Other Livestock Diseases

Programme Leaders: Dr Bryan Charleston and Dr Geraldine Taylor

In addition to Foot-and-Mouth Disease, Jenner Investigators at the Institute for Animal Health conduct research into vaccines against a range of other economically important livestock diseases:

Rift Valley Fever
African Swine Fever
Eimeria
Marek's Disease
Rinderpest and Peste des petits ruminants
Respiratory syncytial viruses
Theileria parva

Rift Valley Fever

Group Leader, Jenner Institute: Dr George Warimwe

Aims of the project

The Institute's research into a vaccine against Rift Valley Fever proposes:

1. To develop a safe and effective Rift Valley fever vaccine for use in sheep.
2. To develop a safe and effective Rift Valley fever vaccine for use in future human clinical trials.

Work leading up to the project

Rift Valley Fever (RVF) is a viral zoonosis caused by the RVF virus (RVFV), an RNA virus of the Bunyaviridae family that was first isolated from livestock on a Kenyan farm in 1930. It is primarily a disease of ruminants such as sheep, goats and cattle but human infections occur following close contact with infected animal tissue and body fluids. The effects of RVF are most pronounced in newborn lambs and pregnant ewes where mortality and abortion rates approach 100%, respectively. In humans, the clinical spectrum varies from a mild febrile illness to the more severe manifestations of encephalitis and haemorrhagic diathesis that are frequently fatal.

RVFV is mainly transmitted by Aedes spp. mosquitoes, with a wide range of other mosquito species playing a role in virus dissemination during epizootics. The global distribution of the mosquito vectors has contributed, in part, to the spread of RVFV to much of Africa and parts of the Middle East and there are growing concerns of RVFV spread to other parts of the world. This, together with its potential use as a biological weapon, underlies the strict animal import controls and the inclusion of RVFV on the lists of notifiable diseases in many countries where the disease has not yet occurred.

To date, Kenya has had the highest frequency of RVF epizootics and the causative virus is now enzootic in six of the eight provinces in the country. Because RVF epizootics tend to be worst in areas where the virus is enzootic, Kenya and other countries with previous RVFV incursions will continue to bear the brunt of RVF for years to come unless effective control measures, including vector control and vaccination of susceptible hosts, are put in place. Two vaccines, one live-attenuated and the other formalin-inactivated, are available for livestock use. However, the formalin-inactivated vaccine requires repeat immunizations to achieve protective efficacy and, though the live-attenuated vaccine (termed Smithburn vaccine) confers long-lasting immunity, it is not safe for use in pregnant animals. No licensed vaccine is available for use in humans.

Recent approaches to RVF vaccine development have focused on two viral glycoproteins, Gn and Gc, encoded by the M segment of the RVFV genome. Mounting evidence shows that recombinant vaccines based on these glycoproteins induce neutralizing antibodies that confer protection from experimental challenge in mice and sheep. However, these studies are geared more towards livestock vaccines and the vectors used for the vaccine constructs have not been tested for safety in humans as part of any other licensed or experimental product and are very unlikely to be licensed for safety reasons. Using vaccine types with a known safety profile in humans obviates the need for extensive safety studies of new attenuated or inactivated viruses in human trials should a promising vaccine construct and schedule be identified. Here, Dr Warimwe proposes to develop a safe and effective human vaccine based on Gn and Gc RVFV glycoproteins encoded by two viral vectors: modified vaccinia virus Ankara (MVA) and a simian Adenovirus, ChAdOx1.

The choice of these vectors is informed by the following observations from human clinical trials using MVA and ChAd63 (a group E simian adenovirus similar to ChAdOx1)-vectored malaria antigens: 1) both are safe, 2) highly immunogenic, 3) their optimal doses and routes of administration have already been established and, 4) neither is prone to significant anti-vector immunity and thereby subsequent attenuation of responses to vaccine constructs. Thus, ChAdOx1-GnGc and MVA-GnGc vaccine constructs will be prepared and their immunogenicity and protective efficacy will be evaluated.

African Swine Fever

Vaccinology Group Research Leader, IAH: Dr Geraldine Taylor
Head of Vector-borne Viral Diseases Programme, IAH: Prof Peter Mertens

African swine fever virus (ASFV) causes an acutely fatal haemorrhagic fever of pigs which has devastating economic consequences in affected countries. In contrast, in its natural hosts - warthogs, bushpigs and soft ticks of the Ornithodoros species - the virus can persist over long periods with no signs of disease. ASFV has a large DNA genome, which replicates in the cytoplasm and encodes 150 to 165 proteins. These include a large number of proteins that help the virus to evade host defence systems.

