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A Safety and Efficacy Study of R21 +/- ChAd63/MVA ME-TRAP

Primary Purpose

Malaria

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
R21 with Matrix-M1
ChAd63 ME-TRAP
MVA ME-TRAP
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Malaria

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Healthy adults aged 18 to 45 years.
  • Able and willing (in the Investigator's opinion) to comply with all study requirements.
  • Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner.
  • Women only: Must practice continuous effective contraception* for the duration of the study.
  • Agreement to refrain from blood donation during the course of the study and for at least 3 years after the end of their involvement in the study.
  • Written informed consent to participate in the trial.
  • Reachable (24/7) by mobile phone during the period between CHMI and completion of antimalarial treatment.
  • Willingness to take a curative anti-malaria regimen following CHMI.
  • For volunteers not living close to their designated malaria challenge follow-up site (Oxford or Southampton): agreement to stay in a hotel room close to the trial centre during a part of the study (from at least day 6.5 post mosquito bite until anti-malarial treatment is completed).
  • Answer all questions on the informed consent quiz correctly.

Exclusion Criteria:

  • History of clinical malaria (any species).
  • Travel to a clearly malaria endemic locality during the study period or within the preceding six months
  • Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin)
  • Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period.
  • Prior receipt of an investigational vaccine likely to impact on interpretation of the trial data as assessed by the investigator. If any volunteers in Group 1-3 undergo rechallenge, this exclusion criterion does not extend to the vaccines previously received in the VAC065 trial
  • For Group 3 volunteers only: prior receipt of a non-malaria MVA or non-malaria adenovirus vectored experimental vaccine
  • Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed).
  • Use of immunoglobulins or blood products within 3 months prior to enrolment.
  • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine (e.g. egg products, Kathon) or malaria infection.
  • Any history of anaphylaxis post vaccination.
  • History of clinically significant contact dermatitis.
  • History of sickle cell anaemia, sickle cell trait, thalassaemia or thalassaemia trait or any haematological condition that could affect susceptibility to malaria infection.
  • Pregnancy, lactation or intention to become pregnant during the study.
  • Use of medications known to cause prolongation of the QT interval and existing contraindication to the use of Malarone
  • Use of medications known to have a potentially clinically significant interaction with Riamet and Malarone
  • Any clinical condition known to prolong the QT interval
  • History of cardiac arrhythmia, including clinically relevant bradycardia
  • Disturbances of electrolyte balance, eg, hypokalaemia or hypomagnesaemia
  • Family history of congenital QT prolongation or sudden death
  • Contraindications to the use of all three proposed anti-malarial medications; Riamet, Malarone and Chloroquine.
  • History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ).
  • History of serious psychiatric condition that may affect participation in the study.
  • Any other serious chronic illness requiring hospital specialist supervision.
  • Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 standard UK units every week.
  • Suspected or known injecting drug abuse in the 5 years preceding enrolment.
  • Hepatitis B surface antigen (HBsAg) detected in serum.
  • Seropositive for hepatitis C virus (antibodies to HCV) at screening (unless has taken part in a prior hepatitis C vaccine study with confirmed negative HCV antibodies prior to participation in that study, and negative HCV RNA PCR at screening for this study).
  • An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system.60
  • Positive family history in 1st and 2nd degree relatives < 50 years old for cardiac disease.
  • Volunteers unable to be closely followed for social, geographic or psychological reasons.
  • Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination.
  • Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.

Sites / Locations

  • NIHR Wellcome Trust Clinical Research Facility, Hammersmith Hospital
  • CCVTM, University of Oxford,
  • Southampton National Institute for Health Research

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Active Comparator

Active Comparator

Active Comparator

No Intervention

No Intervention

No Intervention

Active Comparator

No Intervention

Active Comparator

Arm Label

Standard Dose x3 (Group 1)

High Dose (Group 2)

Combination (Group 3)

Control Group 4a

Control Group 4b

Control Group 4c

Fractional Dose (Group 5)

Long-term Efficacy (Group 6)

Standard Dose x2 (Group 7)

Arm Description

R21 with Matrix-M1. Three vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0, 28 and 56.

R21 with Matrix-M1. Two vaccinations with 50µg R21/50µg Matrix-M1 on days 0 and 28 and one vaccination with 10 µg R21/ 50 µg Matrix M1 on day 56.

R21 with Matrix-M1, ChAd63 ME-TRAP and MVA ME-TRAP. Three vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0 , 28 and 56. Plus one vaccination with ChAd63 ME-TRAP on day 7 and one vaccination with MVA ME-TRAP on day 63.

These volunteers will not be vaccinated and will serve as infectivity controls when groups 1-3 undergo challenge.

