Safety and Immunogenicity of a Candidate Rift Valley Fever Vaccine (RVF003)

Phase 2 Trial to Assess the Immunogenicity and Safety of the ChAdOx1 RVF Vaccine Against Rift Valley Fever in Adults in Kenya

The goal of this clinical trial is to learn if ChAdOx1 RVF, a candidate vaccine against RVF, provides an adequate immune response and determine its safety among Kenyan adults. The main aims are:

• To assess the proportion of individuals mounting an immune response following vaccination with a single dose of ChAdOx1 RVF
• To monitor occurrence of any adverse events following vaccination
• To assess whether two doses of ChAdOx1 RVF elicit an immune response that is more durable than that generated by a single dose of ChAdOx1 RVF

Researchers will compare ChAdOx1 RVF vaccine to a rabies vaccine in 240 participants. Participants will be randomly allocated to one of three study groups and vaccinated with ChAdOx1 RVF or a control Rabies vaccine as follows.

Group 1, composed of 120 participants, will receive a single dose of ChAdOx1 RVF vaccine at baseline and a single dose of rabies vaccine 3 months later. Group 2, composed of 60 adults, will receive two doses of ChAdOx1 RVF; the first dose at baseline and the second dose 3 months later. Group 3, composed of 60 adults, will receive two doses of rabies vaccine; the first dose at baseline and the second dose 3 months later.

Participants will receive daily phone calls after each vaccination for the following six days to gather information on any symptoms they may experience. Participants will be instructed to contact the study team at any time should they experience any clinical symptoms. Blood samples will be collected at baseline (before vaccination) and at scheduled follow-up visits (8 visits over the duration of the study, i.e. days 7, 14, 28, 84, 91, 112, 365 and 540 after the first vaccination) for monitoring of immune responses. Up to 20mls of blood will be collected at each scheduled visit. Participants will be followed-up for 18 months from the first dose of vaccine.

Adverse events following vaccination will be monitored throughout the study and reviewed by an independent Data and Safety Monitoring Board (DSMB)

Rift Valley fever (RVF) is a mosquito-borne viral illness that was first discovered in Kenya in 1930 and is now present in many parts of the country including Kilifi and other coastal counties. The disease primarily affects humans and livestock (sheep, goats, cattle) and has spread throughout much of Africa and part of the Middle East. In humans, RVF is characterized by a wide range of symptoms ranging from self-limiting febrile illness to life-threatening bleeding complications and miscarriage in pregnant women. Overall mortality from RVF is thought to be <1%; however, case fatality rates among patients with bleeding complications can be as high as 50% and other serious outcomes of disease such as blindness can occur with some forms of the disease. In livestock, more than 90% of young animals affected by RVF die and spontaneous abortion in almost all pregnant animals on a farm is typical. Vaccines against RVF are available for livestock, but no licensed vaccines are currently available for human use. Owing to the potential for a public health emergency arising from RVF epidemics, both the World Health Organization (WHO) and the African Union have identified the development of a human RVF vaccine as an urgent priority.

The aim of the trial is to answer the question of whether ChAdOx1 RVF, a candidate vaccine against RVF, provides an adequate immune response and determine its safety among Kenyan adults. The vaccine has been found to be safe, able to generate a strong durable immune response, and to confer protection against RVF in all major livestock species affected by the disease. In human phase 1 trials in adults in the United Kingdom and Uganda, a single dose of ChAdOx1 RVF was also shown to be safe and able to generate a strong immune response. Further evaluation of ChAdOx1 RVF in larger populations in areas where RVF epidemics occur is necessary for subsequent licensure and deployment of the vaccine. This study will evaluate the safety of, and immune response generated by ChAdOx1 RVF vaccine in adults in Kenya. The main aim is to assess the proportion of individuals mounting an immune response following vaccination with a single dose of ChAdOx1 RVF, and occurrence of any adverse events following vaccination. A secondary aim of the study is to assess whether two doses of ChAdOx1 RVF elicit an immune response that is more durable than that generated by a single dose of ChAdOx1 RVF.

This phase 2 vaccine trial will be conducted among adults aged 18-50 years resident within the Kilifi Health and Demographic Surveillance System (KHDSS) in Kilifi County, Kenya where RVF outbreaks have previously occurred. A total of 240 enrolled adults will be randomly allocated for vaccination with ChAdOx1 RVF or with rabies vaccine as a control.

