Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05139524 |
| Other study ID # |
KEMRI/SERU/CGHR/356/4169 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 8, 2021 |
| Est. completion date |
December 31, 2025 |
Study information
| Verified date |
November 2021 |
| Source |
Washington State University |
| Contact |
Jeanette A Dawa, PhD |
| Phone |
+254750653696 |
| Email |
jeanette.dawa[@]wsu.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Rift Valley fever (RVF), a disease transmitted from livestock (cattle, sheep, goats, camels)
to humans more commonly occurs in the East and Central Africa (ECA) regions where more than
15 major epidemics affecting more than one country have been reported over the past 50 years.
Within the region, there are specific areas, referred to as hotspots, which support RVF virus
maintenance via low-level virus circulation between animals, humans, and mosquitoes. Most
outbreaks originate from these hotspots. Our goal is to conduct studies in RVF hotspots in
four ECA countries, Kenya, Uganda, Tanzania, and Democratic Republic of Congo (DRC) to
determine the burden of RVF disease among humans, wildlife and livestock during
inter-epidemic periods (IEPs) and discover circulation of undetected infectious diseases.
This information is important for use in developing an early warning system and possibly a
vaccination strategy. The study will take place in Uganda, Kenya, Tanzania and Democratic
Republic of Congo
Description:
STUDY BACKGROUND
The East and Central Africa (ECA) region represents a unique environment to investigate RVF
virus maintenance and transmission as it has reported the largest number of RVF epidemics.
Recent studies have identified hotspots characterized by continuous low levels of human and
livestock virus infections during the inter-epidemic periods (IEPs).
Although sheep are at highest risk of severe disease, how virus-host interactions differ
between animal species is an area for further research. Seroprevalence and incidence studies
at the wildlife, livestock, human interface are also important in understanding the nature of
cross-species transmission. Our study will investigate the public health threat posed by RVFV
during IEPs by determining the burden of human and livestock diseases, and the degree of
sustained viral transmission in animal species during cryptic cycles. This will be carried
out through surveillance among humans, livestock and wildlife. Understanding virus
maintenance especially within the environment, vectors and wildlife populations will aid in
identifying potential risk factors for RVFV infection in order to prevent future outbreaks.
While disease occurrence among animals may frequently go unnoticed due to inadequate animal
surveillance systems and low levels of animal abortion, human disease may be the first
indication that RVF virus amplification is occurring at high levels in a particular region .
Furthermore, understanding the social aspects of disease transmission through human studies
exploring human behaviour and cultural practices that lead to direct exposure to infected
animal blood, tissues, secretions and excretions could provide valuable information to
disease spill over dynamics . Additional knowledge of how routes for human exposure e.g.
through mosquito bites or contact with infected animal products affect the immune response
and disease outcomes is required . This will enhance global efforts in preparing for, and
preventing, the possible spread of RVF disease to new regions.
While RVF may be an under-diagnosed cause of febrile illness within the ECA region it is
important to consider the occurrence of other unknown or undiagnosed infectious diseases.
Serious clinical disease due to a variety of pathogens in humans or animals is most likely
missed in settings where health care access is limited and diagnostics scarce. Notably,
multiple studies from the region report low levels of hospital visits, particularly among
marginalized communities, including those in remote rural arid lands that have few health
facilities and poorly functioning transport infrastructure that discourages traveling long
distances to access health care. Over a third of suspected infectious diseases among humans
go undiagnosed even when considerable testing is carried out; thus, many retrospective
studies of emerging pathogens uncover cases in the region that occurred long before the
pathogen was identified and epidemics reported.
HYPOTHESIS AND OBJECTIVES
Hypothesis and Goal
Our working hypothesis is that RVF virus, maintained through cryptic vertebrate-mosquito
cycling during inter-epidemic periods is a substantial public health burden. The overall goal
is to determine the public health threat posed by RVF virus during IEPs in East and Central
Africa region and identify potential opportunities for prevention and control strategies to
reduce the likelihood of major outbreaks.
Primary objectives
(i) Determine whether low-level RVF virus transmission and disease among or between animals
and humans occurs during the inter-epidemic periods (IEPs)
(ii) Conduct detailed niche modelling of RVF high risk and low risk ecologies to determine
the important ecological risk factors associated with persistence of RVF virus and recurrence
of outbreaks in animals and humans
(iii) Investigate impact of climate change on the RVF permissive ecologies and its effect on
RVF virus transmission
Secondary objective
(iv) Conduct pathogen discovery on human, livestock, and wildlife samples collected from ECA
countries to identify other circulating emerging infectious pathogens which are of epidemic
or pandemic potential.
DESIGN AND METHODOLOGY
We will conduct the field studies in four countries as listed below, but with the
understanding that other emerging RVF hotspots in the region could be added.
