A Challenge Study to Assess the Safety, Immunogenicity and Efficacy of a Malaria Vaccine Candidate

Study Overview
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Brief Summary
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This is an open-label, multi-centre Phase I/IIa dose escalation blood-stage malaria CHMI trial to assess the safety, immunogenicity and efficacy of the candidate malaria vaccine RH5.1/AS01. All volunteers recruited will be healthy, malaria naïve adults aged between 18 and 45 years. Volunteers will be recruited and vaccinated at the CCVTM, Oxford; Guys and St Thomas' NIHR CRF, London; and the NIHR WTCRF, Southampton for the Phase Ia part of the trial, and at the CCVTM, Oxford and Guys and St Thomas' NIHR CRF, London for the Phase IIa stage.

Detailed Description
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This is a descriptive phase I trial to assess the safety and immunogenicity of the RH5.1/AS01 vaccine in healthy volunteers at different doses, and to establish whether the RH5.1/AS01 vaccine can demonstrate a reduced parasite multiplication rate in vaccinated subjects compared to infectivity controls in a blood-stage controlled human malaria infection model. There will be 6 study groups across two phases of the trial, with a total of 66 - 78 volunteers. Vaccination of groups will be sequential from Group 1 to Group 3. Group 3 and 4 can be recruited simultaneously. Volunteers will be able to choose which group they are allocated to. The vaccination dose for Group 5 has been decided following the analysis of safety and exploratory immunology assays from Groups 1, 2 and 4. They will undergo blood-stage CHMI 2 weeks after the final vaccination and will be followed up until approximately 6 months after the final vaccination. Group 6 volunteers will be infectivity controls, so will not receive any vaccinations. Volunteers will be recruited and undergo screening visits, vaccination and clinic visits post-vaccination at their local trial site. Procedures will be performed on the visit time points indicated in the schedule of attendances.. Additional procedures or laboratory tests may be performed, at the discretion of the Investigators.

Official Title
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A Phase I/IIa Clinical Trial to Assess the Safety, Immunogenicity and Efficacy of the Blood-stage Plasmodium Falciparum Malaria Vaccine Candidate RH5.1/AS01

Conditions
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Malaria

Intervention / Treatment
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* Biological: RH5.1/ ASO1


