Malaria, Vivax
Conditions
Keywords
PvDBP, efficacy
Brief summary
This is an open label, Phase IIa, controlled human malaria infection (CHMI) study aimed to assess whether the new vivax malaria vaccines ChAd63 PvDBP and MVA PvDBP can protect against malaria infection. The participants will receive one or two doses of ChAd63 PvDBP followed by one dose of MVA PvDBP 8 weeks later. Approximately 4 weeks after the second vacccination, the volunteers will be challenged (deliberately infected) with malaria by intravenous injection blood-stage
Detailed description
Volunteers will be recruited and vaccinated at the CCVTM, Oxford. There will be two groups vaccinated in the trial, with an optional third group included if fewer than 6 volunteers complete group 2. Up to 19 volunteers will be included in total. These will be compared to a matched number of infectivity controls, receiving no vaccination, who will be recruited as part of a separate study (VAC069 - NCT03797989).
Interventions
BIOLOGICALChAd63 PvDBP and MVA PvDBP
one dose of 5 x 10\^10 vp ChAd63 PvDBP and one dose of 2 x 10\^8 pfu MVA PvDBP 8 weeks later, in a heterologous prime-boost regimen.
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 adult aged 18 to 45 years. * Red blood cells positive for the Duffy antigen/chemokine receptor (DARC). * Normal serum levels of Glucose-6-phosphate dehydrogenase (G6PD). * 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. * Women only: Must practice continuous effective contraception\* for the duration of the study * Agreement to permanently refrain from blood donation * Written informed consent to participate in the trial. * Reachable (24/7) by mobile phone during the period between CHMI and completion of all antimalarial treatment. * Willing to take a curative anti-malarial regimen following CHMI. * Willing to reside in Oxford for the duration of the study, until antimalarials have been 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 malaria challenge could pose a serious risk to both maternal health and the unborn foetus.
Exclusion criteria
* History of clinical malaria (any species). * Travel to a clearly malaria endemic locality during the study period or within the preceding six months. * Current or planned treatment with 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, trimethoprim-sulfamethoxazole for recurrent urinary tract infections, etc.). * Weight less than 50kg, as measured at the screening visit. * Receipt of immunoglobulins within the three months prior to planned administration of the vaccine candidate. * Receipt of blood products (e.g., blood transfusion) at any time in the past. * Peripheral venous access unlikely to allow twice daily blood testing (as determined by the Investigator). * Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period. * Receipt of any vaccine in the 30 days preceding enrolment, or planned receipt of any other vaccine within 30 days preceding or following each study vaccination, with the exception of licensed COVID-19 vaccines, which should not be received within 14 days before or 7 days after any study vaccination. * Planned receipt of a COVID-19 vaccine between 2 weeks before the day of CHMI until completion of antimalarial treatment * Concurrent involvement in another clinical trial or planned involvement during the study period. * Prior receipt of an investigational vaccine likely to impact on interpretation of the trial data or the P. vivax parasite as assessed by the Investigator. * History of sickle cell anaemia, sickle cell trait, thalassaemia or thalassaemia trait or any haematological condition that could affect susceptibility to malaria infection. * 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). * History of allergic disease or reactions likely to be exacerbated by any component of the vaccine e.g. egg products, Kathon, aminoglycosides. * History of allergic disease or reactions likely to be exacerbated by malaria infection. * History of clinically significant contact dermatitis. * Any history of anaphylaxis in reaction to vaccinations. * 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. * History of cardiac arrhythmia, including clinically relevant bradycardia. * Disturbances of electrolyte balance, e.g. hypokalaemia or hypomagnesaemia. * Family history of congenital QT prolongation or sudden death. * Contraindications to the use of both of the proposed anti-malarial medications; Riamet 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 or (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. Procedures for identifying laboratory values meeting
