Age De-escalation Safety Trial of PfSPZ-LARC2 Vaccine in Burkina Faso

Sanaria

Status and phase: Begins enrollment this month; Phase 1

Conditions: Malaria Infection; Malaria Falciparum

Treatments: Biological: PfSPZ-LARC2 Vaccine; Biological: Normal Saline (Placebo)

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06652737

BFSPZL1

Details and patient eligibility

About

This is a first-in-humans randomized, double-blind, placebo-controlled Phase 1 trial of Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) malaria vaccine (PfSPZ-LARC2 Vaccine) administered to healthy, malaria-exposed adults, children, and (optionally) infants by direct venous inoculation (DVI) to determine safety, tolerability, and immunogenicity. The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double genetic deletion, of the Mei2 and LINUP genes, and undergo developmental arrest in the late liver stages without releasing merozoites into the blood stream (no blood stage parasites are produced). Because Pf parasites with the LARC phenotype replicate in the liver, they are expected to be a potent immunogen to induce anti-malarial immunity, similar to replication-competent chemo-attenuated Sanaria® PfSPZ-CVac (chloroquine). Because the parasites are also intrinsically attenuated, they are expected to be highly safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine and to the single-gene(Mei2)-deleted GA2 vaccine (also LARC phenotype) tested at the Leiden University Medical Center. The genetically attenuated PfSPZ-LARC2 Vaccine should thus combine the best-in-class efficacy of PfSPZ-CVac (chloroquine) with the excellent safety and tolerability of intrinsically attenuated PfSPZ Vaccine and GA2 vaccine.

This trial is designed to test the hypotheses that:

1. The vaccine is safe and well tolerated in each age groups.
2. The true rate of breakthrough blood stage infection (or other concerning adverse events) is less than about 5%, with an 95% confidence level (this will be the level of confidence that there are no breakthroughs if no breakthroughs occur in the 60 participants receiving PfSPZ-LARC2 Vaccine).

Full description

This is a randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial. The dose of PfSPZ will be 2.0x105, the same as the dose used in an NIH study which resulted in 100% vaccine efficacy against a heterologous controlled human malaria infection (CHMI) conducted 12 weeks after immunization, which represents the best protection ever recorded for a malaria vaccine. However, in the initial adult group, 15 participants will be administered three times this dose - 6.0x105 PfSPZ - to assess the risk of breakthrough more stringently in a malaria-experienced adult population who are at low risk for serious complications of malaria infection. If this high dose does not break through in adults, it is unlikely that a 3-fold smaller dose will break through in children.

Each group will be composed of 15 participants, 10 to receive PfSPZ-LARC2 Vaccine, and 5 to receive normal saline (NS) placebo, with randomized, blinded 2:1 allocation to vaccine and placebo in each group. As the core of the study, there will be three cohorts of participants initiated in staggered fashion (2 groups in cohort 1 followed by 2 groups in cohort 2 followed by 1 group in cohort 3), with Safety Monitoring Committee (SMC) review of safety and tolerability before proceeding to the next cohort. Each group will begin with a pilot group of 2 vaccinees and 1 placebo recipient three days before the rest of the cohort initiates, as a safety precaution.

Cohort 1 Group 1 (20-50-year-olds): 15 participants receive single injection of 2.0x105 PfSPZ or NS.

Group 2 (20-50-year-olds): 15 participants receive single injection of 6.0x105 PfSPZ or NS.

Cohort 2 Group 3 (11-19-year-olds): 15 participants receive single injection of 2.0x105 PfSPZ or NS.

Group 4 (6-10-year-olds): 15 participants receive single injection of 2.0x105 PfSPZ or NS.

Cohort 3 Group 5 (1-5-year-olds): 15 participants receive three 4-weekly injections of 2.0x105 PfSPZ or NS.

In addition to these three cohorts, there is an optional fourth cohort, consisting of infants. This will be included if resources are adequate and if the safety data from the first three cohorts, when reviewed by the SMC, is deemed supportive of progressing to infants.

Cohort 4 (optional) Group 6 (5-11-month-olds): 15 participants receive single injection of 2.0x105 PfSPZ or NS.

