| Protocol No: | ECCT/19/11/01 | Date of Protocol: | 17-05-2019 |
| Study Title: | Safety, immunogenicity, and efficacy of R21/Matrix M (R21/MM) and ChAd63/MVA-ME-TRAP in the context of controlled human malaria infection: A Phase IIb Trial in Kenyan Adults. |
| Study Objectives: |
2.2. Primary objective(s)
1. To assess the safety and tolerability of adjuvanted R21/MM and heterologous prime- boost regime of ChAd63-MVA ME-TRAP in healthy adult volunteers.
2. To assess the safety of intradermal sporozoite infection dose in semi-immune healthy adult volunteers.
3. To assess the efficacy (occurrence of P. falciparum parasitemia, (assessed by qPCR) of adjuvanted R21 and heterologous prime- boost regime of ChAd63-MVA ME-TRAP against malaria sporozoite challenge, in healthy adult volunteers.
2.3. Secondary objective(s)
1. To assess humoral immunogenicity generated in individuals of adjuvanted R21(R21/MM) and heterologous prime-boost regime of ChAd63-MVA ME-TRAP at different time points.
2. To assess cell-mediated immunogenicity by IFN-ƴ ELISPOT generated in individuals of heterologous prime-boost regime of ChAd63-MVA ME-TRAP at different time points.
3. To assess any differences in efficacy estimates with ID versus DVI challenge in individuals receiving R21/MM by assessing parasite density dynamics by qPCR.
4. To measure and compare the parasite growth rates and liver to blood inoculum in individuals receiving DVI versus ID sporozoite challenge in relation to naturally acquired immunity.
2.4. Tertiary objective(s)
To evaluate cell-mediated immunogenicity using flow cytometry with intracellular cytokine staining and other exploratory immunological end points.
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| Laymans Summary: |
Lay Title: A study to determine if candidate malaria vaccines are safe, effective, and induce immunity among Kenyan adults.
What is the problem/background? Malaria deaths have fallen with the advent of new drug combinations and widespread use of insecticide treated bed nets, but the hope of malaria eradication is threatened by emerging resistance to these drugs and insecticides. RTS,S, is the only malaria vaccine in advanced clinical development albeit with low efficacy. It is being evaluated for use in an infant vaccine schedule recommended by WHO, while determining the significance of any safety concerns. However, with RTS,S only a small proportion of the vaccine is made up of the malaria parasite protein. We have developed a malaria vaccine candidate, R21, which is also based on the same protein in RTS,S. The majority of RTS,S is composed of the Hepatitis B surface protein which may interfere with the immune response in infants; whereas R21 has very little of this protein on its surface. R21 also induces a good immune response and there is a good case for further clinical development of this vaccine.
What questions are we trying to answer? We plan to evaluate whether the malaria vaccine candidates R21 administered with Matrix M (MM) and ChAd63/MVA-ME-TRAP, are safe and effective in a Controlled Human Malaria Infection (CHMI) and induce good vaccine responses in healthy Kenyan adults (aged 18-45 years). We plan to investigate the immune responses following vaccination and CHMI.
Where is the study taking place, how many people does it involve and how are they selected? The study is taking place in Kilifi County (Ngerenya) as well as at KEMRI-CGMRC where we will recruit and screen healthy adult volunteers. A total number of 64 eligible volunteers will be required after assessment of eligibility at the screening visit to be enrolled for the vaccine efficacy study. This will be done after a programme of sensitization and information giving about the study.
What does the study involve for those who are in it? The following procedures are involved for those who volunteer to participate in the study. Blood samples will be taken at screening, a day prior to vaccine enrolment, prior to each vaccination, and post vaccination, a day before malaria infection, during infection and after infection treatment.
Screening Procedures: For individuals who are screened for potential participation, 8ml of blood will be drawn at the screening visit for serology; haematology; biochemistry and malaria testing. Medical history will also be obtained and a clinical assessment including a check of the functioning of the heart to exclude any significant heart problems. Those that pass screening will be invited to attend a pre-enrolment visit. At the enrolment visit, all eligible volunteers will be re-assessed and a blood sample of 37ml taken for haematology, biochemistry, malaria testing, and immunology.
Vaccine Enrolment and Vaccination Procedures: On the day of enrolment, a total of 64 eligible volunteers will be randomised into one of 4 groups as follows: group 1, receiving R21/MM (N=20); group 2 receiving ChAd63/MVA-ME-TRAP (N=20); group 3, receiving R21/Matrix M (N=10); and group 4 receiving no vaccine (control group). The R21/MM vaccine will be administered as a three-dose regimen at intervals of 28 days (days 0, 28 and 56) whilst the ChAd63/MVA-ME-TRAP will be administered as a prime-boost regimen at days 0 and 56. At each vaccination visit (except for day 0), a blood sample of 33ml will be taken from each of the volunteers. All volunteers in the vaccination groups (groups 1 to 3). Two weeks after each vaccine administration, a blood sample will be taken from each volunteer (30ml or 34ml after the final vaccination). Repeat blood samples may be taken to verify abnormal results. If volunteers are found to have malaria 2 weeks after the final vaccination (day 70), they will be given anti-malarial monotherapy and a blood sample taken post-treatment to test for malaria (4ml). A blood sample from the volunteers in the control group will also be collected at (day 70) for the purposes of checking for malaria and treatment initiated if found positive with a post-treatment sample taken to ensure malaria infection has been cleared.
