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

NCT ID: NCT02905019

Last Updated: 2018-06-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 63 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2017-12-21

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.

Conditions

Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

Standard Dose x3 (Group 1)

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

Group Type: ACTIVE_COMPARATOR

R21 with Matrix-M1

Intervention Type: BIOLOGICAL

Vaccine

High Dose (Group 2)

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.

Group Type: ACTIVE_COMPARATOR

R21 with Matrix-M1

Intervention Type: BIOLOGICAL

Vaccine

Combination (Group 3)

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.

Group Type: ACTIVE_COMPARATOR

R21 with Matrix-M1

Intervention Type: BIOLOGICAL

Vaccine

ChAd63 ME-TRAP

Intervention Type: BIOLOGICAL

Vaccine

MVA ME-TRAP

Intervention Type: BIOLOGICAL

Vaccine

Control Group 4a

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Control Group 4b

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Control Group 4c

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Fractional Dose (Group 5)

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.

Group Type: ACTIVE_COMPARATOR

R21 with Matrix-M1

Intervention Type: BIOLOGICAL

Vaccine

Long-term Efficacy (Group 6)

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Standard Dose x2 (Group 7)

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

Group Type: ACTIVE_COMPARATOR

R21 with Matrix-M1

Intervention Type: BIOLOGICAL

Vaccine

Interventions

R21 with Matrix-M1

Vaccine

Intervention Type: BIOLOGICAL

ChAd63 ME-TRAP

Vaccine

Intervention Type: BIOLOGICAL

MVA ME-TRAP

Vaccine

Intervention Type: BIOLOGICAL

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Adrian V Hill, DPhil FRCP

Role: PRINCIPAL_INVESTIGATOR

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hosptal, Oxford, United Kingdom

Locations

NIHR Wellcome Trust Clinical Research Facility, Hammersmith Hospital

London, , United Kingdom

CCVTM, University of Oxford,

Oxford, , United Kingdom

Southampton National Institute for Health Research

Southampton, , United Kingdom

Countries

United Kingdom

References

Venkatraman N, Silman D, Bellamy D, Stockdale L, Bowyer G, Edwards NJ, Griffiths O, Lopez FR, Powlson J, Mair C, Folegatti PM, Datoo MS, Morter R, Minassian AM, Poulton I, Collins KA, Brod F, Angell-Manning P, Berrie E, Brendish N, Glenn G, Fries L, Baum J, Blagborough AM, Roberts R, Lawrie AM, Angus B, Lewis DJM, Faust SN, Ewer KJ, Hill AVS. R21 in Matrix-M adjuvant in UK malaria-naive adult men and non-pregnant women aged 18-45 years: an open-label, partially blinded, phase 1-2a controlled human malaria infection study. Lancet Microbe. 2025 Mar;6(3):100867. doi: 10.1016/S2666-5247(24)00083-1. Epub 2025 Jan 10.

Reference Type: DERIVED

PMID: 39805301 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30774635 (View on PubMed)

Other Identifiers

VAC065

Identifier Type: -

Identifier Source: org_study_id