Dr Riks Maas and Professor Jeroen Kortekaas discuss the pioneering work of Wageningen Bioveterinary Research in the fields of viral vaccine development and animal infectious diseases.
Wageningen Bioveterinary Research (WBVR) is a Netherlands-based institute dedicated to safeguarding animal and public health through research into the prevention, eradication and control of animal infectious diseases. Founded in 1904 as the National Serum Institute and originally based in Rotterdam, WBVR is today the Dutch national reference institute for animal diseases of farm animals, fish, shellfish and wildlife, and boasts an international reputation in the field of applied veterinary research.
Lelystad: at the forefront of vaccine development
The history of Lelystad in animal health
WBVR’s current setting in the municipality of Lelystad is particularly apt, Professor Jeroen Kortekaas tells Health Europa, because it was there that the porcine reproductive and respiratory syndrome virus (PRRSV) – originally called the ‘Lelystad virus’ – was first discovered, a pathogen belonging to the Arteriviridae family that causes so-called ‘blue ear disease’ in pigs.
It was also in Lelystad that a vaccine was developed to eradicate Aujeszky’s disease in the Netherlands, where it had once posed a huge challenge. “What’s more,” says Kortekaas, an extraordinary professor of veterinary arbovirology, “the vaccine was developed using a live, genetically modified virus and was based on the DIVA principle.”
Differentiating between infected and vaccinated animals
DIVA describes a method of differentiating between infected and vaccinated animals. Vaccines based on this principle lack a gene encoding a protein that is pathogen-specific and highly immunogenic, and thus stimulates an immune response different from that induced by natural infection. Diagnostic and serological tests, such as enzyme-linked immunosorbent assays (ELISAs), can then be used to identify which animals are infected and which have been vaccinated.
“This is hugely important for trade,” elaborates Dr Riks Maas, the head of WVBR’s Department of Virology. “If there is a disease outbreak in your country and you want to transport animals or animal products, you have to show that they are not infected, which can be problematic if a traditional vaccine has been used because you cannot prove that the pathogen isn’t there. DIVA vaccines allow trade restrictions to be lifted more quickly and trade to resume once an outbreak has been brought under control.”
The DIVA principle was invented in Lelystad and is today used across the world.
Wageningen Bioveterinary Research has achieved similar acclaim for its work on live-attenuated vaccines – that is, vaccines designed using viruses that have been weakened or made less virulent in the laboratory. Kortekaas’ own research in this area has led to the development of a novel DIVA vaccine against Classical swine fever, a highly contagious and often fatal disease affecting pigs and wild boar. Wageningen Bioveterinary Research is currently collaborating with an animal health company to develop and take the vaccine to market.
Live-attenuated DIVA vaccines against Bluetongue, an insect-borne disease affecting ruminants such as sheep and goats, and the deadly African horse sickness, are also under development at WBVR, with a view to one day being transferred to industry.
BunyaVax: advanced platform technology
Much of Kortekaas’ attention is now focused on bunyaviruses, which he describes as “RNA viruses that are transmitted by insects and can be manipulated very easily”. Using these, Kortekaas and his group at WVBR have developed a type of vaccine platform technology which can not only render the viruses avirulent, but also make them incapable of spreading in, between and among animals.
This work led to the founding of spin-out company BunyaVax BV in 2017, which was set up with the objective of exploiting the vaccine platform technology developed by Kortekaas in order to develop safe and efficacious vaccines within a timeframe of just a few weeks.
Its technology is divided into two strands: Bunya LIVE (bunyavirus-based live-attenuated viruses) and Bunya RNA (bunyavirus-based RNA particles).
Bunya LIVE is used to create live-attenuated vaccines which have the double advantage of being cost-effective to produce, while also providing long-lasting protection with just one vaccination. Using reverse-genetics, a technique by which the genes of a virus are deliberately manipulated in order to produce a specific virus phenotype, Kortekaas and his team have developed an effective vaccine against the human and animal illness Rift Valley fever, which has been identified on the World Health Organization’s blueprint list of priority diseases as having the ‘potential to cause a public health emergency’. The vaccine, which is based on an avirulent four-segmented Rift Valley fever virus (RVFV-4s), has already been proven to induce sterile immunity in lambs, goats and cattle after a single vaccination, and has also been safely tested in pregnant ewes, the most susceptible target animals.
