Sanaria, Inc.

This is a phase 2 clinical trial of a Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) vaccine (Sanaria® PfSPZ-LARC2 Vaccine) that will assess field efficacy in Africa.
The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double deletion of the genes encoding the Mei2 and LINUP proteins, both of which are required for transition from liver to blood stage malaria. As a result, mei2-/linup- parasites undergo developmental arrest in the late liver stages without releasing merozoites into the blood stream. No blood stage parasites are produced, either asexual or sexual, and the parasite life cycle does not progress. Because Pf parasites with the LARC phenotype replicate in the liver before disintegrating, they amplify and diversify parasite protein expression and are expected to be a potent immunogen to induce anti-malarial immunity, equaling or exceeding the potency and efficacy of the replication-competent chemo-attenuated Sanaria® PfSPZ-CVac (chloroquine) vaccine approach. Because the parasites are intrinsically attenuated, they are expected to be safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine, to the replication deficient, early arresting PfSPZ-GA1 Vaccine, and to the single-gene(mei2)-deleted GA2 (LARC1) parasites tested at the Leiden University Medical Center that provided 90% protection against CHMI after a single dose.
The active treatments to be assessed for efficacy are one immunization of 6.0x10^5 PfSPZ or two immunizations with 4.0x10^5 PfSPZ of PfSPZ-LARC2 Vaccine four weeks apart, timed so that the immunization of the one dose regimen coincides with the second immunization of the two dose regimen.
The alternative treatment is immunization with normal saline (placebo group), which is indistinguishable from the test article.
The primary variable of interest is whether and when trial participants develop Pf malaria parasitemia during surveillance. Malaria parasitemia will be detected by thick blood smear (TBS), which will be performed every two weeks starting two weeks after the second vaccination (to allow time for the vaccine to work) and extending to week 26 after the second vaccination (24-week surveillance period). Surveillance will continue for 40 weeks but the primary outcome will be determined at 24 weeks of surveillance so the data are comparable to other studies of PfSPZ vaccines.

This is a first-in-human, randomized, double-blind, placebo-controlled Phase 1 trial of Plasmodium falciparum (Pf) sporozoite (SPZ) late-arresting replication-competent (LARC) malaria vaccine (PfSPZ-LARC2 Vaccine) administered to healthy, malaria-naive study participants in Germany by direct venous inoculation (DVI) to determine safety, tolerability, and vaccine efficacy (VE) against controlled human malaria infection (CHMI). PfSPZ-LARC2 Vaccine contains a deletion of two genes, the Mei2 and LINUP genes, and undergoes developmental arrest in the late liver stages without releasing merozoites into the blood stream (blood stage parasites).
The primary objective of the study is to assess the safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population.
Studies of PfSPZ-LARC2 in FRG mice indicate that Plasmodium falciparum LARC2 parasites halt development in their late liver life cycle stages and do not generate viable merozoites able to initiate blood stage infection. Attenuation in this assay system has been a good predictor of attenuation in humans, indicating that blood stage infection in this trial of PfSPZ-LARC2 Vaccine will not occur. Recent data from Leiden University where a Mei2 single deletion parasite was administered to human participants by mosquito bite confirmed that removing this single gene by itself confers complete attenuation. PfSPZ-LARC2 Vaccine has both Mei2 and LINUP deleted, so it should be completely attenuated.
In order to better understand what side effects might look like, on the small chance that PfSPZ-LARC2 Vaccine is not adequately attenuated, it is important to briefly describe the safety data from studies of PfSPZ-CVac (chloroquine), a whole Plasmodium falciparum sporozoite (PfSPZ) immunization approach that uses cGMP produced, aseptic, purified, cryopreserved, non-attenuated, fully infectious PfSPZ administered under chloroquine cover. This is because the safety and tolerability data from PfSPZ-CVac represent a worst case scenario for what could happen with PfSPZ-LARC2 Vaccine with respect to safety and tolerability, as recipients of PfSPZ-CVac always have blood stage infection after the first immunization, even if small doses are administered. The current standard regimen in malaria-naive adults receiving PfSPZ-CVac is 2.0x10^5 PfSPZ, 62.5-fold higher than the 100% infective dose for controlled human malaria infection (CHMI) in malaria-naive individuals, which is 3.2x10^3 PfSPZ. The blood stage infection is detectable by ultrasensitive qPCR on days 7 to 9 after PfSPZ administration and then clears due to the schizonticidal action of chloroquine. Doses used for PfSPZ-CVac have been escalated to as high as 2x10^5 PfSPZ in malaria-naive adults and 4.0x10^5 PfSPZ in malaria-exposed adults, and are generally well tolerated; however, some individuals experienced symptoms of malaria on days 7 and 8 during the period of transient parasitemia, including Grade 3 adverse events, which can largely be prevented by the administration of drugs such as ibuprofen, naproxen or acetaminophen starting the morning of day 7 or after symptoms appear. Once the first dose of 2x10^5 PfSPZ is administered, immunity develops rapidly, and when the second and third doses are administered at 4-week intervals, there have been no Grade 3 adverse events recorded even in the absence of ibuprofen, naproxen or acetaminophen.
These data from PfSPZ-CVac are relevant because they represent a possible worst-case scenario for PfSPZ-LARC2 Vaccine. In other words, even if the attenuation of PfSPZ-LARC2 parasites is not realized in vivo, the density of parasitemia should not be any higher nor the tolerability any worse than what has already been experienced with non-attenuated PfSPZ-CVac administered at the same PfSPZ dose. On the contrary, we would expect the percentage of participants with a blood stage infection to be lower following PfSPZ-LARC2 Vaccine administration due to its intrinsic attenuation than with non-attenuated PfSPZ, and in individuals with a blood stage infection, the numbers of parasites released from the liver to be lower than with non-attenuated PfSPZ.
This will be the first assessment of PfSPZ-LARC2 Vaccine in humans. While we anticipate that vaccine efficacy (VE) in humans will be similar to that of PfSPZ-CVac, we have no data at this point, and it will be important to collect these comparative data. However, in the Leiden trial, where the Mei2 single knockout called GA2 was administered by mosquito bite, there was good protection after 3 immunizations by exposure to 50 infected mosquitoes (8/9 participants protected against homologous CHMI using 5 infected mosquitoes).

This is a single centre, randomized, placebo-controlled phase 1/2 study comparing two malaria vaccine candidates. The first vaccine candidate PfSPZ-CVac (Plasmodium falciparum sporozoites (PfSPZ) challenge administered with a chemoprophylactic antimalarial) will be chemoattenuated in vivo with the antimalarial Pyramax. The second vaccine candidate is prime- target vaccination with viral vectored vaccine candidate regime MVA ME-TRAP (Modified Vaccinia Ankara (MVA) multiple epitope thrombosponin-related adhesion protein (ME-TRAP)) and ChAd63 ME-TRAP (Chimpanzee adenovirus 63 (ChAd63). The safety and protective efficacy of both vaccine candidates will be to assessed by controlled human malaria infection with PfSPZ Challenge strain NF54 administered intravenously by syringe.