Safety, Tolerability and Efficacy Against Controlled Human Malaria Infection of PfSPZ-LARC2 Vaccine in Malaria-naïve Adults
Sanaria Inc.
58 participants
Apr 1, 2026
INTERVENTIONAL
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).
Eligibility
Inclusion Criteria8
- 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.
Exclusion Criteria29
- 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.
- Anticipated use of medications known to:
- Be substrates, inhibitors or strong inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, and/or St. John's wort) \[strong inducers of CYP3A4 when taken concomitantly with artemether and/or lumefantrine can result in decreased concentration(s) and loss of antimalarial efficacy\].
- Be metabolized by the cytochrome enzyme CYP2D6 (e.g., primaquine, tafenoquine, flecainide, imipramine, amitriptyline, clomipramine).
- Have a mixed effect on CYP3A4 (e.g., antiretrovirals).
- Prolong the QT interval (e.g., quinine, quinidine, halofantrine, mefloquine, procainamide, disopyramideamiodarone, sotalol, pimozide, ziprasidone, tetracycline, doxycline, fluoroquinolone, imidazole, and triazole antifungal agents). Note: in the case of halofantrine, this drug may not be used within a month of artemether/lumefantrine due to its very significant effect on QT interval.
- Positive HIV, HBsAg or HCV serology.
- An abnormal electrocardiogram, defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions, but excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block; or other clinically significant abnormalities on the electrocardiogram.
- History of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
- Family history (grandparents, parents or siblings) of congenital prolongation of the QT interval or sudden death.
- History of disturbances of the electrolyte balance (e.g., hypokalemia or hypomagnesemia).
- History of severe renal impairment (creatinine clearance <30 mL/min) (risk of pancytopenia in patients with severe renal impairment treated with proguanil).
- History of chronic liver disease.
- Any clinically significant deviation from the normal range in biochemistry or hematology tests measured at screening and not resolving.
- Any medical, psychiatric, social, behavioral or occupational condition or situation (including active alcohol or drug abuse) that, in the judgment of the site PI, impairs the participant's ability to give informed consent, increases the risk to the participant of participation in the study, affects the ability of the participant to participate fully in the study, or might negatively impact the quality, consistency, integrity or interpretation of data derived from their participation in the study. This includes persons in emergency situations such as refugees.
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Interventions
The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI.
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).
Main cohort participants will undergo homologous CHMI using DVI of 3.2x10\^3 PfSPZ of PfSPZ Challenge (NF54), which are infectious cryopreserved Pf sporozoites.
Locations(1)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT06862453