Meanwhile, Bunya RNA makes use of highly infectious, reverse genetics-engineered RNA particles which, although similar to authentic viruses, cannot spread autonomously and are thus inherently safe. The ‘plug and play’ nature of the Bunya RNA platform is such that any gene can be easily inserted into the RNA particle genome in order to rapidly produce a vaccine in response to an outbreak – a highly valuable asset in instances of newly emerging viruses which can very quickly spread across and between continents.
Other projects in the pipeline at BunyaVax include:
- Evaluation of the potential of RNA particles and RVFV-4s for human application;
- Evaluation of an RNA particle-based influenza vaccine that can be quickly updated to match circulating field strains and is suitable for use in both humans and animals;
- Development of vaccines against other (emerging) infectious diseases with epidemic potential; and
- Development of novel cancer immunotherapies.
In April, BunyaVax was awarded a €50,000 grant under the European Commission’s SME Instrument, a Horizon 2020 initiative designed to support breakthrough innovation projects with market-creating potential. The funding will allow BunyaVax to prepare for co-development partnerships with industry and to scale up the manufacturing process of its vaccine platform technology.
It comes shortly after the company was presented with the 2018 Innovation Showcase Award at Animal Health Investment Europe – a London-based event committed to highlighting to investors the most innovative emerging animal health companies within the companion, aquaculture and production animal space – and is further recognition of the mark BunyaVax is already making just a year on from its creation.
Rapid responses to emerging epidemics
Maas and Kortekaas see huge potential for the platform technology developed at WVBR and BunyaVax to contribute to efforts in Europe to accelerate the response to emerging epidemics. But, unfortunately, the regulatory environment of vaccine development in Europe has not kept pace with technological progress in this field.
Maas explains: “Technology is now so far advanced that we can develop very effective vaccines within a very short time period – both at our institute and elsewhere. The biggest problem that we face is that the most effective vaccines that we can develop are based on genetically engineered viruses, whether live-attenuated or in the form of RNA particles, and European regulations prohibit us from using these vaccines very quickly as the emergency use of GMOs in the field requires approval from all the member states.
“This is different to the situation in the USA, where RNA particles can already be used to respond very quickly to outbreaks. In other words, if a farmer is experiencing an outbreak of a known disease but a different strain of it, they can now – within just a few weeks’ time – produce a suitable vaccine and use it in the field.
“By contrast, in Europe, you have to jump through a lot of hoops to register the vaccine and it then takes years to bring it to the field, which is too long; outbreaks can spread across the whole of Europe within just a few months.”
Kortekaas agrees. “What we really need,” he says, “is legislation that allows us to use vaccines in the field much more quickly, and one way of doing that is to get licensing opportunities for platform technologies.”
Zoonotic Anticipation and Preparedness Initiative
This goal is closely aligned to that of the five-year Zoonotic Anticipation and Preparedness Initiative (ZAPI), in which Wageningen Bioveterinary Research is a partner. Funded to the tune of €22m under the Innovative Medicines Initiative (IMI) public private partnership, ZAPI has the ambitious aim of accelerating the response to major new infectious disease threats in Europe and throughout the world.
To this end, the 20-strong consortium (which unites industry with academia and, alongside WBVR, includes MedImmune and Boehringer Ingelheim Animal Health) is working to design new, scalable manufacturing processes for the delivery of effective vaccines, antibody therapies and other control tools against (re-)emerging zoonotic diseases with pandemic potential within a few months after the first cases occur.
One Health: success stories and ongoing projects
Wageningen Bioveterinary Research’s collaborative activities do not stop there. Its commitment to One Health, the term given to the inter-relatedness of animal, human and environmental health, is for instance reflected in its participation in multiple One Health initiatives at the national and international levels. Among them, Wageningen Bioveterinary Research is co-responsible for the joint research projects and educational work package in the One Health European Joint Programme, an EU initiative aimed at aligning medical, veterinary and food research agendas in order to establish a sustainable One Health framework in Europe, and is also one of several partners of the Netherlands Centre for One Health (NCOH), which brings together world-leading Dutch academic research institutes to tackle the twin challenge of infectious diseases and antimicrobial resistance.
