Trial of a Falciparum Malaria Protein (FMP012), E. Coli-expressed PfCelTOS, in Healthy Malaria-Naive Adults

Study Overview
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Brief Summary
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Malaria has remained a major concern for the US military. During World War II, malaria was the leading cause of disease and non-battle injury with 500-700 men infected per day, resulting in 24,000 malaria-related casualties.(10) Currently, the methods used for protecting troops against malaria are insecticidal nets, clothing, and antimalarial treatment. To be effective, these methods must be self-administered and be used consistently, often unattainable in field or combat situations. The United States Army Medical Research and Development Command (USAMRMC), through the United States Army Medical Materiel Development Activity (USAMMDA) and the Walter Reed Army Institute of Research (WRAIR) are actively pursuing the development of an effective vaccine against P. falciparum malaria; development of such a vaccine is a high priority for the US military and other individuals who travel to endemic regions, and is equally important to populations residing in those areas. A Phase 1 study using FMP012, a recombinant E.coli expressed malaria protein (CelTOS) vaccine will assess the safety and reactogenicity of candidate P. falciparum malaria vaccine FMP012/GLA-SE Secondary: measure the humoral immune response to FMP012/GLA-SE using enzyme-linked immunosorbent assay (ELISA) assess the protective efficacy of FMP012/GLA-SE against a P. falciparum sporozoite challenge.

Detailed Description
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Single center, non-randomized, open label, dose escalation Phase 1study with sporozoite challenge. The antigen FMP012 will be adjuvanted with Glucopyranosyl lipd A stable emulsion (GLA-SE), a proprietary adjuvant produced by the Infectious Disease Research Institute (IDRI). This is a first-in-human study of FMP012. Thirty subjects, divided into 3 groups (10 subjects per group), will receive 3 doses of the FMP012/GLA-SE vaccine. Group 1 will receive 10 µg of FMP012 formulated with 2 µg GLA-SE adjuvant and Group 2 will receive 10 µg of FMP012 formulated with 5 µg GLA-SE adjuvant. Group 3 will receive 50 µg of FMP012 formulated with either 5 µg GLA-SE adjuvant (Group 3a) or 2 µg GLA-SE adjuvant (Group 3b). Determination of whether to proceed with Group 3a or Group 3b will be made by the principal investigator (PI) and the independent medical monitor after the second vaccination dose in Group 2 has been completed, based on predefined safety and group hold criteria in this protocol. There will be a staggered start for Group 1 and Group 2 separated by a minimum of 14 days. Group 3a or Group 3b will start vaccinations 2 weeks after the second vaccination for Group 2. The first and second vaccination doses in each group will be separated by 28 days and all groups will receive the third vaccination dose on the same day. The second and third vaccination doses in Group 1 will be separated by 84 days, Group 2 by 70 days, and Group 3 by 28 days. Six non-immunized infectivity control subjects will be enrolled prior to the challenge phase. All subjects from the Vaccination Group and Infectivity Control Group will participate in the primary malaria sporozoite challenge and will be required to stay at a hotel for evaluation for a maximum of 10 nights starting 9 days after the challenge. A directly monitored, sequentially allocated, open-label oral regimen of chloroquine or artemether/lumefantrine will be administered to all parasitemic subjects.

Official Title
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Phase 1 Study With the Vaccine Candidate Plasmodium Falciparum Malaria Protein (FMP012), an E.Coli-expressed Cell-Traversal Protein, Administered Intramuscularly in Healthy Malaria-Naive Adults

Conditions
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Malaria

Intervention / Treatment
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* Biological: Group 1: 10 ug FMP012 with 2 ug GLA-SE
* Biological: Group 2: 10 ug FMP012 with 5 ug GLA-SE
* Biological: 50 ug FMP012 with 5 ug GLA-SE or 2 ug GLA-SE
* Other: Controlled group-Challenged Only: no vaccination