Total sample size: 15 x 5 = 75 participants ; if Group 6 included, 90 participants

SMC meetings will be scheduled to review safety and parasitology data collected for two weeks after each dose in cohorts 1-3. If there are no vaccine strain breakthrough infections in a given cohort (cohorts 1-3), and if the vaccine is well-tolerated, the SMC will be asked to consider recommending proceeding to the next cohort (cohorts 2-4). If there are vaccine strain breakthroughs, the trial may continue on SMC recommendation, but the restructured trial design will require IRB review and approval.

Note that there are three doses planned for Group 5 in the third cohort - the target (pre-school) population for the Phase 2 trial described above. These are included in case, unexpectedly, the adverse event profile after the second or third doses differs from after the first.

Participants will be followed for parasitemia by TBS and for solicited and unsolicited adverse events after immunization. TBS to monitor for Pf blood stage infections will be performed every two days from Day 7 (day +6) to Day 19 (day +18) and then on Days 21, 24 and 29 (days +20, +23 and +28). In addition to TBS follow-up, samples will be obtained at key timepoints for retrospective qPCR. Retrospective qPCR will be performed if there is a scientific need. However, the qPCR using the samples collected on day +28 after the last immunization will be performed on all participants to document that no parasite is present in the blood at the end of active follow-up.

Additional TBS will be performed when clinically indicated. This includes: (1) when a study participant develops a fever (axillary temperature in adults > 37.5°C [>99.5°F] or tympanic temperature in children of >38.0°C [>100.4°F]) and symptoms suggestive of malaria or (2) the investigator perceives, for any reason, a need for a rapid evaluation.

Any density of parasitemia identified by TBS will be considered indicative of malaria infection and will be treated after a sample is obtained to allow genomic analysis of the parasite (to determine if it is vaccine strain or wild-type Pf infection).

Solicited and unsolicited adverse events will be recorded for 28 days after each immunization, and serious adverse events (SAEs) will be monitored throughout the trial. Laboratory tests will be done pre-immunization, day of vaccination and one and four weeks after the immunization (complete blood count, creatinine, aspartate aminotransferase, alanine aminotransferase).

Three and six months after the final immunization, there will be a follow-up visit to ascertain the participant's health.

Definition of blood stage parasitemia during the immunization phase: Any positive TBS showing normal appearing parasites confirmed by a second reader (with a third reader used to resolve disagreements between the first two).

If the TBS turns positive during follow-up: If a participant develops parasitemia, they will be treated as soon as parasitemia is identified even if asymptomatic. A blood sample adequate for genetic analysis (required) and culture (optional) will be obtained by venipuncture prior to treatment. The drugs for treatment will be dihydroartemisinin-piperaquine (DHAP) or artemether-lumefantrine (AL). In addition, any participant shown to have a breakthrough LARC2 parasite will be administered a single low dose of primaquine to kill any gametocytes and prevent transmission.

Genetic analyses will be performed to determine whether the parasite is the vaccine strain or a wild type (naturally acquired) Pf strain. If it is a wild type parasite, the trial will continue without SMC consultation. If the parasite is vaccine strain, the Sponsor will be notified and the SMC consulted with regard to measures required to assure safety of the participants.

Clearance of parasitemia prior to immunization: Because the study is being done in malaria-exposed individuals, some of whom may have chronic parasitemia, it will be important to clear any existing parasitemia prior to immunization. Otherwise, these pre-existing parasitemias could recrudesce during follow-up, confusing the ability to identify breakthroughs. Clearance will be administered to all participants because it is not possible to determine which participants have latent infection, even if the most sensitive PCR is used. Clearance will be done using a full treatment course of atovaquone-proguanil (AP) with dosing adjusted for age/body weight and using directly observed treatment (DOT). This drug combination is selected based on the relatively short half-lives of the drugs compared to artemisinin combination therapies. A short half-life is needed so that the drug does not interfere with the detection of any breakthrough parasitemias post immunization. If possible, the study will be performed in a location or during a period of the year when transmission levels are low. However, if naturally acquired parasitemia occurs during immunization and follow-up, it will be possible to distinguish these parasites from the PfNF54 strain that comprises the vaccine by genetic analysis based on PCR as described.

