Safety, tolerability, and parasite clearance kinetics in controlled human malaria infection after direct venous inoculation of Plasmodium falciparum sporozoites : a model for evaluating new blood-stage antimalarial drugs

Plasmodium falciparum sporozoite (PfSPZ) direct venous inoculation (DVI) using cryopreserved, infectious PfSPZ (PfSPZ Challenge [Sanaria, Rockville, Maryland]) is an established controlled human malaria infection model. However, to evaluate new chemical entities with potential blood-stage activity, more detailed data are needed on safety, tolerability, and parasite clearance kinetics for DVI of PfSPZ Challenge with established schizonticidal antimalarial drugs. This open-label, phase Ib study enrolled 16 malaria-naïve healthy adults in two cohorts (eight per cohort). Following DVI of 3,200 PfSPZ (NF54 strain), parasitemia was assessed by quantitative polymerase chain reaction (qPCR) from day 7. The approved antimalarial artemether-lumefantrine was administered at a qPCR-defined target parasitemia of ≥ 5,000 parasites/mL of blood. The intervention was generally well tolerated, with two grade 3 adverse events of neutropenia, and no serious adverse events. All 16 participants developed parasitemia after a mean of 9.7 days (95% CI 9.1–10.4) and a mean parasitemia level of 511 parasites/mL (95% CI 369–709). The median time to reach ≥ 5,000 parasites/mL was 11.5 days (95% CI 10.4–12.4; Kaplan–Meier), at that point the geometric mean (GM) parasitemia was 15,530 parasites/mL (95% CI 10,268–23,488). Artemether-lumefantrine was initiated at a GM of 12.1 days (95% CI 11.5–12.7), and a GM parasitemia of 6,101 parasites/mL (1,587–23,450). Mean parasite clearance time was 1.3 days (95% CI 0.9–2.1) and the mean log(10) parasite reduction ratio over 48 hours was 3.6 (95% CI 3.4–3.7). This study supports the safety, tolerability, and feasibility of PfSPZ Challenge by DVI for evaluating the blood-stage activity of candidate antimalarial drugs

Safety and immunogenicity of a measles-vectored SARS-CoV-2 vaccine candidate, V591 / TMV-083, in healthy adults: results of a randomized, placebo-controlled Phase I study

International audienceBackground V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein.Methods We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a dou- ble-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each compris- ing 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 £ 105 median Tissue Culture Infectious Dose [TCID50]), one or two injections of a high dose vaccine (1 £ 106 TCID50), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immuno- genicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298.Findings Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment- related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiv- ing the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine.Interpretation While V591 was generally well tolerated, the immunogenicity was not sufficient to support further development