Clinical development of "DDVaX" A human vaccine candidate for Rift Valley fever

Introduction

This four-year project aims to generate compelling evidence from both Phase I and II trials, demonstrating that DDVax can safely provide a high level of immunogenicity and probable protection against Rift Valley Fever in a country where the disease is prevalent.

Funded by the Coalition of Epidemic Preparedness Innovations (CEPI), the project anticipates delivering safety and efficacy data to facilitate rapid progression towards larger scale IIb /III trials to support vaccine licensure. This progression aims to bolster the vaccine's deployment efforts, either through emergency use authorizations or full commercial licensure.

Background

There is critical and urgent need for attention and resources to address Rift Valley fever (RVF), a mosquito-borne zoonotic disease causing periodic and significant outbreaks in humans and livestock across Africa and parts of the Arabian Peninsula.

Livestock, including sheep, cattle, and goats, are highly susceptible to RVFV infection, often leading to severe and fatal diseases. In humans, RVFV infections typically result in mild to moderate, self-limiting illnesses, but a minority may progress to severe diseases, contributing to increased fetal death and spontaneous abortion among infected women. The severe form of RVF in humans may manifest with bleeding.

Despite the severe impact of RVF outbreaks on human and animal health, food security, and the economy, there is currently no vaccine available.

East Africa, including Tanzania, experiences explosive RVFV outbreaks approximately every 10 to 15 years, with devastating consequences. The 2006/2007 RVFV outbreak across Tanzania, Kenya, and Somalia reported approximately 300 human deaths from 1,000 cases over a 5-month period.

Project Implementation

The project has several work packages which include an Epidemiology study and Clinical trials (Phase I and II). The Epidemiology study's main objective is to conduct a prospective epidemiological study to evaluate RVFV prevalence among humans, livestock, and mosquito vectors within the study areas, and to provide robust epidemiological data for Phase I and II clinical trials of RVF vaccine candidates. 

Specific objectives for the Epidemiology study include:
i.    Measure the seroprevalence and exposure status (circulating IgG & IgM antibody titers) against viral envelop glycoprotein (Gn & Gc) in human and livestock populations within the potential vaccine trial Phase I/II study sites.
ii.    Characterize humoral and cellular immunity against RVFV in humans. 
iii.    Establish and validate laboratory assays (immuno assays: Virus Neutralization Test (VNT) or plaque reduction neutralizing antibody titer (PRNT) & Standardized ELISA for detection of antigen-specific IgG & IgM) and (molecular assays: RT-qPCR) that will be used during Phase I/II vaccine trials.
iv.    Determine RVFV infection status of mosquito vectors at the potential Phase I/II study sites.
v.    Develop, evaluate, and parameterize ecological and epidemiological models to estimate RVFV exposure risk and the potential benefits of utilizing an RVF vaccine strategically. 
vi.    Assess Knowledge, Attitude and Practice related to RVFV and RFV vaccine pre- and post- vaccination among the study communities.

On the other hand, the Clinical trial (Phase Ia) will involve first-in-human administration of DDVax. Defining safety, maximum tolerated dose, and immunogenicity of DDVax in healthy adult volunteers (including both RVFV seronegative and seropositive volunteers) is a critical first step in the further clinical development of DDVax. In this first stage, four escalating doses of DDVax will be evaluated (including sentinel volunteers) to determine the safe ideal dose to move forward to a Phase IIa stage of the trial.

This Phase's primary objectives include:

1. To assess the safety and tolerability of different doses of RVF candidate vaccine DDVax administered intramuscularly in RVFV seronegative and seropositive healthy adults (18-45 years) residing in Bagamoyo, Tanzania.
2. To assess the vaccine-specific antibody levels following immunization with DDVax vaccine in RVFV seronegative and seropositive healthy adults (18-45 years), residing in Bagamoyo, Tanzania. 
3. To identify the ideal dose of DDVax in RVFV seronegative and seropositive healthy adults residing in Bagamoyo, Tanzania.

The second stage of the Clinical Trial (Phase IIa) will provide more precise estimates of safety and immunogenicity data on DDVax at a selected dose in a larger adult population. It will also provide an opportunity to study in more detail the potential observation of RVFV seroconversions among the control vaccinees from naturally acquired infection during the 12-month follow-up time period.  In addition, these trials will investigate the safety and immunogenicity of the DDVax in healthy, but previously RVFV exposed adults. 

The primary objectives for the Clinical Trial (Phase IIa) include:

1. Assessment of safety of DDVax in up to 600 healthy adults (18-45 years), administered the single ideal dose identified in the Phase Ia stage of the study.  

While the secondary objectives will include,

1. Assessment of immunogenicity of DDVax in study population as measured by anti-RVFV antibody concentrations (total IgM/G ELISA, and FRNT neutralizing antibodies) measured 1, 6, 12 months after single vaccination.
2. Evaluation of the anti-RVFV specific T cell activation and immune profile responses to DDVax among the study population.

Study locations

The initiative is set to take place in Tanzania, with research conducted at various study sites, including Kiwangwa, Fukayosi, Lugoba Msata, and Miono councils within the Bagamoyo district.

Ifakara Health Institute will play a key role in both Phase I and II trials, collaborating with UC Davis (UCD), Colorado State University (CSU), University of Pittsburgh (UPitt), and IQVIA.

Dr. Ally Olotu, serving as the Principal Investigator, and Dr. Grace Mwangoka, the Project Leader, both affiliated with Ifakara Health Institute, will lead the project.