These volunteers will not be vaccinated and will serve as infectivity controls when group 5-7 and sterilely protected volunteers from groups 1-3 undergo challenge.

These volunteers will not be vaccinated and will serve as infectivity controls if any volunteers from groups 5 and 7 are rechallenged.

R21 with Matrix-M1. Two vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0 and 28 and one vaccination with 2µg R21/ 50 µg Matrix-M1 on day 56.

Volunteers in this group have received vaccinations in a different malaria vaccine trial. These volunteers will not receive any vaccinations in this trial, but will undergo controlled human malaria infection as part of this study.

R21 with Matrix-M1. Two vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0 and 28.

Outcomes

Primary Outcome Measures

Efficacy of adjuvanted R21 at two different doses and adjuvanted R21 + ChAd63 and MVA encoding ME-TRAP in healthy malaria-naïve volunteers as assessed by number of completely protected individuals.
Use statistical analysis to compare number of completely protected individuals (those who do not, by Day 21 following sporozoite challenge, develop blood stage infection measured by occurrence of P. falciparum parasitemia, assessed by blood slide) in the vaccine groups compared to the controls.
Safety of adjuvanted R21 at two different doses and adjuvanted R21 + ChAd63 and MVA encoding ME-TRAP in healthy malaria-naïve volunteers as assessed by frequency of adverse events.
Solicited and unsolicited adverse event data will be collected at each clinic visit from diary cards, clinical review, clinical examination (including observations) and laboratory results. This AE data will be tabulated and frequency, duration and severity of AEs compared between groups.

Secondary Outcome Measures

Humoral immunogenicity generated in malaria naïve individuals with adjuvanted R21 at two different doses
Antibody response to the circumsporozoite protein generated by vaccination with adjuvanted R21.
Cell-mediated immunogenicity generated in malaria naïve individuals with ChAd63 and MVA encoding ME-TRAP
T-cell responses to the TRAP antigen of the malaria parasite generated by vaccination with ChAd63 and MVA encoding ME-TRAP .
Efficacy measured as time to P. falciparum parasitemia assessed by PCR against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
Statistical analyses using blood stage infection as defined by 500 or more parasites/ml in peripheral blood by quantitative PCR.
Efficacy measured as time to P. falciparum parasitemia assessed by blood slide against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
Statistical analyses using blood stage infection defined by a composite of symptoms, blood film result and parasitaemia.
Efficacy measured as time to P. falciparum parasitemia assessed by parasite density dynamics assessed by PCR against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
Statistical analyses using blood stage malaria infection as defined by 20 or more P. falciparum parasites/ml in peripheral blood by quantitative PCR.

Full Information

First Posted
July 28, 2016
Last Updated
June 12, 2018
Sponsor
University of Oxford
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1. Study Identification

