Assessment of the Malaria Vaccine Candidate SumayaVac-1 in Healthy Adults Aged 18-45 Years Living in a Malaria Endemic Country

Malaria remains a major infectious disease causing a heavy burden of mortality and morbidity in populations living in tropical and subtropical regions. Large, international research efforts have been invested into the development of anti-malaria vaccination strategies, however, currently there is only one malaria vaccine approved for use in the pediatric population, which provides a moderate and short-lived protection. Therefore, there is a need to develop a malaria vaccine that will be essential to further strengthen malaria control measures in future.

A Phase Ia trial with the same IMP (SumayaVac-1 vaccine developed using a full-length recombinant MSP-1 administered along with the adjuvant GLA-SE) in Caucasians in Heidelberg, Germany, proved to be well tolerated and safe. However, a Phase Ib clinical trial on healthy participants residing in a malaria endemic country would be essential to evaluate the safety and reactogenicity in the target population. The project aims to investigate the safety, reactogenicity, immunogenicity of the candidate malaria vaccine, SumayaVac-1 (SUM-101) in 40 healthy participants (men and women) of African origin in Bagamoyo, Tanzania.

Objectives:

To evaluate in healthy adults of African origin previously exposed to the malaria parasite receiving SumayaVac-1 (SUM-101) versus rabies control (Verorab®) vaccine:

Primary Objectives

* Safety and reactogenicity of SumayaVac-1 (SUM-101).
* Immunogenicity of SumayaVac-1 (SUM-101).

Secondary Objectives

• SumayaVac-1 (SUM-101) vaccine-induced antibody levels, in vitro effector functions.

Exploratory Objectives

* Comparison of SumayaVac-1 (SUM-101) induced immunoglobulin isotype distribution and duration between malaria pre-exposed and malaria naïve participants from the previous Phase Ia study in Heidelberg.
* Fine scale epitope mapping of SumayaVac-1 (SUM-101) specific antibodies using peptide arrays, to investigate humoral immune response at baseline with vaccine induced responses.
* Comparison of SumayaVac-1 (SUM-101) induced cellular immunity between malaria pre-exposed and malaria naïve participants from the previous Phase Ia study in Heidelberg including fine scale epitope mapping of MSP-1 specific CD4+ and CD8+ T cells.
* Investigation of the B- and T-Cell repertoire before and after SumayaVac-1 (SUM-101) vaccination.
* Integrated transcriptome and immunoglobulin gene repertoire analyses of MSP-1 specific B-cells using single-cell technologies.
* Glycosylation patterns of MSP-1 specific functional antibodies.
* Investigate off-target IgG and IgM repertoire after SumayaVac-1 (SUM-101) vaccination using immunoproteomics.
* Investigate the structure of MSP-1 protein bound to functional antibodies by cryo-electron tomography to map conformational epitopes.
* To evaluate mechanisms of malaria specific antibody diversity generation, post-translational modification of antibodies, and B- and T-cell memory generation and maintenance.
* Ex vivo assessment of changes in human peripheral blood transcriptome in participants having received SumayaVac-1 (SUM-101) versus Verorab® rabies vaccine.
* Description of ɣδ T-cell receptor repertoire, transcriptome, functional activity and phenotypes in participants having received SumayaVac-1 (SUM-101) versus Verorab® rabies vaccine.
* Investigate impact of presence of intestinal helminth infections on SumayaVac-1(SUM-101) induced humoral immune response.
* Investigate impact of presence of intestinal helminth infections on SumayaVac-1(SUM-101) induced cellular immune response.

Study Design:

This is a randomised, controlled, double-blind, parallel group, single center Phase Ib trial to assess the safety, reactogenicity, and immunogenicity of SumayaVac-1 (SUM-101) in healthy, malaria-exposed adults of African origin aged 18-45 years.

In total, 40 participants will be enrolled (male and female). 20 participants will be randomised to receive three monthly inoculations (on D0, D28 and D56) with the investigational product, SumayaVac-1 (SUM-101), and 20 participants will be randomised to receive the registered rabies vaccine, Verorab®, as controls.

For operational reasons the participants will be split in two groups of 20 participants.

* Group 1 will have a sentinel subgroup (2 SumayaVac-1 (SUM-101) \& 1 Verorab® rabies vaccine) with a 48 hours safety surveillance period before the remaining 17 participants (8 SumayaVac-1 (SUM-101) \& 9 Verorab® rabies vaccine) of the group 1 receive their 1st vaccination.
* Group 2 will be composed of 20 participants (10 SumayaVac-1 (SUM-101) \& 10 Verorab® rabies vaccine). All visits in group 2 will be shifted by at least 3 weeks compared to group 1 to create minimal overlap of study-related activities.

After each vaccination (done on D0, D28 and D56), the participants will remain at the facility for 2 hours prior to their discharge for home. The participant will be called daily by phone (or home visits if required) until 6 days post vaccination for follow-up.

For all participants, vaccination follow-up visits at the site will occur at 7, 14 and 28 days after each vaccination.

Measurements and Procedures:

Written informed consent will be taken prior to any study procedure. Healthy participants will be screened and randomised before administration of the study IMP.

On the day of the 1st vaccination, the health status of the participant is re-checked and eligibility confirmed. Samples for safety, humoral, cellular and exploratory measurements are taken before 1st vaccination (baseline). Vaccination is administered and the participant remains at site for 2 hours before being discharged. Telephone follow-ups (or home visits if required) will be performed daily until 6 days after each vaccination. On 7, 14 and 28 days after each vaccination (done on D0, D28 and D56), the participant will be invited to come back to the facility and health status is checked.

