Trial to Evaluate the Safety, Immunogenicity and Protective Efficacy of Three or Five Administrations of GAP3KO Sporozoites

NCT03168854 | Completed Phase 1 FDA Drug

• 1 other identifier: 14-0088
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase 1 trial will include 16 subjects who will receive the Genetically-attenuated p52-/p36-/sap1- Plasmodium falciparum Parasites (GAP3KO) vaccine administered by the bite of approximately 200 infected Anopheles stephensi Mosquitoes in a controlled clinical environment and 12 Controlled Human Malaria Infection (CHMI) infectivity controls (six for each of the two CHMIs). Subjects will be observed for adverse events after each GAP3KO administration. Solicited local and systemic Adverse Events (AEs) will be recorded on a memory aid beginning of the day of first vaccine administration and continuing through 28 days after the last administration. During the vaccination phase clinical laboratory evaluations for safety will be performed on venous blood. Unsolicited AEs will be collected from the day of first vaccination through 28 days after last vaccination and serious adverse events (SAEs) will be collected from the day of first GAP3KO administration through the end of study follow-up. Subjects will be monitored for possible breakthrough peripheral parasitemia with qRT-PCR testing. Four weeks after the last GAP3KO administration, all subjects who completed the immunization phase (up to 16) and a group of six malaria-naïve infectivity controls will be challenged on the same day with wild-type Plasmodium falciparum NF54 sporozoites. Approximately twenty-six weeks after that challenge, all of the protected subjects in Arms 1 and 2 (up to 16) and another six malaria-naïve infectivity controls will receive five infectious A. stephensi mosquito bites on the same day using standard CHMI procedures. For subjects in Study Arms 1 and 2 without documented parasitemia additional post-CHMI follow-ups will occur. For subjects in Study Arms 1 and 2 with documented parasitemia after the first CHMI or who are discontinued for other reasons after the first CHMI, and for the infectivity controls, additional follow ups will occur. Serious Adverse Events (SAEs) will be recorded from the day of CHMI through the end of study follow up and clinical laboratory evaluations for safety will be performed on Day 29 and as clinically indicated (all subjects) and, for subjects with documented parasitemia, on the day malaria treatment is initiated and three days after malaria treatment is initiated. The primary objectives are: 1) To assess the safety and reactogenicity of candidate GAP3KO malaria vaccine when administered by the bite of approximately 200 infected mosquitoes on a five dose schedule, with the first four vaccinations given four weeks apart and the fifth vaccination given eight weeks after the fourth vaccination, and on a three dose schedule, with the second vaccination given four weeks after the first vaccination and the third vaccination given eight weeks after the second vaccination, to healthy malaria-naïve adults aged 18 through 50 years , 2) To confirm attenuation of GAP3KO parasites by assessing the occurrence of breakthrough peripheral parasitemia from the time of first GAP3KO administration through 28 days after last GAP3KO administration.

Conditions

Plasmodium Falciparum Infection

Keywords

Anopheles stephensi Mosquitoes; GAP3KO; Genetically-attenuated; Malaria-Naïve Adults; Phase 1; Plasmodium falciparum

Outcome Measures

Primary Outcomes (6)

• Breakthrough peripheral parasitemia defined as two positive qRT-PCR assays with parasite densities of > /= 20 estimated parasites/mL from blood samples obtained at least six hours apart or a positive TBS

  First GAP3KO administration through 28 days after last GAP3KO administration

• Laboratory toxicities related to vaccination that are classified as Grade 3(Severe). Grade 3 being defined as events that interrupt the subject's usual daily activities and may require systemic drug therapy or other treatment.

  First GAP3KO administration through 14 days after last GAP3KO administration

• Serious adverse events (SAEs) considered related to vaccination

  First GAP3KO administration through the end of study follow-up, up to 20 months after first study visit.

• Solicited local adverse events (AEs)

  First GAP3KO administration through 28 days after last GAP3KO administration

• Solicited systemic adverse events (AEs)

  First GAP3KO administration through 28 days after last GAP3KO administration

• Unsolicited AEs considered related to vaccination

  First GAP3KO administration through 28 days after last GAP3KO administration

Secondary Outcomes (3)

• Documented malaria infection, defined as a positive qRT-PCR assays with parasite densities of > /= 20 estimated parasites/mL, from blood samples obtained at least six hours apart or a positive TBS

  28 days following CHMI

• Frequencies of PBMCs and PBMC subsets secreting specific cytokines on stimulation with whole sporozoites and potentially specific malaria antigens by intracellular cytokine staining (ICS) of cells

  Pre-vax visit, Pre-CHMI visit

• Levels of IgG antibodies to circumsporozoite protein (CSP) measured by ELISA on serum samples

  Pre-vax visit, Pre-CHMI visit

Study Arms (3)

GAP Arm 1

EXPERIMENTAL

10 subjects will receive 5 vaccinations: the GAP3KO vaccine administered by the bite of approximately 200 infected A. Stephensi mosquitoes at weeks 0, 4, 8, 12, and 20 for a maximum cumulative dose of 1000 GAP3KO bites per subject

