Lay Title: A study to assess whether a new vaccine called ChAdOx1 RVF will be safe and work well against Rift Valley Fever in adults in Kenya

What is the problem/background?

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 thew 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.

What questions are we trying to answer?

We aim 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. In this study, we will evaluate the safety of, and immune response generated by ChAdOx1 RVF vaccine in adults in Kenya. Our 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.

Where is the study taking place, how many people does it involve and how are they selected?

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. We will enroll a total of 240 adults who will be randomly allocated for immunization with ChAdOx1 RVF vaccine (180 adults) or with rabies vaccine as a control (60 adults).

What does the study involve for those who are in it?

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. Those 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).

What are the benefits and risks/costs of the study for those involved? 

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 at the rate of KES500, 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.

How will the study benefit society? 

The unmet need for a human vaccine against RVF is well recognized among clinicians and public health practitioners in Kenya and other countries in Africa. This has led to the prioritization of RVF for urgent vaccine research by the WHO and the African Union. 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.

When does the study start and finish?

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. We anticipate 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.

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that primarily affects domestic livestock (sheep, goats, cattle) and humans in Africa. RVF was first identified in Kenya in 1930 and is characterized by a wide range of symptoms in humans, ranging from self-limiting febrile illness to life-threatening hemorrhagic manifestations and miscarriage in pregnant women. Overall mortality from RVF is thought to be <1%; however, case fatality rates among patients with hemorrhagic disease can be as high as 50% and debilitating sequelae such as blindness and neurological deficits can occur following ocular and encephalitic forms of the disease. In livestock, RVF causes high rates (>90%) of death in young animals and spontaneous abortion (typically >90%) in those that are pregnant. Licensed vaccines are available for livestock, but no licensed RVF vaccines are available for human use. This, together with the potential for RVF to cause epidemics and a public health emergency, has led the World Health Organization (WHO) and the African Union to include RVF on a shortlist of diseases prioritized for accelerated vaccine research and development. We previously designed and developed a replication-deficient adenovirus vectored RVF vaccine, ChAdOx1 RVF, and assessed its performance in livestock. The vaccine was found to be safe, able to generate a strong durable immune response, and conferred protection against RVF in all major livestock species affected by the disease. In recent human phase 1 trials in adults in the United Kingdom and Uganda, a single dose of ChAdOx1 RVF was shown to be safe and to generate a strong immune response. Further evaluation of ChAdOx1 RVF in larger populations in areas where RVF epidemics occur is required to support subsequent licensure and deployment of the vaccine.

In this randomized controlled double-blinded study, we will evaluate the immunogenicity and safety of ChAdOx1 RVF in adults aged 18-50 years in Kenya in comparison to control rabies vaccine. The study will take place in Kilifi County where RVF outbreaks have previously occurred. We will enroll a total of 240 adults from the general population who will be randomly allocated to one of three groups. 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 at 3 months later. Group 3, also composed of 60 adults, will receive two doses of rabies vaccine; the first dose at baseline and the second dose at 3 months later. Participants will be followed up for 18 months from the first dose of vaccine. The primary objective of the trial is to assess the rate of seroconversion for RVFV neutralizing antibodies at 28 days post-vaccination with a single dose of ChAdOx1 RVF. The secondary objective of the trial is to describe the kinetics of the immune response generated by ChAdOx1 RVF vaccine when administered as a single dose or as a two-dose regime. The safety objective is to assess the safety, tolerability and reactogenicity of ChAdOx1 RVF in the study population. Results from this trial will support further development of the vaccine for emergency use authorization should an RVF epidemic occur, with a future phase 3 trial supporting vaccine licensure.