Unique Protocol Identification Number
NCT02905019
Brief Title
A Safety and Efficacy Study of R21 +/- ChAd63/MVA ME-TRAP
Official Title
A Phase I/IIa Sporozoite Challenge Study to Assess the Safety and Protective Efficacy of Adjuvanted R21 at Two Different Doses and the Combination Malaria Vaccine Candidate Regimen of Adjuvanted R21 + ChAd63 and MVA Encoding ME-TRAP.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2017
Overall Recruitment Status
Completed
Study Start Date
August 2016 (undefined)
Primary Completion Date
December 21, 2017 (Actual)
Study Completion Date
December 21, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess the safety and efficacy of adjuvanted R21 alone and in combination with a viral-vectored vaccine regimen (constituting adjuvanted R21 + ChAd63 and MVA encoding ME-TRAP) against malaria sporozoite challenge in healthy malaria-naive volunteers. Healthy adult volunteers will be recruited in London, Oxford and Southampton. All vaccinations will be administered intramuscularly. The study involves having either two, three or five vaccinations and then undergoing challenge infection with malaria, or receiving no vaccinations then undergoing challenge infection with malaria.
Detailed Description
Vaccination phases and challenge procedures have been staggered over the trial period into 2 parts, challenges A and B. Challenge A: Groups 1-3 consist of volunteers receiving either R21 alone or R21 + ChAd63-MVA ME-TRAP followed by CHMI by sporozoite challenge (mosquito bite) at week 12. Twelve volunteers will be recruited to each group. Group 4a will serve as infectivity controls, these volunteers will not be vaccinated. Challenge B: Sterilely protected volunteers in groups 1 - 3 may be rechallenged to assess durability of efficacy, 5-12 months after the initial challenge. Groups 5-7 will also be enrolled to participate in challenge B. Group 5 (8 volunteers) will test the efficacy of standard dose R21 with a fractional third dose followed by CHMI at week 12. Group 6 will test the long-term efficacy of the standard dose R21 vaccination regimen (volunteers in this group will have already received their vaccinations whilst enrolled in the VAC053 malaria trial and will therefore not receive any additional vaccinations before undergoing challenge). Group 7 (8 volunteers) will test the efficacy of a two dose R21 vaccination regimen followed by CHMI at week 8. Group 4b will serve as infectivity controls for groups 5-7 and sterilely protected group 1-3 volunteers. Group 4c volunteers will be used as infectivity controls if any volunteers from groups 5 and 7 are rechallenged.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard Dose x3 (Group 1)
Arm Type
Active Comparator
Arm Description
R21 with Matrix-M1. Three vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0, 28 and 56.
Arm Title
High Dose (Group 2)
Arm Type
Active Comparator
Arm Description
R21 with Matrix-M1. Two vaccinations with 50µg R21/50µg Matrix-M1 on days 0 and 28 and one vaccination with 10 µg R21/ 50 µg Matrix M1 on day 56.
Arm Title
Combination (Group 3)
Arm Type
Active Comparator
Arm Description
R21 with Matrix-M1, ChAd63 ME-TRAP and MVA ME-TRAP. Three vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0 , 28 and 56. Plus one vaccination with ChAd63 ME-TRAP on day 7 and one vaccination with MVA ME-TRAP on day 63.
Arm Title
Control Group 4a
Arm Type
No Intervention
Arm Description
These volunteers will not be vaccinated and will serve as infectivity controls when groups 1-3 undergo challenge.
Arm Title
Control Group 4b
Arm Type
No Intervention
Arm Description
These volunteers will not be vaccinated and will serve as infectivity controls when group 5-7 and sterilely protected volunteers from groups 1-3 undergo challenge.
Arm Title
Control Group 4c
Arm Type
No Intervention
Arm Description
These volunteers will not be vaccinated and will serve as infectivity controls if any volunteers from groups 5 and 7 are rechallenged.
Arm Title
Fractional Dose (Group 5)
Arm Type
Active Comparator
Arm Description
R21 with Matrix-M1. Two vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0 and 28 and one vaccination with 2µg R21/ 50 µg Matrix-M1 on day 56.
Arm Title
Long-term Efficacy (Group 6)
Arm Type
No Intervention
Arm Description
Volunteers in this group have received vaccinations in a different malaria vaccine trial. These volunteers will not receive any vaccinations in this trial, but will undergo controlled human malaria infection as part of this study.
Arm Title
Standard Dose x2 (Group 7)
Arm Type
Active Comparator
Arm Description
R21 with Matrix-M1. Two vaccinations with 10 µg R21/ 50 µg Matrix-M1 on days 0 and 28.
Intervention Type
Biological
Intervention Name(s)
R21 with Matrix-M1
Intervention Description
Vaccine
Intervention Type
Biological
Intervention Name(s)
ChAd63 ME-TRAP
Intervention Description
Vaccine
Intervention Type
Biological
Intervention Name(s)
MVA ME-TRAP
Intervention Description
Vaccine
Primary Outcome Measure Information:
Title
Efficacy of adjuvanted R21 at two different doses and adjuvanted R21 + ChAd63 and MVA encoding ME-TRAP in healthy malaria-naïve volunteers as assessed by number of completely protected individuals.
Description
Use statistical analysis to compare number of completely protected individuals (those who do not, by Day 21 following sporozoite challenge, develop blood stage infection measured by occurrence of P. falciparum parasitemia, assessed by blood slide) in the vaccine groups compared to the controls.
Time Frame
6 months
Title
Safety of adjuvanted R21 at two different doses and adjuvanted R21 + ChAd63 and MVA encoding ME-TRAP in healthy malaria-naïve volunteers as assessed by frequency of adverse events.
Description
Solicited and unsolicited adverse event data will be collected at each clinic visit from diary cards, clinical review, clinical examination (including observations) and laboratory results. This AE data will be tabulated and frequency, duration and severity of AEs compared between groups.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Humoral immunogenicity generated in malaria naïve individuals with adjuvanted R21 at two different doses
Description
Antibody response to the circumsporozoite protein generated by vaccination with adjuvanted R21.
Time Frame
6 months
Title
Cell-mediated immunogenicity generated in malaria naïve individuals with ChAd63 and MVA encoding ME-TRAP
Description