Clearance of parasitemia four weeks after immunization: As a safety precaution, all individuals will be treated again four weeks after immunization. DHA-P or AL will be used, as there is no concern about drug half-lives in this case.

Long-term Follow-up: Participants (or their parents) will be contacted at 3 months and 6 months to obtain follow-up, recording any episodes of clinical malaria or unexplained SAEs. Clinical malaria that is not identified by the study team and reported historically by parents, guardians or participants will be defined as a positive diagnostic test (TBS or rapid diagnostic test) plus fever (as defined previously) plus symptoms consistent with malaria. Any such individual will have a blood smear examined.

Enrollment: 90 estimated patients

Sex: All

Ages: 5 months to 50 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. Healthy males and females, based on clinical and laboratory findings
2. From the age 5 months to 50 years
3. Adults with a Body Mass Index (BMI) 18 to 30 Kg/m2; or adolescents, children and infants with Z-score of the selected indicator ([weight-for-height], [(height and BMI) for age]) category within ±2SD.
4. Residence in the study area for the duration of the study.
5. Agreement to release medical information and to inform the study doctor concerning contraindications for participation in the study
6. Willingness to be attended to by a study clinician and take all necessary medications prescribed during study period
7. Agreement to provide contact information of a third party household member or close friend to study team
8. Agreement not to participate in another clinical trial during the study period
9. Agreement not to donate blood during the study period (until final clearance is completed)
10. Able and willing to complete the study visit schedule over the study follow up period.
11. Willingness to undergo HIV, hepatitis B (HBV), hepatitis C (HCV), and sickle cell anemia tests
12. Volunteer participant (subjects 21 years of age and older) or the parent / guardian signing the informed consent (for subjects <21 years of age) is able to demonstrate their understanding of the study by responding correctly to 9 out of 10 true/false statements (in a maximum of two attempts for those who failed to respond correctly to all true/false statements in the first attempt)
13. Signed written informed consent, in accordance with local practice, provided by adult volunteers, parents or legal representatives and relevant assent for children participants as applicable
14. Has not been treated with any antimalarial medication for at least two weeks prior to the initial clearance treatment.
15. Female volunteers aged 12 years and above must be non-pregnant (as demonstrated by a negative urine pregnancy test), and provide consent / assent of their willingness to take protocol-defined measures not to become pregnant during the study and safety follow-up period. Acceptable measures to not become pregnant include 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. 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.
16. One additional inclusion criterion is demonstration of the ability to complete pre-vaccination drug clearance without significant untoward effects.

Exclusion criteria

1. Unable to provide informed consent including inability to pass the test of understanding.
2. Receipt of a malaria vaccine in a prior clinical trial.
3. History of a splenectomy or sickle cell disease.
4. History of a neurologic disorder (including non-febrile seizures or complex febrile seizures) or formal history of migraine headache.
5. Current use of systemic immunosuppressant pharmacotherapy.
6. 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.
7. Women who are breast-feeding, pregnant or planning to become pregnant during the study period.
8. Known allergy to atovaquone-proguanil (AP), dihydroartemisinin-piperaquine (DHA-P), artemether-lumefantrine (AL), or any component of the investigational products.
9. History of anaphylaxis or other life-threatening reaction to a vaccine.
10. 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.
11. Evidence of increased cardiovascular disease risk; defined as >10% five-year risk by non-laboratory method (Gaziano, 2008).
12. Plan to participate in another investigational vaccine/drug research during the study.
13. Plan for major surgery between enrollment until last study visit.
14. Use or planned use of any drug with anti-malarial activity that would precede or coincide with vaccination through to 28 days after the last dose of vaccine.
15. Anticipated use of medications known to cause drug interactions with DHAP (antiarrhythmics, neuroleptics, macrolide antibiotics, fluoroquinolones, imidazole and triazole antifungal agents, quinine, halofantrine, pentamidine and saquinavir, certain non-sedating antihistamines, all of which can affect QT intervals - see Section2.2.1.3) or AL (the same list of drugs affecting QT intervals plus rifampin, carbamazepine, phenytoin, St. John's wort and antiretroviral drugs).
16. Positive HIV, HBsAg or HCV serology.
17. History of or evidence for other chronic disease conditions including cancer, diabetes, renal failure, hypertension, tuberculosis, etc.
18. History of arrythmias or cardiac disease, or an abnormal electrocardiogram, defined as one showing prolonged QT interval, 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.
19. Any clinically significant deviation from the normal range in biochemistry or hematology tests measured at screening and not resolving (grade 1 abnormalities are allowed).
20. Any medical, psychiatric, social, behavioral or occupational condition or situation (including active alcohol or drug abuse affecting social function) 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.
21. One additional exclusion criterion is inability to take a course of malaria treatment prior to receipt of investigational product.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Triple Blind

