This was a randomized, dose-escalation Phase I/IIa study 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.
Part A of this study was observer-blind and assessed the reactogenicity, safety, and immunogenicity of up to 9 dose combinations in a 3-dose regimen of the 3 components of BNT165e. Participants were randomized 5:1 active:placebo. In Cohorts 1 to 9, the initial two doses of the investigational medicinal product (IMP) were administered \~8 weeks apart and the third dose was administered \~18 weeks after the second dose (given at 0-2-6 months). In Cohort 10, each of the three doses of IMP was administered 28 days apart (given at 0-1-2 months). Participants who were out of window for dosing in the event of a study pause could have been discontinued from further vaccination. If a participant was discontinued either from further vaccination or from the study, the sponsor could decided to replace this participant with a new participant. Participants were randomized to the IMP in the open cohort until that cohort has filled. Per protocol, the number of participants was increased to 163 due to participant replacement or re-enrollment. The study duration was up to a maximum of 89 weeks for each participant in Cohorts 1 to 9 (planned study duration of 84 weeks plus 30 days window extension for Dose 3 due to study pause), and 66 weeks for each participant in Cohort 10. The initially planned Part B with a controlled human malaria infection model was not performed.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
163
AMR Tempe
Tempe, Arizona, United States
University of Maryland, Center for Vaccine Development
Baltimore, Maryland, United States
AMR Las Vegas
Las Vegas, Nevada, United States
AMR Knoxville
Knoxville, Tennessee, United States
Clinical Trials of Texas
San Antonio, Texas, United States
Number and Percentage of Participants With Solicited Local Reactions at the Injection Site
A solicited reaction was defined as an adverse reaction observed and reported under the conditions (symptom and onset) and pre-listed (that is, solicited) in the e-diary. Solicited local reactions included: pain at the injection site, erythema/redness, and induration/swelling. The intensity of AEs was graded by the study participant. Confirmation by an investigator or medically qualified person was required for all Grade 3 or 4 reactogenicity events. Grades were defined as: Grade 1 - Mild; does not interfere with the study participant's activity; Grade 2 - Moderate; interferes with the study participant's activity; Grade 3 - Severe; prevents study participant's daily activity; and Grade 4 - Potentially life-threatening; emergency room visit or hospitalization for severe pain. Participants may have been counted more than once if they reported multiple episodes of the event for the specified doses.
Time frame: Up to 7 days after each IMP dose, (i.e., post-Dose 1, post-Dose 2, and post-Dose 3)
Number and Percentage of Participants With Solicited Systemic Reactions
A solicited reaction was defined as an adverse reaction observed and reported under the conditions (symptom and onset) and pre-listed (that is, solicited) in the e-diary. Solicited systemic reactions included: vomiting, diarrhea, headache, fatigue/tiredness, muscle pain/joint pain, and fever. The intensity of AEs was graded by the participant but only an investigator or medically qualified person was able to classify a systemic reaction as Grade 3 or 4. Grades were defined as: Grade 1 - Mild; does not interfere with the study participant's activity; Grade 2 - Moderate; some interference with the study participant's activity; Grade 3 - Severe; prevents the trial participant's daily routine activity; and Grade 4 - Potentially life-threatening; Emergency room visit or hospitalization. Fever was categorized as 38.0 - 38.4 °C, 38.5 - 38.9 °C, 39.0 - 40.0 °C \& \>40.0 °C. Participants may have been counted more than once if they reported multiple episodes of the event for the specified doses.
Time frame: Up to 7 days after each IMP dose, (i.e., post-Dose 1, post-Dose 2, and post-Dose 3)
Number of Participants With at Least One Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered with a pharmaceutical product, and which did not necessarily have a causal relationship with this treatment. The intensity of AEs was graded by the investigator. Grade 1 - Mild; does not interfere with the trial subject's usual function; Grade 2 - Moderate; interferes to some extend with the trial subject's usual function Grade 3 - Severe; interferes significantly with the trial subject's usual function; and Grade 4 - Potentially life-threatening; life-threatening consequences, urgent intervention required. Participants may have been counted more than once if they reported multiple episodes of the event for the different doses. Includes all unsolicited AEs and also solicited events that persisted beyond 7 days post-dose, qualify as an SAE, or are delayed local reactions.
Time frame: From administration of each IMP dose (i.e., Dose 1, Dose 2, and Dose 3) up to 28 days after the respective IMP dose
Number of Participants With at Least One Medically Attended Adverse Event (MAAE)
An MAAE was defined as an AE for which the participants received medical attention defined as hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, including emergency room visits. Includes all unsolicited AEs and also solicited events that qualify as an MAAE.
Time frame: From Dose 1 up to 24 weeks after last received IMP dose, up to 13 months.
Number of Participants With at Least One Serious Adverse Event (SAE)
An SAE was defined as any untoward medical occurrence that, at any dose, resulted in death or was life-threatening. It also included any event requiring hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, caused a congenital anomaly or birth defect, or any other event determined as SAE as per medical or scientific judgment. Includes all unsolicited AEs and solicited events that qualify as an SAE.
Time frame: From Dose 1 up to 24 weeks after last received IMP dose, up to 13 months.
Descriptive Statistics on Antibody Levels (Including Geometric Means and 95% Confidence Interval) at Assessed Timepoints
For each cohort - Anti-CSP immunoglobulin G
Time frame: Up to 365 days after last received IMP dose
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