A Clinical Trial to Evaluate the Safety, Efficacy and Immune Responses After Vaccination With an Investigational RNA-based Vaccine Against Malaria
Study Details
Study Description
Brief Summary
This is a randomized, dose-escalation Phase I/IIa trial with controlled human malaria infection to evaluate safety, tolerability, immunogenicity (Part A) and efficacy (Part B) of an investigational RNA-based vaccine (BNT165e) for prevention of P. falciparum malaria in healthy malaria-naive adults.
The multi-antigen malaria vaccine (designated BNT165e) is a combination of three distinct RNAs, BNT165c and BNT165d (composed of BNT165d1 and BNT165d2), encoding P. falciparum antigens encapsulated in lipid nanoparticles (LNPs). The BNT165c RNA encodes the Plasmodium falciparum circumsporozoite protein (PfCSP). The BNT165d1 and BNT165d2 RNAs both encode conserved, immunogenic segments of liver stage-expressed proteins.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
The trial will consist of two parts:
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Part A will be observer-blind and assess the reactogenicity, safety, and immunogenicity of up to 8 dose combinations in a 3-dose regimen of the 3 components of BNT165e. Subjects will be randomized 5:1 active:placebo.
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Part B will be open-label and assess efficacy of BNT165e in preventing P. falciparum parasitemia in a homologous controlled human malaria infection (CHMI, NF54).
In Part B, subjects recruited to receive investigational medicinal product (IMP) will be assigned in a 1:1 ratio to either Cohort MB (CHMI via mosquito bite [MB]) or Cohort DVI (CHMI via direct venous inoculation [DVI] of P. falciparum sporozoites). At the time point of CHMI and for each modality of infection (MB versus DVI), an additional 6 subjects will be recruited to act as infectivity controls and will be challenged with the respective modality of infection.
The initial two doses will be administered ~8 weeks apart in both Part A and B and the third dose in Part A will be administered ~18 weeks after the second dose.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part A - BNT165e Escalating dose levels |
Biological: BNT165e
Multi-antigen RNA-based vaccine for active immunization against malaria administered as intramuscular injection
|
| Placebo Comparator: Part A - Placebo
|
Other: Placebo
Isotonic NaCl solution (0.9%)
|
| Experimental: Part B - BNT165e Cohort DVI CHMI will be performed using DVI of NF54 P. falciparum sporozoites |
Biological: BNT165e
Multi-antigen RNA-based vaccine for active immunization against malaria administered as intramuscular injection
|
| Experimental: Part B - BNT165e Cohort MB CHMI will be performed using NF54 P. falciparum-infected mosquitoes |
Biological: BNT165e
Multi-antigen RNA-based vaccine for active immunization against malaria administered as intramuscular injection
|
| No Intervention: Part B - No intervention - Cohort DVI CHMI will be performed using DVI of NF54 P. falciparum sporozoites |
|
| No Intervention: Part B - No intervention - Cohort MB CHMI will be performed using NF54 P. falciparum-infected mosquitoes |
Outcome Measures
Primary Outcome Measures
- Part A and Part B - Frequency of solicited local reactions at the injection site (pain, erythema/redness, induration/swelling) recorded up to 7 days after each dose [Up to 7 days after each dose]
For each cohort in subjects receiving at least one dose of trial intervention.
- Part A and Part B - Frequency of solicited systemic reactions (vomiting, diarrhea, headache, fatigue, muscle/joint pain, and fever) recorded up to 7 d after each dose [Up to 7 days after each dose]
For each cohort in subjects receiving at least one dose of trial intervention.
- Part A and Part B - Frequency of subjects with at least one adverse event (AE) occurring until 28 days after each dose [Up to 28 days after each dose]
For each cohort in subjects receiving at least one dose of trial intervention.
- Part A and Part B - Frequency of subjects with at least one medically attended adverse event (MAAE) occurring until 28 days after each dose [Up to 28 days after each dose]
For each cohort in subjects receiving at least one dose of trial intervention
- Part A - Frequency of subjects in each cohort with at least one serious adverse event (SAE) occurring until 24 weeks after Dose 3 [Up to 24 weeks after Dose 3]
For each cohort in subjects receiving at least one dose of trial intervention.
- Part B - Number and proportion of subjects protected from blood stage parasitemia 5 days to 28 days after CHMI [Up to 28 days after CHMI]
For both Cohorts MB and DVI, in subjects who received the full dose schedule, underwent CHMI and did not receive any medication with antimalarial activity before the assessment of the primary endpoint.
- Part B - Frequency of subjects with at least one AE occurring until 28 days after CHMI [Up to 28 days after CHMI]
For each cohort in subjects receiving at least one dose of trial intervention.
- Part B - Frequency of subjects with at least one MAAE occurring until 28 days after CHMI [Up to 28 days after CHMI]
For each cohort in subjects receiving at least one dose of trial intervention.