Researchers at the Institute for Animal Health are investigating the role of these viral proteins in evasion of host defences and this knowledge is being applied to the development of candidate vaccine strains by sequential deletion of ASFV genes that encode proteins involved in virus virulence and evasion of host defences. In addition, since recent studies have highlighted an important role for CD8+ T cells in immunity, we are characterizing the role of various CD8+ T cell subsets in protection; identifying the ASFV proteins recognized by these cells; and investigating vaccine strategies that induce protective ASFV-specific CD8+ T-cell responses in the pig.

Eimeria

Protozoan parasites of the genus Eimeria cause enteritis (coccidiosis) in many animals, being transmitted by the faecal-oral route. They rapidly invade gut cells, causing severe damage, and lead to the build-up of heavy parasite loads in the environment. In the absence of sustainable measures to control Eimeria, outbreaks of severe clinical coccidiosis with high levels of mortality are inevitable. In order to develop improved vaccines against Eimeria, we are exploiting parasite genetics to identify regions of the parasite genome that encode antigens that elicit protective immune responses.

In addition, researchers at the Institute for Animal Health are investigating fundamental mechanisms of immune induction and regulation in the gut, and identifying immune protective mechanisms that operate against gut pathogens. Much of the work is related to the function of various T cell compartments in the gut environment and has broad implications for both human and animal health.

Marek’s Disease

Viral Onconogenesis Research Leader, IAH: Prof Venugopal Nair

Marek’s disease (MD) is a widespread neoplastic disease of poultry caused a highly contagious herpesvirus, designated Marek’s disease virus (MDV). Due to its highly contagious nature, rapid onset, long-term persistence both within the infected chickens as well as in the poultry house environment, MDV is arguably one of the most economically significant pathogens of poultry with an estimated annual loss of up to US $2 billion worldwide. The disease is controlled by vaccination and MD vaccines are one of the first and best examples of the use of successful vaccines against any cancer.

The dependence of the poultry industry on MD vaccines is evident from the use of more than 22 billion doses annually. MD vaccines are generally effective in preventing the losses from the disease as shown by their widespread use in the last 40 years. However, the widespread use of vaccines has not prevented the evolution of MDV to greater virulence that has necessitated the introduction of new generations of vaccines at regular intervals. Today, the poultry industry uses MD vaccines derived from all the 3 serotypes of the virus singly or in combinations.

Viral oncogenesis group at the Institute for Animal Health and one of the OIE (World Organisation for Animal Health) Reference Centres on MD, headed by Prof. Venugopal Nair, examines the molecular mechanisms of MD pathogenicity. They have developed infectious bacterial artificial chromosome (BAC) clones of vaccine strains of all the 3 serotypes of MDV that enables them to use of reverse genetics to examine the functions of viral genes as molecular determinants of immunity. The group also examines the use of molecularly-defined mutant viruses of pathogenic MDV strains as new generations of vaccines to combat the continuing increase in virulence of MDV.

Rinderpest and Peste des petits ruminants

Head of Livestock Viral Diseases Programme, IAH: Dr Bryan Charleston

The economic consequences of epizootics of rinderpest (cattle plague) and peste des petits ruminants (PPR) (sheep and goat plague) can be devastating. Over the past 20 years we have been involved in the Global Rinderpest Eradication Programme (GREP), which has been very successful in reducing the incidence of rinderpest to practically zero. There have been no new outbreaks reported for several years and the target date for an official declaration of eradication of the disease remains 2010. In contrast, over the same time period severe epizootics of PPR have occurred in the Middle East and across the Indian sub-continent and the virus is now in China.

PPR virus infection has for many years been one of the most important constraints to the increased production of small ruminants in sub-Saharan Africa. The main thrust of current research is to produce rationally attenuated marker vaccines for use in virus control programmes, with a strong emphasis on PPR virus. In addition, we have developed recombinant poxvirus vaccines for rinderpest and PPR, based on the use of vaccinia and capripox viruses as vectors to express immunogenic proteins of the viruses.

These vaccines have the advantage of being “marker vaccines” enabling differentiation of vaccinated animals from ones which have recovered from natural infection. This greatly aids sero-epidemiological studies to monitor control strategies. The vaccinia recombinants were shown to protect African cattle from rinderpest for up to 3 years. Similar work carried out with the capripox recombinant viruses have shown that they can protect cattle both from virulent rinderpest and lumpy skin disease, which is caused by a virus in the capripox group. The capripoxvirus recombinants may be more readily accepted than vaccinia recombinants by government safety agencies for field use since they are not hazardous to humans and the vector is already used as a vaccine to protect against capripoxvirus infections in sheep and goats.

