A Clinical Trial to Evaluate the Safety, Efficacy and Immune Responses After Vaccination With an Investigational RNA-based Vaccine Against Malaria

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.

Inclusion criteria

• Have given informed consent by signing and dating the informed consent form (ICF) before initiation of any study-specific procedures.
• Were willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions and other requirements of the study. This included that they were able to understand and follow study-related instructions.
• Were aged 18 to 55 years, have a body mass index over 18.5 kg/m^2 and under 35 kg/m^2 and weighed at least 45 kg at Visit 0.
• Were 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.

• 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, could have been included.
• Agreed not to enroll in another study with an IMP starting from Visit 0 and until 12 weeks after receiving Dose 3.
• Have not traveled and agreed 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.
• Negative human immunodeficiency virus -1 and -2 blood test result at Visit 0.
• 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 0.
• Volunteers of childbearing potential (VOCBP) that had 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 were postmenopausal or permanently sterilized were not be considered VOCBP.
• VOCBP who agreed to practice a highly effective form of contraception starting at Visit 0 and continuously until 90 days after receiving Dose 3.
• VOCBP who agreed not to donate or cryopreserve eggs (ova, oocytes) for the purposes of assisted reproduction during study, starting at Visit 0 and continuously until 90 days after receiving Dose 3.
• Men who have not had a vasectomy and are sexually active with partners of childbearing potential and who agreed to use condoms and to practice a highly effective form of contraception with their sexual partners of childbearing potential during the study, starting at Visit 0 and continuously until 90 days after receiving Dose 3.
• Men who were willing to refrain from sperm donation, starting at Visit 0 and continuously until 90 days after receiving Dose 3.

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 3.
• 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).
• Presence 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:

• Used a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
• Used high dose inhaled corticosteroids (per American Academy of Allergy Asthma and Immunology), or
• In the year prior to study inclusion has had either of the following:

• Greater than one exacerbation of symptoms treated with oral/parenteral corticosteroids
• Needed hospitalization, or intubation for asthma.
• History of Diabetes mellitus type 1 or type 2, including cases controlled with diet alone or elevated hemoglobin A1C ≥6.5% at screening (not excluded: history of isolated gestational diabetes).
• Hypertension:

• If a person had a history of hypertension, or elevated blood pressure detected during screening, the person was excluded for blood pressure that was not well controlled. Well controlled blood pressure was 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.
• Malignancy within 5 years of screening, excluding localized basal or squamous cell skin cancer.
• Any presence or history of cardiovascular diseases, (e.g., myocarditis, pericarditis, myocardial infarction, congestive heart failure, cardiomyopathy or clinically significant arrhythmias), unless such disease was not considered relevant for participation in this study in the investigator's judgment.
• An abnormal screening ECG (i.e., showing the corrected QT interval by Fridericia [QTcF] greater than 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 greater than 120 ms]; second-or third-degree atrioventricular block); or other clinically significant abnormalities on the ECG at the investigator's discretion.
• Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions).
• Seizure disorder: History of seizure(s) within the past 3 years or had used medications in order to prevent or treat seizure(s) at any time within the past 3 years.
• 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 have interfered with participation and follow-up as outlined by the study.
• The following diseases associated with immune dysregulation:

• Primary immunodeficiencies.
• History of solid organ or bone marrow transplantation.
• Asplenia: any condition resulting in the absence of a functional spleen.
• Existing or history of autoimmune disease including and not limited to thyroid autoimmune disease, multiple sclerosis, psoriasis, etc.
• Previous vaccination with an approved or investigational malaria vaccine at any time or having taken part in a human malaria challenge study.
• Receipt of any investigational product within 28 days before Visit 0.
• Any planned non-study vaccinations starting at Visit 0 and continuously until 28 days after Dose 3.

• Note: Seasonal influenza and Coronavirus Disease 2019 (COVID-19) vaccines were allowed; however, they should been administered at least 14 days before or 28 days after any IMP administration. Emergency vaccinations, such as tetanus, were allowed to be administered when medically indicated.
• Received blood/plasma products, monoclonal antibodies or immunoglobulin within 120 days before Visit 1 or planned administration starting at Visit 0 and continuously until the last study visit (365 days after Dose 3).
• Received allergy treatment with antigen injections within 28 days before and after each IMP administration.
• Ongoing 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 28 days after Dose 3. Intraarticular, intrabursal, or topical (skin or eyes) corticosteroids were permitted.
• Had a history of alcohol abuse or drug addiction within 1 year before Visit 0 or had a history (within the past 5 years) of substance abuse, which in the opinion of the investigator, could have compromised their wellbeing if they participated as participants in the study, or that could have prevented, limited, or confounded the protocol specified assessments.
• Any existing condition which may have affected vaccine injection and/or assessment of local reactions at the injection site, e.g., tattoos, severe scars, etc.
• Were vulnerable individuals as per International Council for Harmonisation (ICH) E6 definition, i.e., were individuals whose willingness to volunteer in a clinical study may been 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.
• Any screening hematology and/or blood chemistry laboratory value (per the US FDA 2007) that met the definition of a Grade ≥2 abnormality or a Grade 1 abnormality at the investigator's discretion at Visit 0 or a Visit 0 troponin above the reference range. Individuals with abnormal but not clinically significant parameters not included in the toxicity guidance may have been considered eligible at discretion of investigator, with the exception of abnormal troponin values.