First-in-Human PfSPZ-LARC2 Vaccination/CHMI

NCT06735209 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 23-00105UM1AI148684-04
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This randomized, double-blind, placebo-controlled, Phase 1 trial will enroll up to 22 malaria-naïve, adult participants to test safety, tolerability, immunogenicity, and efficacy of the genetically attenuated Plasmodium falciparum sporozoite vaccine (PfSPZ-LARC2) Vaccine. PfSPZ-LARC2 Vaccine is a late-arresting, replication-competent whole Plasmodium falciparum sporozoite product. We hypothesize that the PfSPZ-LARC2 Vaccine will be safe from breakthrough infection by virtue of deletion of two key parasite genes Mei2 and LINUP and may be more immunogenic and protective than previously tested early arresting sporozoite vaccines. The primary objective is to assess the tolerability and safety of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation.

Conditions

Malaria

Keywords

Artemether/lumefantrine (Coartem(R)); Atovaquone/proguanil (Malarone(R)); CHMI; controlled; First-in-human; Malaria; Plasmodium falciparum; Saline; Sanaria(R) PfSPZ Challenge (7G8); Sanaria(R) PfSPZ-LARC2; Sentinel; Vaccine

Outcome Measures

Primary Outcomes (7)

• Occurrence of Grade 3 laboratory toxicities related to vaccination

  Through 14 days after the last vaccination

• Occurrence of serious adverse events (SAEs) considered related to vaccination

  Through 180 days post-CHMI

• Occurrence of solicited local adverse events (AEs) related to the vaccine

  Through 6 days after each vaccination

• Occurrence of solicited systemic adverse events (AEs) related to the vaccine

  Through 6 days after each vaccination

• Occurrence of unsolicited adverse events (AEs) considered related to vaccination

  Through 28 days after the last vaccination

• Proportion of participants with breakthrough blood-stage infection

  defined as two positive qRT-PCR assays with at least one parasite density of \>/=250 estimated parasites/mL from blood samples obtained at least six hours apart or a positive Thick Blood Smear (TBS)

  Through 28 days after last vaccination

• Solicited systemic adverse event (AE) related to the breakthrough infections

  Through 28 days after each vaccination

Secondary Outcomes (3)

• Median Net Optical Density (OD) 1.0 IgG antibodies to Plasmodium falciparum Circumsporozoite Protein (PfCSP)

  Up to 16 weeks post-vaccination

• Percentage of malaria specific CD4+, CD8+, and gamma delta T cells expressing IFN-gamma and/or IL-2

  Up to 16 weeks post-vaccination

• Proportion of participants with Malaria infection following Controlled Human Malaria Infection (CHMI)

  Through 28 days following Controlled Human Malaria Infection (CHMI)

Study Arms (4)

Group 1

EXPERIMENTAL

Healthy malaria-naïve participants aged between 18 and 45 years will receive 2x10\^5 PfSPZ of Plasmodium falciparum sporozoite vaccine (PfSPZ-LARC2) vaccine on Days 1, 29, and 57 followed by 3.2x10\^3 PfSPZ Challenge (7G8) Controlled Human Malaria Infection (CHMI) on Day 169 administered by direct venous inoculation (DVI). Placebo participants that drop out prior to CHMI will be replaced with infectivity controls. Infectivity controls will receive PfSPZ Challenge (7G8) CHMI N=3

Biological: PfSPZ Vaccine; Biological: PfSPZ (7G8) Challenge

Group 2

PLACEBO COMPARATOR

Healthy malaria-naïve participants aged between 18 and 45 years will receive saline placebo on Days 1, 29, and 57 followed by 3.2x10\^3 PfSPZ Challenge (7G8) Controlled Human Malaria Infection (CHMI) on Day 169 administered by direct venous inoculation (DVI). Placebo participants that drop out prior to CHMI will be replaced with infectivity controls. Infectivity controls will receive PfSPZ Challenge (7G8) CHMI N=1

Biological: PfSPZ (7G8) Challenge; Other: Sodium Chloride, 0.9%

Group 3

EXPERIMENTAL

Healthy malaria-naïve participants aged between 18 and 45 years will receive 2x10\^5 PfSPZ of Plasmodium falciparum sporozoite vaccine (PfSPZ-LARC2) vaccine on Days 1, 29, and 57 followed by 3.2x10\^3 PfSPZ Challenge (7G8) Controlled Human Malaria Infection (CHMI) on Day 141 administered by direct venous inoculation (DVI). Placebo participants that drop out prior to CHMI will be replaced with infectivity controls. Infectivity controls will receive PfSPZ Challenge (7G8) CHMI N=12

Biological: PfSPZ Vaccine; Biological: PfSPZ (7G8) Challenge

Group 4

PLACEBO COMPARATOR

Healthy malaria-naïve adult participants with no prior history of malaria vaccine study involvement and no exposure to Plasmodium parasites in the past two years, aged between 18 and 45 years will receive saline placebo on Days 1, 29, and 57 followed by 3.2x10\^3 PfSPZ Challenge (7G8) Controlled Human Malaria Infection (CHMI) on Day 141 administered by direct venous inoculation (DVI). Placebo participants that drop out prior to CHMI will be replaced with infectivity controls. Infectivity controls will receive PfSPZ Challenge (7G8) CHMI N=6

Biological: PfSPZ (7G8) Challenge; Other: Sodium Chloride, 0.9%

Interventions

PfSPZ Vaccine BIOLOGICAL

PfSPZ is a candidate vaccine, it consists of a suspension of purified, live-attenuated cryopreserved Pf sporozoites in a cryoprotectant.

