Malaria
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALRH5.1/ ASO1
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.
Sponsors
University of Oxford
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Measured during CHMI | 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. |
| Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 8 months | 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. |
| the in Vitro Growth Inhibition Activity (GIA) Against 3D7 Clone P. Falciparum Parasites of IgG Purified From the Serum of Vaccinees. | 2 weeks post final vaccination | The specific endpoints for GIA in vitro will be assessed from a titration of the purified IgG in the assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 2 weeks post final vaccination | Antibody responses to the RH5.1 protein generated by vaccination |
| the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 2 weeks post final vaccination | T cell responses to the RH5.1 protein generated by vaccination |
| Immunological Readouts for Association With a Reduced Parasite Multiplication Rate. | 8 months | 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. |
Countries
United Kingdom
Participant flow
Pre-assignment details
Group 5 and 6 volunteers were invited to join the re-challenge study and formed Groups 7 and 8
Participants by arm
| Arm | Count |
|---|---|
| Group 1 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. | 12 |
| Group 2 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.
RH5.1/ ASO1: 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. | 12 |
| Group 3 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).
RH5.1/ ASO1: 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. | 12 |
| Group 4 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) RH5.1/ ASO1: 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. | 14 |
| Group 5 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).
RH5.1/ ASO1: 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.
Note, group 7 constitutes volunteers from groups 5 so is not presented separately | 17 |
| Group 6 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.
Note, group 8 constitutes volunteers from groups 6 so is not presented separately | 15 |
| Group 9 Group 9 are new infectivity controls | 6 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Initial Recruitment | Adverse Event | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Initial Recruitment | Withdrawal by Subject | 0 | 1 | 1 | 4 | 1 | 1 | 0 | 0 | 2 |
| Invitation for Additional Challenge | Pregnancy | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 9 | Group 1 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 14 Participants | 17 Participants | 15 Participants | 6 Participants | 12 Participants | 88 Participants |
| Age, Continuous | 28 Years | 29 Years | 31 Years | 27 Years | 27 Years | 24 Years | 32 Years | 29 Years |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 9 Participants | 12 Participants | 6 Participants | 4 Participants | 9 Participants | 55 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 5 Participants | 5 Participants | 9 Participants | 2 Participants | 3 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 14 | 0 / 17 | 0 / 15 | 0 / 9 | 0 / 8 | 0 / 6 |
| other Total, other adverse events | 9 / 12 | 11 / 12 | 9 / 12 | 10 / 14 | 14 / 17 | 0 / 15 | 3 / 9 | 0 / 8 | 0 / 6 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 1 / 12 | 0 / 14 | 1 / 17 | 0 / 15 | 1 / 9 | 0 / 8 | 0 / 6 |
Outcome results
Primary
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.
Time frame: Measured during CHMI
Population: Group 5 vs Group 6 and Group 7 vs Group 9 compared as vaccinees versus primary infectivity controls
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 5-Phase IIa | 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. | 8.12 Parisite multiplication rate (PMR) | Standard Deviation 1.13 |
| Group 6-Phase IIa | 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. | 9.75 Parisite multiplication rate (PMR) | Standard Deviation 2.46 |
| Group 7-Phase IIa | 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. | 7.62 Parisite multiplication rate (PMR) | Standard Deviation 1.44 |
| Group 9 -Phase IIa | 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. | 11.22 Parisite multiplication rate (PMR) | Standard Deviation 1.92 |
Primary
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.
Time frame: 8 months
Population: Note, detailed adverse event data is outlined within the study publication. Groups 6, 8 and 9 were not assessed for adverse events as part of this objective as they did not receive the trial vaccine. This objective is assessing the safety of the vaccine itself and therefore is not applicable to these groups.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1-Phase Ia | Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 9 Participants |
| Group 2- Phase Ia | Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 11 Participants |
| Group 3-Phase Ia | Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 9 Participants |
| Group 4-Phase Ia | Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 10 Participants |
| Group 5-Phase IIa | Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 14 Participants |
| Group 6-Phase IIa | Safety of RH5.1/AS01 in Healthy Malaria-naïve Adults in the UK. | 3 Participants |
Primary
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.
Time frame: 2 weeks post final vaccination
Population: GIA activity of 10mg/ml purified IgG was measured at 2 weeks following final vaccination (D70 for Groups 1, 2 \& 4 and D196 for Group 3).~Objective is not applicable for groups 5-9.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Group 1-Phase Ia | the in Vitro Growth Inhibition Activity (GIA) Against 3D7 Clone P. Falciparum Parasites of IgG Purified From the Serum of Vaccinees. | 75.2 percentage of growth inhibition | Standard Deviation 20.25 |
| Group 2- Phase Ia | the in Vitro Growth Inhibition Activity (GIA) Against 3D7 Clone P. Falciparum Parasites of IgG Purified From the Serum of Vaccinees. | 69.9 percentage of growth inhibition | Standard Deviation 11.65 |
| Group 3-Phase Ia | the in Vitro Growth Inhibition Activity (GIA) Against 3D7 Clone P. Falciparum Parasites of IgG Purified From the Serum of Vaccinees. | 71.3 percentage of growth inhibition | Standard Deviation 13.76 |
| Group 4-Phase Ia | the in Vitro Growth Inhibition Activity (GIA) Against 3D7 Clone P. Falciparum Parasites of IgG Purified From the Serum of Vaccinees. | 71.6 percentage of growth inhibition | Standard Deviation 13.18 |
Secondary
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.
Time frame: 8 months
Secondary
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
Time frame: 2 weeks post final vaccination
Population: RH5-specific T cell responses were assessed by ex-vivo IFN-γ ELISPOT in fresh PBMC following stimulation with either RH5.1 protein at 2 weeks post final vaccination in Groups 1-4.~This objective is not applicable to groups 5-9.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Group 1-Phase Ia | the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 570 SFU per million PBMC | Standard Deviation 439.4 |
| Group 2- Phase Ia | the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 140.7 SFU per million PBMC | Standard Deviation 343.9 |
| Group 3-Phase Ia | the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 277.3 SFU per million PBMC | Standard Deviation 328.4 |
| Group 4-Phase Ia | the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 713.3 SFU per million PBMC | Standard Deviation 396.4 |
Secondary
the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens.
Antibody responses to the RH5.1 protein generated by vaccination
Time frame: 2 weeks post final vaccination
Population: Anti-RH5\_FL IgG (ug/mL) at 2 weeks post final vaccination in groups 1-4, Fig 1C.~This objective is not applicable to groups 5-9
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Group 1-Phase Ia | the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 86.9 ug/mL | Standard Deviation 51.75 |
| Group 2- Phase Ia | the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 88.1 ug/mL | Standard Deviation 40.11 |
| Group 3-Phase Ia | the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 124.4 ug/mL | Standard Deviation 81.62 |
| Group 4-Phase Ia | the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens. | 95.6 ug/mL | Standard Deviation 56.07 |