Safety and Immune Responses After Vaccination With Two Investigational RNA-based Vaccines Against Tuberculosis in BCG Vaccinated Volunteers

Study Overview
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Brief Summary
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This randomized, placebo-controlled, observer-blind, safety and dose-finding Phase Ib trial will be conducted in countries in Africa, including Republic of South Africa. This trial will evaluate three dose levels of the BNT164 investigational vaccines (BNT164a1 and BNT164b1) to select a safe and tolerable dose in a three-dose schedule.

Detailed Description
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Enrollment for BNT164a1 and BNT164b1 will be conducted independently, and in parallel. The trial will enroll participants into six dose groups by dose level who will be stratified by interferon gamma release assay (IGRA) status and then randomized 5:1 for BNT164 (BNT164a1 or BNT164b1):placebo. The trial will use a staggered dose escalation schema, i.e., enrollment into the next higher dose level is done sequentially and subject to safety data from the previous dose levels, with sentinel participants for Dose 1 in all dose groups.

Official Title
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A Phase Ib, Randomized, Placebo-controlled, Observer-blind, Dose-finding Evaluation Trial to Describe the Safety, Reactogenicity, and Immunogenicity of Two Investigational Vaccines Against Active Tuberculosis in BCG Vaccinated, HIV-negative Subjects