T-cell responses to the TRAP antigen of the malaria parasite generated by vaccination with ChAd63 and MVA encoding ME-TRAP .
Time Frame
6 months
Title
Efficacy measured as time to P. falciparum parasitemia assessed by PCR against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
Description
Statistical analyses using blood stage infection as defined by 500 or more parasites/ml in peripheral blood by quantitative PCR.
Time Frame
6 months
Title
Efficacy measured as time to P. falciparum parasitemia assessed by blood slide against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
Description
Statistical analyses using blood stage infection defined by a composite of symptoms, blood film result and parasitaemia.
Time Frame
6 months
Title
Efficacy measured as time to P. falciparum parasitemia assessed by parasite density dynamics assessed by PCR against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
Description
Statistical analyses using blood stage malaria infection as defined by 20 or more P. falciparum parasites/ml in peripheral blood by quantitative PCR.
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Long term protective efficacy of adjuvanted R21 at two different doses and adjuvanted R21 + ChAd63 and MVA encoding ME-TRAP
Description
Long term efficacy of the vaccination regimens will be assessed by re-challenging any sterilely protected individuals at 5 - 7 months after the first sporozoite challenge (~12 months after the start of the study) and comparing the number of re-challenges who develop blood stage infection with unvaccinated controls.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy adults aged 18 to 45 years. Able and willing (in the Investigator's opinion) to comply with all study requirements. Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner. Women only: Must practice continuous effective contraception* for the duration of the study. Agreement to refrain from blood donation during the course of the study and for at least 3 years after the end of their involvement in the study. Written informed consent to participate in the trial. Reachable (24/7) by mobile phone during the period between CHMI and completion of antimalarial treatment. Willingness to take a curative anti-malaria regimen following CHMI. For volunteers not living close to their designated malaria challenge follow-up site (Oxford or Southampton): agreement to stay in a hotel room close to the trial centre during a part of the study (from at least day 6.5 post mosquito bite until anti-malarial treatment is completed). Answer all questions on the informed consent quiz correctly. Exclusion Criteria: History of clinical malaria (any species). Travel to a clearly malaria endemic locality during the study period or within the preceding six months Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin) Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period. Prior receipt of an investigational vaccine likely to impact on interpretation of the trial data as assessed by the investigator. If any volunteers in Group 1-3 undergo rechallenge, this exclusion criterion does not extend to the vaccines previously received in the VAC065 trial For Group 3 volunteers only: prior receipt of a non-malaria MVA or non-malaria adenovirus vectored experimental vaccine Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed). Use of immunoglobulins or blood products within 3 months prior to enrolment. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine (e.g. egg products, Kathon) or malaria infection. Any history of anaphylaxis post vaccination. History of clinically significant contact dermatitis. History of sickle cell anaemia, sickle cell trait, thalassaemia or thalassaemia trait or any haematological condition that could affect susceptibility to malaria infection. Pregnancy, lactation or intention to become pregnant during the study. Use of medications known to cause prolongation of the QT interval and existing contraindication to the use of Malarone Use of medications known to have a potentially clinically significant interaction with Riamet and Malarone Any clinical condition known to prolong the QT interval History of cardiac arrhythmia, including clinically relevant bradycardia Disturbances of electrolyte balance, eg, hypokalaemia or hypomagnesaemia Family history of congenital QT prolongation or sudden death Contraindications to the use of all three proposed anti-malarial medications; Riamet, Malarone and Chloroquine. History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ). History of serious psychiatric condition that may affect participation in the study. Any other serious chronic illness requiring hospital specialist supervision. Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 standard UK units every week. Suspected or known injecting drug abuse in the 5 years preceding enrolment. Hepatitis B surface antigen (HBsAg) detected in serum. Seropositive for hepatitis C virus (antibodies to HCV) at screening (unless has taken part in a prior hepatitis C vaccine study with confirmed negative HCV antibodies prior to participation in that study, and negative HCV RNA PCR at screening for this study). An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system.60 Positive family history in 1st and 2nd degree relatives < 50 years old for cardiac disease. Volunteers unable to be closely followed for social, geographic or psychological reasons. Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination. Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrian V Hill, DPhil FRCP
Organizational Affiliation
Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hosptal, Oxford, United Kingdom
Official's Role
Principal Investigator
Facility Information:
Facility Name
NIHR Wellcome Trust Clinical Research Facility, Hammersmith Hospital
City
London
Country
United Kingdom
Facility Name
CCVTM, University of Oxford,
City
Oxford
ZIP/Postal Code
OX3 7LE
Country
United Kingdom
Facility Name
Southampton National Institute for Health Research
City
Southampton
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
30774635
Citation
Ssemaganda A, Giddam AK, Zaman M, Skwarczynski M, Toth I, Stanisic DI, Good MF. Induction of Plasmodium-Specific Immune Responses Using Liposome-Based Vaccines. Front Immunol. 2019 Feb 1;10:135. doi: 10.3389/fimmu.2019.00135. eCollection 2019.
Results Reference
derived

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A Safety and Efficacy Study of R21 +/- ChAd63/MVA ME-TRAP

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