Safety and Efficacy of R0.6C Vaccine

This is a first-in-human phase I, open-label, single-site, dose escalation study to determine the safety, tolerability and Plasmodium falciparum transmission reducing activity of the R0.6C vaccine in two different adjuvant combinations.

Thirty-two healthy adult volunteers will be recruited and divided over the study arms that will receive four vaccinations on days 0, 28, 56 and 168 with either 30μg or 100μg of R0.6C adjuvanted with Alhydrogel alone, or combined with Matrix-M1.

Three volunteers (Group 1A, n=3) will receive four vaccinations with the lower dose of 30μg R0.6C with Alhydrogel, and, in parallel, three volunteers (Group 1B, n=3) will receive four vaccinations with the lower dose of 30μg R0.6C with Alhydrogel and Matrix-M1. Volunteers will be closely monitored for adverse events for a period of minimally 14 days after the first vaccination. If safe, an additional 5 volunteers per adjuvant arm (groups 2A and 2B) will then receive four vaccinations with the lower dose (30μg R0.6C). If considered safe following a minimum of 14 days of follow-up after the first R0.6C administration of groups 2A and 2B, three volunteers per adjuvant arm (groups 3A and 3B) will start the vaccination regimen with the higher dose of 100μg R0.6C. Finally, a minimum of 14 days after administration of the first vaccination in groups 3A and 3B, if considered safe, an additional 5 volunteers per adjuvant arm (groups 4A and 4B) will initiate the vaccination regimen with the higher dose of 100μg R0.6C. There will be no placebo group. All volunteers will be followed up for adverse events until 84 days after the last immunisation. Total trial duration is approximately 8 months for each subject. Blood will be collected to assess functional Plasmodium falciparum transmission reducing activity (TRA) and transmission blocking activity (TBA) by standard membrane feeding assay (SMFA), as well as immunogenicity, at pre-specified time points after R0.6C vaccinations compared to pre-vaccination values.

Eligibility Criteria:
Inclusion Criteria:

1. Subject must sign written informed consent to participate in the trial.
2. Subject is a male or non-pregnant and non-lactating female age ≥ 18 and ≤ 55 years and in good health.
3. Subject is able to understand planned study procedures and demonstrate comprehension of the protocol procedures and knowledge of study by passing a quiz (assessment of understanding).
4. In the opinion of the investigator, the subject can and will comply with the requirements of the protocol.
5. Subjects are available to attend all study visits and are reachable by phone throughout the entire study period from day -1 until day 224 (end of study).
6. The subject will remain within reasonable travelling distance from the study center from day -1 until day 7 after each R0.6C administration and agrees not to travel to a malaria-endemic area during the study period
7. Subject agrees to their general practitioner (GP) being informed about participation in the study and agrees to sign a form to request the release by their GP, and medical specialist when necessary, of any relevant medical information concerning possible contra-indications for participation in the study to the investigator(s).
8. The subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period according to current Sanquin guidelines.
9. Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause. All subjects of childbearing potential must agree to use continuous adequate contraception\* until 2 months after completion of the study. Female subjects must agree not to breastfeed from 30 days prior to R0.6C administration until 2 months after completion of the study. Female subjects must have a negative pregnancy test at the inclusion visit.

Exclusion Criteria:

1. Acute or chronic disease at time of R0.6C administration, clinically significant pulmonary, cardiovascular, hepatic, renal, neurological or immunological functional abnormality, as determined by medical history, physical examination or laboratory screening tests:

   1. Acute disease is defined as the presence of a moderate or severe illness with or without fever. For subjects with an illness on the day of R0.6C administration, the vaccination may be postponed up to 7 days.
   2. Fever is defined as an oral, axillary or tympanic temperature ≥ 38.0°C.
   3. Any abnormal and clinically significant baseline laboratory screening tests of ALT, AST, creatinine, hemoglobin, platelet count or total white blood cell count, as defined in the protocol according to the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Subjects Enrolled in Preventative Vaccine Clinical Trials (appendix 1).
2. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years.
3. Chronic use of i) immunosuppressive drugs, iii) or other immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral anti-histamines exempted) or expected use of such during the study period.
4. History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset, positive urine toxicology test for cocaine or amphetamines at screening or at inclusion.
5. Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV).
6. Use of any other investigational or non-registered product (drug or vaccine) during the study period.
7. Known hypersensitivity to macrolides.
8. Participation in any other clinical study involving an investigational product in the 30 days prior to the start of the study or during the study period.
9. Receipt of any other vaccination within 30 days prior to the first R0.6C vaccination or planned vaccinations during the study period. Exceptions are made for vaccination against influenza and the novel coronavirus SARS-CoV2.
10. Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study or CHMI.
11. Body weight \> 115 kg
12. Being an employee or student of the department of Medical Microbiology of the Radboudumc at the time of screening, or a person otherwise related to the investigator.
13. Any other condition or situation that would, in the opinion of the investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.