title: Towards a self-disseminating vaccine to control vampire bat rabies in its reservoir
Creators: name: Griffiths, Megan Eva
Publisher: name: University of Glasgow
Year: 2022

description: Viruses that circulate in wildlife can have devastating health and economic consequences when they enter human and livestock populations. Efforts to mitigate the burden of these zoonotic pathogens currently tend to focus on the spillover hosts; however, since this approach does not address the reservoir of disease, it prolongs the risk of re-emergence as viruses continue to circulate unimpeded in wildlife. Vaccination of wildlife reservoirs has the potential to prevent spillover, but is hampered by the logistical challenge of delivering vaccine to and achieving sufficient coverage in large, reclusive animal populations. Whilst orally available vaccines held inside edible baits have seen success in combating disease in some wildlife reservoirs, unique dietary requirements or behaviours can preclude the use of this strategy. The obligate blood-feeding common vampire bat Desmodus rotundus, reservoir host of rabies virus and primary source of rabies cases throughout Latin America, is one species in which edible baits are unsuitable, and other management strategies have thus far failed. Virally vectored transmissible vaccines which utilise the replicative capabilities of live viral vectors to spread autonomously between hosts, offer a potential solution. However, progress towards real world use of such vaccines is hampered by the selection of vaccine vectors which will prove both safe and efficacious. A betaherpesvirus recently identified in vampire bats (Desmodus rotundus betaherpesvirus; DrBHV) presents a promising candidate vector. In this thesis, I aimed to identify the key characteristics of DrBHV, and evaluate its biological and epidemiological suitability to vector a transmissible vaccine targeting rabies virus. The results presented here are based on field-collected samples, subjected to a combination of PCR, deep sequencing, and computer modelling. In Chapter 2, I aimed to assess the prevalence and host specificity of DrBHV, and the similarity of its genome composition to other betaherpesviruses currently considered for use as vaccine vectors. I used PCR to amplify a conserved region of the herpesvirus genome in saliva samples from Peruvian bats, with 96.9% of vampire bats testing positive, regardless of demographic group. Sanger sequencing of these regions and those from other positive bats revealed specificity of DrBHV to the Phyllostomidae family. Thus, DrBHV is able to spread efficiently within vampire bats, with only rare infection of closely related and cohabitating bat species. Metagenomic sequencing was able to construct a full genome consensus sequence for DrBHV similar in length and composition to betaherpesviruses in other species. This sequencing also showed the presence of multiple strain infections, suggesting that DrBHV may have the capacity to superinfect individuals, evading the host immune response. I aimed to further explore superinfection and DrBHV diversity in Chapter 3, by the amplification and deep sequencing of the highly variable gene encoding glycoprotein B. I identified eleven strains of DrBHV which varied in prevalence and geographic distribution across Peru. The phylogeographic structure of these strains was predictable from both host genetics and landscape topology, informing long-term DrBHV-vectored vaccine deployment strategies. Multi-strain infections were observed in 79% of infected bats and resampling of marked individuals showed strain acquisitions by already infected individuals, implying that pre-existing immunity and strain competition are unlikely to inhibit vaccine spread. Finally, in Chapter 4, I used the strain-specific prevalence data to fit models of DrBHV transmission. I identified the most likely model to include lifelong, persistent infection with cycles of latency and re-activation, a mechanism which would allow vaccinated individuals to boost their own immunity, and continually transmit vaccines to other bats throughout their lifetime. Simulations of vaccine spread show that a DrBHV-vectored vaccine can reach a population equilibrium coverage of &gt;80% after a single introduction of vaccine, resulting in a 95% decrease in the size of rabies outbreaks. Furthermore, ongoing vaccine transmission is able to maintain these levels of vaccine coverage long-term, even in the presence of realistic levels of reversion, negating the need for recurrent and costly vaccination campaigns. In summary, the work presented in this thesis supports DrBHV as a candidate to vector a transmissible vaccine targeting a major source of rabies in Latin America and shows how accessible genomic data can enlighten vector selection and deployment strategies for transmissible vaccines. This work constitutes a fundamental step towards what would be the first deployment of a transmissible vaccine to prevent spillover of a zoonotic virus, thus allowing the management of disease to shift from reactive damage control to proactive prevention.