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of the ChAd63 and MVA PvDBP Vaccines, Administered in a Heterologous Prime-boost Regimen, Assessed by a Reduced Parasite Multiplication Rate in Vaccinated Subjects | 3 months post CHMI | Quantitative PCR-derived parasite multiplication rate (PMR) will be the primary efficacy endpoint and a comparison of the endpoint between Groups 1, 2 and 3 (pooled data) and malaria-naïve controls partaking in simultaneous CHMI, under identical conditions, will constitute the primary analysis for efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Within 28 days following each vaccination. Vaccinations occurred at 0 and 2 months in Groups 1 and 3 (ChAd63, MVA PvDBP); and at 0, 17 and 19 months in Group 2 (ChAd63, ChAd63, MVA PvDBP). | No of participants reporting adverse event |
| The Humoral Immunogenicity ChAd63 and MVA PvDBP Vaccine Candidates, Administered in a Heterologous Prime-boost Regimen | 14 days after the final vaccination. Final vaccinations (MVA PvDBP) occurred at 2 months in Groups 1 and 3; and at 19 months in Group 2. | Total IgG antibody response to the P. vivax Duffy-binding protein (PvDBP) |
| The Cellular Immunogenicity ChAd63 and MVA PvDBP Vaccine Candidates, Administered in a Heterologous Prime-boost Regimen | 14 days after the final vaccination. Final vaccinations (MVA PvDBP) occurred at 2 months in Groups 1 and 3 ; and at 19 months in Group 2. | PvDBPII-specific CD4+ CD45RA- CCR7- effector memory T cells producing IFN-γ |
| Immunological Readouts for Association With a Reduced Parasite Multiplication Rate | 3 months post CHMI | Statistical correlation between anti-PvDBP antibody responses induced by the ChAd63 and MVA PvDBP vaccines and PMR. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 3 volunteers receiving 5 x 10\^10 vp ChAd63 PvDBP and 2 x 10\^8 pfu MVA PvDBP 8 weeks later, in a heterologous prime-boost regimen, followed by blood-stage CHMI 2-4 weeks later. | 3 |
| Group 2 Up to 10 volunteers receiving one dose of 5 x 10\^10 vp ChAd63 PvDBP, 12-18 months later receiving a second dose of 5 x 10\^10 vp ChAd63 PvDBP and 8 weeks later 2 x 10\^8 pfu MVA PvDBP, followed by blood-stage CHMI 2-4 weeks later. | 10 |
| Group 3 If fewer than 6 volunteers complete the study in Group 2, then new volunteers will be recruited into Group 3, to make up a total of 6 volunteers between Groups 2 and 3 who complete all vaccinations and CHMI.
Volunteers in Group 3 will receive 5 x 10\^10 vp ChAd63 PvDBP and 2 x10\^8 pfu MVA PvDBP 8 weeks later, in a heterologous prime-boost regimen, followed by blood-stage CHMI 2-4 weeks later. | 3 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 7 | 0 |
Baseline characteristics
| Characteristic | Group 2 | Group 3 | Group 1 | Total |
|---|---|---|---|---|
| Age, Continuous | 28 years | 25 years | 32 years | 28 years |
| Race/Ethnicity, Customized Arab | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 3 Participants | 3 Participants | 13 Participants |
| Region of Enrollment United Kingdom | 10 participants | 3 participants | 3 participants | 16 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 8 |
| other Total, other adverse events | 2 / 16 | 2 / 8 |
| serious Total, serious adverse events | 0 / 16 | 0 / 8 |
Outcome results
Primary
Efficacy of the ChAd63 and MVA PvDBP Vaccines, Administered in a Heterologous Prime-boost Regimen, Assessed by a Reduced Parasite Multiplication Rate in Vaccinated Subjects
Quantitative PCR-derived parasite multiplication rate (PMR) will be the primary efficacy endpoint and a comparison of the endpoint between Groups 1, 2 and 3 (pooled data) and malaria-naïve controls partaking in simultaneous CHMI, under identical conditions, will constitute the primary analysis for efficacy.
