Dose Escalation PfSPZ-CVac

Phase 1

Completed

Conditions: Malaria

Interventions: Drug: Pyrimethamine
Drug: Chloroquine Phosphate
Biological: Sanaria PfSPZ Challenge

Registration Number: NCT03083847

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

Brief Summary: Background:

People get malaria from bites from infected mosquitos. Researchers are studying a vaccine strategy. They will give people malaria parasites by injecting them with live infectious malaria parasites with antimalarial medications and then see if this strategy prevents malaria infection while off antimalarial medications.

Objective:

To see if combining a high dose of live, infectious malaria parasites (known as Sanaria PfSPZ Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine \[PYR\] OR chloroquine \[CQ\]) is safe and can provide people protection against malaria.

Eligibility:

Healthy adults ages 18-50 who:

* are not pregnant or breastfeeding or planning on becoming pregnant while in the study

* are not infected with HIV, Hepatitis B or Hepatitis C

* have reliable early morning access to the NIH Clinical Center

* are able to come to the outpatient clinic frequently, sometimes daily

* have not been diagnosed with malaria within the past 10 years

Design:

* Participants will be screened with medical history and physical exam. They will have heart, blood, and urine tests.

* Participants will have blood drawn for tests at most visits.

* Participants will keep track of their temperature and symptoms during some sections of the study.

* Participants will join one part of the study.

Part 1 is one month:

* Participants will get the parasites by an injection into a vein on day 1 and receive antimalarial medications.

* They will have daily visits on days 7-14

* They will take another antimalarial at visits on days 15-17.

* The final visit will be on day 29.

Part 2 is seven months:

* For the first 3 months, participants will get the parasite injection into a vein for 3 injections in total. Each injection will occur once per month while taking an antimalarial drug.

* They will have daily visits on days 7-14 after the first injection, and on days 7-11 after the second and third injection.

* They will have a final (fourth) injection around month 6 without any antimalarial medication.

* After this fourth injection, participants may have up to 21 daily visits from day 7 after injection until end of study.

Part 3 is one month:

* Participants will get the parasites by injection into a vein on day 1 without antimalarial medications.

* They will have visits almost every day starting day 7 from injection.

* They will take an antimalarial medication when they are diagnosed with malaria

* They will return for final end of study visit on days 27-29.

Detailed Description: Human studies have shown that immunization by the bite Plasmodium falciparum (Pf) sporozoite(SPZ)-infected mosquitoes under drug coverage with chloroquine, an approach called chemoprophylaxis with sporozoites (CPS) or infection treatment vaccination (ITV), can provide high level, long term protection against homologous controlled human malaria infection (CHMI). The Sanaria PfSPZ chemoprophylaxis vaccination (PfSPZ CVac) approach duplicates this with an injectable SPZ regimen. In both approaches, whether mosquitoes or syringes are used for SPZ administration, when chloroquine is used as the chemoprophylactic agent, transient, limited, asexual erythrocytic stage is seen in the majority of participants. Thus the question remains whether the significant protective efficacy seen can be achieved with pre-erythrocytic (sporozoite/liver stage) exposure only.

Previously, we performed a phase 1 study to investigate the safety, tolerability, immunogenicity, and protective efficacy of Sanaria PfSPZ CVac with chloroquine (sporozoites, liver, and blood stage) or pyrimethamine with chloroquine (sporozoites and liver stage only) to further describe stage specific sterile protection (NIAID protocol #15-I-0169). In this study, we demonstrated that pyrimethamine is safe to administer, well tolerated, and can prevent subpatent and patent parasitemia (qPCR and blood smear negative) 100% of the time during Sanaria PfSPZ CVac. The study also duplicated the results previously reported with Sanaria PfSPZ CVac with chloroquine in terms of safety profile and protective efficacy against homologous CHMI. Although a combination of Sanaria PfSPZ- CVac with pyrimethamine and PfSPZ Challenge at 51,200 PfSPZ did not provide a significant protection level against homologous CHMI, we demonstrated that some subjects did develop protective immunity without any evidence of blood stage exposure during PfSPZ-CVac.