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: BNT164a1
* Biological: BNT164b1
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given informed consent by signing and dating an informed consent form before initiation of any trial-specific procedures. Are 18 to 55 years of age inclusive and have a body mass index over 18.5 kg/m^2 and under 35 kg/m^2 and weigh at least 50 kg. 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. Have a history or evidence (scar) of Bacillus Calmette-Guérin (BCG) vaccination. Are overall healthy in the clinical judgment of the investigator based on the medical history and clinical assessment (including physical examination, vital signs, clinical laboratory tests, and 12-lead electrocardiogram [ECG]). Hemoglobin ≥12.0 g/dL for volunteers who were born female, ≥13.0 g/dL for volunteers who were born male. Volunteers of childbearing potential (VOCBP) must have a negative serum beta-human chorionic gonadotropin pregnancy test at Visit 0 and negative urine pregnancy test results before each investigational medicinal product (IMP) administration. Volunteers born female that are postmenopausal (confirmed by follicle stimulating hormone) or permanently sterilized (verified by medical records) will not be considered VOCBP. VOCBP who agree to practice a highly effective form of contraception and to require their male partners to use condoms, starting at Visit 0 and continuously until 90 days after receiving their last IMP injection in this trial. VOCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at Visit 0 and continuously until 90 days after receiving their last IMP injection in this trial. Men who are sexually active with a partner of childbearing potential and have not had a vasectomy who agree to use condoms and to practice a highly effective form of contraception during the trial, starting at Visit 0 and continuously until 90 days after receiving their last IMP injection in this trial. Men who are willing to refrain from sperm donation, starting at Visit 0 and continuously until 90 days after receiving their last IMP injection in this trial. Exclusion Criteria: Any existing condition which may affect vaccine injection and/or assessment of local reactions assessment at the injection site, e.g., tattoos, severe scars, etc. Any bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. Baseline clinical screening questionnaire positive for pulmonary tuberculosis disease or history of sputum sample positive for tuberculosis, or history of treatment for active or latent tuberculosis. Current febrile illness (body temperature ≥38.0°C) or other acute illness at Visit 0. Current or history of the following medical conditions: Cardiovascular diseases, e.g., myocardial infarction, congestive heart failure, cardiomyopathy, or clinically significant arrhythmias, myocarditis, or pericarditis. Hypertension If a person has been found to have elevated blood pressure or hypertension during screening or previously, 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 ≤90 mm Hg diastolic at enrollment. If a person does not have a history of elevated blood pressure or hypertension previously or during screening, also exclude for systolic blood pressure ≥150 mm Hg at enrollment or diastolic blood pressure ≥100 mm Hg at enrollment. Diabetes mellitus type 1 or type 2 cases requiring medication Thyroidectomy, or thyroid disease requiring medication during the last 12 months Malignancy within 5 years of Visit 0, excluding localized basal or squamous cell cancer Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) Seizure disorder: History of seizure(s) within past 3 years. Also exclude if participant has used medications in order to prevent or treat seizure(s) at any time within the past 3 years An abnormal screening or Visit 1 ECG (i.e., showing the corrected QT interval by Fridericia (QTcF) >450 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 block); or other clinically significant abnormalities on the ECG at the investigator's discretion History of syncope (fainting) in association with administration of injectable vaccines. Known or suspected immunodeficiency. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the trial IMP. Positive test result at Visit 0 or history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). History of previous administration of experimental tuberculosis vaccines, or any planned non-trial vaccinations within 28 days before Dose1 and continuously until 28 days after Dose 3 (Visit 11). Note: Licensed vaccines (including inactivated, mRNA, and live attenuated vaccines) are allowed to be given at least 28 days before or 28 days after each IMP administration. Current or planned treatment with immunosuppressive therapy, including systemic corticosteroids (if systemic corticosteroids are administered for ≥14 days at a dose of ≥5 mg/day of prednisone or equivalent) starting at Visit 0 and continuously until 28 days after Dose 3 (Visit 11), for an autoimmune disease. Intraarticular, intrabursal, or topical (skin or eyes) corticosteroids are permitted. Have received or plan to receive blood/plasma products or immunoglobulin from 120 days before Dose 1 and continuously until 28 days after Dose 3 (Visit 11). Use of any non-trial IMP within 28 days before Dose 1 in this trial (Visit 1) or planned receipt continuously until Visit 14 in this trial, or participate in the active treatment phase of another interventional clinical trial. Are subject to exclusion periods from another investigational clinical trial. Are breastfeeding or are planning pregnancy within 90 days after Dose 3 in this trial or to father children during the trial or within 90 days after Dose 3 in this trial. Any screening hematology and/or blood chemistry laboratory value that meets the definition of a Grade ≥1 abnormality at Visit 0. For laboratory values for which toxicity grading guidance is not available, participant eligibility will be determined at the discretion of the investigator. Note: Trial participants with any stable Grade 1 abnormalities (according to the toxicity grading scale) may be considered eligible at the discretion of the investigator. A stable Grade 1 laboratory abnormality is defined as a report of Grade 1 on an initial blood sample that remains Grade ≤1 upon repeat testing on a second sample from the same participant. History of psychiatric illness, including alcohol abuse or drug addiction within 1 year before Visit 0, or a history (within the past 5 years) of substance abuse or known medical, psychological, or social conditions which, in the opinion of the investigator, could compromise their wellbeing if they participate as participants in the trial, or that could prevent, limit, or confound the protocol specified assessments. Are vulnerable individuals as per International Council on Harmonisation 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. IGRA status at Visit 0 is negative or positive and enrollment for the respective IGRA-negative or IGRA-positive stratum has already been reached.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BNT164a1<br>Escalating dose levels | Biological: BNT164a1<br>* Multi-antigen ribonucleic acid (RNA) vaccine for active immunization against tuberculosis administered as intramuscular injection<br>|
| Experimental: BNT164b1<br>Escalating dose levels | Biological: BNT164b1<br>* Multi-antigen ribonucleic acid (RNA) vaccine for active immunization against tuberculosis administered as intramuscular injection<br>|
| Placebo Comparator: Placebo<br>Isotonic NaCl solution (0.9%) | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of solicited local reactions (pain, erythema/redness, induration/swelling) at the injection site up to 7 days after each dose |  | Up to 7 days after each dose | 
| Frequency of solicited systemic reactions (vomiting, diarrhea, headache, fatigue, muscle pain & joint pain, chills, and fever) up to 7 days after each dose |  | Up to 7 days after each dose | 
| Proportion of participants with at least one adverse event (AE) occurring from each dose to 28 days after each dose |  | From each dose up to 28 days after each dose | 
| Proportion of participants with at least one unsolicited AE occurring from Dose 1 to 28 days post-Dose 3 |  | From Day 1 until Day 197 | 
| Proportion of participants with at least one serious AE or AE of special interest occurring from Dose 1 up to 168 days post-Dose 3 |  | From Day 1 until Day 337 | 
| Number of unsolicited AEs from Dose 1 to 28 days post-Dose 3 |  | From Day 1 until Day 197 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention of tuberculosis, RNA Vaccine, Vaccine, TB