A Randomized, Dose-escalation Phase I/IIa Trial With Controlled Human Malaria Infection to Evaluate Safety, Tolerability, Immunogenicity and Efficacy of an Investigational RNA-based Vaccine for Prevention of P. Falciparum Malaria in Healthy Malaria naïve Adults
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Malaria
- Sponsor
- BioNTech SE
- Enrollment
- 163
- Locations
- 10
- Primary Endpoint
- Frequency of solicited local reactions at the injection site (pain, erythema/redness, induration/swelling) recorded up to 7 days after each dose
- Status
- Completed
- Last Updated
- 17 days ago
Overview
Brief Summary
This is a randomized, dose-escalation Phase I/IIa trial to evaluate safety, tolerability, immunogenicity and efficacy 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. The BNT165c RNA encodes the full Plasmodium falciparum circumsporozoite protein. The BNT165d1 and BNT165d2 RNAs both encode conserved, immunogenic segments of liver stage-expressed proteins.
Detailed Description
Part A of this trial will be observer-blind and assess the reactogenicity, safety, and immunogenicity of up to 9 dose combinations in a 3-dose regimen of the 3 components of BNT165e. One dose combination will also be tested in a Day 1, Day 29, and Day 57 dosing schedule in Cohort 10. Participants will be randomized 5:1 active:placebo. In Cohorts 1 to 9, the initial two doses will be administered \~8 weeks apart and the third dose will be administered \~18 weeks after the second dose. In Cohort 10, the investigational medicinal product (IMP) will be administered 28 days apart on Day 1, Day 29, and Day 57. Participants who are out of window for dosing in the event of a trial pause can be discontinued from further vaccination. If a participant is discontinued either from further vaccination or discontinued from the trial, the sponsor can decide to replace this participant with a new participant. Participants will be randomized to the vacancy in the open cohort until that cohort has filled. The number of participants may be increased up to 177 in the event of participant replacement or re-enrollment. The planned trial duration is up to a maximum of 84 weeks for each participant in Cohorts 1 to 9, and 66 weeks for each participant in Cohort 10. Trial duration may exceed the listed maximum time in the event of a trial pause. An amendment will be submitted to the Health Authorities detailing Part B, which will explore the efficacy of BNT165e in a controlled human malaria infection model.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have given informed consent by signing and dating the informed consent form (ICF) before initiation of any trial-specific procedures.
- •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.
- •Are aged 18 to 55 years, have a body mass index over 18.5 kg/m\^2 and under 35 kg/m\^2 and weigh at least 45 kg at Visit
- •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
- •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.
- •Agree not to enroll in another trial with an IMP starting from Visit 0 and until 12 weeks after receiving Dose
- •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
- •Negative human immunodeficiency virus -1 and -2 blood test result at Visit
- •Negative Hepatitis B surface antigen test result at Visit 0 and negative anti-Hepatitis C virus (anti-HCV) antibodies, or negative HCV polymerase chain reaction test result if the anti-HCV is positive at Visit
- •Volunteers of childbearing potential (VOCBP) that have a negative serum beta-human chorionic gonadotropin 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.
Exclusion Criteria
- •History of Plasmodium parasitemia (any species) based on volunteer-reported medical history.
- •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.
- •Breastfeeding or intending to become pregnant or to father children starting with Visit 0 and continuously until 90 days after receiving Dose
- •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).
- •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:
- •Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
- •Uses high dose inhaled corticosteroids (per American Academy of Allergy Asthma and Immunology), or
- •In the past year has either of the following:
- •Greater than one exacerbation of symptoms treated with oral/parenteral corticosteroids
Arms & Interventions
Placebo
Participants received 3 intramuscular injections of isotonic NaCl solution (0.9%). Includes placebo participants of all dose levels with a 0-2-6 months dose regimen. Doses were given on Day 1, Day 57, and Day 183.
Intervention: Placebo
BNT165e
Escalating dose levels
Intervention: BNT165e
Outcomes
Primary Outcomes
Frequency of solicited local reactions at the injection site (pain, erythema/redness, induration/swelling) recorded up to 7 days after each dose
Time Frame: Up to 7 days after each dose
For each cohort in participants receiving at least one dose of trial intervention.
Frequency of solicited systemic reactions (vomiting, diarrhea, headache, fatigue, muscle/joint pain, and fever) recorded up to 7 d after each dose
Time Frame: Up to 7 days after each dose
For each cohort in participants receiving at least one dose of trial intervention.
Frequency of participants with at least one adverse event occurring until 28 days after each dose
Time Frame: Up to 28 days after each dose
For each cohort in participants receiving at least one dose of trial intervention.
Frequency of participants with at least one medically attended adverse event occurring until 24 weeks after last received IMP dose
Time Frame: Up to 24 weeks after last received IMP dose
For each cohort in participants receiving at least one dose of trial intervention
Frequency of participants in each cohort with at least one serious adverse event occurring until 24 weeks after last received IMP dose
Time Frame: Up to 24 weeks after last received IMP dose
For each cohort in participants receiving at least one dose of trial intervention.
Secondary Outcomes
- Descriptive statistics on antibody levels (including geometric means and 95% confidence interval) at assessed timepoints(Up to 365 days after last received IMP dose)