| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Plasmodium falciparum infection |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety and tolerability of adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers, and the efficacy (prevention of occurrence of P. falciparum parasitemia, assessed by PCR) of adjuvanted R21 against malaria sporozoite challenge, in healthy malaria-naïve volunteers using two immunisation regimes. |
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| E.2.2 | Secondary objectives of the trial |
To assess humoral immunogenicity generated in malaria-naïve individuals by adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers.
To further assess the efficacy using different thresholds, measured as time to P. falciparum parasitemia, assessed by PCR of adjuvanted R21 in two different vaccination regimes and compared to R21 against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The volunteer must satisfy all the following criteria to be eligible for the study:
• 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 or access this medical history electronically.
• 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.
• Agree to refrain from blood donation 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 the malaria challenge follow-up site (CCVTM, Oxford) 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.*
Female volunteers are required to use an effective form of contraception during the course of the study as there is no information about the effect of these vaccines on a foetus.
Acceptable forms of contraception for female volunteers include:
• Established use of oral, injected or implanted hormonal methods of contraception.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
• Total abdominal hysterectomy
• Barrier methods of contraception (condom or occlusive cap with spermicide)
• Male sterilisation, if the vasectomised partner is the sole partner for the subject.
• True abstinence, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence and withdrawal are not acceptable methods of contraception).
* Not applicable for volunteers who do not undergo CHMI (Groups 1, 4 and 5)
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| E.4 | Principal exclusion criteria |
The volunteer may not enter the study if any of the following apply:
• History of clinical malaria (any species).
• Travel to a clearly significantly malaria endemic locality planned for 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.
• 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) 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 and existing contraindication to the use of Malarone.*
• History of cardiac arrhythmia, including clinically relevant bradycardia and existing contraindication to the use of Malarone.*
• Clinically significant disturbances of electrolyte balance, eg, hypokalaemia or hypomagnesaemia
• Family history of congenital QT prolongation or sudden death and existing contraindication to the use of Malarone.*
• Contraindications to the use of both Riamet and Malarone*
• 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 25 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).
• Positive family history in both 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. In the event of abnormal test results, confirmatory repeat tests will be requested.
• 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.
*Not applicable for volunteers who do not undergo CHMI (Groups 1, 4 and 5)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary safety endpoints:
• Occurrence of each solicited adverse event within 7-day follow-up period (day of vaccination and 6 subsequent days) after each vaccination.
• Occurrence of unsolicited adverse events within 28 days (day of vaccination and 27 subsequent days) after each vaccination, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.
• Occurrence of serious adverse events within 28 days (day of vaccination and 27 subsequent days) after each vaccination and over the whole study duration, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.
Primary efficacy endpoint:
The number of completely protected individuals will be presented for each vaccination group and controls. Completely protected individuals are those who do not, by Day 21 following sporozoite challenge, develop blood stage infection as defined in Section 9.5 in the protocol based on PCR thresholds.
This is the first study assessing the efficacy of the novel malaria vaccine candidate, R21 in a CHMI study. Therefore, we are unable to power this study to detect a difference between vaccination groups (2 and 3). However, the proportions protected in vaccinated groups will be compared to controls by Fisher exact tests to ask if there is more protection in any of the vaccine groups than controls.
Solicited and unsolicited AE data will be collected at each clinic visit. It will be collected 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.
Hematological (hemoglobin, WBC and platelets) and biochemical (creatinine and ALT) laboratory values will be presented according to toxicity grading scales and tabulated by group.
SAEs, AEs of special interest and withdrawal due to AE(s)/SAE(s) will be described in detail.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the adverse events following vaccination will begin as soon as the first vaccine is given, and will continue throughout the remainder of the trial. It will be assessed by analysing adverse event data collected from diary cards,
clinical review of volunteers, and laboratory measurements. Any adverse events persisting at the end of the trial will be followed up until there is a satisfactory resolution or stabilisation occurs or until a non study related causality is found.
Evaluation for blood stage malaria infection will occur from Day 6.5 following malaria challenge to Day 21 following malaria challenge. |
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| E.5.2 | Secondary end point(s) |
The specific aims for the immunogenicity assessment are as follows:
• To document immunogenicity measures, capturing humoral and cellular immune responses to R21 as follows: Anti-CS antibody titers.
Further measures of vaccine efficacy will be used, as secondary endpoints, to provide more detailed quantitative assessment (such as delay to parasitaemia or parasite burden at day 7) of the dynamics of malaria infection in sporozoite-challenged volunteers. These measures enable more powerful distinction, than the use of sterile efficacy rates, between the performance of different vaccination regimens, and between individuals receiving the same vaccination regimen, as has been shown for previous efficacy trials. This maximises the yield of information from the volunteers in this study that is used to assess the primary objective. These measures of efficacy will be the same as used in the VAC055,VAC059, VAC 065 and VAC 067 clinical trials.
Kaplan-Meier analyses will be performed for each vaccination regimen and for controls. Separate analyses will be done using various outcome measures for malaria blood stage infection including: (i) parasitaemia as defined by 10,000 or more parasites/ml in peripheral blood by quantitative PCR or composite of symptoms and PCR > 1000 p/ml, (ii) parasitaemia >1,000 p/ml on PCR, (iii) parasitaemia > 500 p/ml on PCR (iv) parasitaemia > 20 p/ml. A statistically significant difference between a vaccination regimen and controls by log rank analysis of Kaplan Meier curves any endpoint, will be considered as an indicator of likely vaccine efficacy compared to controls.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Immunology investigations will be collected on blood specimens taken from volunteers across the course of their participation in the trial.
PCR data will be collected from Day 6.5 to day 21 (or until malaria diagnosis) to establish time to 20 parasites per ml and time to 500 parasites per ml. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Unvaccinated volunteers who undergo malaria challenge |
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| E.8.2.4 | Number of treatment arms in the trial | 9 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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