Multivalent Attenuated Vaccine against Viral and Bacterial Zoonoses in Ruminants

BACKGROUND: Infected animals and animal products are the most common route by which highly pathogenic microbes enter the human population. The list of these zoonotic (transmitted from animals to humans) microbes is extensive, but includes such viruses as Ebola and Lassa haemorrhagic viruses, SARS, MERS, and Rift Valley Fever virus (RVFV); and the bacterial causes of plague (Yersinia pestis) and Q fever (Coxiella burnetii, CB). The rate at which these microbes is entering the human population is on the increase, but unfortunately our ability to control their emergence remains severely limited. This problem is further complicated by the emergence of these microbes most commonly occurring in under-resourced, low-and middle-income countries (LMICs). The realization of this capacity gap underpins this current UK Vaccine Network Competition Brief. APPROACH: Vaccination of animal populations involved in zoonotic transmission is one effective means of reducing pathogen emergence into the human population. The aim of the current project is to construct a single attenuated (reduced virulence*) multivalent vaccine targeting both RVFV and CB. It takes advantage of the near complete overlap of RVFV and CB in terms of their disease characteristics, including: i) animals they infect (ruminants: cattle, sheep, goats and camels), ii) geographic distribution, iii) at-risk human populations (farm and abbatoir workers, and veterinarians), iv) conditions under which they transmit zoonotically to humans, and v) symptomology both in humans and in animals (both microbes associated with abortion storms in goats and sheep). We will use bovine herpesvirus-4 (BoHV-4) as the platform for this vaccine, which has been shown to create an immune response in all common domestic ruminant animals tested. The BoHV-4-based vaccine will be attenuated by removal of a region of the virus called ORF73. Deletion of ORF73 results in the vaccine only being able to replicate for a transient, short period of time in animals. This further increases the safety of the vaccine, but does not affect its ability to induce a good immune response (this will also be confirmed during the 12 month project). Such attenuation is 'conditional' in that it prevents long-term replication in the animal, but does not affect ease/low cost of vaccine manufacture. A conditionally-attenuated BoHV-4 targeting both RVFV and CB is therefore suited for production and use in LMICs endemic for RVFV and Q fever. It will be safe, inexpensive to produce and able to create an immune response in the domestic ruminant animals involved in transmission of RVFV and CB to humans. It also has the potential for providing long-lasting immunity after only a single dose, further reducing vaccination costs. Finally, developing a vaccine for the animal populations involved in transmission, rather than for humans, considerably reduces the time to vaccine commercialization and use in the field due to the lower threshold of requirements for approval of animal compared to human vaccines. [*As even the wild-type version of BoHV-4 is not reproducibly associated with disease, deletion of ORF73 of BoHV-4 is included to provide an additional tier of safety].