(i) Tana river, Marsabit, Isiolo and Murangá counties in Kenya (ii) Kabale, Rubanda and
Isingiro districts in Uganda (iii) North and South Kivu provinces in DRC (iv) Any other site
in the 4 countries emerging as a RVF hotspot or site of
STUDY PROCEDURES
1. In and outpatient health facility-based studies:
We will conduct a 2-year hospital-based study at each site to determine the burden of
RVF infections in humans, risk factors associated with infection, and severity of
disease during IEPs. A sample size of 707-1,500 human participants will be recruited
over the 2 years at each site, based on assumptions of RVFV seroprevalence. At each
health facility, longitudinal acute febrile illness (AFI) surveillance will be
established. Patients, both adults and children presenting with acute fever or reported
fever in the last 4 weeks, will be included prospectively over a period of two years in
order to capture seasonal variability. We will focus on cases of undifferentiated fever,
hence those with a clearly defined clinical disease, for example, malaria, an acute
upper respiratory tract infection or urinary tract infection will be excluded. However,
twenty percent of samples from patients who test positive for malaria by rapid
diagnostic test or blood smear will be included in the study as there are common risk
factors for both malaria and RVF infection. A clinical history and physical examination
by a clinical officer/nurse on-ground will provide information on clinical manifestation
and severity of illness. Consenting patients will be enrolled, serum collected and
tested for RVFV RNA, and IgM and IgG antibodies. Convalescent serum will be collected 4
weeks after the date of enrolment for RVFV antibodies. In addition, the individual may
be contacted to provide blood specimen up to 24 months after enrolment for analysis of
peripheral blood mononuclear cells (PBMCs). The specimens will also be tested for other
etiology for acute febrile illness including brucellosis, q-fever, coronaviruses and
potentially other novel and emerging pathogens by molecular methods. Using a standard
questionnaire, we will collect information on contact with domestic animals including
assisting with birth, slaughter, handling hides and skins, and consuming raw milk or
blood. Data on contact with wildlife including eating bush meat will also be collected.
2. Community studies:
To determine burden of disease in livestock, 2 - 6 cross-sectional surveys at each site
will be conducted over 5 years, primarily during rainy seasons. The livestock sample
size, assuming an average RVF seroprevalence of 4%, precision of 2%, confidence level of
95%, and power of at least 80% is 369 animals per survey. To account for herd
clustering, a design effect of 1.5 is included for a total of 554 animals per site for
each survey. The number of cattle, sheep, goats will be selected proportionate to animal
species population size in the area. Where no animal census records are available in an
area the number of animals per species will be divided equally (approx. 185 animals of
each species). At the Marsabit site, camels will be included. At the start of the
survey, we will develop a sampling frame of the number of households in the study site.
To provide a geographically representative sample, households will be randomly selected
from the study site. The breed of animal whether exotic or indigenous will be captured.
Livestock blood samples will be collected and tested for RVFV RNA, and anti-viral IgM
and IgG antibodies.
The household members of the selected field sites will be included in a seroprevalence
(and sero-conversion) study, to be able to link animal, vector and human infection. All
consented household members will be included. Each participant will provide a sample for
serological analysis and social behaviour will be assessed, using the standard
questionnaire - to collect information on contact with domestic animals including
assisting with birth, slaughter, handling hides and skins, and consuming raw milk or
blood. Data on contact with wildlife including eating bush meat will also be collected.
3. Slaugther house studies:
Sampling of cattle and goats will also be performed at slaughter houses in Goma. Most of
these animals originate from neighbouring countries. Sheep that are rarely slaughtered
at Goma will also be sampled when available. Slaughter house sampling will be conducted
at the same occasion with livestock sampling. All the samples analysed using serological
and molecular techniques for the detection of anti-RVFV antibodies and RVFV nucleic
acid.
4. Wildlife sampling:
Convenient wildlife sampling will be carried out in the field sites or nearby national
conservation areas in Kenya, Uganda, Tanzania and DRC. Primarily blood/serum samples
collected by wildlife officers during animal disease surveillance and/or translocation;
and blood/serum and tissue samples from dead or killed wildlife will be collected. We
will also obtain archived samples from these locations. The samples will be tested for
RVF RNA and antibodies, and for pathogen discovery to detect other circulating emerging
pathogens.
5. Vector studies:
Our approach to investigating the role of vectors in cryptic cycles during IEPs will be
guided by the fact that only a small proportion of mosquitoes are normally infected,
even during epidemics. Therefore, to identify which areas to test for presence of
infected mosquitoes we will interpret acute RVFV infections (presence of viral RNA) as a
measure of presence of infected mosquitoes and mosquito-to-vertebrate transmission. In
these areas with acute RVFV infection we will collect and test mosquito pools in the
community grazing areas and households during livestock sampling, identify the species
and test for RVFV RNA.