- Part B - Frequency of subjects in each cohort with at least one SAE occurring until 28 days after CHMI [Up to 28 days after CHMI]
For each cohort in subjects receiving at least one dose of trial intervention.
Secondary Outcome Measures
- Part A - Descriptive statistics on antibody levels at assessed timepoints [Up to 365 days after Dose 3]
For each cohort - Anti-CSP IgG
- Part B - Time to blood stage parasitemia, i.e., P. falciparum by quantitative polymerase chain reaction (qPCR) after the CHMI [Up to 28 days after CHMI]
For each cohort
- Part B - Descriptive statistics on antibody levels at assessed timepoints [Up to 28 days after CHMI]
For each cohort - Anti-CSP IgG
Eligibility Criteria
Criteria
Inclusion Criteria:
Part A and B:
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Have given informed consent by signing and dating the informed consent form (ICF) before initiation of any trial-specific procedures.
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Are willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.
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Are aged 18 to 55 (Part A) and 18 to 50 (Part B) years, have a body mass index over 18.5 kg/m2 and under 35 kg/m2 and weigh at least 45 kg at Visit 0.
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Are healthy, in the clinical judgment of the investigator based on volunteer-reported medical history data, and physical examination, 12-lead electrocardiogram (ECG), vital signs, and clinical laboratory test outcomes at Visit 0.
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Note: Healthy volunteers with pre-existing stable disease (e.g., obesity, hypertension), defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 90 days before Visit 0, can be included.
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Agree not to enroll in another trial with an IMP starting from Visit 0 and until 12 weeks after receiving Dose 3 (Visit 19, Part A) or until 28 days after receiving CHMI (Part B).
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Have not traveled and agree not to travel to a malaria-endemic region, as defined per Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/malaria/travelers/country_table/a.html) starting 6 months before Visit 0 and continuously until 28 days after receiving Dose 3 (Visit 18, Part A) or 28 days after CHMI (Part B).
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Negative human immunodeficiency virus (HIV) -1 and -2 blood test result at Visit 0.
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Negative Hepatitis B surface antigen (HBsAg) test result at Visit 0 and negative anti Hepatitis C virus (anti-HCV) antibodies, or negative HCV polymerase chain reaction (PCR) test result if the anti-HCV is positive at Visit 0.
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Volunteers of childbearing potential (VOCBP) that have a negative serum beta-human chorionic gonadotropin (β-HCG) pregnancy test result at Visit 0 and negative urine pregnancy test results before each IMP administration. Volunteers born female who are postmenopausal or permanently sterilized will not be considered VOCBP.
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VOCBP who agree to practice a highly effective form of contraception starting at Visit 0 and continuously until 90 days after receiving Dose 3 (Part A) or or 60 days after CHMI (Part B).
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VOCBP who agree not to donate or cryopreserve eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at Visit 0 and continuously until 90 days after receiving Dose 3 (Part A) or 60 days after CHMI (Part B).
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Men who have not had a vasectomy and are sexually active with partners of childbearing potential and who agree to use condoms and to practice a highly effective form of contraception with their sexual partners of childbearing potential during the trial, starting at Visit 0 and continuously until 90 days after receiving Dose 3 (Part A) or 60 days after CHMI (Part B).
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Men who are willing to refrain from sperm donation, starting at Visit 0 and continuously until 90 days after receiving Dose 3 (Part A) or 60 days after CHMI (Part B).
Part B only:
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Are willing to refrain from blood donation for 3 years after CHMI.
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Are willing to take curative antimalarial treatment after CHMI.
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Are reachable (24/7) by phone during the period between CHMI and the end of trial.
Exclusion Criteria:
Part A and B:
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History of Plasmodium parasitemia (any species) based on volunteer-reported medical history.
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Prior residence for ≥6 months continuously in a malaria-endemic region as defined per CDC (https://www.cdc.gov/malaria/travelers/country_table/a.html) at any point during their lifetime.
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Breastfeeding or intending to become pregnant or to father children starting with Visit 0 and continuously until 90 days after receiving Dose 3 (Part A) and 60 days after receiving CHMI (Part B).
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History of any serious adverse reactions to vaccines or to vaccine components such as lipids, and including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded from participation: a volunteer who had an anaphylactic adverse reaction to pertussis vaccine as a child).
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Current or history of the following medical conditions:
- Uncontrolled or moderate or severe respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease); symptoms of asthma severity as defined in the US National Asthma Education and Prevention Program Expert Panel report, 2020 - e.g., exclude a volunteer who:
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Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
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Uses high dose inhaled corticosteroids (per American Academy of Allergy Asthma & Immunology), or
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In the past year has either of the following:
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Greater than one exacerbation of symptoms treated with oral/parenteral corticosteroids
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Needed hospitalization, or intubation for asthma.
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History of Diabetes mellitus type 1 or type 2, including cases controlled with diet alone or elevated hemoglobin A1C (HbA1c) ≥6.5% at screening (not excluded: history of isolated gestational diabetes).
