Solidarity/Tokomeza Ebola Trial

The TokomezaPlus Ebola trial is a phase I/II double blind randomised clinical trial designed to assess the safety and immunogenicity of candidate SUDV vaccines in Uganda during the inter outbreak period. Uganda is prone to Ebola virus disease outbreaks especially those caused by the Ebola Sudan (SUDV) species. TokomezaPlus Ebola Vaccine trial protocol has two main components: a) Safety b) Immunogenicity and is designed to create a living protocol that will be used to study the safety and immunogenicity of SUDV-candidate vaccines in the East African EVD-prone countries.

The Sudan ebolavirus and the Zaire ebolavirus are classified as different species, and vaccines and monoclonal antibodies that are effective against Zaire ebolavirus disease are unlikely to be of any use against SUVD. But, the epidemiology of SUVD is thought to be similar to that of Zaire ebolavirus disease.

There is an urgent need to test the safety and immunogenicity of the candidate vaccine(s) developed against Sudan ebolavirus. Once safety and immunogenicity (including extended immunogenicity) have been proven, these vaccines could be deployed for future outbreaks as part of the response.

OBJECTIVES Phase 1 Objectives

1. To determine the safety of rVSV-SUDV candidate SUDV vaccine among healthy volunteers
2. To determine the immunogenicity of rVSV-SUDV candidate SUDV vaccine

Phase 2 Primary objectives

1. To determine the safety of ChAdox1, CAd3 and rVSV-SUDV candidate SUDV vaccine(s) among healthy volunteers and persons with stable comorbidities.
2. To determine the immunogenicity of the three candidate SUDV vaccines.

Secondary objectives

1. To determine the durability of SUDV-specific induced immune responses following vaccination with ChAdox1, CAd3 and rVSV-SUDV candidate SUDV vaccine(s).
2. To determine the factors associated with vaccine-induced immune responses.
3. To determine the putative cross reactivity \& protection exerted by the SUDV vaccine candidates against other ebolaviruses (e. g. Bundibugyo ebolavirus (BUDV) and EBOV).

Exploratory objectives

1. To determine the effect of SUDV vaccines on host gene expression
2. To determine the T and B cell specific responses and immune profiling in response to vaccination
3. To determine the effect of SUDV vaccines on the host metabolome
4. To determine the effect of SUDV vaccines on host immune responses

END POINTS

Primary Endpoints

1. Number of solicited, unsolicited adverse and serious adverse events that are determined as possibly, probably and definitely related to the investigational products.
2. Binding antibody titres, neutralization activity and cell mediated immune responses.

Secondary Endpoints

1. Durability of SUDV-specific induced immune responses following vaccination.
2. Factors associated with vaccine-induced immune responses.
3. To determine the putative cross reactivity \& protection exerted by the SUDV vaccine candidates against other ebolaviruses (e. g. Bundibugyo ebolavirus (BUDV) and EBOV).

TRIAL PARTICIPANTS This trial will enroll a total 250 healthy, adult volunteers (18-50 years) (150 intervention arm and 100 placebo arm) for the phase I rVSV-SUDV vaccine. The DSMB will review day 28 post vaccination safety data for all the phase I participants and day 56 post vaccination binding antibody IgG and IgM data for 50 participants randomly selected who receive the rVSV SUDV and 10 participants who receive the placebo to make a recommendation regarding proceeding to phase II. Participants enrolled in phase I of the rVSV-SUDV candidate vaccine will contribute data to phase II for this vaccine. For the Phase II trial (ChAdox1, CAd3 and rVSV-SUDV vaccines), 2121 volunteers aged 6 - 65 years will be included (606 for each of the vaccine arms and 303 to placebo). A randomly selected subset of120 participants per vaccine and 50 placebo recipients will participate in extended immunogenicity studies (long term immunogenicity and exploratory studies). 100 participants from each intervention arm participating in extended immunogenicity will randomly be selected to receive a homologous booster 12months post vaccination.

