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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2016-001718-31
    Trial protocol
    		 GB  
    Global end of trial date
    27 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Sep 2020
    First version publication date
    17 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VAC063
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02927145
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford, CTRG
    Sponsor organisation address
    Old Road, Oxford, United Kingdom, OX3 7LE
    Public contact
    Angela Minasian, University of Oxford, 0044 01865611425, angela.minassian@ndm.ox.ac.uk
    Scientific contact
    Angela Minasian, University of Oxford, 0044 01865611425, angela.minassian@ndm.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety of the RH5.1/AS01 vaccine in healthy volunteers at different doses. 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.
    Protection of trial subjects
    - Volunteers given at least 24 hours to read VIS before being seen and then given plenty of opportunity to ask questions prior to agreeing to take part in a study. - Volunteers for Groups 5-9 asked to complete a questionnaire testing their understanding of the trial as part of the consent process to ensure that individuals understand the trial sufficiently to give informed consent. - Screening visit including full medical history, physical examination and baseline blood tests to ensure volunteers are healthy prior to enrolment. - Vaccination carried out in clinical environment with staff trained in resuscitation in case of allergic reaction. - Safety review prior to dose escalation (LSM) - Volunteers seen within 1 - 3 days of vaccination for safety review and provided with 24/7 contact number for trial clinician and emergency contact card for the department. - Inclusion of AE related safety stopping/holding rules at both a group and individual level in the protocol. - Volunteers given emergency contact card detailing that they have been infected with malaria. - Volunteers seen twice daily once blood stage malaria is possible with twice daily malaria films and PCR - Malaria treated promptly when diagnosed with highly efficacious medication and at least half of doses directly observed. - Volunteers provided with symptomatic treatment (antipyretic/analgesic and antiemetic) in case of malaria symptoms. - Volunteers who remained undiagnosed with malaria at Day 21 given a treatment course of anti-malarials. - Volunteers followed up until at least 2 consecutive negative blood films seen or two consecutive qPCR results with substantial reduction in genome copies/mL. - Volunteers observed for 1 hour after vaccination to monitor for any immediate adverse effects. - Total blood volume taken during study kept to volume that should not compromise healthy volunteers.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    90
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Volunteers were recruited by use of advertisements, formally approved by the ethics committee, distributed or posted in public places (including newspapers, social media, stalls at fairs and public transport) or via email distribution, including to individuals who have registered an interest in taking part in clinical trials at the study sites.

    Pre-assignment
    Screening details
    		 Inclusion / Exclusion criteria Informed Consent Questionnaire Informed Consent Medical History Physical Examination Urinalysis Electrocardiogram (Groups 5, 6, 9) beta-HCG urine (women only) Review contraindications Physical Observations HBV, HCV, HIV Haematology Biochemistry

    Period 1
    Period 1 title
    Phase I & IIa
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Group 1 - Phase 1a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 2µg RH5.1/0.5 mL AS01 intramuscularly
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 2 - Phase 1a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 10µg RH5.1 in 0.5mL AS01 intramuscularly
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 3 - Phase 1a
    Arm description
    		 2 vaccinations (Days 0/28) 50µg RH5.1 in 0.5mL AS01 followed by a third vaccination (Day 182) of 10µg RH5.1 in 0.5mL AS01.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 4 - Phase 1a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 50µg RH5.1 in 0.5mL AS01 intramuscularly
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 5 - Phase 2a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 10μg RH5.1 in 0.5mL AS01 intramuscularly, followed by primary CHMI 2 weeks post 3rd vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 6 - Phase 2a
    Arm description
    		 Primary CHMI controls (for primary CHMI in Group 5 and 7)
    Arm type
    		 CHMI controls

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group 7 - Phase 2a
    Arm description
    		 Subset of Group 5. 4 vaccinations (Days 0/28/56/~4 months after 3rd vaccination) of 10μg RH5.1 in 0.5mL AS01. Primary CHMI 2 weeks post 3rd vaccination. Secondary CHMI 1-2 weeks post 4th vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 8 - Phase 2a
    Arm description
    		 Subset of Group 6 undergoing secondary CHMI. Controls for secondary CHMI in Group 7.
    Arm type
    		 CHMi controls

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group 9 - Phase 2a
    Arm description
    		 Primary CHMI controls (for secondary CHMI in Group 7 and 8)
    Arm type
    		 CHMI controls

