Safety, Tolerability and Efficacy Against Controlled Human Malaria Infection of PfSPZ-LARC2 Vaccine in Malaria-naïve Adults

This is a first-in-humans, randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial in two parts, with the performance of Part B conditional on the outcome of Part A. In Part A, eligible healthy participants (N = 5) will be enrolled as a sentinel group that receives a single dose of 2x105 PfSPZ of PfSPZ-LARC2 Vaccine by direct venous inoculation (DVI) on Day 1 and will be followed for 28 days (to Day 29) to identify any breakthrough infections. If there are no breakthrough infections by Day 29, the main cohort (n = 24) will undergo immunization. Participants in the verum group (n = 18) of the main cohort will also receive 2x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 2x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine or normal saline administered on Days 1, 6 and 29. Participants in both the sentinel group and main cohort will be followed up for parasitemia and adverse events after immunization. After the first immunization on Day 1 in the sentinel group, qPCR will be performed to monitor for P. falciparum blood stage infections daily from Day 7 (day +6) to Day 21 (day +20) and then every other day to Day 29 (day +28) when terminal treatment begins. Thick blood smears (TBS) to monitor for blood stage parasitemia by microscopy will be made on the days that qPCR is performed and read in real-time. TBS will also be done whenever the physician investigator requests a rapid diagnostic test (for whatever reason). If blood stage parasitemia is not detected during 28 days of follow-up of the sentinel group, the participants will be treated presumptively under direct observation with a three day regimen of atovaquone-proguanil or artemether-lumefantrine), to assure malaria-free status at the end of their participation in the trial. As soon as the Day 29 qPCR of the sentinel volunteers is determined to be negative, the 24 participants of the main cohort may receive their first immunization with PfSPZ-LARC2 Vaccine or placebo. Following a first immunization on Day 1, the main cohort will receive a second immunization five days later, on Day 6. The qPCR follow-up for the first immunization begins on the next day (Day 7) and will be performed daily from Day 7 (day +6) to Day 12 (day +11), then every other day to Day 22 (day +21) and then weeky thereafter until four weeks after the third immunization, noting that the chance of breakthrough should be much reduced after the first and second immunizations due to the development of immunity. TBS will be performed concurrently as described above and read in real-time. Twelve weeks after the third immunization dose, the 24 main cohort participants will undergo homologous CHMI using DVI of 3.2x103 PfSPZ of PfSPZ Challenge (NF54). The follow-up for CHMI is described below. The outcome of CHMI will determine what is done for Part B. As the goal is to achieve 100% protection against homologous CHMI at 12 weeks (this parallels what 2x10\^5PfSPZ of PfSPZ-CVac (chloroquine) achieved against heterologous CHMI using the same dose of PfSPZ), if any vaccinee in Part A develops Pf parasitemia following CHMI, and if the safety monitoring committee (SMC) has recommended that the study should continue, the study will proceed to Part B in which the dose of PfSPZ-LARC2 Vaccine will be doubled to 4x10\^5 PfSPZ. In other respects, Part B will be the same as Part A, with a sentinel group receiving one dose, and the main cohort three doses on Days 1, 6 and 29, and all 24 participants from the main cohort undergoing CHMI 12 weeks later using standard DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54) as in Part A. The rationale for Part B is that protection may be improved by using a higher dose for immunization. This dose of 4x10\^5 PfSPZ has been administered using the fully infectious, non-attenuated PfSPZ of PfSPZ-CVac to 158 adult Africans and was well tolerated. Moreover, doses of fully attenuated (irradiated) PfSPZ as high as 2.7x10\^6 - 6.75-fold higher than the 4x10\^5 PfSPZ dose proposed here - have been administered to both malaria-naive and malaria-exposed adults and were well tolerated. Thus, we do not expect safety issues to be associated with this dose. Definition of blood stage parasitemia during the immunization phase: qPCR following immunization may be transiently positive early on during follow-up by detecting circulating parasite nucleic acids released from infected hepatocytes, even if there are no viable parasites released into the blood. Thus, an early positive qPCR signal will not be considered an indication of presence of blood stage parasite infection. Rather, the trial will require a qPCR signal that crosses a pre-determined threshold of 1x10\^2 parasites/mL on one qPCR result and then registers an at-minimum 4 times higher value on a subsequent result after at least 48 hours to be recognized as failure in genetic attenuation of PfSPZ-LARC2 Vaccine. This will be counted as blood stage infection whether or not the participant experiences symptoms. A positive TBS will also be considered an indication of blood stage parasite infection. In case of blood stage infection during immunization phase: If the qPCR threshold for blood stage infection is met in any participants or a TBS is positive, they will be treated. The SMC and the clinical and IND Sponsors will be convened. The SMC, Clinical Sponsor and IND Sponsor will decide on the continuation of the study participant with immunization and/or CHMI procedures as well as on the continuation of the overall study. Additional safety evaluations: Although blood stage infection is the primary focus of the safety evaluation, adverse events will be recorded. Solicited local AEs will be followed for seven days after each immunization, solicited systemic AEs will be followed from the first vaccination until 28 days after the last immunization, and unsolicited AEs will also be followed from the first vaccination until 28 days after the last immunization. In addition, laboratory testing (complete blood count, creatinine, aspartate aminotransferase) will be done before each of the three immunizations and during the follow-up period to assess laboratory abnormalities. Finally, at the day of PfSPZ Challenge administration for CHMI solicited local AEs will be followed for seven days, solicited systemic AEs will be followed for seven days, and unsolicited AEs will be monitored through day +21 to assess the tolerability of any parasitemias that develop in challenged research participants. In addition, during the period of any antimalarial treatment and continuing for three days after the last day of treatment, solicited systemic adverse events will be monitored. Serious adverse events (SAEs) and medically-attended adverse events (MAAEs) will be followed throughout the study. CHMI and last study visit: The follow-up for CHMI in the main groups will be for 21 days, with daily qPCR and TBS performed from CHMI day +6 to day +21 (corresponds to CHMI Day 7 to CHMI Day 22). Those developing parasitemia by qPCR or TBS will be treated under direct observation with a three day regimen of atovaquone-proguanil or artemether-lumefantrine. Any participant still negative on CHMI day +21 will be treated under direct observation as a safety precaution on CHMI day +21, day +22 and day +23, with the last in-person study visit on day CHMI+23 (corresponds to CHMI Day 24). If qPCR is positive on day +23, however, daily qPCR will continue until there have been two consecutive negative days. There will be one additional study interview six months after last immunization in all groups, which may be done by telephone call, to make sure all participants remain in good health. Definition of parasitemia during the challenge phase: Parasitemia following CHMI is defined as one qPCR result above 1x10\^2 parasites/mL after CHMI with PfSPZ Challenge or a positive TBS.