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

NCT02927145 | Completed Phase 1 Results DMC

• 1 other identifier: VAC063
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 2

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.

Conditions

Malaria

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• the Humoral Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens.

  2 weeks post final vaccination

• the Cellular Immunogenicity of RH5.1/AS01 Using Different Vaccine Doses and Vaccination Regimens.

  2 weeks post final vaccination

• Immunological Readouts for Association With a Reduced Parasite Multiplication Rate.

  8 months

Study Arms (9)

Group 1-Phase Ia

ACTIVE COMPARATOR

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

Group 2- Phase Ia

ACTIVE COMPARATOR

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

Group 3-Phase Ia

ACTIVE COMPARATOR

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

Group 4-Phase Ia

ACTIVE COMPARATOR

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

Group 5-Phase IIa

ACTIVE COMPARATOR

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

Group 6-Phase IIa

NO INTERVENTION

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.

Group 7-Phase IIa

ACTIVE COMPARATOR

Group 7 are Group 5 volunteers who will receive a fourth dose of IMP (10µg RH5.1/ 0.5mL AS01)

Biological: RH5.1/ ASO1

Group 8 -Phase IIa

NO INTERVENTION

Group 8 are infectivity controls who were originally in Group 6.

Group 9 -Phase IIa

NO INTERVENTION

Group 9 are new infectivity controls

Interventions

RH5.1/ ASO1 BIOLOGICAL

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.

Group 1-Phase Ia; Group 2- Phase Ia; Group 3-Phase Ia; Group 4-Phase Ia; Group 5-Phase IIa; Group 7-Phase IIa

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (2)

Guys and St Thomas' NIHR CRF

London, United Kingdom

Location

Nihr Wtcrf

Southampton, United Kingdom

Location

Related Publications (4)

• Salkeld J, Themistocleous Y, Barrett JR, Mitton CH, Rawlinson TA, Payne RO, Hou MM, Khozoee B, Edwards NJ, Nielsen CM, Sandoval DM, Bach FA, Nahrendorf W, Ramon RL, Baker M, Ramos-Lopez F, Folegatti PM, Quinkert D, Ellis KJ, Poulton ID, Lawrie AM, Cho JS, Nugent FL, Spence PJ, Silk SE, Draper SJ, Minassian AM. Repeat controlled human malaria infection of healthy UK adults with blood-stage Plasmodium falciparum: Safety and parasite growth dynamics. Front Immunol. 2022 Aug 22;13:984323. doi: 10.3389/fimmu.2022.984323. eCollection 2022.

  PMID: 36072606 DERIVED

• Willcox AC, Huber AS, Diouf A, Barrett JR, Silk SE, Pulido D, King LDW, Alanine DGW, Minassian AM, Diakite M, Draper SJ, Long CA, Miura K. Antibodies from malaria-exposed Malians generally interact additively or synergistically with human vaccine-induced RH5 antibodies. Cell Rep Med. 2021 Jun 21;2(7):100326. doi: 10.1016/j.xcrm.2021.100326. eCollection 2021 Jul 20.

  PMID: 34337556 DERIVED

• Minassian AM, Silk SE, Barrett JR, Nielsen CM, Miura K, Diouf A, Loos C, Fallon JK, Michell AR, White MT, Edwards NJ, Poulton ID, Mitton CH, Payne RO, Marks M, Maxwell-Scott H, Querol-Rubiera A, Bisnauthsing K, Batra R, Ogrina T, Brendish NJ, Themistocleous Y, Rawlinson TA, Ellis KJ, Quinkert D, Baker M, Lopez Ramon R, Ramos Lopez F, Barfod L, Folegatti PM, Silman D, Datoo M, Taylor IJ, Jin J, Pulido D, Douglas AD, de Jongh WA, Smith R, Berrie E, Noe AR, Diggs CL, Soisson LA, Ashfield R, Faust SN, Goodman AL, Lawrie AM, Nugent FL, Alter G, Long CA, Draper SJ. Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination. Med. 2021 Jun 11;2(6):701-719.e19. doi: 10.1016/j.medj.2021.03.014.

  PMID: 34223402 DERIVED

• Nielsen CM, Ogbe A, Pedroza-Pacheco I, Doeleman SE, Chen Y, Silk SE, Barrett JR, Elias SC, Miura K, Diouf A, Bardelli M, Dabbs RA, Barfod L, Long CA, Haynes BF, Payne RO, Minassian AM, Bradley T, Draper SJ, Borrow P. Protein/AS01B vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors. Cell Rep Med. 2021 Feb 22;2(3):100207. doi: 10.1016/j.xcrm.2021.100207. eCollection 2021 Mar 16.

  PMID: 33763653 DERIVED

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Dr Angela Minassian
• Organization: University of Oxford

angela.minassian@ndm.ox.ac.uk

0044 01865611425

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 5, 2016
• First Posted: October 6, 2016
• Study Start: October 17, 2016
• Primary Completion: June 27, 2019
• Study Completion: June 27, 2019
• Last Updated: February 18, 2022
• Results First Posted: February 18, 2022

Record last verified: 2019-08

Locations

GB (2)