Participation Criteria
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Eligibility Criteria
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Healthy adults (male or non-pregnant, non-lactating female) 18 to 50 years of age at the time of screening If the subject is female, Non-childbearing potential , abstinent or using adequate contraceptive precautions during this study and must agree to continue such precautions until three months after challenge A negative pregnancy test at the time of enrollment Free of significant health problems as established by medical history, laboratory, and clinical examination before entering the study Low cardiac risk factors Available to participate and reachable by phone for duration of study (approximately 8 months) No plans to travel to outside the Washington DC area between the day of challenge and either completion of treatment course (post-challenge) or, if subject remains uninfected, 28 days post-challenge No plans to travel to a malaria endemic area during the course of the study Written informed consent must be obtained from the subject before screening procedures Subjects must score at least 80% correct on a multiple-choice quiz that assesses their understanding of this study Active duty military must obtain approval from his or her supervisor Exclusion Criteria: History of malaria infection History of travel to P. falciparum endemic areas in the 3 months prior to day of first vaccination or day of challenge History of receiving a malaria vaccine Receipt of any licensed vaccine within 7 days prior to first vaccination History of receipt of malaria prophylaxis during the 2 months prior to day of first vaccination or day of challenge History of use of any drugs with significant antimalarial activity during the course of the study period Prior receipt of any vaccine containing either QS-21, MPL or GLA-SE in the previous 5 years (including Cervarix®, GSK) Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of study vaccine or planned use during the study period. Any history of allergic reaction or anaphylaxis to previous vaccination Allergy to kanamycin, nickel, or imidazole Pregnant or lactating female at screening or plans to become pregnant or breastfeed from the time of enrollment until three months after challenge Allergy to antimalarial drugs or use of medications known to interact with both CQ and artemether/lumefantrine Significant (eg, systemic) hypersensitivity reactions to mosquito bites History of sickle cell disease History of psoriasis or porphyria History of splenectomy Any confirmed or suspected immunodeficiency, including HIV infection Administration of chronic (defined as more than 14 days) immunosuppressive drugs or other immune-modifying drugs within six months of vaccination Inhaled and topical steroids are allowed A family history of congenital or hereditary immunodeficiency Acute or chronic, clinically significant, pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by history, physical examination, or laboratory evaluation Chronic or active neurologic disease including seizure disorder and chronic migraine headaches Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or any planned administration during the study period Any abnormal baseline laboratory screening tests listed below (normal values are defined in the adverse event section of this protocol): Seropositive for HIV or Hepatitis C virus or HBsAg positive Hepatomegaly, right upper quadrant abdominal pain or tenderness An abnormal baseline screening EKG. Suspected or known current alcohol or drug abuse as determined from the medical history or by physical examination Any other significant finding that in the opinion of the PI would increase the risk of having an adverse outcome from participating in this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 10 ug FMP012 with 2 ug GLA-SE<br>Single center, non-randomized, open label, dose escalation Phase 1 study with sporozoite challenge. The antigen FMP012 will be adjuvanted with Glucopyranosyl lipd A stable emulsion. This is a first-in-human study of FMP012. 30 subjects, divided into 3 groups, will receive 3 doses of the FMP012/GLA-SE vaccine. Biological/vaccine; E-coli expressed malaria antigen FMP012 adjuvanted with Glucopyranosyl lipid A Stable emulsion (GLA-SE), a proprietary adjuvant | Biological: Group 1: 10 ug FMP012 with 2 ug GLA-SE<br>* Biological/vaccine; E-coli expressed malaria antigen FMP012 adjuvanted with Glucopyranosyl lipid A Stable emulsion (GLA-SE), a proprietary adjuvant<br>|
| Experimental: Group 2: 10 ug FMP012 with 5 ug GLA-SE<br>Biological/vaccine; E-coli expressed malaria antigen FMP012 adjuvanted with Glucopyranosyl lipid A Stable emulsion (GLA-SE), a proprietary adjuvant | Biological: Group 2: 10 ug FMP012 with 5 ug GLA-SE<br>* E-coli expressed antigen FMP012 will be adjuvanted with Glucopyranosyl lipd A stable emulsion (GLA-SE), a proprietary adjuvant<br>|
| Experimental: Group 3: 50 ug FMP012 with 5 ug GLA-SE or 2 ug GLA-SE<br>Biological/vaccine; E-coli expressed malaria antigen FMP012 adjuvanted with Glucopyranosyl lipid A Stable emulsion (GLA-SE), a proprietary adjuvant | Biological: 50 ug FMP012 with 5 ug GLA-SE or 2 ug GLA-SE<br>* E-coli expressed malaria antigen FMP012 adjuvanted with Glucopyranosyl lipd A stable emulsion (GLA-SE), a proprietary adjuvant<br>|
| Other: Control group-Challenged Only<br>Biological/vaccine; E-coli expressed malaria antigen FMP012 adjuvanted with Glucopyranosyl lipid A Stable emulsion (GLA-SE), a proprietary adjuvant | Other: Controlled group-Challenged Only: no vaccination<br>* The control group participated in the primary malaria sporozoite challenge.E-coli expressed antigen FMP012 will be adjuvanted with Glucopyranosyl lipd A stable emulsion (GLA-SE), a proprietary adjuvant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Solicited or Unsolicited Symptoms Reporting During the Post-vaccination Period | Number of participants for each dose (1 through 3) that experienced any symptom, general solicited symptoms, and local solicited symptoms | From vaccination day through 7 days post vaccination (for all three doses) | 
| Number of Participants With Solicited or Unsolicited Symptoms Reporting During the Post-vaccination Period | Incidence of erythema and pain (solicited local symptoms) reported after each dose (1-3) of vaccination. Results for groups 1, 2 and 3 only as control group did not receive any vaccinations and only participated in the malaria challenge portion of the study. | From vaccination day through 7 days post vaccination for each does (1-3) | 
| Subjects Reporting the Occurrence of Unsolicited Adverse Events Related to Vaccination | Number of participants with at lease one administered dose presenting with at least one specified symptom within 28 days after vaccination | 28 days after each vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral Immune Response to FMP012/GLA-SE | Seroconversion was defined as a post-second vaccination titer (serum dilution of 1:100) that is 3 standard deviations higher than the average of the negative or pre-vaccination serum measured using enzyme-linked immunosorbent assay (ELISA). Values reported as below the detection limit were given a value of 50 units. The safety population was used for immunogenicity analysis. Only subjects who received vaccinations or were challenged were included in the analysis of immunogenicity. Subjects who withdrew from the study had data collected to the point of withdraw. Geometric mean titers (GMT) were obtained by first calculating the mean and 95% confidence intervals for log-transformed values of the ELISA results, followed by exponentiation of the values. Among those vaccinated, all values were below the detection limit until post-dose II. | Up to 1 year | 
| Time to Onset of Parasitemia Following Sporozoite Challenge | Protective Efficacy of FMP012/GLA-SE Measured against a P falciparum sporozoite challenge. Vaccinated subjects were compared to infectivity controls to assess for delayed onset of parasitemia. Time of onset of parasitemia was based on the date of sporozoite challenge to the date of first positive blood smear detection. | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interference of malaria infection