Sanaria PfSPZ Challenge With Pyrimethamine or Chloroquine Chemoprophylaxis Vaccination (PfSPZ-CVac Approach): A Randomized Double Blind Placebo Controlled Phase I/II Trial to Determine Safety and Protective Efficacy Against Natural Plasmodium Falcipa...

Phase 1

Completed

Conditions: Malaria

Interventions: Biological: PfSPZ Challenge
Drug: Chloroquine Phosphate
Drug: Pyrimethamine
Drug: Coartem
Drug: ibuprofen

Registration Number: NCT03952650

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: Background:

Malaria remains a major global health problem. Malaria is spread by the bite of mosquitos. Africa is the region of the world where most people get malaria. Sanaria PfSPZ Challenge is a malaria vaccine. Researchers want to see if the vaccine combined with partner drugs can help protect against malaria.

Objective:

To test if injections with 3 monthly doses of Sanaria PfSPZ Challenge, combined with either pyrimethamine (PYR) or chloroquine as a partner drug, is safe, tolerable, and effective.

Eligibility:

Healthy people ages 18-50 years who live in Bancoumana, Mali, or nearby

Design:

Participants will be screened with the Malaria Comprehension Exam to check their understanding of the study. They will have a medical history. They will have a physical exam. They will have blood tests, urine tests, and heart tests.

Participants will join either the pilot study or the main study.

Participants will be assigned to groups. Depending on their group, they will get at least one injection of either a placebo or the vaccine. They may have up to 3 vaccines, 4 weeks apart. The injection will be into a vein with a needle.

Participants will also take pyrimethamine or chloroquine by mouth. They will also take standard doses of antimalarial drugs by mouth.

Participants will have blood tests throughout the study.

Participants may develop a rash or injection site reaction. If this happens, photos of the site may be taken.

Participants will be observed for infection for many days after the injections.

Detailed Description: Human studies have shown that immunization by the bite of Plasmodium falciparum (Pf) sporozoite (SPZ)-infected mosquitoes (chemoprophylaxis with sporozoites \[CPS\]) or by injecting aseptic, purified, cryopreserved sporozoites (SPZ) with needle and syringe (PfSPZ chemoprophylaxis vaccination, Sanaria PfSPZ-CVac) under drug coverage with chloroquine can provide \>80% protection against homologous controlled human malaria infection (CHMI) (Roestenberg, McCall et al. 2009, Roestenberg, Teirlinck et al. 2011, Mordmuller, Surat et al. 2017). The protective immunity induced by CPS/PfSPZ-CVac is thought to target sporozoite and liver stage antigens, but the transient parasitemia observed under chloroquine prophylaxis may additionally induce immune responses targeting blood stage parasites that contribute to protection. It is important to understand the contribution of each stage in this model as transient parasitemia in the immunization process adds a safety concern and may impair the development of immunity.

We have conducted two phase 1 studies to explore whether significant protective efficacy can be achieved with exclusively pre-erythrocytic (sporozoite/liver stage) exposure in this model using PYR chemoprophylaxis. This drug, unlike chloroquine, kills the parasites in the liver, so there is no period of transient parasitemia following immunization. These studies in malaria na(SqrRoot) ve adults demonstrated that PfSPZ-CVac (with PYR administered 2 \& 3 days after injection) is safe, well-tolerated, and can prevent subpatent and patent parasitemia after PfSPZ injection. The NCT02511054 study used the same dose (5.12x104 PfSPZ) that has resulted in \>80% protection in previous trials of PfSPZ-CVac (chloroquine), showed only 2/9 vaccinees were protected against a homologous (same strain of Pf as the vaccine) CHMI. In trials using irradiated SPZ, increasing the dose of PfSPZ used for immunization has resulted in higher protective efficacy. Therefore, in an ongoing trial, NCT03083847, we have increased the PfSPZ dose about 4-fold up to 2.0x105 PfSPZ, with preliminary results show markedly improved protection against both homologous and heterologous CHMI in healthy US adults (7/8 and 4/4 study subjects uninfected, respectively). This is the first demonstration that the PfSPZ-CVac approach can confer sterile protection without blood stage exposure.

Building on these promising results from PfSPZ-CVac (pyrimethamine) in the US, this proposed study in a malaria-endemic, adult population in Bancoumana, Mali will initially assess, in a pilot phase, the safety and tolerability of still higher doses of PfSPZ Challenge (4.0x105 PfSPZ) in combination with PYR (day 0;) or chloroquine (days -2, +5). The higher PfSPZ dose is hypothesized to be necessary to achieve significant efficacy against naturally transmitted malaria in malaria-experienced populations. Once this higher dose of PfSPZ is determined to be safe and tolerable and that earlier PYR dosing prevents patent parasitemia, the main phase will explore the effect of both earlier PYR dosing and a higher dosage of PfSPZ used for immunization in the development of protective immunity against natural malaria infection. The results of this study will contribute to understanding the targets and mechanisms of immunity against Pf malaria infection, and how the degree of prior exposure to the parasite (pre-erythrocytic and/or erythrocytic stages) impacts these responses and subsequent protective efficacy in field settings.