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 5 - Phase 2a Group 6 - Phase 2a Group 7 - Phase 2a Group 8 - Phase 2a Group 9 - Phase 2a
    Started
    12
    12
    12
    14
    17
    17
    9
    8
    6
    Completed
    12
    12
    12
    11
    17
    14
    8
    8
    4
    Not completed
    0
    0
    0
    3
    0
    3
    1
    0
    2
         Consent withdrawn by subject
    -
    -
    -
    2
    -
    1
    -
    -
    2
         Physician decision
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Pregnancy
    -
    -
    -
    -
    -
    -
    1
    -
    -
         Back-up volunteers for CHMI (not required)
    -
    -
    -
    -
    -
    2
    -
    -
    -
    Period 2
    Period 2 title
    Optional long-term follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Group 1 - Phase 1a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 2µg RH5.1/0.5 mL AS01 intramuscularly. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 2 - Phase 1a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 10µg RH5.1 in 0.5mL AS01 intramuscularly. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 3 - Phase 1a
    Arm description
    		 2 vaccinations (Days 0/28) 50µg RH5.1 in 0.5mL AS01 followed by a third vaccination (Day 182) of 10µg RH5.1 in 0.5mL AS01. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 4 - Phase 1a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 50µg RH5.1 in 0.5mL AS01 intramuscularly
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 5 - Phase 2a
    Arm description
    		 3 vaccinations (Days 0/28/56) of 10µg RH5.1 in 0.5mL AS01 intramuscularly, followed by primary CHMI 2 weeks post 3rd vaccination. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10µg RH5.1 in 0.5mL AS01

    Arm title
    		 Group 7 - Phase 2a
    Arm description
    		 Subset of Group 5 . 4 vaccinations (Days 0/28/56/~4 months after 3rd vaccination) of 10µg RH5.1 in 0.5mL AS01. Primary CHMI 2 weeks post 3rd vaccination. Secondary CHMI 1-2 weeks post 4th vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RH5.1 with adjuvant AS01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10µg RH5.1 in 0.5mL AS01

    Number of subjects in period 2
    		Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 5 - Phase 2a Group 7 - Phase 2a
    Started
    9
    10
    7
    4
    3
    6
    Completed
    9
    10
    7
    4
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I & IIa
    Reporting group description
    		 -

    Reporting group values
    		 Phase I & IIa Total
    Number of subjects
    		 90 90
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 90 90
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 56 56
        Male
    		 34 34

    End points

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    End points reporting groups
    Reporting group title
    Group 1 - Phase 1a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 2µg RH5.1/0.5 mL AS01 intramuscularly

    Reporting group title
    Group 2 - Phase 1a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 10µg RH5.1 in 0.5mL AS01 intramuscularly

    Reporting group title
    Group 3 - Phase 1a
    Reporting group description
    		 2 vaccinations (Days 0/28) 50µg RH5.1 in 0.5mL AS01 followed by a third vaccination (Day 182) of 10µg RH5.1 in 0.5mL AS01.

    Reporting group title
    Group 4 - Phase 1a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 50µg RH5.1 in 0.5mL AS01 intramuscularly

    Reporting group title
    Group 5 - Phase 2a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 10μg RH5.1 in 0.5mL AS01 intramuscularly, followed by primary CHMI 2 weeks post 3rd vaccination.

    Reporting group title
    Group 6 - Phase 2a
    Reporting group description
    		 Primary CHMI controls (for primary CHMI in Group 5 and 7)

    Reporting group title
    Group 7 - Phase 2a
    Reporting group description
    		 Subset of Group 5. 4 vaccinations (Days 0/28/56/~4 months after 3rd vaccination) of 10μg RH5.1 in 0.5mL AS01. Primary CHMI 2 weeks post 3rd vaccination. Secondary CHMI 1-2 weeks post 4th vaccination.

    Reporting group title
    Group 8 - Phase 2a
    Reporting group description
    		 Subset of Group 6 undergoing secondary CHMI. Controls for secondary CHMI in Group 7.

    Reporting group title
    Group 9 - Phase 2a
    Reporting group description
    		 Primary CHMI controls (for secondary CHMI in Group 7 and 8)
    Reporting group title
    Group 1 - Phase 1a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 2µg RH5.1/0.5 mL AS01 intramuscularly. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.

    Reporting group title
    Group 2 - Phase 1a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 10µg RH5.1 in 0.5mL AS01 intramuscularly. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.