Since it is difficult to establish colonies of the known RVF vectors, Aedes mcintoshi
and Aedes ochraceus, for laboratory studies, we will carry out suitability studies in
the field using two approaches. First, eggs and larvae of mosquitoes will be collected
during the long (April - July) and short (October - November) rains from dambos located
at low elevation in all five field sites in Kenya, Uganda, Tanzania, and DRC and
geocodes recorded in areas around the study site that have solonetz, planosol,
solonchak, or vertisol soil types. Larvae in 3rd, 4th stages and pupae will be collected
using dippers into plastic whirl-pack bags for transportation (in cool boxes) to the
laboratory. Once in the laboratory, the immatures will be reared to adults and then
identified morphologically. Adult mosquitoes around dambo habitats will be sampled using
odour-baited traps including collections of those resting on vegetation using backpack
aspirators for eventual transport and sorting according to site and species. The
physico-chemical properties of water from selected dambos will be determined and the
soil types identified. Water from each of the dambos will be subject to headspace
volatile trapping and chemical analyses to identify potential oviposition cues for
eventual development of tools for monitoring gravid mosquito cohorts.
For vector adaptation studies, A. mcintoshi and A. ochraceous mosquitoes collected from
the five field sites will be subjected to the expected temperatures and rainfall/water
conditions and their adaptability assessed. Assessment of adaptability will include
observations of overall survival, egg survival, changes in biting habits, feeding
preferences and resting behaviour within a controlled environment.
6. RVF modelling studies:
Modelling studies support RVFV transmission during IEPs in areas associated with RVF
epidemics. The studies predict that the continuous cycling of RVFV is powered by
presence of mosquito vectors throughout the year (but varying densities), and rapid
turnover of livestock populations, particularly sheep, goats, and cattle to sustain the
high herd susceptibility required for new infections. We will use mathematical modelling
to predict the timelines and locations of major RVF human and domestic animal epidemics;
these data will in turn guide prevention and control efforts. We will investigate why
there are areas with RVF circulation but no apparent human infections considering that
some of these areas are adjacent to areas where epidemics occur. This is important since
it is possible that RVFV circulating at low levels has the potential for causing human
epidemics during El Nino events. Human, livestock, and vector data from all field sites
conducting RVFV transmission studies will be fed into the model. Model parameters will
be optimized by fitting simulations to field observations (e.g. the seroprevalence data
in humans or livestock) using Bayesian inference techniques (e.g. MCMC and POMP models).
Comparative analysis of all study sites will help elucidate the factors associated with
RVFV transmission and emergence. The model will factor data from areas associated with
RVFV epidemics (e.g. Tana river in Kenya and Kabale district in Uganda), and areas where
virus circulation is evident but no epidemics have occurred (e.g. Udzungwa Mountains in
Tanzania) in order to understand differences in transmission dynamics. These data may
give new insights on the epidemic risk. Comparative analysis will look into the
spatio-temporal heterogeneity of transmission in the four countries. Other important
data to be collected from our field studies and published literature include vector
species/vector density/vector RVFV positivity, animal presence/animal density/animal
RVFV positivity, human-animal contact, population density/population positivity,
spectrum of disease presentation and severity, co-circulation of other arboviruses, and
genetic characterization of RVFV in various areas.
7. Testing of archived samples:
This approach will be utilised in DRC using samples collected from the following studies:
Study A: A cross-sectional study including outpatient acute febrile syndromes in both
children and adults, between November 2015 and June 2016 in Kinshasa, DRC: 342 patients, aged
2 to 68 years, were included. The study was registered in a public repository
(https://www.clinicaltrials.gov/ct2/show/NCT02656862); and funded under framework agreement
between the Institute of Tropical Medicine and the Belgian development cooperation and
Vlaamse Interuniversitaire Raad - Universitaire Ontwikkelingssamenwerking (VLIR-UOS, Grant
reference ZRDC2014MP083). These sampes will be analysed using serological and molecular
techniques for the detection of anti-RVF antibodies or RVFV nucleic acid.
Study B: Archived samples were collected from cattle and goats in Goma abattoirs, and in
cattle farms in the North-Kivu province in 2017. Some of these animals originated from
neighboring countries and provide useful materials to assess the risk of RVFV circulation in
the region. Serological and molecular techniques will be used for the detection of anti-RVF
antibodies and RVFV nucleic acid.
Study C: Archived samples collected from wild animals in Virunga Park and kept at the
Veterinary Laboratory in Goma will be screened for the presence of anti-RVF antibodies and
RVFV nucleic acid. Most of these samples originated from non-human primates raised in close
contact with the local population. Such samples will provide useful information on the
circulation of the RVF at the interface wild animal - human interface within the game park.