STATISTICAL ANALYSIS The primary analysis is the comparison of occurrence of solicited (within 7 days) and unsolicited adverse events (occurring within 56 days) considered possibly, probably or definitely related to vaccines as well as adverse and SAEs occurring within 24 months' post-vaccination between each candidate vaccine and placebo. AEs will be summarized with counts, percentages, and, when provided, exact 95% CIs will be provided. SAEs will be graded according to DAIDS. The primary analysis for the immunogenicity is the change in serum IgG and IgM titres from baseline to 56days post vaccination.

Eligibility Criteria:
Inclusion Criteria:

Phase 1

* Healthy volunteers aged 18-50 years from study communities
* Healthy volunteers with a permanent home address
* Able and willing to complete and provide written informed consent. In case the participant cannot read or write, the procedures must be explained to him/her and informed consent must be witnessed by a literate third party not involved with the conduct of the study
* Participant must pass the informed consent test of understanding (TOU)
* Participant must be healthy in the investigator's clinical judgement on the basis of medical history, physical examination, vital signs and point of care tests (where applicable) performed at screening
* If female of child-bearing potential and heterosexually active, practice of adequate contraception for 28 days prior to injection, negative pregnancy test on the day of vaccination, and agreement to continue adequate contraception until 90 days after vaccination
* Male participants are eligible to participate in the study if they agree to use a male condom during any heterosexual intercourse with a female of childbearing potential until 90 days after vaccination

Phase 2

* Healthy volunteers aged 6 years-65 years from study communities. Individuals with comorbidities assessed as stable will be allowed to participate
* With a permanent home address
* Able and willing to complete and provide written informed consent or assent as applicable. In case the participant cannot read or write, the procedures must be explained to him/her, and informed consent must be witnessed by a literate third party not involved with the conduct of the study.
* Participant must pass the informed consent or assent test of understanding (TOU)
* Participant must be healthy according to the investigator's clinical judgement on the basis of medical history, physical examination, vital signs and point of care tests (where applicable) performed at screening
* If female of child-bearing potential and heterosexually active, practice of adequate contraception for 28 days prior to injection, negative pregnancy test on the day of vaccination, and agreement to continue adequate contraception until 180 days after vaccination
* Male participants are eligible to participate in the study if they agree to abstain from any heterosexual intercourse with a female of childbearing potential or must agree to use a male condom

Exclusion Criteria:

Phase 1

* History of confirmed ebola virus diseases (SUDV, EBOV or BUDV)
* Unwillingness of female participants to use effective contraception
* Participation in an interventional clinical trial within 90 days of participation in this trial
* Prior vaccination with any Ebola vaccine
* Breastfeeding or planning to conceive within 2 months following study vaccination
* Has history of fever (\>100.4ºF/38.0ºC) within 48 hours prior to enrolment into the study
* Received systemic corticosteroids exceeding physiologic replacement doses (\~5 mg/d prednisone equivalent) within 14 days prior to study entry
* Received any live virus vaccine within 30 days or any non-live virus vaccine within 14 days prior to study entry
* Has a known allergy/sensitivity or contraindication to investigational vaccines or its/their excipients?
* History of malignancy ≤5 years
* Major surgery within the 4 weeks prior to screening or planned major surgery through the course of the study (from screening until completion of the study)
* Presence of any condition that can interfere with the subject's participation for the full duration of the trial.
* HIV positive
* Hepatitis B positive

Phase 2

* History of confirmed SUDV
* Unwillingness of female participants to use effective contraception
* Participation in an interventional clinical trial within 90 days of start of this trial
* Prior vaccination with any Ebola vaccine
* Breastfeeding or planning to conceive within 2 months following study vaccination
* Has history of fever (\>100.4ºF/38.0ºC) within 48 hours prior to vaccination
* Received systemic corticosteroids exceeding physiologic replacement doses (\~20 mg/d prednisone or equivalent) for 14 days within a month prior to study entry.
* Immunosuppressive medication within 3 months
* Received any live virus vaccine within 30 days or any non-live virus vaccine within 14 days prior to study entry
* Has a known allergy/sensitivity or contraindication to investigational vaccines or its/their excipients?
* History of malignancy ≤5 years
* Major surgery within the 4 weeks prior to screening or planned major surgery through the course of the study (from screening until completion of the study)
* Presence of any condition that can interfere with the subject's participation for the full duration of the trial