Malaria Infection Procedures: A clinical assessment will be repeated a day before infection including collection of a urine sample and measurement of weight and height. At this visit, volunteers will be enrolled as residents at Pwani University under medical supervision for up to 25days depending on when they are diagnosed with malaria. This will also include volunteers from the control group who did not go through the vaccination procedures (group 4, N=14). The malaria infection will be given either via the intradermal route-into the skin (groups 1, 2, and 4) or via direct venous injection (into the blood stream) (group 3) of PfSPZ Challenge, which leads to a blood-stage malaria infection after 6.5 days of incubation in the liver. Blood samples will also be taken: a day before the malaria infection (57mls); day five after infection (32mls); twice daily every day from day seven after infection up to the time that signs and symptoms of malaria are detected and malaria treatment initiated and completed (usually between seven to twenty-four days, 238ml); and on days thirty-five and ninety after infection (35ml at each of these time points). A total of 308ml of blood per volunteer will be drawn during this period. Observed treatment for malaria will be administered on the day of diagnosis or after twenty-one days for those who do not develop an infection.
What are the benefits and risks/costs of the study for those involved? Participants may benefit from receipt of the vaccine if it demonstrates that the efficacy in a Kenyan population is favourable and the vaccine is safe. Participants will also have close oversight and treatment support from the study team although this will primarily be for risk monitoring. There will also be wider benefit in the field of malaria vaccine research in building on data available on safety, efficacy and immune responses to R21/MM and ChAd63/MVA ME-TRAP. Controlled human malaria infection challenge via the intradermal route and direct venous injection has been conducted in seventy-eight and one hundred and eighty-four individuals respectively and has been safe and well-tolerated. The first ever controlled malaria infection study in Kenya by intramuscular injection was safely conducted in Nairobi with twenty-eight individuals. We have since conducted a controlled malaria infection study in Kenya by direct venous injection in another one hundred and sixty-one individuals in Kilifi. The risks relate to the possibility of developing an allergic reaction upon administration of the malaria infection. In addition, participants may develop signs and symptoms of malaria after infection which are unpleasant and may develop some side effects to the drugs used to treat the infection. During malaria infection, volunteers are required to be resident in a guest-house for safety monitoring and reduce the risk of acquiring field malaria infections. This is a considerable cost to the volunteers on their time but is a requirement for the study to be successful. There are no direct benefits to individuals participating in this study other than information about their health. There might be a perception of benefit from receipt of a vaccine, clinical assessment and laboratory screening.
How will the study benefit society? Controlled human malaria infection provides a way of studying immunity to malaria in a very detailed way that is not possible using natural infections, and we believe that this step is now necessary to inform vaccine design. This study will also evaluate promising malaria vaccine candidates, which will inform the design of a phase III study, contribute further to the area of malaria research and hopefully provide a possible tool to contribute to future eradication.
When does the study start and finish?
The study will start upon receipt of ethical and regulatory approval; data collection, analysis and write up will take place over 2 years.
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| Abstract of Study: | In the era of anti-malaria drug resistance and resistance to insecticide treated bed nets, there is an urgent need for a highly efficacious vaccine. We plan to evaluate the immunogenicity and efficacy of candidate malaria vaccines incorporating the sporozoite antigen R21 (P. falciparum circumsporozoite protein co-expressed with hepatitis B antigen) administered as protein-in-adjvuvant with the Matrix M and viral-vectored vaccines expressing the liver antigen TRAP (P. falciparum multiple epitope thrombospondin adhesion protein, ME-TRAP expressed in Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara administered in a heterologous prime-boost regimen). There is evidence of safety and immunogenicity utilising these two vaccines. We plan to conduct a phase IIb trial in malaria-exposed individuals to assess the immunogenicity and efficacy of the two vaccines in the context of controlled human malaria infection. P. falciparum sporozoite challenge, PfSPZ Challenge. Healthy adults aged between 18-45 years will be recruited to participate in the study after a process of information giving and sensitisation about the study. Those that provide informed consent to participate in the study will be screened to ensure they are in good health based on clinical assessment and laboratory results. Each participant will have blood tests undertaken, and physical and clinical examination to ensure suitability prior to vaccination and PfSPZ Challenge. A total of 64 participants will be enrolled for challenge and divided into four groups as follows: 20 participants to receive R21/Matrix M (R21/MM) with intradermal PfSPZ Challenge; 20 participants to receive viral-vectored ME-TRAP with intradermal PfSPZ Challenge; 10 participants to receive R21/MM with direct venous inoculation PfSPZ Challenge; and 14 participants comprising of the control group with intradermal PfSPZ Challenge. Blood tests and clinical assessments will be conducted to screen out participants with health conditions that may impact participation in the study. Blood samples will be taken at screening and a day prior to vaccine and PfSPZ Challenge enrolment. Blood will also be taken prior to each vaccination as well as after PfSPZ Challenge administration until diagnosis with malaria, endpoint. A set threshold for malaria diagnosis will be met and once this is achieved, participants will be treated with the recommended anti-malaria drug treatment. Blood samples to assess immunogenicity will be taken prior to vaccination, and throughout the study to assess vaccine-induced immune responses. Efficacy will be assessed in relation to the control group with serial quantitative polymerase chain reaction (PCR) monitoring of parasitaemia during PfSPZ Challenge. A day before PfSPZ Challenge, participants will be enrolled residents at Pwani University where they will be monitored daily up to a period of 25 days depending on when they are diagnosed with malaria. There will be follow-up after exit from residence for up to 90 days after PfSPZ Challenge. |