Group 1; Group 3

PfSPZ (7G8) Challenge BIOLOGICAL

PfSPZ (7G8) Challenge consists of cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) that have been developed to be used to infect volunteers in controlled human malaria infection (CHMI) to assess the efficacy of antimalarial drugs and vaccines. The PfSPZ Challenge (7G8) contains a laboratory malaria clone derived from Brazil.

Group 1; Group 2; Group 3; Group 4

Sodium Chloride, 0.9% OTHER

0.9% Sodium Chloride Injection

Group 2; Group 4

Eligibility Criteria

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

You may qualify if:

• Provides written informed consent prior to the initiation of any study procedures.
• Able to understand and agrees to adhere to all planned study procedures and be available for all study visits.
• Male or non-pregnant female, 18 to 45 years of age (inclusive) at time of enrollment.
• BMI 18.0-35.0 kg/m\^2 at screening.
• Females of childbearing potential\* must agree to use or have practiced true abstinence\*\* or use at least one acceptable primary form of contraception\*\*\*,\*\*\*\*,\*\*\*\*\* Note: These criteria are applicable to females in a heterosexual relationship and child-bearing potential (i.e., the criteria do not apply to participants in a same sex relationship).
• \*Not of childbearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy, or Essure(R) placement).
• \*\*True abstinence is 100 percent of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception). If true abstinence changes, then participant agrees to use at least one form of acceptable primary contraception.
• \*\*\*Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more prior to the participant's enrollment visit (Visit 1), intrauterine devices, birth control pills, barrier methods with spermicide and injectable/implantable/insertable hormonal birth control products.
• Must use at least one acceptable primary form of contraception for at least 30 days prior to the enrollment visit (Visit 1) and at least one acceptable primary form of contraception for 60 days after the last vaccination or until 28 days post-CHMI, whichever is later.
• If the participant is treated with Coartem(R) (artemether/lumefantrine - second-line anti-malarial treatment in this study), participants must agree to add an additional barrier method of contraception during treatment.
• Females of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to enrollment.
• Males of childbearing potential: use condoms with a female partner of childbearing potential from their enrollment visit (Visit 1), to 60 days after last vaccination or 28 days post-Controlled Human Malaria Infection (CHMI), whichever is later.\*,\*\*
• \*This does not apply to males in an exclusively same-sex relationship.
• \*\*Biological males who are post-pubertal and considered fertile until permanently sterile by bilateral orchiectomy or vasectomy.
• Male participants agree to refrain from sperm donation from the time of first vaccination until 60 days after the last vaccination or until 28 days post-CHMI, whichever is later.

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 malaria infection within 2 years prior to study participation.
• History of a splenectomy or sickle cell disease.
• History of a non-febrile seizures or complex febrile seizures.
• Current use of systemic immunosuppressant/immunomodulatory pharmacotherapy.
• Receipt of a live vaccine within 4 weeks of first vaccination or of 3 or more non-live vaccines within 2 weeks of first vaccination.
• Receipt of a live vaccine within 4 weeks of CHMI for infectivity controls or of 3 or more non-live vaccines within 2 weeks of CHMI for infectivity controls.
• Females who are breast-feeding, pregnant or planning to become pregnant during the study period.
• Known allergy to atovaquone-proguanil (Malarone(R)), artemether-lumefantrine (Coartem(R)), or any component of the investigational products.
• History of anaphylaxis or other life-threatening reaction to a vaccine.
• Participation in any study of investigational vaccine/drug \<4 weeks before enrollment that in the estimation of the site PI might adversely affect safety or data quality.
• Evidence of increased cardiovascular disease risk (defined as \>10 percent five-year risk by non-laboratory method or prior history of myocardial infarction or myocarditis.
• Plan to participate in another investigational vaccine/drug research during the study.
• Plan for major surgery between enrollment until 28 days post-CHMI.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

The University of Washington - Virology Research Clinic

Seattle, Washington, 98104, United States

Location

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Clinic Study Staff (except for Pharmaceutical Operations), Study Statistician and Lab staff will be unaware of the treatment group assignment. Products for administration will be indistinguishable to the participants, the persons administering vaccine, and persons conducting laboratory assays, and this blinding will be maintained by study staff for clinical evaluations thereafter until after the CHMI phase is completed.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2024
• First Posted: December 16, 2024
• Study Start: July 23, 2025
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): March 30, 2027
• Last Updated: May 1, 2026

Record last verified: 2025-05-20

Locations

US (1)