Safety, Tolerability and Efficacy of PfSPZ-LARC2 Vaccine Against CHMI 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 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.

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

Study Officials

• Peter Kremsner, MD

  Universitätsklinikum Tübingen Institut für Tropenmedizin

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Peter Kremsner, MD

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: March 12, 2026
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: June 22, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)