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Hypertension:
- If a person has a history of hypertension, or elevated blood pressure detected during screening, exclude for blood pressure that is not well controlled. Well controlled blood pressure is defined as consistently ≤140 mm Hg systolic and ≤90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤150 mm Hg systolic and ≤100 mm Hg diastolic at screening and enrollment.
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Malignancy within 5 years of screening, excluding localized basal or squamous cell skin cancer.
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Any current or history of cardiovascular diseases, e.g., myocarditis, pericarditis, myocardial infarction, congestive heart failure, cardiomyopathy or clinically significant arrhythmias, (in Part A only: unless such disease is not considered relevant for participation in this trial in the investigator's judgment). In addition, for Part B, evidence of higher than 10% five-year cardiovascular risk by the non-laboratory method.
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An abnormal screening ECG (i.e., showing the corrected QT interval by Fridericia (QTcF) >150 ms; significant ST-T wave changes suggestive of myocardial ischemia or of an acute or indeterminate-age myocardial infarction; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions; complete right or left bundle branch block [QRS >120 ms]; second-or third-degree atrioventricular [AV] block); or other clinically significant abnormalities on the ECG at the investigator's discretion.
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Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions).
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Seizure disorder: History of seizure(s) within the past three years or has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.
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Documented major psychiatric illness, including bipolar disorder, major depressive disorder, schizophrenia, autism, and attention deficit-hyperactivity disorder that at the discretion of the investigator could interfere with participation and follow-up as outlined by the trial.
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The following diseases associated with immune dysregulation:
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Primary immunodeficiencies.
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History of solid organ or bone marrow transplantation.
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Asplenia: any condition resulting in the absence of a functional spleen.
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Currently existing or history of autoimmune disease including and not limited to thyroid autoimmune disease, multiple sclerosis, psoriasis, etc.
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Previous vaccination with an approved or investigational malaria vaccine at any time or having taken part in a human malaria challenge study.
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Receipt of any investigational product within 28 days before Visit 0.
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Any planned non-trial vaccinations starting at Visit 0 and continuously until Visit 18 (28 days after Dose 3) (Part A), and 28 days after CHMI (Visit 31) (Part B).
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Note: Seasonal influenza and Coronavirus Disease 2019 (COVID-19) vaccines are allowed; however, they should be administered at least 14 days before or 28 days after any IMP administration or CHMI. Emergency vaccinations, such as tetanus, are allowed to be administered when medically indicated.
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Received blood/plasma products, monoclonal antibodies or immunoglobulin within 120 days before Visit 1 or planned administration starting at Visit 0 and continuously until Visit 21 (Part A) and 28 days after CHMI (Visit 31) (Part B).
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Received allergy treatment with antigen injections within 28 d before and after each IMP administration (Part A and B) or 28 days before and after CHMI (Part B only).
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Current or planned treatment with immunosuppressive therapy, including systemic corticosteroids (if systemic corticosteroids are administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent) starting at Visit 0 and continuously until Visit 18 (28 days after Dose 3) (Part A) or until Visit 31 (28 days after CHMI) (Part B). Intraarticular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.
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Have a history of alcohol abuse or drug addiction within 1 year before Visit 0 or have a history (within the past 5 years) of substance abuse, which in the opinion of the investigator, could compromise their wellbeing if they participate as subjects in the trial, or that could prevent, limit, or confound the protocol specified assessments.
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Any existing condition which may affect vaccine injection and/or assessment of local reactions at the injection site, e.g., tattoos, severe scars, etc.
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Are vulnerable individuals as per International Council for Harmonisation (ICH) E6 definition, i.e., are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.
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Any screening hematology and/or blood chemistry laboratory value that meets the definition of a Grade ≥2 abnormality or a Grade 1 abnormality at the investigator's discretion at Visit 0. Individuals with abnormal but not clinically significant parameters not included in the toxicity guidance may be considered eligible at discretion of investigator.
Part B only:
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History of any serious adverse reactions to atovaquone/proguanil or artemether/lumefantrine, including but not limited to anaphylaxis and related symptoms, such as hives, respiratory difficulty, angioedema, and/or abdominal pain.
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Current or planned treatment with any drug that has antimalarial activity (including, but not limited to artemisinins, TMP-SMX, mefloquine, chloroquine, hydroxychloroquine, atovaquone, tetracycline antibiotics, macrolide antibiotics, quinolone antibiotics, or clindamycin) within 28 days before and after planned CHMI.
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Have a history of any SAEs to atovaquone/proguanil and artemether/lumefantrine.
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Current or planned use of medications causing drug-interactions with atovaquone-proguanil or an artemisinin-based combination therapy (including, but not limited to cimetidine, metoclopramide, antacids, and kaolin) within 28 days before and after planned CHMI.
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Sickle cell disease.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- BioNTech SE
Investigators
- Study Director: BioNTech Responsible Person, BioNTech SE
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- BNT165-02