After completion of follow up in the main phase, all participants that are still enrolled in the study will be offered a booster dose of the vaccine (4th dose) with a single dose of 4x10\^5 PfSPZ Challenge or normal saline (aligned with what they received in the main phase of the study) at approximately 11 months post 3rd vaccination. The booster dose is timed to allow administration well before the beginning of the ensuing malaria transmission season. Participants will then be followed for approximately 6 months to assess safety and vaccine efficacy through this second transmission season.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 252

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1a	PfSPZ Challenge	Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
1b	PfSPZ Challenge	Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
2a	PfSPZ Challenge	Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ
2b	PfSPZ Challenge	Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ
3a	PfSPZ Challenge	Receiving 400,000 PfSPZ with chloroquine 2 days prior + 5 days post PfSPZibuprofen (if necessary)
3b	PfSPZ Challenge	Receiving 400,000 PfSPZ with weekly chloroquineibuprofen (if necessary)
5a	PfSPZ Challenge	Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ (if necessary)
5a	Pyrimethamine	Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ (if necessary)
5b	PfSPZ Challenge	Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
6a	PfSPZ Challenge	Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ (if necessary)
6b	PfSPZ Challenge	Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ (if necessary)
1a	Pyrimethamine	Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
1a	Coartem	Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
1b	Pyrimethamine	Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
1b	Coartem	Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
2a	Coartem	Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ
2a	Pyrimethamine	Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ
2b	Pyrimethamine	Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ
2b	Coartem	Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ
3a	Chloroquine Phosphate	Receiving 400,000 PfSPZ with chloroquine 2 days prior + 5 days post PfSPZibuprofen (if necessary)
3a	ibuprofen	Receiving 400,000 PfSPZ with chloroquine 2 days prior + 5 days post PfSPZibuprofen (if necessary)
3a	Coartem	Receiving 400,000 PfSPZ with chloroquine 2 days prior + 5 days post PfSPZibuprofen (if necessary)
3b	Chloroquine Phosphate	Receiving 400,000 PfSPZ with weekly chloroquineibuprofen (if necessary)
3b	ibuprofen	Receiving 400,000 PfSPZ with weekly chloroquineibuprofen (if necessary)
3b	Coartem	Receiving 400,000 PfSPZ with weekly chloroquineibuprofen (if necessary)
4a	Pyrimethamine	Receiving normal saline with 75 mg pyrimethamine day 0 post injection
4b	Pyrimethamine	Receiving normal saline with 75 mg pyrimethamine days 2\&3 post injection
4a	Coartem	Receiving normal saline with 75 mg pyrimethamine day 0 post injection
4b	Coartem	Receiving normal saline with 75 mg pyrimethamine days 2\&3 post injection
4c	Chloroquine Phosphate	Receiving normal saline with weekly chloroquineibuprofen (if necessary)
4c	Coartem	Receiving normal saline with weekly chloroquineibuprofen (if necessary)
5a	Coartem	Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ (if necessary)
4c	ibuprofen	Receiving normal saline with weekly chloroquineibuprofen (if necessary)
5b	Pyrimethamine	Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
6a	Pyrimethamine	Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ (if necessary)
6a	Coartem	Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ (if necessary)
5b	Coartem	Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
6b	Pyrimethamine	Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ (if necessary)
6b	Coartem	Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2\&3 post PfSPZ (if necessary)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Positive Sensitive Blood Smear (sBS)	7 -12 days post-inoculation	Count of participants with positive sensitive blood smear (sBS) occurring after PfSPZ-CVac immunization starting on day 7 post DVI. Only pilot phase arms (Arms 1a, 2a) were analyzed for this outcome measure. Arms 5a and 6a were not performed, as no patent parasitemia was observed in either Arms 1a or 2a, per the protocol.
Number of Participants With Local and Systemic Grade 3 Adverse Events (AEs) and Serious Adverse Events (SAEs)	From day of inoculation to 14 days post-inoculation	Count of participants with local and systemic grade 3 signs or symptoms lasting more than 48 hours despite adequate management and serious adverse events (SAEs) occurring after PfSPZ-CVac DVI. Only arm 3a was analyzed for this outcome measure, per the protocol objectives.
Number of Participants With Local and Systemic Adverse Events (AEs) and Serious Adverse Events (SAEs)	For the main phase: from the day of inoculation to approximately 6 months post-3rd inoculation. For the booster phase: from the time of inoculation to approximately 6 months post-booster inoculation	Count of participants with local and systemic adverse events (AEs) and serious adverse events (SAEs) occurring after PfSPZ-CVac immunization. This outcome measure applies to main phase arms 1b, 2b, 4a, and 4b. Arms 5b and 6b were not performed as patent parasitemia with the higher dose of PfSPZ was not observed in the pilot phase (Arms 1a, 2a).