Time frame: 3 months post CHMI
Population: Primary efficacy analysis conducted as per protocol on pooled data from all volunteers across groups 1, 2 and 3 who underwent CHMI. Numbers in each group too small for meaningful summary statistics to be reported for each group separately.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Groups 1, 2 and 3 Volunteers Completing CHMI | Efficacy of the ChAd63 and MVA PvDBP Vaccines, Administered in a Heterologous Prime-boost Regimen, Assessed by a Reduced Parasite Multiplication Rate in Vaccinated Subjects | 5.4 parasite multiplication rate per 48hr |
Comparison: Comparison of pooled data from Groups 1, 2 and 3 volunteers who completed CHMI with pooled data of infectivity controls (unvaccinated) from CHMI study running in parallel (VAC069 study)p-value: 0.14Wilcoxon (Mann-Whitney)
Secondary
Immunological Readouts for Association With a Reduced Parasite Multiplication Rate
Statistical correlation between anti-PvDBP antibody responses induced by the ChAd63 and MVA PvDBP vaccines and PMR.
Time frame: 3 months post CHMI
Secondary
Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers
No of participants reporting adverse event
Time frame: Within 28 days following each vaccination. Vaccinations occurred at 0 and 2 months in Groups 1 and 3 (ChAd63, MVA PvDBP); and at 0, 17 and 19 months in Group 2 (ChAd63, ChAd63, MVA PvDBP).
Population: Adverse events following vaccinations are analysed by IMP administered
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Groups 1, 2 and 3 Volunteers Completing CHMI | Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Any grade 3 solicited adverse event | 1 Participants |
| Groups 1, 2 and 3 Volunteers Completing CHMI | Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Any grade 3 unsolicited adverse event | 0 Participants |
| Groups 1, 2 and 3 Volunteers Completing CHMI | Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Any grade 3 laboratory adverse event | 1 Participants |
| Following MVA PvDBP Vaccination | Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Any grade 3 solicited adverse event | 2 Participants |
| Following MVA PvDBP Vaccination | Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Any grade 3 unsolicited adverse event | 0 Participants |
| Following MVA PvDBP Vaccination | Safety of the ChAd63 and MVA PvDBP Vaccines Andidates, Administered in a Heterologous Prime-boost Regimen in a CHMI Study in Healthy Volunteers | Any grade 3 laboratory adverse event | 0 Participants |
Secondary
The Cellular Immunogenicity ChAd63 and MVA PvDBP Vaccine Candidates, Administered in a Heterologous Prime-boost Regimen
PvDBPII-specific CD4+ CD45RA- CCR7- effector memory T cells producing IFN-γ
Time frame: 14 days after the final vaccination. Final vaccinations (MVA PvDBP) occurred at 2 months in Groups 1 and 3 ; and at 19 months in Group 2.
Population: Immunological analysis conducted as per protocol on pooled data from all volunteers across groups 1, 2 and 3 who completed vaccinations. Numbers in each group too small for meaningful summary statistics to be reported for each group separately.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Groups 1, 2 and 3 Volunteers Completing CHMI | The Cellular Immunogenicity ChAd63 and MVA PvDBP Vaccine Candidates, Administered in a Heterologous Prime-boost Regimen | 0.6825 Percentage of IFN-γ+ cells |
Secondary
The Humoral Immunogenicity ChAd63 and MVA PvDBP Vaccine Candidates, Administered in a Heterologous Prime-boost Regimen
Total IgG antibody response to the P. vivax Duffy-binding protein (PvDBP)
Time frame: 14 days after the final vaccination. Final vaccinations (MVA PvDBP) occurred at 2 months in Groups 1 and 3; and at 19 months in Group 2.
Population: Immunological analysis conducted as per protocol on pooled data from all volunteers across groups 1, 2 and 3 who completed vaccinations. Numbers in each group too small for meaningful summary statistics to be reported for each group separately.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Groups 1, 2 and 3 Volunteers Completing CHMI | The Humoral Immunogenicity ChAd63 and MVA PvDBP Vaccine Candidates, Administered in a Heterologous Prime-boost Regimen | 29 μg/mL |