NMRC-M3V-Ad-PfCA Vaccine - Clinical Trial 1

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a new investigational malaria vaccine is safe, well tolerated and effective against experimental exposure to malaria when given to healthy people with no previous exposure to malaria. The vaccine consists of a modified form of a relatively common virus, adenovirus, that has been rendered incapable of replicating itself and modified to deliver the malaria gene of interest to the body's cells allowing the cell to manufacture the protein encoded by the gene and present it to the body's immune system in a more natural and presumably effective way.

Detailed Description
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The vaccine, called NMRC-M3V-Ad-PfCA (key: NMRC + Multi-antigen Multi-stage, Malaria Vaccine + Adenovectored + P. falciparum CSP & AMA1 antigens), is a combination of two recombinant adenovirus-derived constructs (adenovectors), one expressing the pre-erythrocytic stage antigen circumsporozoite protein (CSP) and the other expressing the erythrocytic stage antigen Apical Membrane Antigen 1 (AMA1), both from the 3D7 strain of P. falciparum. The vector is an attenuated, replication-deficient adenovirus derived from wildtype serotype 5 adenovirus through the deletion of several genes. The vaccine is formulated in a buffered saline solution (Final Formulation Buffer = FFB). This is a Phase 1/2a, randomized, open-label, dose-escalating trial of the NMRC-M3V-Ad-PfCA vaccine administered intramuscularly to healthy, malaria-naïve adult volunteers. All volunteers will be seronegative (< 1:500, by a luciferase-based neutralizing antibody assay; VRC, Bethesda) for adenovirus serotype 5. In the first part of the study (dose-escalation phase, Part A), 1 x 10^10 particle units (pu) per construct or 2 x 10^10 pu total will be administered to six volunteers as a single dose to assess safety, and 4 weeks later, 5 x 10^10 pu per construct or 1 x 10^11 pu total dose (five-fold dose escalation) will be administered to six additional volunteers. In the second part of the study (regimen-comparison phase, Part B), three regimens for administration will be compared: one dose, two doses administered ten days apart, and two doses administered 16 weeks apart. Separate groups will receive one dose of the individual components of the vaccine (NMRC-MV-Ad-PfC and NMRC-MV-Ad-PfA). Following immunization, volunteers participating in the regimen-comparison phase as well as several non-immunized control volunteers (serving as infectivity controls) will be challenged with P. falciparum sporozoites in order to assess vaccine efficacy against non-immunized controls challenged at the same time. The proposed design of the regimen-comparison phase will provide information to direct selection of an appropriate dosing regimen for subsequent studies, and will also indicate whether the two constituent antigens, when co-formulated, act synergistically, independently, or interfere with each other in the induction of antigen-specific immune responses and protective immunity.

Official Title
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A Two Part Clinical Trial Assessing the Safety, Tolerability, Immunogenicity and Protective Efficacy of NMRC-M3V-Ad-PfCA, a Multivalent, Adenovirus-Vectored Plasmodium Falciparum Malaria Vaccine, in Healthy, Malaria-Naïve Adults

Conditions
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Plasmodium Falciparum

Intervention / Treatment
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* Biological: NMRC-M3V-Ad-PfCA
* Biological: NMRC-MV-Ad-PfC, NMRC-M3V-Ad-PfCA


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Between the ages of 18-50 (inclusive) Negative results of HIV ELISA, HbSAg, anti-HCV antibody, and no other clinically significant abnormal laboratory results from screening. Adenovirus serotype 5 (Ad5) titer <1:500 Able to provide written informed consent. Complete an Assessment of Understanding and verbalize an understanding of any questions answered incorrectly. In good general health without clinically significant medical history or physical exam abnormalities at screening. Willing to continue immunogenicity and clinical follow-ups for one year and telephone or mail (electronic/U.S. Postal) contact as long term safety monitoring provision for an additional four years (totaling five years of participation; immunized volunteers only). Male and female participants being immunized and female participants being challenged agree to use effective means of birth control (an FDA approved contraceptive, abstinence) between screening and 60 days following last clinical study visit or able to provide evidence of no reproductive capability. EXCLUSION CRITERIA: Have a history of malaria infection, exposure to malaria infection(i.e. you have been to an area that has malaria within the past two years),lived in a country with malaria for more than 5 years or receipt of certain candidate malaria vaccines Known immune system disease Known blood, heart, liver, kidney disease At known significant risk for developing heart disease A positive result on HIV testing at screening A positive result on Hepatitis B or C testing at screening Removal of your spleen Taking medication that suppresses the immune system within 30 days of immunization. Received or will be receiving another vaccine within 30 days of immunization Received blood products (e.g. transfused with blood cells, platelets, plasma or serum) within 120 days of the immunization Have had serious adverse reactions to other vaccines including hives, anaphylaxis, respiratory difficulty, tongue/mouth/neck/throat/body swelling or abdominal pain Pregnant, breastfeeding, or planning to become pregnant during the next year Plan to participate (or have participated in the last 30 days) in any other research study including an investigational drug or device Unwilling or unable to participate/complete all study elements Evidence of previous infection with adenovirus 5 or prior receipt of an adenovirus containing vaccine.

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation<br>NMRC-M3V-Ad-PfCA | Biological: NMRC-M3V-Ad-PfCA<br>* Malaria Vaccine<br>|
| Experimental: Regimen-comparison<br>NMRC-MV-Ad-PfC, NMRC-M3V-Ad-PfCA | Biological: NMRC-MV-Ad-PfC, NMRC-M3V-Ad-PfCA<br>* Malaria Vaccines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A Dose-Escalation: Number of Participants Who Experienced Any Serious Adverse Events Related To Vaccine Administration | To assess the safety and tolerability of NMRC-M3V-Ad-PfCA, in a dose-escalation design (Part A), in healthy malaria-naïve adults. Part A was a dose escalation of NMRC-M3V-AdPfCA (2 antigen combination) using two dose groups, 2x10^10 pu (Group 1) and 1x10^11 pu (Group 2). Subjects received a single intramuscular injection with the injections in the 2 groups staggered by 4 weeks in order to assess the safety and tolerability of the vaccine and define the dose to be used in Part B. The vaccine was to be considered safe and well-tolerated if there were no severe or serious adverse events related to vaccine administration. | Through Study Completion, an average of 1 year | 
| Part B Regimen-Comparison: Number of Participants With Any Serious Adverse Events Related to Vaccine Administration | To assess the safety and tolerability of NMRC-M3V-Ad-PfCA, in a regimen-comparison design (Part B), in healthy malaria-naïve adults. Subjects in part B received 2 intramuscular injections given 16 weeks apart: Group 3 NMRC-M3V-Ad-PfCA (2 antigen combination) at a dose of 2x10^10 pu, or Group 4 NMRC-MV-Ad-PfC (single antigen) at 1x10^10 pu dose. The vaccine was to be considered safe and well-tolerated if there were no severe or serious adverse events related to vaccine administration. | Through Study Completion, an average of 1 year | 
| Part B Regimen Comparison: Time to Parasitemia to Assess the Protective Efficacy Against Sporozoite Challenge (Pf, 3D7 Strain) | Protective efficacy was assessed by conducting a homologous 3D7 strain sporozoite challenge 3 weeks after the second NMRCMV-Ad-PfC immunization. Time to parasitemia was measured in both vaccinated and unvaccinated volunteers (infectivity controls) in Group 3 (NMRC-M3V-Ad-PfCA (2 antigen combination) at a dose of 2x10^10 pu) and Group 4 (NMRC-MV-Ad-PfC (single antigen) at 1x10^10 pu dose). Infectivity control subjects were challenged with Group 3 and Group 4. Each volunteer was monitored for the onset of signs and symptoms of malaria and by daily Giemsa-stained thick blood films with positive films confirmed by a second reader. The identity of immunized and non-immunized volunteers was known to the clinical trial staff but not to the microscopists reading the malaria smears. | Through Study Completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A Dose-Escalation: To Assess the Immunogenicity of NMRC-M3V-Ad-PfCA in Healthy Malaria-Naïve Adults Using ELISpot IFN-γ Responses | The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). In Group 1 healthy volunteers received one intramuscular injection of 2x10^10 pu at Week 0 and in Group 2 a five-fold higher dose of 1 x 10^11 pu at Week 4. Immunogenicity was assessed by ELISpot IFN-γ responses against synthetic peptides derived from CSP and AMA1 as the range of spot forming cells/million peripheral blood mononuclear cells [sfc/m]. | One month post immunization | 
| Part B Regimen-Comparison: To Assess the Immunogenicity of NMRC-M3V-Ad-PfCA in Healthy Malaria-Naïve Adults Using ELISpot IFN-γ Responses in Group 3 | The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 3 healthy volunteers received 2 intramuscular injections of NMRC-M3V-Ad-PfCA (2 antigen combination) at a dose of 2x10^10 pu at Week 16 and Week 32. Immunogenicity was assessed by ELISpot IFN-γ responses against synthetic peptides derived from CSP and AMA1 using peripheral blood mononuclear cells during the study. IFN-γ ELISpot responses were measured as the range of spot forming cells/million peripheral blood mononuclear cells [sfc/m]. | 22-23 days post immunization | 
| Part B Regimen-Comparison: To Assess the Immunogenicity of NMRC-MV-Ad-PfC in Healthy Malaria-Naïve Adults Using ELISpot IFN-γ Responses in Group 4 | Group 4 healthy volunteers received 2 intramuscular injections of NMRC-MV-Ad-PfC (single antigen) at a dose of 1x10^10 pu at Week 16 and Week 32. Immunogenicity was assessed by ELISpot IFN-γ responses against synthetic peptides derived from circumsporozoite protein (CSP) using peripheral blood mononuclear cells during the study. IFN-γ ELISpot responses measured as the range of spot forming cells/million peripheral blood mononuclear cells [sfc/m]. | 4 weeks post immunization | 
| Part A Dose-Escalation: To Assess the Immunogenicity of NMRC-M3V-Ad-PfCA in Healthy Malaria-Naïve Adults Using Intracellular Cytokine Staining of CD4+ and CD8+ T Cell IFN-γ Responses | The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). In Group 1 healthy volunteers received one intramuscular injection of 2x10^10 pu at Week 0 and in Group 2 a five-fold higher dose of 1 x 10^11 pu at Week 4. Immunogenicity was assessed by Intracellular Cytokine Staining of CD4+ and CD8+ T cell IFN-γ responses to AMA1 and CSP using peripheral blood mononuclear cells during the study. CD4+ and CD8+ T cell IFN-γ responses were measured as percentage (%) range of positive responses. | One month post immunization | 
| Part B Regimen-Comparison: To Assess the Immunogenicity of NMRC-M3V-Ad-PfCA in Healthy Malaria-Naïve Adults Using Intracellular Cytokine Staining CD4+ and CD8+ T Cell IFN-γ Responses in Group 3 | The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 3 healthy volunteers received 2 intramuscular injections of NMRC-M3V-Ad-PfCA (2 antigen combination) at a dose of 2x10^10 pu at Week 16 and Week 32. Immunogenicity was assessed by Intracellular Cytokine Staining of CD4+ and CD8+ T cell IFN-γ responses to AMA1 and CSP measured using peripheral blood mononuclear cells during the study. CD4+ and CD8+ T cell IFN-γ responses were measured as percentage (%) range of positive responses. | 22-23 days post immunization | 
| Part B Regimen-Comparison: To Assess the Immunogenicity of NMRC-MV-Ad-PfC in Healthy Malaria-Naïve Adults Using Intracellular Cytokine Staining of CD4+ and CD8+ T Cell IFN-γ Responses in Group 4 | Group 4 healthy volunteers received 2 intramuscular injections of NMRC-MV-Ad-PfC (single antigen) at a dose of 1x10^10 pu at Week 16 and Week 32. Immunogenicity was assessed by Intracellular Cytokine Staining of CD4+ and CD8+ T cell IFN-γ responses to synthetic peptides derived from circumsporozoite protein (CSP) using peripheral blood mononuclear cells during the study. CD4+ and CD8+ T cell IFN-γ responses were measured as percentage (%) range of positive responses. | 4 weeks post immunization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria Vaccine, Adenovirus, Plasmodium falciparum