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

NCT06862453 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: DESPZL1
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Malaria Falciparum

Keywords

malaria; Plasmodium falciparum; PfSPZ-LARC2 Vaccine

Outcome Measures

Primary Outcomes (3)

• Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: infection

  Number of trial participants with blood stage infection during the first 28 days after immunization.

  28 days after immunization

• Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: related AEs

  Incidence of at least possibly related grade 3 solicited adverse events (AE) and grade 3 abnormal laboratory values occurring in the 7 days after injection of PfSPZ-LARC2 Vaccine .

  7 days after injection of PfSPZ-LARC2 Vaccine

• Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: related SAEs

  Incidence of related serious adverse events (SAEs)

  Time of first immunization to the end of the study

Secondary Outcomes (2)

• Vaccine Efficacy (VE) (1 minus the risk ratio) against homologous CHMI with PfSPZ Challeng(NF54) conducted 12 weeks after 3rd immunization in the modified ITT (mITT) population

  21 days following CHMI

• Humoral immune responses to PfCSP and their relationship to VE.

  The day before immunization until 21 days post CHMI

Study Arms (6)

Part A Sentinel Group PfSPZ-LARC2

EXPERIMENTAL

A sentinel group of 5 volunteers in part A that receives a single dose of 2x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine by direct venous inoculation (DVI) on Day 1, will be followed for 28 days (to Day 29) to identify any breakthrough infections.

Biological: PfSPZ-LARC2 Vaccine

Part A Main Cohort PfSPZ-LARC2 verum group

EXPERIMENTAL

If there are no breakthrough infections by Day 29 in the sentinel, the verum group in the main cohort (n = 18) will undergo immunization. Participants will receive 2x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose 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 administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54).

Biological: PfSPZ-LARC2 Vaccine; Biological: PfSPZ Challenge (NF54)

Part A Main Cohort Normal Saline control group

PLACEBO COMPARATOR

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 of normal saline administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54). Edit

Other: Normal Saline (Placebo); Biological: PfSPZ Challenge (NF54)

Part B Sentinel Group PfSPZ-LARC2

EXPERIMENTAL

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. A sentinel group of 5 volunteers in part B that receives a single dose of 4x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine by direct venous inoculation (DVI) on Day 1, will be followed for 28 days (to Day 29) to identify any breakthrough infections.

Biological: PfSPZ-LARC2 Vaccine

Part B Main Cohort PfSPZ-LARC2 verum group

EXPERIMENTAL

If there are no breakthrough infections by Day 29 in the sentinel, the verum group in the main cohort (n = 18) will undergo immunization. Participants will receive 4x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 4x10\^5 PfSPZ of PfSPZ-LARC2 Vaccine administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54).

Biological: PfSPZ-LARC2 Vaccine; Biological: PfSPZ Challenge (NF54)

Part B Main Cohort Normal Saline control group

PLACEBO COMPARATOR

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 of normal saline administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54).

Other: Normal Saline (Placebo); Biological: PfSPZ Challenge (NF54)

Interventions

Normal Saline (Placebo) OTHER

The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI.

Part A Main Cohort Normal Saline control group; Part B Main Cohort Normal Saline control group

PfSPZ-LARC2 Vaccine BIOLOGICAL

Plasmodium falciparum (Pf) sporozoite (SPZ) late-arresting replication-competent (LARC) malaria vaccine (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).

Part A Main Cohort PfSPZ-LARC2 verum group; Part A Sentinel Group PfSPZ-LARC2; Part B Main Cohort PfSPZ-LARC2 verum group; Part B Sentinel Group PfSPZ-LARC2

PfSPZ Challenge (NF54) BIOLOGICAL

Main cohort participants will undergo homologous CHMI using DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54), which are infectious cryopreserved Pf sporozoites.

Part A Main Cohort Normal Saline control group; Part A Main Cohort PfSPZ-LARC2 verum group; Part B Main Cohort Normal Saline control group; Part B Main Cohort PfSPZ-LARC2 verum group

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults (male or non-pregnant female) 18 to 45 years of age.
• Able and willing to participate for the duration of the study.
• Able and willing to provide written informed consent.
• Physical examination and laboratory results without clinically significant findings.
• Women of childbearing potential must agree to use effective means of birth control (e.g. oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner) during the entire study.
• Due to the potential for reduced effectiveness of hormonal contraceptives during artemether and/or lumefantrine treatment, participants will be counseled to add an additional barrier method of contraception during treatment.
• Women with a history of surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other) must provide written documentation of the procedure from a health care provider.
• Agree not to travel to a malaria endemic region during the course of the trial.

You may not qualify if:

• Unable to provide informed consent including inability to pass the test of understanding.
• Receipt of a malaria vaccine in a prior clinical trial.
• History of a splenectomy or sickle cell disease.
• History of a neurologic disorder (including non-febrile seizures or complex febrile seizures) or formal history of migraine headache.
• Current use of systemic immunosuppressant pharmacotherapy.
• Receipt of a live vaccine within 4 weeks of first immunization or of 3 or more non-live vaccines within 2 weeks of first immunization.
• Women who are breast-feeding, pregnant or planning to become pregnant during the study period.
• Known allergy or hypersensitivity reaction (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone-proguanil (Malarone®), artemether-lumefantrine (Coartem®), any components of these formulations, or any component of the investigational products.
• History of anaphylaxis or other life-threatening reaction to a vaccine.
• Participation in any study involving investigational vaccine or drug within 4 weeks prior to enrollment that in the estimation of the site PI might adversely affect the individual's safety or the quality of data to be collected.
• Evidence of increased cardiovascular disease risk; defined as \>10% five-year risk by non-laboratory method (Gaziano, 2008) \[80\].
• Plan to participate in another investigational vaccine/drug research during the study.
• Plan for major surgery between enrollment until 28 days post-CHMI.
• Use or planned use of any drug with anti-malarial activity that would precede or coincide with malaria challenge or vaccination.
• Anticipated use of medications known to cause drug reactions with atovaquone-proguanil or artemether-lumefantrine such as tetracycline, rifampin, rifabutin, cimetidine, metoclopramide, antacids, anti-coagulants such as coumarin, indinavir, and kaolin.

Sponsors & Collaborators

• Sanaria Inc.: lead
• Universitätsklinikum Tübingen, Institut für Tropenmedizin Wilhelmstrasse: collaborator
• UCLA David Geffen School of Medicine and Fielding School of Public Health: collaborator
• Stanford University: collaborator
• Leiden University: collaborator

Study Sites (1)

University of Tubingen

Tübingen, D-72074, Germany

RECRUITING

MeSH Terms

Conditions

Malaria, Falciparum; Malaria

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Central Study Contacts

Peter Kremsner, PhD

CONTACT

+49 7071 2987197; peter.kremsner@uni-tuebingen.de

Andrea Kreidenweiss, PhD

CONTACT

+49 7071 2985569; andrea.kreidenweiss@uni-tuebingen.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Access to the unblinded randomization list will be limited exclusively to the syringe preparation team (Pharmaceutical Operations team) and the independent statistician(s) at the data management vendor. These individuals will be unblinded and will not be involved in evaluation or care of the study participants. A copy of participant treatment assignments will be retained at the site in a secure file by the unblinded Pharmaceutical Operations staff.
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 2, 2025
• First Posted: March 6, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: April 16, 2026

Record last verified: 2026-03

Locations

DE (1)