    Reporting group title
    Group 3 - Phase 1a
    Reporting group description
    		 2 vaccinations (Days 0/28) 50µg RH5.1 in 0.5mL AS01 followed by a third vaccination (Day 182) of 10µg RH5.1 in 0.5mL AS01. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.

    Reporting group title
    Group 4 - Phase 1a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 50µg RH5.1 in 0.5mL AS01 intramuscularly

    Reporting group title
    Group 5 - Phase 2a
    Reporting group description
    		 3 vaccinations (Days 0/28/56) of 10µg RH5.1 in 0.5mL AS01 intramuscularly, followed by primary CHMI 2 weeks post 3rd vaccination. Optional long term follow-up at approximately 1.5-2.5 years after 3rd vaccination.

    Reporting group title
    Group 7 - Phase 2a
    Reporting group description
    		 Subset of Group 5 . 4 vaccinations (Days 0/28/56/~4 months after 3rd vaccination) of 10µg RH5.1 in 0.5mL AS01. Primary CHMI 2 weeks post 3rd vaccination. Secondary CHMI 1-2 weeks post 4th vaccination.

    Primary: Efficacy of the RH5.1/AS01 vaccine as assessed by a reduction in the PCR-derived parasite multiplication rate (PMR) in vaccinated subjects compared to infectivity controls

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    End point title
    		 Efficacy of the RH5.1/AS01 vaccine as assessed by a reduction in the PCR-derived parasite multiplication rate (PMR) in vaccinated subjects compared to infectivity controls [1] [2]
    End point description
    Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point type
    Primary
    End point timeframe
    8 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point values
    		 Group 6 - Phase 2a Group 7 - Phase 2a Group 8 - Phase 2a Group 9 - Phase 2a
    Number of subjects analysed
    14
    9
    8
    4
    Units: no of participants
    14
    9
    8
    4
    No statistical analyses for this end point

    Primary: Safety of RH5.1/AS01 in healthy malaria-naïve adults in the UK asssed by actively and passively collected data on adverse events.

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    End point title
    		 Safety of RH5.1/AS01 in healthy malaria-naïve adults in the UK asssed by actively and passively collected data on adverse events. [3]
    End point description
    Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point type
    Primary
    End point timeframe
    Main study: 8 months. For subset of subjects: up to 2.5 years (optional long-term follow-up).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point values
    		 Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 5 - Phase 2a Group 7 - Phase 2a Group 5 - Phase 2a Group 6 - Phase 2a Group 7 - Phase 2a Group 8 - Phase 2a Group 9 - Phase 2a
    Number of subjects analysed
    12
    12
    12
    11
    9
    10
    7
    4
    3
    6
    17
    14
    9
    8
    4
    Units: Percentage
    12
    12
    12
    11
    9
    10
    7
    4
    3
    6
    17
    14
    9
    8
    4
    No statistical analyses for this end point

    Secondary: Humoral and cellular immunogenicity of RH5.1/AS01 when administered to healthy volunteers at different doses.

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    End point title
    		 Humoral and cellular immunogenicity of RH5.1/AS01 when administered to healthy volunteers at different doses. [4]
    End point description
    Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point type
    Secondary
    End point timeframe
    8 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point values
    		 Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 5 - Phase 2a Group 7 - Phase 2a
    Number of subjects analysed
    12
    12
    12
    11
    17
    9
    Units: n/a (multiple units)
        number (not applicable)
    12
    12
    12
    11
    17
    9
    No statistical analyses for this end point

    Secondary: Immunological readouts for association with a reduced parasite multiplication rate.

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    End point title
    		 Immunological readouts for association with a reduced parasite multiplication rate. [5]
    End point description
    Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point type
    Secondary
    End point timeframe
    8 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point values
    		 Group 5 - Phase 2a Group 6 - Phase 2a Group 7 - Phase 2a Group 8 - Phase 2a Group 9 - Phase 2a
    Number of subjects analysed
    17
    14
    9
    8
    4
    Units: n/a (multiple units)
        number (not applicable)
    17
    14
    9
    8
    4
    No statistical analyses for this end point

    Secondary: Durability of any reduction in parasite multiplication rate (PMR) in vaccinated subjects in a second CHMI, ~4 months after the primary CHMI, compared to unvaccinated controls receiving a second challenge and newly recruited malaria-naive primary controls