Biological: Genetically-attenuated p52-/p36-/sap1- Plasmodium falciparum parasite (GAP3KO) strain; Other: Malaria challenge

GAP Arm 2

EXPERIMENTAL

6 subjects will receive 3 vaccinations: the GAP3KO vaccine administered by the bite of approximately 200 infected A. Stephensi mosquitoes at weeks 8, 12, and 20 for a maximum cumulative dose of 600 GAP3KO bites per subject

Biological: Genetically-attenuated p52-/p36-/sap1- Plasmodium falciparum parasite (GAP3KO) strain; Other: Malaria challenge

Malaria-naive Infectivity Control Arm

ACTIVE COMPARATOR

6 healthy volunteers will receive challenge with wild type Plasmodium falciparum NF54 sporozoites through the bites of five infectious A. stephensi moquitoes using standard CHMI procedures

Other: Malaria challenge

Interventions

Genetically-attenuated p52-/p36-/sap1- Plasmodium falciparum parasite (GAP3KO) strain BIOLOGICAL

Genetically attenuated parasite created by triple deletion (GAP3KO) by deleting the P52, P36, and SAP1 genes in the NF54 wild-type (WT) strain of Plasmodium falciparum (Pf p52(-)/p36(-)/sap1(-) GAP).

GAP Arm 1; GAP Arm 2

Malaria challenge OTHER

Exposure to mosquitoes infected with P. falciparum.

GAP Arm 1; GAP Arm 2; Malaria-naive Infectivity Control Arm

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• through 50 years of age, inclusive.
• Able and willing to participate for the duration of the study and able to understand and comply with planned study procedures.
• Able and willing to provide written (not proxy) informed consent.
• Provides informed consent before initiation of any study procedure, correctly answers = / \> 80 percent of questions\* on the post consent quiz and is available for all study visits.
• \*Subjects who score less than 80 percent may retake the quiz one time and are excluded if the second test is also less than 80 percent.
• Is in good health, as judged by the investigator, and determined by medical history and physical examination.

You may not qualify if:

• Women of childbearing potential\* must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to each mosquito exposure\*\*.
• Not sterilized via bilateral tubal ligation, bilateral oophorectomy, or hysterectomy, or, if menopausal, still menstruating or \< 1 year of the last menses.
• Study vaccination or CHMI
• Women of childbearing potential must have used a highly effective form of contraception\* in the 30 days prior to their first mosquito exposure\*\*.
• \*Highly effective single forms of contraception include abstinence from sexual activity that could lead to pregnancy, monogamous relationship with vasectomized partner who has been vasectomized for six months or more prior to enrollment, successful Essure (R) placement (permanent, non-surgical, non-hormonal sterilization) with documented confirmation test at least three months after the procedure, or use of effective intrauterine devices or the contraceptive implant (Nexplanon). If none of the highly effective single forms of contraception is used, a combination of an acceptable barrier method and an acceptable hormonal method must be used. Acceptable barrier methods include condom (male or female) and a spermicide (cream, film, foam, or gel), diaphragm or cervical cap with spermicide, and the birth control sponge. Acceptable hormonal methods include birth control patch, shot (Depo-Provera), and pills, and the vaginal ring (NuvaRing).
• \*\*Study vaccination or CHMI.
• Women of childbearing potential must agree to continue use of a highly effective form of contraception through 90 days after their last mosquito exposure.
• For women, must not be breastfeeding or plan to start breastfeeding at any time before the end of study follow up.
• At low (\< / = 10 percent) 5-year cardiovascular risk\*. \*Per the risk prediction method of Gaziano (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864150/). Risk for persons \< 35 years of age will be based on the age 35-44 group.
• No history of malaria infection or vaccination, residence in a malaria-endemic area for \> / = 5 years, or participation in a malaria research study\*.
• No receipt of malaria prophylaxis or travel to a malaria-endemic area in the six months prior to first mosquito exposure.
• No receipt of blood products or immunoglobulin within six months prior to, or donation of a unit of blood within two months prior to, enrollment.
• Weight \> / = 50 kg and body mass index (BMI) \< 35 kg/m\^2.
• Negative serology for HIV 1/2\*.
• \*If the ELISA is positive, HIV confirmation should be performed. If the HIV Western Blot is not consistent with HIV infection, the subject may be enrolled. A past subject in an HIV vaccine trial who has a positive antibody ELISA may participate if the Western Blot is not consistent with pending seroconversion or positive or an HIV PCR assay result is below the level of detection of HIV.

Sponsors & Collaborators

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

Study Sites (1)

Kaiser Permanente Washington Health Research Institute

Seattle, Washington, 98101-1466, United States

Location

MeSH Terms

Conditions

Malaria, Falciparum

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 30, 2017
• Study Start: July 26, 2017
• Primary Completion: August 16, 2019
• Study Completion: August 16, 2019
• Last Updated: February 24, 2025

Record last verified: 2017-12-11

Locations

US (1)