Research Areas:

Mosquito-borne Diseases

Dengue virus, West Nile virus, Rift Valley fever virus and Zika virus are mosquito-borne viruses that cause a transient infection in people. In most people the infection is transient and without clinically relevant illness. Approximately 1% of the patients suffer from complications. Nowadays, over 700 million people get infected with a mosquito-borne virus each year. Due to the growth of the human population and global warming this number is expected to increase dramatically over the next decades.

So far vaccines are only available for Dengue virus and Yellow fever virus but these vaccines have severe limitations as are not advised for the ones that run the highest risk for complications, namely children, older people and those people with an impaired immune system.

BPRC developed several infection models to investigate mosquito-borne viruses. In 2018 these models were mainly used for proof of concept-studies for vaccines and antiviral medicines.

An antiviral medicine dengue virus

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There are four different types of dengue viruses. A first infection results in lifelong protection against infection with the same serotype. However if the second infection occurs with another serotype the patient has in increased chance to develop disease. This phenomenom is called antibody dependent enhancement (ADE). Severe dengue disease is a potentially deadly complication due to plasma leakage, fluid accumulation, respiratory distress, severe bleedings, or organ impairment. Every year half a million patients require hospitalization and about 20,000 people die of severe dengue.

In collaboration with a European partner we performed a preclinical study to evaluate an antiviral medicine. The results of this proof of concept-study were promising. The treated animals had less virus in their blood compared to the non-treated animals. But more research is needed before this medicine can go to the clinic.

 

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A new DNA-vaccine technology platform tested in rhesus macaques

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Yellow fever is a vaccine-preventable mosquito-borne virus infection. However, the commercially available vaccines are so called life-attenuated vaccines and cannot be used in children and older people. In addition, the production of these vaccines is time consuming, requires batch-to-batch evaluation and the distribution requires a so called cold chain. This hampers a rapid response in case of an outbreak. On top of that, recent outbreaks caused a severe vaccine shortage.

New generation vaccines may overcome these problems. DNA vaccines are safe, can be rapidly produced and do not require a cold chain. However, not all DNA vaccines are effective.

BPRC is collaborating in a consortium funded by the EU. The project aims to develop a dual-target rabies/flavivirus DNA vaccine. The first step in this project was to investigate if the DNA-vaccine that encodes for a live-attenuated yellow fever virus still works as a vaccine. To test this, we performed a proof of concept study in monkeys. Our study showed that the DNA vaccine was indeed capable of inducing an immune response. Yet, not in all animals. Currently our collaborators in the project are modifying this DNA-vaccine so that it can also induce an immune response against rabies.

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Rift Valley fever virus

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Rift Valley fever virus (RVFV) is transmitted by mosquitoes. It primarily affects animals but can also infect humans. In cattle and sheep the virus causes abortions. Most human RVFV infections manifest as a transient, flu-like illness. A small percentage of humans develop encephalitis or hemorrhagic fever, which may be fatal. Currently Rift Valley Fever virus outbreaks are restricted to African counties but it was shown that also the most prevalent European mosquito (Culex pipiens) is also capable of transmitting the virus. An outbreak of Rift Valley Fever virus in The Netherlands will cause dramatic direct and indirect economic damage. As partner in Castellum, a collaborative consortium that includes the Dutch National Institute for Public Health and the Environment of the Ministry of Health, Welfare and Sports, the Wageningen Bioveterinary Research group was asked to develop a veterinary vaccine against Rift Valley Fever virus. As part of this program BPRC performed a proof of concept-study in monkeys to investigate if the 4S vaccine was safe for (non-human) primate species. Our study showed no adverse effects in common marmosets and there was no evidence for virus replication. The vaccine will be further developed by the Wageningen Bioveterinary Research group.

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Development of in vitro methods for mosquito-borne viruses

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HONOURs is an international Innovative Training Network funded by the European Commission. The aim of the project is to train 15 PhD students in all aspects involved in host switching pathogens, infectious outbreaks and zoonosis. Preparedness requires expertise in many areas. The Early Stage Researchers are therefore located at academia and research institutes throughout Europe that together cover the entire field of outbreak-control. BPRC is involved as expert on modeling infectious diseases in non-human primates. In this program we focus on the development of in vitro methods to evaluate pathological events after infection with mosquito-borne viruses.

As part of HONOURS, BPRC organized a 4-day course for all 15 students. During this course presentations were given from BPRC staff members, as well as guest speakers from the Erasmus University Medical Center in Rotterdam. The presentations focused on different non-human primate models for infectious diseases and neurological disorders, but also dealt with biosafety, study design, ethics, genetics, ethology, animal training and colony management. In addition, a one-day workshop was included with various laboratory techniques that are widely used in our virus research projects.

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