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    End point title
    		 Durability of any reduction in parasite multiplication rate (PMR) in vaccinated subjects in a second CHMI, ~4 months after the primary CHMI, compared to unvaccinated controls receiving a second challenge and newly recruited malaria-naive primary controls [6]
    End point description
    Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point type
    Secondary
    End point timeframe
    12 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point values
    		 Group 5 - Phase 2a Group 6 - Phase 2a Group 7 - Phase 2a Group 8 - Phase 2a Group 9 - Phase 2a
    Number of subjects analysed
    17
    14
    9
    8
    4
    Units: no of participants
    17
    14
    9
    8
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Data on solicted adverse events were collected for 7 days after vaccinated and unsolicited adverse events for 28 days post-vaccination. Data on serious adverse events and adverse events of special interest were collected for the study duration.
    Adverse event reporting additional description
    Following each vaccination, volunteers completed an electronic diary card for 28 days with adverse event data. Solicited AEs, collected for 7 days, included local AEs (pain, erythema, warmth, swelling and itching) and systemic AEs (headache, malaise, myalgia, arthralgia, feverishness, nausea, fatigue, and measured fever
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Group 1 - Phase 1a
    Reporting group description
    		 -

    Reporting group title
    Group 2 - Phase 1a
    Reporting group description
    		 -

    Reporting group title
    Group 3 - Phase 1a
    Reporting group description
    		 -

    Reporting group title
    Group 4 - Phase 1a
    Reporting group description
    		 -

    Reporting group title
    Group 5 - Phase 2a
    Reporting group description
    		 -

    Reporting group title
    Group 7 - Phase 2a
    Reporting group description
    		 -

    Serious adverse events
    		 Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 5 - Phase 2a Group 7 - Phase 2a
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Group 1 - Phase 1a Group 2 - Phase 1a Group 3 - Phase 1a Group 4 - Phase 1a Group 5 - Phase 2a Group 7 - Phase 2a
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    5 / 17 (29.41%)
    0 / 9 (0.00%)
    General disorders and administration site conditions
    Local reaction
    Additional description: Reaction at injection site
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    1
    3
    1
    0
    Chills
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    4 / 17 (23.53%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2016
    Addition of information regarding the use of the informed consent questionnaire. Correction of schedule of attendances table/blood volumes. Addition of wording to clarify that stated vaccine and adjuvant doses are nominal and may vary slightly due to dilution, mixing and administration techniques. Clarification added regarding ECG as part of screening procedures for Group 5-6. Change in wording of exclusion criterion regarding prior receipt of an investigational malaria vaccine. “History of splenectomy” removed as a separate exclusion criterion.
    29 May 2017
    Selection of dose of RH5.1/AS01 (10 μg) for Group 5 in the Phase IIa study. Guy’s and St. Thomas’ NIHR CRF to continue as a recruitment and vaccination site for the Phase IIa study. Removal of Cardiovascular Risk Score and checking of cholesterol levels from the protocol. Correction of blood volumes in schedule of attendances. Clarification of vaccination of 2 back-up volunteers in Group 5. Clarification of challenge at 2 weeks post final vaccination. Blinding of all Investigators (except the Principal Laboratory Investigator) to the malaria qPCR results during the post-challenge phase.
    11 Sep 2017
    Modification of bleed schedule for Groups 5 and 6. Correction/clarifications to footer of schedule of attendances tables.
    23 Nov 2017
    Addition of conflicts of interest statements of Investigators. Correction of minor typographical errors in the bleeding schedule tables.
    23 Jan 2018
    Addition of 3 new groups to assess the durability of the vaccine-induced reduction in PMR (Group 7 = Phase IIa malaria-exposed vaccinees; Group 8 = Phase IIa malaria-exposed controls; Group 9 = newly recruited malaria-naïve controls). Removal of microscopy as a diagnostic tool in the second homologous CHMI, and adjustment of the qPCR diagnostic criteria for commencing anti-malarials. Addition of 2 new exclusion criteria (Groups 5-9): G6PD deficiency and abnormal haemoglobinopathy screen. Clarification of 2 exclusion criteria (relating to Hepatitis C serology and contraindications relating to use of malarone and riamet).
    07 Feb 2018
    Clarification of scientific rationale for re-challenge of healthy volunteers.
    10 Oct 2018
    Addition of last visit for all vaccinated volunteers (Groups 1-4, 5 and 7) to assess durability of immune responses 1-2.5 years since their final vaccination.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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