Respiratory syncytial viruses

Vaccinology Group Research Leader, IAH: Dr Geraldine Taylor

Respiratory disease in young calves is a major animal welfare problem, affecting approximately 1.9 million calves in the UK each year, at a cost of £54 million. BRSV is the most important primary viral cause of respiratory disease in young calves in the UK. This virus is structurally and antigenically related to human (H)RSV, which is the single most important cause of bronchiolitis and pneumonia in infants. The high degree of similarity between HRSV and BRSV indicates that comparative studies of the immunobiology of these viruses will yield important insights that should benefit both man and cattle.

The development of safe and effective RSV vaccines has been hampered by the need to induce protective immunity within the first month of life, at a time when maternal antibodies can pose a major obstacle to successful vaccination; and the observation that vaccination can exacerbate RSV disease. Because vaccine-augmented disease is associated with inactivated virus, it has been proposed that a live, attenuated virus administered intranasally would make a safer and more effective vaccine.

The lack of disease potentiation following natural RSV infection is a critical safety advantage of the live vaccine strategy. The mucosal route of vaccination would directly stimulate local immunity, prime CD8+ T cells, which are important in virus clearance, and overcome the immunosuppressive effects of maternally-derived antibodies. Recent advances in the molecular biology of negative-sense RNA viruses have provided a means to manipulate the genome of BRSV and opened the way for producing genetically stable, attenuated BRSV vaccine candidates.

The research group led by Dr Geraldine Taylor at the Institute for Animal Health is currently comparing a number of live, attenuated mutant BRSV vaccine candidates for their ability prime bovine T cells, induce local and humoral antibody responses and protect against challenge with virulent virus. In addition, we have developed recombinant vaccinia virus vaccines and DNA vaccines which induce a protective immune response against experimental BRSV challenge in calves or against HRSV in a mouse model and we are currently exploring other vaccine vectors for greater efficacy against RS viruses.

Theileria parva

Theileria parva is the causative agent of East Coast fever (ECF) in cattle, and a close relative of Plasmodium, the parasite that causes malaria in humans. Whereas the vector for Plasmodium species is the mosquito, Theileria is carried by ticks, and is responsible for loss of cattle in 12 countries in sub-Saharan Africa. One million cattle die each year from ECF with annual economic costs estimated to be $168 million.

T. parva is transmitted by the brown-ear tick Rhipicephalus appendiculatus. Cattle lymphocyctes are invaded by sporozoites after the animal is bitten by an infected tick. The presence of the parasite within the lymphocyte induces the malignant transformation of the host cell. The host cell and the schizont divide synchronously, resulting in the clonal expansion of the infected lymphocytes. Infected animals develop a lymphoma-like disorder that is rapidly fatal, with most animals dying within 3-4 weeks of infection. Some parasites form merozoites and are released into the bloodstream by rupture of the host cell, where they invade erythrocytes and develop into intra-erythrocytic forms called piroplasms. Ticks ingest the piroplasms during a blood meal. Following a sexual cycle in the gut, kinetes migrate to the salivary glands of the tick. Sporogony is initiated when the tick attaches to a host animal, resulting in the release of sporozoites into the salivary glands, ready for transmission to the host.

Attempts to control or eradicate ECF have focused on either vector control by using insecticides to kill ticks, or on vaccine development. Insecticide resistance has increased, but naturally acquired immunity in cattle that recover from infection is long-lasting, indicating that achieving immunity by vaccination should be possible. ‘Infection and treatment’, a process that involves simultaneous inoculation of cryopreserved sporozoites and a long acting tetracycline has been used on a small scale. Several lines of evidence indicate that cellular immune responses, including CD8+ T cells directed against the schizont infected lymphocytes are responsible for protection, and there is also an antibody response to sporozoite antigens. Trials of an experimental subunit vaccine comprised of the major sporozoite surface protein p67 demonstrated a reduction of cases of severe ECF by 50%.

The genome of T. parva has been sequenced, in a collaboration between The Institute for Genomic Research (TIGR) in the USA and The International Livestock Research Institute (ILRI) in Kenya. This lead to the indentification of protective antigens suitable for use in vaccine development (see references below). Sarah Gilbert of the Jenner Institute has collaborated with scientists at ILRI to produce and test new sub-unit vaccines against T. parva.

Many of the problems faced in development of vaccines against T. parva are shared with malaria vaccine development, and as with malaria in humans, efficacy of new vaccines can be tested rapidly in controlled challenge experiments. Parallel development of malaria vaccines for humans and theileria vaccines for cattle will continue to provide advances in both fields.