Kate Aspden, University of Cape Town
Recombinant vaccine* technology is an innovative method for producing novel vaccines for use in a wide variety of hosts. Vaccinia virus (previously used as the smallpox vaccine) has been used as a vector for producing recombinant vaccines with great success based on the knowledge gained through the smallpox epidemic. Unfortunately, with the advent of HIV, this vector is no longer safe as it can cause disseminated infections in immunocompromised individuals. Kate Aspden and her supervisor, Prof Anna-Lise Williamson, developed a recombinant rabies vaccine (Caprirab) using the lumpy skin disease virus (LSDV) vaccine as a vector during the course of her PhD at the University of Cape Town. The LSDV vector is safe because productive replication is restricted to cattle cells and is an attenuated vaccine strain of LSDV. Caprirab successfully protects cattle, mice and rabbits against rabies infection. It is expected to produce long-term immunity to rabies that, in cattle, requires only a single immunisation. Work is in progress to increase the value of Caprirab by testing its ability to be administered orally (in baits) and by inserting genes from multiple disease-causing pathogens thereby making a multivalent vaccine.
Rabies is a severe and fatal disease of the central nervous system of warm-blooded animals, including man. It is caused by an infection with Rabies Virus (RV), a member of the Rhabdoviridae family. Recent statistics reveal that 600-700 cases of rabies are diagnosed in domestic and wild animals each year in South Africa. Dogs, cattle and the yellow mongoose collectively constitute 85% of all animals in which the disease is confirmed.
The disease has proved to be particularly difficult to control in the rural and peri-urban settlements of KwaZulu-Natal, where dogs roam freely and civil unrest has hampered vaccination campaigns. Cattle rabies is a problem, mainly in developing countries including South Africa, Namibia, Botswana, Zimbabwe, Mexico, Venezuela and Brazil. Lithuania, Denmark, and Hungary have also reported cases of cattle rabies. During the last century, the number of cattle rabies cases recorded was second only to the number of domestic dog rabies cases in South Africa and Zimbabwe. However, in Namibia and Botswana, cattle rabies was the most commonly reported rabies infection.
Canid rabies is commonly transmitted to cattle via the bite of carnivores such as jackals or dogs in Africa. However, since so many vectors exist, in Africa, herd vaccination may be the most viable method of disease prevention in cattle. In support of this, 39 959 rabies vaccinations have been given to cattle in South Africa between 1993 and 2001, in order to prevent further rabies outbreaks.
It has been estimated that 30 000 cattle die annually in Brazil from RV infections, where sylvatic rabies is usually transmitted to cattle via a bite from a vampire bat (Desmodus rotundus). The physical manifestations of rabies virus infections are not unlike those seen in other species. The clinical signs include: excessive salivation, behavioural changes, muzzle tremors, bellowing, aggression, hyperaesthesia and/or hyper excitability, and pharangeal paresis/paralysis. Rabies in cattle usually lasts 2-6 days depending on the severity of the infectious bite, however, the shorter the clinical course, the more prominent the nervous symptoms. Lumpy Skin Disease (LSD) is caused by a capripoxvirus (of the family Poxviridae) of which the prototype strain, "Neethling", was first isolated in South Africa. The disease is an acute, subacute or unnoticeable viral disease that primarily infects cattle. It is characterised by fever and necrotic skin nodules. Nodules may also appear in the skeletal muscles and mucosae of the digestive and respiratory tracts. LSD has a mortality rate of 40% or lower but is economically important because of the effects it has on cattle herds. Milk herds can stop producing milk as well as becoming debilitated; beef herds become emaciated and useless as beef producers; and bulls as well as cows can become infertile after contracting LSD. In addition, the lesions cause permanent damage to the hides of infected cattle, which impacts heavily on the leather industry. Thus for economic reasons, vaccination against LSD is necessary. The image to the right is an electron micrograph of a negatively stained Caprirab particle. In (A), the surface of the particle can be seen whereas in (B), the stain has penetrated the rabies glycoprotein-coated particle and the internal view is seen. Caprirab is a live recombinant lumpy skin disease virus (Neethling vaccine strain) expressing the glycoprotein** of rabies virus in such a manner that rabies-specific immunity is induced in vaccines. LSDV is a Capripoxvirus that like many other poxviruses has the potential to be used as an effective vaccine vector, or "carrier". Caprirab is aimed at cattle and will confer dual immunity to both lumpy skin disease (LSD), a disfiguring disease of cattle, and rabies, a fatal neurological disease of mammals. It is envisaged with more widespread testing that Caprirab may be used as a rabies vaccine for a wide variety of animals. Caprirab results in a cell-mediated immune response, which is typified by defensive action taken by the infected individual at a cellular level as well as an antibody-mediated immune response, where antibodies against rabies protect the cells against infection. It has the potential of being given orally in bait form because of its stability. This gives the advantage of potential use in wildlife.
In Europe and North America, there is currently a recombinant oral rabies vaccine in use to eradicate rabies from carriers such as foxes, raccoons and coyotes. This vaccine is a recombinant vaccinia virus expressing the rabies virus glycoprotein gene and has proved to be extremely efficient up to now. Vaccinia virus was previously developed as the vaccine against smallpox during the global outbreak. However, reports have indicated that individuals with less than optimum immune systems such as those who are pregnant, those that are infected with HIV-1 or even those who have skin conditions such as eczema are at the risk of contracting a disseminated vaccinia virus infection that can result in disfigurement, loss of limbs or even death. This occurs because vaccinia virus manages to replicate in most cell types (it is not host-restricted to one species) and can be spread between species.
Caprirab is a new-era recombinant vaccine that is host-restricted to cattle and thus is safer than vaccinia virus as a recombinant rabies vaccine. The LSDV vaccine, used as the base of Caprirab confers lifelong immunity against lumpy skin disease after a single vaccination and thus we also expect Caprirab to elicit lifelong immunity against both rabies and LSD after a single vaccination. Furthermore, due to its stability, the maintenance of a cold chain is unnecessary. This is a huge advantage for vaccines aimed at the developing world.
*Recombinant virus: a virus that has been genetically modified to express a protein from another pathogen with the aim of inducing an immune response to the expressed protein and thus protection against the said pathogen. **Glycoprotein: coat protein that surrounds a virus. The primary protein against which immunity is conferred.