Participation Criteria
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Eligibility Criteria
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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 (GP). For females only, willingness to practice continuous effective contraception (see below) during the study and a negative pregnancy test on the day(s) of screening and vaccination, and on the day prior to blood-stage CHMI, and prior to the start of antimalarial treatment for Group 5 and 6 volunteers. Agreement to refrain from blood donation during the course of the study. Provide written informed consent. Additional Inclusion Criteria for Groups 5 - 6 Agreement to permanently refrain from blood donation, as per current UK Blood Transfusion and Tissue Transplantation Services guidelines. Reachable (24 hours a day) by mobile phone during the period between CHMI and completion of antimalarial treatment. Willingness to take a curative anti-malaria regimen following CHMI. Answer all questions on the informed consent questionnaire correctly. Exclusion Criteria: Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period. Prior receipt of an investigational malaria vaccine or any other investigational vaccine likely to impact on interpretation of the trial data. Any medical condition that in the judgment of the investigator would make intramuscular (IM) injection unsafe. Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate. Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 20 mg/day (for adult subjects), or equivalent. Inhaled and topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab). Chronic use of antibiotics with antimalarial effects (e.g. tetracyclines for dermatologic patients, sulfa for recurrent urinary tract infections, etc.). History of malaria chemoprophylaxis within 60 days prior to vaccination. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Any history of anaphylaxis in relation to vaccination. Pregnancy, lactation or willingness/intention to become pregnant during the study. History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ). History of serious psychiatric condition likely to 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 units every week. Suspected or known injecting drug abuse in the 5 years preceding enrolment. Seropositive for hepatitis B surface antigen (HBsAg). Seropositive for hepatitis C virus (antibodies to HCV). History of clinical malaria (any species). Travel to a malaria endemic region during the study period or within the previous six months. Any clinically significant abnormal finding on screening biochemistry or haematology blood tests or urinalysis. 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. Inability of the study team to contact the volunteer's GP to confirm medical history and safety to participate. Additional exclusion criteria for groups 5 - 6 Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin). History of sickle cell anaemia, sickle cell trait, thalassaemia or thalassaemia trait or any haematological condition that could affect susceptibility to malaria infection. 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. Contraindications to the use of all three proposed anti-malarial medications; Riamet, Malarone and Chloroquine. Any clinical condition known to prolong the QT interval. Family history of congenital QT prolongation or sudden death. Positive family history in 1st and 2nd degree relatives < 50 years old for cardiac disease. History of cardiac arrhythmia, including clinically relevant bradycardia. Volunteer unable to be closely followed for social, geographic or psychological reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1-Phase Ia<br>The study is designed to assess a 'standard' protein-in-adjuvant vaccination regimen- 2µg RH5.1/ 0.5mL AS01- of 3 doses given four weeks apart, with dose escalation to assess the best dose in healthy adults. | Biological: RH5.1/ ASO1<br>* The RH5.1 protein consists of the entire full-length ectodomain of the PfRH5 antigen (amino acids E26 - Q526) with the sequence based on the 3D7 clone of P. falciparum. The AS01 adjuvant system has been developed and manufactured by GlaxoSmithKline (GSK) Biologicals and is presented as a liquid solution in a monodose glass vial. AS01 is a liposome-based Adjuvant System with a specific aim to improve cell-mediated immunity.<br>|
| Active Comparator: Group 2- Phase Ia<br>The dose used will be- 10µg RH5.1/ 0.5mL AS01. The total number of volunteers recruited to Groups 1 and 2 will be decided based on the immunogenicity of the vaccines at the 2 µg and 10 µg doses. If the doses are immunogenic the groups (1 and 2) will be recruited to a total of 12 volunteers. | Biological: RH5.1/ ASO1<br>* The RH5.1 protein consists of the entire full-length ectodomain of the PfRH5 antigen (amino acids E26 - Q526) with the sequence based on the 3D7 clone of P. falciparum. The AS01 adjuvant system has been developed and manufactured by GlaxoSmithKline (GSK) Biologicals and is presented as a liquid solution in a monodose glass vial. AS01 is a liposome-based Adjuvant System with a specific aim to improve cell-mediated immunity.<br>|
| Active Comparator: Group 3-Phase Ia<br>Group 3 will receive 50µg RH5.1/ 0.5mL AS0 The ultimate aim is to assess the safety and immunogenicity of giving the 'standard' first two doses of the vaccine followed by a delayed fractional dose (10 µg). | Biological: RH5.1/ ASO1<br>* The RH5.1 protein consists of the entire full-length ectodomain of the PfRH5 antigen (amino acids E26 - Q526) with the sequence based on the 3D7 clone of P. falciparum. The AS01 adjuvant system has been developed and manufactured by GlaxoSmithKline (GSK) Biologicals and is presented as a liquid solution in a monodose glass vial. AS01 is a liposome-based Adjuvant System with a specific aim to improve cell-mediated immunity.<br>|
| Active Comparator: Group 4-Phase Ia<br>Group 3 and 4 will be recruited simultaneously. The dose of vaccine for this group is same as that of 3 (50µg RH5.1/ 0.5mL AS01) | Biological: RH5.1/ ASO1<br>* The RH5.1 protein consists of the entire full-length ectodomain of the PfRH5 antigen (amino acids E26 - Q526) with the sequence based on the 3D7 clone of P. falciparum. The AS01 adjuvant system has been developed and manufactured by GlaxoSmithKline (GSK) Biologicals and is presented as a liquid solution in a monodose glass vial. AS01 is a liposome-based Adjuvant System with a specific aim to improve cell-mediated immunity.<br>|
| Active Comparator: Group 5-Phase IIa<br>The vaccination dose for Group 5 was decided following the analysis of safety and exploratory immunology assays from Groups 1, 2 and 4. The dose of vaccine for this group is the same as that of group 2 (10µg RH5.1/ 0.5mL AS01). | Biological: RH5.1/ ASO1<br>* The RH5.1 protein consists of the entire full-length ectodomain of the PfRH5 antigen (amino acids E26 - Q526) with the sequence based on the 3D7 clone of P. falciparum. The AS01 adjuvant system has been developed and manufactured by GlaxoSmithKline (GSK) Biologicals and is presented as a liquid solution in a monodose glass vial. AS01 is a liposome-based Adjuvant System with a specific aim to improve cell-mediated immunity.<br>|
| No Intervention: Group 6-Phase IIa<br>Group 6 volunteers will be infectivity controls, so will not receive any vaccinations. Groups 5 and 6 will only be recruited once at least 6 volunteers in Group 4 have completed all vaccinations. | |
| Active Comparator: Group 7-Phase IIa<br>Group 7 are Group 5 volunteers who will receive a fourth dose of IMP (10µg RH5.1/ 0.5mL AS01) | Biological: RH5.1/ ASO1<br>* The RH5.1 protein consists of the entire full-length ectodomain of the PfRH5 antigen (amino acids E26 - Q526) with the sequence based on the 3D7 clone of P. falciparum. The AS01 adjuvant system has been developed and manufactured by GlaxoSmithKline (GSK) Biologicals and is presented as a liquid solution in a monodose glass vial. AS01 is a liposome-based Adjuvant System with a specific aim to improve cell-mediated immunity.<br>|
| No Intervention: Group 8 -Phase IIa<br>Group 8 are infectivity controls who were originally in Group 6. | |
| No Intervention: Group 9 -Phase IIa<br>Group 9 are new infectivity controls | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of the RH5.1/AS01 Vaccine by Demonstrating a Reduced PMR in Vaccinated Subjects Compared to Infectivity Controls Against 3D7 Clone Parasites in a CHMI Model. | PCR-derived parasite multiplication rate (PMR) will be the primary efficacy endpoint for the Phase IIa stage of the trial, and comparison of the endpoint between the Groups 5 and 6 will constitute the primary analysis for efficacy. | Measured during CHMI | 
| Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | Solicited and unsolicited adverse events collected passively and actively for 28 days post each vaccination. Number of volunteers reporting any unsolicited AEs post-any vaccination, as reported to investigators or in electronic diaries. | 8 months | 
| the in Vitro Growth Inhibition Activity (GIA) Against 3D7 Clone P. Falciparum Parasites of IgG Purified From the Serum of Vaccinees. | The specific endpoints for GIA in vitro will be assessed from a titration of the purified IgG in the assay. | 2 weeks post final vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | Antibody responses to the RH5.1 protein generated by vaccination | 2 weeks post final vaccination | 
| the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | T cell responses to the RH5.1 protein generated by vaccination | 2 weeks post final vaccination | 
| Immunological Readouts for Association With a Reduced Parasite Multiplication Rate. | Statistical correlation between anti-RH5 antibody responses induced by the RH5.1 vaccine and PMR. A non-linear regression curve for all samples combined is available in the trial manuscript ; data is not presented here. | 8 months |