A One Health approach to pan-valent morbillivirus vaccines

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Paramyxoviruses are a family of viruses that pose a significant threat to humans and animals alike. For example, Hendra virus outbreaks in Australia have targeted both racehorses and their trainers, while Nipah virus outbreaks in Malaysia spread through pig farms, resulting in 105 human fatalities and the culling of approximately 1.1 million pigs. While such cross-species transmission events may occur relatively infrequently, when they do occur, the consequences can be devastating for humans and animals alike. The Paramyxovirus family also includes the morbillivirus genus of viruses, possibly the most notable of which are measles virus in humans and rinderpest virus in cattle. Morbilliviruses of animals have a very high potential for cross-species transmission, or "zoonosis". Although originally described as a pathogen of dogs, canine distemper virus (CDV) has jumped species into critically endangered lion, tiger, seal and giant panda populations. A closely related morbillivirus of sheep and goats, peste des petits ruminants virus (PPRV) has caused severe disease outbreaks in saiga antelope in Mongolia, buffalo in India and camels in Ethiopia and Sudan. If we are to combat the future spread of such zoonotic morbilliviruses, we need to develop a better understanding of the process of cross-species transmission and how this can be prevented by vaccination.Vaccination against one species of morbillivirus can provide immunity to infection with morbilliviruses from other species; a rinderpest vaccine can protect cattle from rinderpest, a goat from PPRV and a dog from CDV. Vaccination triggers the production of neutralising antibodies (nAbs) targeting the surface glycoproteins of the virus, hence, some of these antibodies must recognize determinants that are conserved across diverse morbilliviruses. In this project, we set out to identify the determinants on the viral surface glycoproteins that are recognised by neutralising antibodies. If these binding sites can be identified, we will be able to design better pan-morbilliviral vaccines, vaccines that will protect against cross-species infection with emerging morbilliviruses.To achieve this goal, we have designed in vitro systems with which we can recreate the cellular environment of the susceptible host species. Morbilliviruses attach to target cells by binding to either of two protein molecules expressed on the cell surface, CD150 or nectin-4. Variations in the amino acid sequences of these molecules are key determinants of which species the viruses target, hence CDV is able to bind to CD150 from many species and thus has a very broad species tropism. Neither CDV nor PPRV bind human CD150 well and hence infect human cells very inefficiently. However, with a small adaptation to the amino acid sequence of the viral glycoproteins, binding is enhanced greatly and the viruses display an enhanced ability to infect human cells. We have developed assays with which we can study the propensity for morbilliviruses to develop such mutations. Moreover, we can assess how efficient antibodies generated in the host by vaccination are at preventing infection with such viruses. In effect, we have developed systems with which we can determine the likelihood of zoonotic transmission occurring and how to prevent it by vaccination. This project will guide the design of the next generation of pan-morbilliviral vaccines and will develop assays systems with which their likely efficacy in preventing zoonoses can be assessed in vitro. By defining the viral targets for neutralising antibodies and by assessing their function against potentially zoonotic viruses, this project offers a unique opportunity to protect both humans and animals alike against the emerging threat posed by novel morbilliviruses.