI. The administration by needle and syringe of this product has been optimized by teams from clinical centers in Africa, Europe and North America, so that PfSPZ Challenge can be used by any clinical center in the world to conduct CHMI. This technical advance has been particularly empowering for African research institutions, which have conducted more than 100 CHMIs in the past few years to advance malaria research in Africa. The Bill & Melinda Gates Foundation is supporting the creation of a repository of PfSPZ Challenge to further facilitate and expand its use by African and other research institutions intent on advancing knowledge of malaria immunity and the development of high efficacy drugs, diagnostics and vaccines.
Also through its affiliation with Sanaria Inc., SIGHTM is advancing the use of SPZ-based vaccines to protect vulnerable populations against Pf malaria. Pf is responsible for nearly all malaria deaths worldwide and is also the type of malaria commonly acquired by international travelers and responsible for most hospitalizations and malaria deaths in the USA. Vulnerable populations include young children, pregnant women, and international travelers. Young children are at risk because they have not acquired the partial protective immunity possessed by older children and adults, which gradually develops over many years following repeated Pf infections during childhood. Pregnant women are also heavily affected, because of their susceptibility to placental malaria infection. A nidus of parasites in the placenta harms the fetus, increasing the risks of low birth weight, preterm birth, fetal growth restriction, miscarriage, stillbirth, and neonatal death, and also harms the mother, increasing the risks of maternal pre-eclampsia, anemia and death.
In a recent study, Sanaria’s first generation vaccine, called PfSPZ Vaccine, provided significant protection against malaria over two transmission seasons in young Malian women who at the time of enrollment into the clinical trial were expecting to get pregnant in the ensuing months. The efficacy of the vaccine administered pre-conception against Pf infection ranged from 41% to 61% in the study population over two transmission seasons, and in those women who became pregnant within 6 months of vaccination, efficacy against infection ranged from 65% to 86%. When efficacy was measured during pregnancy, efficacy against infection was 49% to 57% over the two year study. Because preventing infection also prevents all the pathological consequences of malaria, these efficacies indicate that PfSPZ Vaccine could, at minimum, cut in half the number of pregnancies adversely affected by Pf malaria.
SIGHTM is now supporting Sanaria in its bid to license a SPZ-based vaccine like PfSPZ Vaccine for use in pregnant women. The candidate selected, called PfSPZ-LARC2 Vaccine, is entering clinical trials during the first quarter of 2025 with a goal to achieving licensure by 2028. PfSPZ-LARC2 Vaccine was created by the Seattle Children’s Research Institute using CRISPR-CAS9 technologies to delete two key genes needed for the parasite to transform into the pathogenic blood stages. Without these genes, the parasites harmlessly multiply in the liver, induce a powerful immune response that is many-fold more potent than that achieved by PfSPZ Vaccine, and spontaneously disintegrate without causing blood stage infection, the stage of the parasite life cycle responsible for both disease and transmission. The vaccine is therefore anticipated to block all malaria-related disease and prevent ongoing transmission. Based on the excellence safety results from PfSPZ Vaccine, PfSPZ-LARC2 Vaccine is also expected to be safe and well tolerated. Because of its increased potency, it is anticipated that PfSPZ-LARC2 Vaccine administered pre-conception will show even better efficacies than those documented with PfSPZ Vaccine in the Mali trial.
SIGHTM is also supporting Sanaria’s bid to save the lives of children. There are two partially effective vaccines against this parasitic infection already in use in sub-Saharan Africa, called RTS,S and R21, for use in infants and young children. Like current COVID-19 vaccines, RTS,S and R21 provide partial efficacy against severe disease and death, but do not demonstrate significant efficacy against Pf infection. The World Health Organization has called for much more potent malaria vaccines, setting a target of >90% efficacy. PfSPZ-LARC2 Vaccine is designed to meet this objective. The first trial of PfSPZ-LARC2 Vaccine in children will begin in March, 2025, in Burkina Faso.
The third vulnerable population, malaria-naive international travelers, should also benefit from PfSPZ-LARC2 Vaccine. A recently published study from the Netherlands reports that a prototype gene knock-out vaccine similar to PfSPZ-LARC2 Vaccine was safe, well tolerated, and protected 90% of adults against CHMI after a single vaccine dose. To provide high level protection for weeks after a single injection would be an ideal method to protect travelers to Africa from Pf, replacing chemoprophylaxis during their travel and after returning to the USA.
Ultimately, SIGHTM envisions the use of mass vaccination programs in which a large percentage of the population in a geographic area will be administered PfSPZ-LARC2 Vaccine. If the coverage is sufficiently high, this should permit the regional elimination of Pf transmission. Once proof-of-principle for regional elimination is demonstrated, plans could be made for country by country and eventually global malaria eradication.