Seguridad, tolerabilidad y eficacia contra la infección controlada de la malaria humana de la vacuna PFSPZ-LARC2 en adultos no siete de malaria (LARC-Tu)

This is a randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial in two parts, with the performance and design of Part B conditional on the outcome of Part A. Each study part includes two staggered cohorts (-1, -2). CHMI in the second cohort will be initiated only after at least 14 days have elapsed since the CHMI of cohort 1 and after confirmation that no CHMI-related SAEs have occurred in cohort 1. According to the study schedule, this results in an approximately 2 week delay in the start of vaccination for cohort 2 relative to cohort 1.

In Part A-1, eligible healthy participants will receive a 3-dose immunization regimen with 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine (n=10) or normal saline (n=2) administered on Days 1, 6 and 29. Participants will be followed up for parasitemia and adverse events after immunization. After immunizations on Day 1 (V1) and Day 6 (V2 = V1+5), qPCR and thick blood smears (TBS) will commence to monitor for P. falciparum blood stage infections. These will be done every other day from Day 7 (V1+6) to Day 23 (V1+22) and on Day 28 (V1+27), and then weekly thereafter until two weeks after the third immunization given at Day 29 (V1+28), noting that the chance of breakthrough1 should be much reduced after the first and second immunizations due to the development of immunity. Participants will be instructed to contact the clinical staff if they develop any signs or symptoms suggestive of malaria parasite infection.

Two weeks after the last Part A-1 study participant has received the first vaccination (V1), vaccinations in Part A-2 will begin using the same dose and regimen as in Part A-1. In Part A-2, 8 participants will receive PfSPZ-LARC2 Vaccine, and 1 participant will receive saline as placebo. The follow-up schedule will be identical to that in Part A-1.

Three weeks after the third immunization (V3), corresponding to 8 weeks after first immunization, at Day 50 (V1+49), the 12 participants of Part A-1 will undergo heterologous CHMI using DVI of 3.2x10^3 PfSPZ Challenge (7G8). The follow-up for CHMI is described below. CHMI in the Part A-2 cohort will be initiated only after at least 14 days have elapsed since the last CHMI in Part A-1 and after confirmation that no CHMI-related SAEs have occurred in Part A-1.

Following Part A (Part A-1 and Part A-2), an unblinded interim analysis will be conducted. The goal is to achieve 100% protection against heterologous CHMI at 3 weeks after the third immunization. This parallels what 2x10^5PfSPZ of PfSPZ-CVac (chloroquine) achieved against heterologous CHMI using the same dose of PfSPZ [1]. The outcome of CHMI will determine what is done for Part B.

If any vaccinee in Part A develops Pf parasitemia following CHMI, indicating that the PfSPZ-LARC2 Vaccine dose might not be sufficiently protective, and if the safety monitoring committee (SMC) and the ethics committee agree to continue with the study, the study will proceed to Part B in which the dose of PfSPZ-LARC2 Vaccine will be doubled to 4x10^5 PfSPZ.

The rationale for Part B is that protection may be improved by using a higher dose for immunization. The dose of 4x 10^5 PfSPZ is supported by previous clinical experience with comparable PfSPZ-based products. A dose of 4x10^5 fully infectious, non-attenuated PfSPZ administered as PfSPZ-CVac has previously been evaluated in 158 African adults and was well tolerated. In addition, 4x10^5 PfSPZ-LARC2 Vaccine has been administered to 12 adults in Burkina Faso (NCT06652737) without emerging safety concerns. Further clinical evaluation of PfSPZ-LARC2 Vaccine is ongoing in Burkina Faso, including Day 1 and Day 28 administrations of 4x10^5 PfSPZ-LARC2 Vaccine as well as once a higher dose of 6x10^5 PfSPZ-LARC2 Vaccine (NCT07385287); immunizations have been completed and the available safety experience to date is favourable. 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. Taken together, the available clinical experience with PfSPZ-based vaccines supports the proposed dose increase, and no specific safety concern is anticipated from administration of 4x 105 PfSPZ-LARC2 Vaccine.

In comparison to and based on the results of Part A, Part B will be adapted in regards to the immunization schedule, and CHMI timing. Participants will receive 4x10^5 PfSPZ-LARC2 Vaccine or placebo on Days 1, 29, and 57. After the first vaccination V1, breakthrough monitoring will start on Day 6 and will be performed every second day until Day 21 and Day 28. After the second (V2) and third vaccination (V3), breakthrough monitoring will be performed at 7, 14, 21 and 27 days following each vaccination. Monitoring will include clinical assessment and parasitological testing according to the protocol. Heterologous CHMI with PfSPZ Challenge (7G8) will be performed 12 weeks after the third immunization. The CHMI dose, challenge strain, route of administration, diagnostic monitoring, rescue treatment criteria, pausing rules, and SMC oversight remain unchanged. Beyond safety and tolerability, the aim of the adapted Part B schedule is to assess whether the same vaccine dose administered according to a monthly immunization regimen provides improved protective efficacy compared with the condensed schedule evaluated in Part A. The longer intervals between vaccinations also allow more time for the development of vaccine-induced immune responses, without presuming a specific underlying mechanism. The interval between the third vaccination and CHMI was extended to 12 weeks, consistent with the timing used in the majority of previous PfSPZ DVI CHMI studies and allowing assessment of protection at a later time point after completion of the vaccination regimen.

Additional safety evaluations: Although blood stage infection is a focus of the safety evaluation, local and systemic adverse events (AE) and laboratory abnormalities are equally important and will be recorded. Solicited local and systemic AEs will be followed after each immunization (for 7 days each) 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, liver enzymes creatinine) 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 (7G8) administration for CHMI solicited local and systemic AEs will be followed for seven days as before, and unsolicited AEs will be monitored through day C+30 to assess the tolerability of any parasitemias that develop in challenged clinical trial participants. In addition, during the period of any antimalarial treatment, unsolicited adverse events will be monitored. Serious adverse events (SAEs) will be followed throughout the study.

CHMI and last study visit: The follow-up for CHMI (C) will be for 21 days, with daily qPCR performed from Day 56-63, 65, 67, 69, 71 post V1 (Part A) or Day 147-154, 156, 158, 160 post V1 (Part B) (corresponding to days C+6 to days C+13 and then every other day until day C+21). TBS will be done and read concurrently as described above. On days when blood is not sampled for qPCR, participants will be telephoned for a symptom check, and if symptomatic, qPCR and TBS will be performed on these unscheduled days. Those developing parasitemia by qPCR and TBS will be treated under direct observation with a three-day regimen of atovaquone/proguanil or artemether/lumefantrine. Any participant still negative on Day 71(Part A) or Day 162 (Part B) (day C+21) will be treated with atovaquone/proguanil under direct observation as a safety precaution on Day 71, Day 72, and Day 73 (Part A) and Day 162, Day 163, and Day 164 (Part B) (days C+21, +22, +23). If not achieved within 3 days of treatment, follow-up continues until two consecutive qPCR samples show declining parasitemia. All participants will have a last study visit (LSV) on day C+30 (Day 80 (Part A) or Day 171 (Part B)) with a physical examination, safety labs, AE and SAE review, and qPCR to confirm absence parasitemia and immunology sampling. Prior to treatment on day C+21, a thick blood smear (TBS) will be obtained for retrospective reading.