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.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Malaria | Drug: Chloroquine Phosphate Biological: PfSPZ Challenge Drug: Pyrimethamine Drug: Coartem Drug: ibuprofen | Phase 1 Phase 2 |
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.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 800 participants |
Allocation: | Randomized |
Intervention Model: | Sequential Assignment |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Other |
Official Title: | 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 Falciparum Infection in Bancoumana and Surrounding Areas, Mali |
Actual Study Start Date : | May 23, 2019 |
Estimated Primary Completion Date : | September 30, 2022 |
Estimated Study Completion Date : | April 30, 2023 |
Arm | Intervention/treatment |
---|---|
Experimental: 1a
Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 1b
Receiving 400,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 2a
Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2&3 post PfSPZ
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 2b
Receiving 400,000 PfSPZ with 75 mg pyrimethamine days 2&3 post PfSPZ
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 3a
Receiving 400,000 PfSPZ with chloroquine 2 days prior + 5 days post PfSPZibuprofen (if necessary)
|
Drug: Chloroquine Phosphate
Chloroquine phosphate is approved for suppressive treatment (prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a blood-stage schizonticide, highly active against replicating forms of blood-stage drug- sensitive parasites. As such, it is routinely employed as first-line prophylaxis against development of patent parasitemia and clinical malaria in non-immune travelers to areas with chloroquine sensitive Pf. In the pilot, chloroquine administration will begin with a loading dose 2 days prior to PfSPZ Challenge and finishing with a maintenance dose 5 days after PfSPZ Challenge. In the main phase, chloroquine will be first administered as a loading dose 2 days prior to PfSPZ Challenge and continuing weekly using a maintenance dose for a total of 10 doses, finishing with a last dose 5 days after the third injection with PfSPZ Challenge.
Biological: PfSPZ Challenge PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
Drug: ibuprofen Ibuprofen likewise is not a part of the investigational product/regimen, but will be provided to participants in the chloroquine arm (Arm 4) if required to mitigate typical symptoms of malaria infection such as headache, myalgia, fever and chills.
|
Experimental: 3b
Receiving 400,000 PfSPZ with weekly chloroquineibuprofen (if necessary)
|
Drug: Chloroquine Phosphate
Chloroquine phosphate is approved for suppressive treatment (prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a blood-stage schizonticide, highly active against replicating forms of blood-stage drug- sensitive parasites. As such, it is routinely employed as first-line prophylaxis against development of patent parasitemia and clinical malaria in non-immune travelers to areas with chloroquine sensitive Pf. In the pilot, chloroquine administration will begin with a loading dose 2 days prior to PfSPZ Challenge and finishing with a maintenance dose 5 days after PfSPZ Challenge. In the main phase, chloroquine will be first administered as a loading dose 2 days prior to PfSPZ Challenge and continuing weekly using a maintenance dose for a total of 10 doses, finishing with a last dose 5 days after the third injection with PfSPZ Challenge.
Biological: PfSPZ Challenge PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
Drug: ibuprofen Ibuprofen likewise is not a part of the investigational product/regimen, but will be provided to participants in the chloroquine arm (Arm 4) if required to mitigate typical symptoms of malaria infection such as headache, myalgia, fever and chills.
|
Placebo Comparator: 4a
Receiving normal saline with 75 mg pyrimethamine day 0 post injection
|
Drug: Pyrimethamine
Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Placebo Comparator: 4b
Receiving normal saline with 75 mg pyrimethamine days 2&3 post injection
|
Drug: Pyrimethamine
Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Placebo Comparator: 4c
Receiving normal saline with weekly chloroquineibuprofen (if necessary)
|
Drug: Chloroquine Phosphate
Chloroquine phosphate is approved for suppressive treatment (prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a blood-stage schizonticide, highly active against replicating forms of blood-stage drug- sensitive parasites. As such, it is routinely employed as first-line prophylaxis against development of patent parasitemia and clinical malaria in non-immune travelers to areas with chloroquine sensitive Pf. In the pilot, chloroquine administration will begin with a loading dose 2 days prior to PfSPZ Challenge and finishing with a maintenance dose 5 days after PfSPZ Challenge. In the main phase, chloroquine will be first administered as a loading dose 2 days prior to PfSPZ Challenge and continuing weekly using a maintenance dose for a total of 10 doses, finishing with a last dose 5 days after the third injection with PfSPZ Challenge.
Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
Drug: ibuprofen Ibuprofen likewise is not a part of the investigational product/regimen, but will be provided to participants in the chloroquine arm (Arm 4) if required to mitigate typical symptoms of malaria infection such as headache, myalgia, fever and chills.
|
Experimental: 5a
Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ (if necessary)
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 5b
Receiving 300,000 PfSPZ with 75 mg pyrimethamine day 0 post PfSPZ
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 6a
Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2&3 post PfSPZ (if necessary)
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Experimental: 6b
Receiving 300,000 PfSPZ with 75 mg pyrimethamine days 2&3 post PfSPZ (if necessary)
|
Biological: PfSPZ Challenge
PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.
Drug: Pyrimethamine Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia. Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses. Drug: Coartem Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.
|
Ages Eligible for Study: | 18 Years to 50 Years (Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Females of childbearing potential must be willing to use reliable contraception (as defined below) from 21 days prior to first PfSPZ Challenge injection to 28 days following last PfSPZ Challenge exposure (or equivalent study day for Arm 5 controls). For the booster phase, this applies from 21 days prior to the booster vaccination to 28 days post booster vaccination.
EXCLUSION CRITERIA:
Pregnancy, as determined by a positive urine or serum human choriogonadotropin (beta-hCG) test (if female)
--NOTE: Pregnancy is also a criterion for discontinuation of any further dosing or non-safety related interventions for that subject.
Contact: Patrick E Duffy, M.D. | (301) 761-5089 | duffype@niaid.nih.gov |
Mali | |
Malaria Vaccine Center STTB/MRTC | Recruiting |
Bamako, Mali | |
Contact: Issaka Sagara (223) 202-2810 isagara@icermali.org |
Principal Investigator: | Patrick E Duffy, M.D. | National Institute of Allergy and Infectious Diseases (NIAID) |
Tracking Information | |||||
---|---|---|---|---|---|
First Submitted Date ICMJE | May 15, 2019 | ||||
First Posted Date ICMJE | May 16, 2019 | ||||
Last Update Posted Date | April 22, 2021 | ||||
Actual Study Start Date ICMJE | May 23, 2019 | ||||
Estimated Primary Completion Date | September 30, 2022 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
safety and tolerability [ Time Frame: starting from day of injection until 14 days post DVI ] local and systemic reactogenicity occurring after PfSPZ-CVac
|
||||
Original Primary Outcome Measures ICMJE | Same as current | ||||
Change History | |||||
Current Secondary Outcome Measures ICMJE |
protective efficacy [ Time Frame: starting 2 weeks after the 3rd vaccination or 4th (booster) vaccination until 26 weeks post 3rd vaccination or 4th (booster) vaccination, respectively, for incidence of P. falciparum blood-stage infection ] incidence of P.falciparum blood-stage infection
|
||||
Original Secondary Outcome Measures ICMJE |
protective efficacy [ Time Frame: starting 4 weeks after the 3rd vaccination until 26 weeks post 3rd vaccination, for a total of 22 weeks ] incidence of P.falciparum blood-stage infection
|
||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | 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... | ||||
Official Title ICMJE | 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 Falciparum Infection in Bancoumana and Surrounding Areas, Mali | ||||
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. |
||||
Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 1 Phase 2 |
||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Sequential Assignment Masking: Double (Participant, Investigator) Primary Purpose: Other |
||||
Condition ICMJE | Malaria | ||||
Intervention ICMJE |
|
||||
Study Arms ICMJE |
|
||||
Publications * |
|
||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
|||||
Recruitment Information | |||||
Recruitment Status ICMJE | Recruiting | ||||
Estimated Enrollment ICMJE |
800 | ||||
Original Estimated Enrollment ICMJE | Same as current | ||||
Estimated Study Completion Date ICMJE | April 30, 2023 | ||||
Estimated Primary Completion Date | September 30, 2022 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE |
EXCLUSION CRITERIA:
|
||||
Sex/Gender ICMJE |
|
||||
Ages ICMJE | 18 Years to 50 Years (Adult) | ||||
Accepts Healthy Volunteers ICMJE | Yes | ||||
Contacts ICMJE |
|
||||
Listed Location Countries ICMJE | Mali | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT03952650 | ||||
Other Study ID Numbers ICMJE | 999919099 19-I-N099 |
||||
Has Data Monitoring Committee | Not Provided | ||||
U.S. FDA-regulated Product |
|
||||
IPD Sharing Statement ICMJE | Not Provided | ||||
Responsible Party | National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ) | ||||
Study Sponsor ICMJE | National Institute of Allergy and Infectious Diseases (NIAID) | ||||
Collaborators ICMJE | Not Provided | ||||
Investigators ICMJE |
|
||||
PRS Account | National Institutes of Health Clinical Center (CC) | ||||
Verification Date | April 20, 2021 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |