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

April 28, 2021 updated by: U.S. Army Medical Research and Development Command

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

59

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20889-5607
        • Naval Medical Research Center (NMRC) Clinical Trials Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 46 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

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
Time Frame: Through Study Completion, an average of 1 year
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
Time Frame: Through Study Completion, an average of 1 year
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)
Time Frame: Through Study Completion, an average of 1 year
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
Time Frame: One month post immunization
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
Time Frame: 22-23 days post immunization
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
Time Frame: 4 weeks post immunization
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
Time Frame: One month post immunization
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
Time Frame: 22-23 days post immunization
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
Time Frame: 4 weeks post immunization
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

U.S. Army Medical Research and Development Command

Collaborators

United States Agency for International Development (USAID)
Naval Medical Research Center
Congressionally Directed Medical Research Programs
Military Infectious Diseases Research Program (MIDRP)

Investigators

  • Principal Investigator: Cindy Tamminga, MD, MPH, Naval Medical Research Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 12, 2006

Primary Completion (Actual)

June 2, 2016

Study Completion (Actual)

September 25, 2017

Study Registration Dates

First Submitted

October 24, 2006

First Submitted That Met QC Criteria

October 24, 2006

First Posted (Estimate)

October 25, 2006

Study Record Updates

Last Update Posted (Actual)

May 21, 2021

Last Update Submitted That Met QC Criteria

April 28, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • S-15-25
  • HSRRB A-13453 (Other Identifier: WRAIR)
  • NMRC.2006.0001 (Other Identifier: NMRC)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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