Prior to enrolment, study participants will complete screening procedures to ensure they are in good health after they have given written informed consent. Participants will be screened for any significant health problems. This will include sampling of blood and urine for a series of tests to ensure eligibility. volunteers found eligible to participate will be randomly allocated to one of three study groups and vaccinated with ChAdOx1 RVF or a control Rabies vaccine as follows. Group 1, composed of 120 participants, will receive a single dose of ChAdOx1 RVF vaccine at baseline and a single dose of rabies vaccine 3 months later. Group 2, composed of 60 adults, will receive two doses of ChAdOx1 RVF; the first dose at baseline and the second dose 3 months later. Group 3, composed of 60 adults, will receive two doses of rabies vaccine; the first dose at baseline and the second dose 3 months later. All screening procedures, sampling and vaccination will be done at the study clinic within the KEMRI-Wellcome Trust Research Programme. The choice of Rabies vaccine as a control is due to its good safety profile and the benefit that rabies vaccination offers participants given the risk of rabies in Kenya. After each vaccination, participants will receive daily phone calls for the following six days to gather information on any symptoms they may experience. Participants will be instructed to contact the study team at any time should they experience any clinical symptoms. Blood samples will be collected at baseline (before vaccination) and at scheduled follow-up visits (8 visits over the duration of the study, i.e. days 7, 14, 28, 84, 91, 112, 365 and 540 after the first vaccination) for monitoring of immune responses. Up to 20mls of blood will be collected at each scheduled visit. Participants will be followed-up for 18 months from the first dose of vaccine. Adverse events following vaccination will be monitored throughout the study and reviewed by an independent Data and Safety Monitoring Board (DSMB).

Participants will benefit by knowledge of their general health status; they will also have close oversight and treatment support from the study team although this will primarily be for risk monitoring. All participants will also be offered the opportunity to receive a complete course of the rabies vaccine at the end of the study. During vaccination and when collecting blood samples, the participants may experience some discomfort, pain and occasionally, bruising at the injection site, which gets better after a short while. With any vaccination there is a risk of rare serious adverse events, such as a severe allergic reaction. In case of this unlikely event, medication for treating allergic reactions is kept in the clinic room and the investigators are appropriately trained in the management of allergic reactions. An extremely rare but serious blood clot condition that can lead to death or serious long-term disability has been observed among individuals vaccinated with a COVID-19 vaccines made using the technology used to make the ChAdOx1 RVF vaccine. A very rare condition that affects the nervous system, called Guillain-Barre Syndrome, has also been observed with COVID-19 vaccines. However, it is not clear whether other vaccines made with the ChAdOx1 technology will carry a similar risk of inducing the clotting condition or the nervous system condition. All participants will be provided with this information via the informed consent form and will be kept updated should further information become available. Participants will be specifically counselled on symptoms that could be warning signs of serious clotting events, and any cases managed as per local Ministry of Health guidelines. Participants will be compensated for study-related out-of-pocket expenses for each clinic study visit, reimbursed for transport costs incurred, and pay for their costs of hospitalization in a government facility for any new illness that develop during the study period.

If found to be safe and good in generating protective immune responses, the ChAdOx1 RVF vaccine will be developed further and licensed for use in controlling RVF in humans. The study will start upon receipt of ethical and regulatory approvals. The estimated trial period, starting from when the first participant is screened for eligibility to when the final participant has had their last follow-up visit and the trial database is locked, will be 24 months. The total study duration including the time taken to obtain ethics and regulatory approvals, community engagement activities and post-study reporting to take approximately 3 years.

Inclusion Criteria:

• Healthy adult aged 18-50 years
• For females only, willingness to practice continuous effective contraception up to one month following the second vaccination (i.e. duration of 4 months starting from enrolment) and a negative pregnancy test on the day(s) of screening. Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly, in accordance with the product label. Examples of these include combined oral contraceptives, injectable progestogen, implants of etenogestrel or levonorgestrel, intrauterine device. Female participants will be asked for written confirmation of any family planning methods used by provision of health records. These records will be reviewed and counselling for adherence done at each study visit as per the protocol schedule of attendances. Participants who do not have adequate methods of contraception will be referred to their local dispensary where this will be dispensed for free or to Kilifi County Hospital (KCH). Costs incurred for obtaining contraception at KCH will be covered by the study.
• Agreement to refrain from blood donation during the course of the study
• Able and willing to provide written informed consent
• Plan to remain resident in the study area for 18 months following vaccination

Exclusion Criteria:

• Prior receipt of any vaccines (licensed or investigational) ≤30 days before enrolment and/or planned receipt of a vaccine ≤30 days after enrolment
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate
• Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed)
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine
• Any history of hereditary angioedema, acquired angioedema, or idiopathic angioedema.
• Any history of anaphylaxis in relation to vaccination
• Pregnancy, lactation or willingness/intention to become pregnant during the study
• History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
• History of serious psychiatric condition likely to affect participation in the study
• Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture
• Any other serious chronic illness requiring hospital specialist supervision
• Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 units every week (e.g., more than 2 bottles of 500mls Tusker (beer) a day, more than 2 large glasses of 12% wine per day)
• Suspected or known injecting drug abuse in the 5 years preceding enrolment
• Seropositive for hepatitis B surface antigen (HBsAg)
• Seropositive for hepatitis C virus (HCV)
• Prior natural exposure to RVFV as determined by seropositivity for RVFV antigens by ELISA
• Any clinically significant abnormal finding on screening biochemistry, hematology or coagulation blood tests or urinalysis
• Any other significant disease, disorder or finding which, in the opinion of the investigator, may significantly increase the risk to the participant because of participation in the study, affect the ability of the individual to participate in the study or impair interpretation of the study data
• History of confirmed major thrombotic event (including cerebral venous sinus thrombosis, deep vein thrombosis, pulmonary embolism), history of antiphospholipid syndrome, or history of heparin induced thrombocytopenia.