Title: Proof of concept studies for an attenuated bovine herpesvirus4 based bTB vaccine
Funder: Department for Environment, Food and Rural Affairs

Abstract: Description Mycobacterium bovis (Mb) remains an urgent problem for the UK cattle industry. Mb infects cattle resulting in bovine tuberculosis (bTB), an endemic zoonotic infectious disease in England and Wales with severe socio-economic consequences and impact on animal health. The development of improved vaccines for cattle forms part of the eradication strategies for bTB for England and Wales. Currently, the only potentially available vaccine, bacille-Calmette-Guerin (BCG) induces protection against Mb only in a subset of cattle and will require frequent booster vaccinations. It also requires a test that allows vaccinated cattle to be distinguished from infected ones (DIVA). Recent cost-benefit analysis indicated that maximising BCG vaccine efficacy, together with a highly specific DIVA test would tip the balance in favour of vaccination being cost-effective. Whilst prototype DIVA skin test reagents promising high specificity are available, increasing BCG efficacy requires a ‘sea-change’ in strategy and technology. We propose an innovative herpesvirus-based vaccine approach to overcome some of the limitations of other viral vectors (e.g. potential interference in protection by pre-exisiting anti-vector immunity, need to develop practical and safe aerosol delovery systems for cattle that deposit vaccine particles directly onto the mucosal surfaces of the lungs, or relaritely short-lived immunity) by providing life-long immunity against bTB. Herpesvirus-based vectors are a new kind of vaccine that has been shown to provide high levels of durable immunity, including mucosal immunity, against targeted pathogens (including the monkey versions of HIV and human Ebola virus) following only a single systemically applied vaccine dose. In these studies, vaccine efficacy was not impaired by pre-existing immunity to the herpesvirus vector. The genetic basis of our single-dose Mb vaccine for cattle will be a herpesvirus called bovine herpesvirus 4 (BoHV-4), which is a benign virus commonly found in these animals. For additional safety, the BoHV-4-based Mb vaccine will be further attenuated and made unable to persist within the vaccinated animal by genetic deletion of ORF73, a BoHV-4 gene required for persistent infection. We have identified 14 Mb proteins that are known to induce immune responses in cattle, but do not compromise the ability to detect Mb-infected animals (i.e. they have no DIVA potential). Following construction of a single prototype vaccine expressing 5 of these 14 Mb proteins, we will confirm vaccine safety (as well as lack of persistent infection) and immunogenicity in an established rabbit model, followed by immunogenicity in a pilot cattle study. This ‘proof-of-concept’ study will provide the critical data for moving the project forward to apply for additional funding for follow-on studies. Objective Objective 1: Generation of BoHV4/TB vaccine Objective 2: Testing vaccine in rabbits (safety and initial immunogenicity) Objective 3: Testing BoHV4/TB vaccine in cattle for immunogenicity


Research activity codes: 3.4 VACCINES
Health categories: INFECTION