Building on these results and taking the lessons learned from other pre-erythrocytic vaccine studies and models that have shown the importance of reaching a minimal antigen threshold required for the development of sterile immunity, this proposed study will assess the safety, tolerability, immunogenicity, and protective efficacy of increasing the dose of Sanaria PfSPZ Challenge sporozoites while receiving the same, or, if needed to successfully prevent parasitemia, a higher dose of pyrimethamine. Unlike the first study, however, pyrimethamine will be administered by itself as the partner drug, and will not be co-administered with chloroquine. The efficacy of PfSPZ-CVac with pyrimethamine will be assessed against CHMI with homologous parasites (Arm 2a) and CHMI with heterologous parasites (Arm 2b). Additionally, we will explore the impact of increasing the dose of Sanaria PfSPZ Challenge sporozoites while receiving chloroquine alone prophylaxis. The efficacy of PfSPZ-CVac with chloroquine will be assessed only against CHMI with heterologous parasites (Arm 3), as protection against homologous parasites has now been shown in two separate trials. It will thus be possible to compare the efficacy of the two partner drugs against heterologous CHMI. The results of this study will contribute to understanding the targets and mechanisms of immunity against Pf malaria infection and how the degree of exposure to the parasite (pre-erythrocytic or erythrocytic stage only or both) impacts these responses and subsequent protective efficacy.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pilot (1a): 1 injection of 5x10^4 PfSPZ Challenge+pyrimethamine	Pyrimethamine	Pilot Phase - 1 injection of 5x10\^4 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection
Pilot (1a): 1 injection of 5x10^4 PfSPZ Challenge+pyrimethamine	Sanaria PfSPZ Challenge	Pilot Phase - 1 injection of 5x10\^4 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection
Pilot (1b):1 injection of 1x10^5 PfSPZ Challenge+pyrimethamine	Sanaria PfSPZ Challenge	Pilot Phase - 1 injection of 1x10\^5 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection
Pilot (1d):1 injection of 2x10^5 PfSPZ Challenge+pyrimethamine	Sanaria PfSPZ Challenge	Pilot Phase - 1 injection of 2x10\^5 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection
Pilot (5a): 1 injection of 1x10^5 PfSPZ Challenge+chloroquine	Sanaria PfSPZ Challenge	Pilot Phase - 1 injection of 1x10\^5 sporozoites of PfSPZ Challenge (NF54) with 1000mg of chloroquine (loading dose) 2 days prior to injections and 500mg (maintenance dose) 5 days post injection
Pilot (5b): 1 injection of 2x10^5 PfSPZ Challenge+chloroquine	Sanaria PfSPZ Challenge	Pilot Phase - 1 injection of 2x10\^5 sporozoites of PfSPZ Challenge (NF54) with 1000mg of chloroquine (loading dose) 2 days prior to injections and 500mg (maintenance dose) 5 days post injection
Main (2a):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+NF54	Sanaria PfSPZ Challenge	Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + pyrimethamine on days 2 and 3 post injection + homologous controlled human malaria infection (CHMI) with 3.2x10\^3 PfSPZ Challenge (NF54) at 12 weeks after third injection
Main (2b):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+7G8	Sanaria PfSPZ Challenge	Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + pyrimethamine on days 2 and 3 post injection + heterologous CHMI with 3.2x10\^3 PfSPZ Challenge (7G8) at 12 weeks after third injection
Main Phase (4b) - Infectivity Control: 7G8 (heterologous) CHMI	Sanaria PfSPZ Challenge	Main Phase - Infectivity Control with 3.2x10\^3 sporozoites of PfSPZ Challenge 7G8 (heterologous) controlled human malaria infection (CHMI)