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90 participants in 11 patient groups, including a placebo group

Cohort 1: Group 1a Adult 2x10e5 PfSPZ-LARC2 Vaccine

Experimental group

Description:

20-50-year-olds: 10 participants receive single injection of 2.0x10e5 PfSPZ-LARC2 Vaccine

Treatment:

Biological: PfSPZ-LARC2 Vaccine

Cohort 1: Group 1b/2b Adult Normal Saline

Placebo Comparator group

Description:

20-50-year-olds: 10 participants receive single injection of normal saline

Treatment:

Biological: Normal Saline (Placebo)

Cohort 1: Group 2a Adult 6x10e5 PfSPZ-LARC2 Vaccine

Experimental group

Description:

20-50-year-olds: 10 participants receive single injection of 6.0x10e5 PfSPZ-LARC2 Vaccine

Treatment:

Biological: PfSPZ-LARC2 Vaccine

Cohort 2: Group 3a 11-17year old 2x10e5 PfSPZ-LARC2 Vaccine

Experimental group

Description:

11-17-year-olds: 10 participants receive single injection of 2.0x10e5 PfSPZ-LARC2 Vaccine

Treatment:

Biological: PfSPZ-LARC2 Vaccine

Cohort 2: Group 3b 11-17 year-olds Normal Saline

Placebo Comparator group

Description:

11-17-year-olds: 5 participants receive single injection of Normal Saline

Treatment:

Biological: Normal Saline (Placebo)

Cohort 2: Group 4a 6-10-year old 2x10e5 PfSPZ-LARC2 Vaccine

Experimental group

Description:

6-10-year-olds: 10 participants receive single injection of 2.0x10e5 PfSPZ-LARC2 Vaccine

Treatment:

Biological: PfSPZ-LARC2 Vaccine

Cohort 2: Group 4b 6-10-year old Normal Saline

Placebo Comparator group

Description:

6-10-year-olds: 5 participants receive single injection of Normal Saline

Treatment:

Biological: Normal Saline (Placebo)

Cohort 3: Group 5a 1-5-year old 2x10e5 PfSPZ-LARC2 Vaccine

Experimental group

Description:

1-5-year-olds: 10 participants receive three 4-weekly injections of 2.0x10e5 PfSPZ-LARC2 Vaccine

Treatment:

Biological: PfSPZ-LARC2 Vaccine

Cohort 3: Group 5b 1-5-year old Normal Saline

Placebo Comparator group

Description:

1-5-year-olds: 5 participants receive three 4-weekly injections of Normal Saline

Treatment:

Biological: Normal Saline (Placebo)

Cohort 4: Group 6a 5-11-month old 2x10e5 PfSPZ-LARC2 Vaccine

Experimental group

Description:

5-11-month-olds: 10 participants receive single injection of 2.0x10e5 PfSPZ-LARC2 Vaccine

Treatment:

Biological: PfSPZ-LARC2 Vaccine

Cohort 4: Group 6b 5-11-month old Normal Saline

Placebo Comparator group

Description:

5-11-month-olds: 5 participants receive single injection of Normal Saline

Treatment:

Biological: Normal Saline (Placebo)