Further participant follow-up visits will take place at D112 (W16) and D140 (W20) post 1st vaccination. Sampling for humoral and cellular responses will be performed at D112 (W16) and D140 (W20). Additionally, sampling for exploratory measurements will be performed at D112 (W16) (Vac1 + 4 month follow-up site visit).

Number of Participants with Rationale:

Vaccination: 40 adult participants Overall: 20 SumayaVac-1 (SUM-101) and 20 Verorab® control

Group 1 Sentinel sub-group

* 2 SumayaVac-1 (SUM-101)
* 1 Verorab® control

Group 1 Follower Group

* 8 SumayaVac-1 (SUM-101)
* 9 Verorab® control

Group 2

* 10 SumayaVac-1 (SUM-101)
* 10 Verorab® control

As this is a Phase I trial, no formal sample size calculation has been done. The sample size is considered sufficient to examine the safety and reactogenicity of SumayaVac-1 (SUM-101), and humoral and cellular immunogenicity.

Study Product / Intervention:

Vaccination: Intra-muscular injection of SumayaVac-1 (SUM-101) composed of 150 µg MSP-1 drug product + 5 μg GLA-SE adjuvant CHMI: Direct venous inoculation of 3.2 x 103 purified, infectious P. falciparum sporozoites

Control Intervention: Vaccination control: Intra-muscular injection of rabies vaccine (Verorab®)

Study Duration: The total study duration including the screening period (\~4 weeks) combining Group 1 and 2 will be approximately 35 weeks.

The study duration for each participant will be \~24 weeks (4 weeks of screening period plus 20 weeks of vaccinations and long-term follow-up visits).

Study Centre: The Ifakara Health Institute Bagamoyo Clinical Trial Facility.

Statistical Analysis incl. Power Analysis:

See above for sample size justification. To evaluate the safety and reactogenicity primary endpoints, AEs and SAEs will be presented according to the endpoint definitions above. AE reporting will include verbatim term, preferred term (PT), system organ class (SOC), treatment, severity, relationship to the interventional products, and seriousness, reporting numbers of participants experiencing each event and total numbers of each event. Laboratory safety parameters will be summarized as absolute values and changes at 28 days after each vaccination compared to baseline (before 1st vaccination) and compared to values just prior to each vaccination.

To evaluate the immunogenicity primary endpoints as defined above, SumayaVac-1 (SUM-101) vaccine induced humoral immunogenicity will be summarized as antibody responses to SumayaVac-1 (SUM-101) by ELISA over time, and fold changes of antibody responses relative to baseline.

For all analyses, data will be listed for each participant. Descriptive analyses will be performed (number of observations, arithmetic or geometric mean, standard deviation, minimum, maximum, median, interquartile range, as appropriate, for continuous data, and counts and percentages for categorical data). Results will be presented by vaccination received.

Further details will be elaborated in a Statistical Analysis Plan (SAP), including for the secondary and exploratory objectives.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent obtained before any study procedure.
2. Literate participants aged 18-45 years of African origin.
3. Female participants practicing contraception from 4 weeks before 1st immunization and both female and male participants willing to practice contraception up to 12 weeks after the last immunization.
4. Available to participate in follow-up for the duration of the study.
5. Contactable by phone during the whole study period.
6. At least two years residence in the Bagamoyo district or nearby districts in Coastal and Dar-es-Salaam regions and planning to reside there for at least 9 more months.
7. Agreement to provide personal contact information and contact information of another household member or close friend.
8. Female participants must be willing to avoid pregnancy if selected for participation in the trial and to undergo multiple serum pregnancy testing.
9. Confirmation of understanding of design, procedures, risk and benefits of the study in a test with maximum of two attempts.
10. General good health based on assessment of medical history and clinical examination.

Exclusion Criteria:

1. Previous participation in any malaria vaccine trial in the last 3 years.
2. Participation in any other clinical trial involving investigational medicinal products within 30 days prior to the screening assessment.
3. Previous history of drug or alcohol abuse interfering with normal social function within one year prior to enrolment.
4. Previous vaccination with a rabies vaccine.
5. Intake of chronic medication, especially immunosuppressive agents (steroids, immunomodulating drugs) during the 13 weeks preceding the screening visit or during the study period.
6. Known hypersensitivity to any of the vaccine components (adjuvant or protein) or anti-malarial treatments.
7. Body mass index (BMI) of \<18 or \>30 Kg/m2.
8. Participants unable to be closely followed for social, geographic or psychological reasons.
9. Any vaccination from 4 weeks prior to the 1st vaccination and (none planned) up to 6 weeks after the 3rd vaccination.
10. Symptoms, physical signs or laboratory values suggestive of systemic disorders, including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric and other conditions, which could interfere with the interpretation of the trial results or compromise the health of the participants.
11. Abnormal electrocardiogram on screening: pathologic Q wave and significant ST-T wave changes, left ventricular hypertrophy, clinically significant arrhythmias, left bundle branch block, secondary or tertiary A-V (atrio-ventricular) heart block.
12. Any clinically significant laboratory values at screening outside of normal ranges for study participants.
13. Malaria positivity at screening (microscopy or qPCR positive).
14. Positive HIV, HBV or HCV tests.
15. For females: Positive pregnancy test or actively breast feeding.