Main (3):3 doses of 2x10^5 PfSPZ Challenge+chloroquine+7G8	Sanaria PfSPZ Challenge	Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + weekly chloroquine (1000mg given 2 days prior to injections and 500mg given 5 days post injection and weekly thereafter until 5 days post third injection) + heterologous controlled human malaria infection (CHMI) with 3.2x10\^3 PfSPZ Challenge (7G8) at 12 weeks after third injection
Main Phase (4a) - Infectivity Control: NF54 (homologous) CHMI	Sanaria PfSPZ Challenge	Main Phase - Infectivity Control with one dose of 3.2x10\^3 sporozoites of PfSPZ Challenge (NF54) (homologous) controlled human malaria infection (CHMI)
Pilot (1b):1 injection of 1x10^5 PfSPZ Challenge+pyrimethamine	Pyrimethamine	Pilot Phase - 1 injection of 1x10\^5 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection
Pilot (1d):1 injection of 2x10^5 PfSPZ Challenge+pyrimethamine	Pyrimethamine	Pilot Phase - 1 injection of 2x10\^5 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection
Pilot (5a): 1 injection of 1x10^5 PfSPZ Challenge+chloroquine	Chloroquine Phosphate	Pilot Phase - 1 injection of 1x10\^5 sporozoites of PfSPZ Challenge (NF54) with 1000mg of chloroquine (loading dose) 2 days prior to injections and 500mg (maintenance dose) 5 days post injection
Pilot (5b): 1 injection of 2x10^5 PfSPZ Challenge+chloroquine	Chloroquine Phosphate	Pilot Phase - 1 injection of 2x10\^5 sporozoites of PfSPZ Challenge (NF54) with 1000mg of chloroquine (loading dose) 2 days prior to injections and 500mg (maintenance dose) 5 days post injection
Main (2a):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+NF54	Pyrimethamine	Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + pyrimethamine on days 2 and 3 post injection + homologous controlled human malaria infection (CHMI) with 3.2x10\^3 PfSPZ Challenge (NF54) at 12 weeks after third injection
Main (2b):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+7G8	Pyrimethamine	Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + pyrimethamine on days 2 and 3 post injection + heterologous CHMI with 3.2x10\^3 PfSPZ Challenge (7G8) at 12 weeks after third injection
Main (3):3 doses of 2x10^5 PfSPZ Challenge+chloroquine+7G8	Chloroquine Phosphate	Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + weekly chloroquine (1000mg given 2 days prior to injections and 500mg given 5 days post injection and weekly thereafter until 5 days post third injection) + heterologous controlled human malaria infection (CHMI) with 3.2x10\^3 PfSPZ Challenge (7G8) at 12 weeks after third injection

Primary Outcome Measures

Name	Time	Method
Number of Participants With P.Falciparum Blood Stage Infection	14 days post PfSPZ Challenge injection	Participants with P. falciparum blood stage infection defined as detection of P. falciparum parasites by qPCR (real time NIH qPCR and sensitive retrospective Laboratory of Malaria Immunology \& Vaccinology (LMIV) qPCR) following Sanaria® PfSPZ Challenge (NF54) via direct venous injection (DVI).
Number of Participants Requiring Treatment With Additional Anti-malarial Medication	12 days post PfSPZ Challenge injection	Incidence of a clinical malaria diagnosis occurring after PfSPZ-Cvac challenge requiring treatment with atovaquone/proguanil (Malarone).
Number of Participants With Local and Systemic Adverse Events (AEs)	7 months	Participants who had one or more episodes of related or/and unrelated adverse events (AEs). An AE is defined as any untoward medical occurrence temporarily associated with the subject's participation in research, whether or not considered related or not. Refer to adverse event table for specific AE.
Number of Participants With Serious Adverse Events (SAEs)	7 months	Participants who had one or more episodes of serious adverse events (SAEs). SAE is defined as a life-threatening reaction or event that results in death.