Maas describes One Health as an increasingly important focus area at the institute; indeed, 70% of newly emerging infectious diseases in humans originate from animals. Bioveterinary research is thus essential to tackling this challenge.
The research of Professor Dr Wim van der Poel, who co-ordinates Global One Health at Wageningen University & Research, focuses on the hepatitis E virus, a small virus that is most commonly transmitted through faecal-contaminated drinking water. The World Health Organization estimates that some 20 million people become infected every year with the hepatitis E virus, which results in mild flu-like symptoms, as well as jaundice, nausea and abdominal pain, and can lead to liver disease and acute liver failure. Genotypes 3 and 4 of the virus have also been found to circulate – without causing disease – in large animals such as deer and wild boar.
To reduce the human disease burden of hepatitis E, WBVR characterises and compares the hepatitis E viruses in pigs in different European countries to assess the actual risk of zoonotic hepatitis E virus infections from swine. It is also working to demonstrate the transmission routes between pig farms, pigs and humans, and to investigate the contamination levels in surface water and meat products in which raw pork livers are processed.
Q fever is a flu-like infection caused byCoxiella burnetii, bacteria found in the birth products, blood, urine and faeces of infected farm animals, and spread to humans in close contact. Between 2007-2010, the Netherlands played host to the largest Q fever outbreak on record, which affected more than 4,000 people. Thanks to efforts to genotype the circulating Q fever bacterium by WBVR researchers, stringent control measures were established in dairy goats and the outbreak was brought under control.
Avian influenza Type A viruses are found naturally in wild aquatic birds, but can also spread to domestic poultry and other bird and animal species through saliva, faeces and nasal secretions. In rare cases, avian influenza can also affect humans.
In November 2016, an outbreak of avian influenza virus infection in the Netherlands left many aquatic birds dead. Researchers at Wageningen Bioveterinary Research were able to identify the virus as the particular subtype H5N8 rapidly. By determining the genetic code of viruses isolated from samples collected on poultry farms, researchers were also able to show that the disease had been caused by the autumn migration of wild birds from Russia. The fact that the viruses were not genetically related allowed inter-farm transmission to be ruled out for most of the contaminated farms, information which was of huge importance for strategies to control the disease.
Neglected zoonotic viruses
Wageningen Bioveterinary Research is also working on neglected zoonotic viruses – that is, poorly known viruses that do not yet present a threat to Europe, but may do so in the future.
“For example,” says Maas, “we are studying viruses that are closely related to the Schmallenberg virus, which has already emerged in Europe, and we run a dedicated virus discovery programme to look for potential new threats.”
Kortekaas points out that this objective is closely aligned to the goals of the World Health Organization which has included ‘Disease X’ on its blueprint list of priority diseases, in recognition of the fact that a ‘serious international epidemic could be caused by a pathogen currently unknown to cause human disease’.
Much of the pioneering work at Wageningen Bioveterinary Research has been made possible thanks to its sophisticated animal and laboratory facilities which are able to accommodate large animals for experimentation, including cattle, sheep, horses, goats and pigs.
The facilities boast a secure, specially designed high containment unit, which is the only one of its kind in the Netherlands and is suitable for experiments with highly infectious pathogens up to biosafety levels 3 (human) and 4 (veterinary).
Upcoming at Wageningen Bioveterinary Research
Looking toward the future, Maas and Kortekaas are committed to working on their vaccine platform technology, which will include establishing proof of principle for a variety of diseases. To this end, they are keen to co-operate with pharmaceutical companies on production and licensing, in the hopes of advancing products to market as quickly as possible.
There can be no doubt that these efforts, combined with those outlined above, will ensure Lelystad’s proud history in vaccine development and animal infectious diseases continues long into the future.
Dr Riks Maas
Department of Virology
Wageningen Bioveterinary Research
+31 320 238891
This is a commercial article that will appear in Health Europa Quarterly issue 6, which will be published in August, 2018.