VACCINE: Development of Novel BRSV Pre-Fusion Protein Recombinant Bovine Vaccine.

Bovine respiratory syncytial virus (BRSV) is a respiratory virus associated bovine respiratory disease complex, which is a major problem for the cattle industry. It results in considerable morbidity and mortality in cattle, and particularly young calves, worldwide. Efficacy of current vaccines is limited and there is a major need for a much more effective vaccine. BRSV is highly similar to Human RSV (HRSV) which is the most common cause of hospitalization in young infants and causes severe disease in elderly. No HRSV vaccines are available to date due to poor efficacy and safety issues. No HRSV vaccines are available to date due to poor efficacy and safety issues. In cattle the response of the immune system of current vaccines is compromised by the presence of maternal antibodies which neutralise the vaccine. This current proposal will target the exploitation of a combination of novel technologies to generate novel BRSV vaccines. Specifically, we will bring together world-renowned expertise in paramyxovirus reverse genetics, structure-based vaccine antigen design, and vaccine development to generate a new generation of BRSV vaccines that we are confident will circumvent many of the limitations of current vaccines. This will include the use of Sendai virus (SeV, a mouse virus) and parainfluenza virus type 5 (PIV5, a dog virus) as vehicles (vectors) to deliver a BRSV gene into the cell and produce the protein (antigen) from this. As neither of these viruses is found in cattle, they infect bovine cells but do not cause disease in cattle and there is no known cross-reactivity with bovine antibodies, problems associated with the presence of maternal antibodies will be circumvented. The use of SeV and PIV5 will facilitate development of a prime/boost vaccine regimen, which will circumvent a virus vector-specific immune response induced by the 1st vaccine administration, as both viruses are antigenically distinct. Such a regimen is likely to maximize immune responses to the BRSV antigen. We will develop both replication competent and incompetent viruses for both SeV and PIV5. The latter are produced by producing virus infectious particles that have one of the genes for further replication removed. However, these particles can enter cells and produce BRSV proteins. Our cumulative data, both published and unpublished, confirms that both replication competent viruses are independently highly efficient vectors for human RSV vaccine antigens in animal models. The development of replication-incompetent SeV and PIV5 viral vectors will address some safety concerns related to environmental dissemination of recombinant viruses, and will involve the generation of novel rescue technologies (production of virus from copies of the virus genes) for both viruses. BRSV and HRSV contain a protein called the fusion (F) protein which allows the virus to get into cells and is in a different form on the virion surface (pre-fusion) compared to when it interacts with a cell (post-fusion). The F protein induces a response by the immune system and the pre-fusion form has recently been shown to produce a several fold higher immune response than the post fusion form (in an experimental HRSV vaccine. We will exploit this finding to design and generate the most highly immunogenic BRSV vaccine, based on the use of a pre-fusion stable F protein. Precedence for this was demonstrated for human RSV pre-fusion F-based experimental vaccine, which was shown to be many fold superior to native F as a vaccine antigen. Finally, we will bring all of these complementary but disparate elements together to develop novel BRSV vaccines and vaccine regimens and test their efficacy in the final host target for the use of these vaccines, i.e., calves. These vaccines and the results from their study will also serve as the basis for design of effective human vaccines for HRSV.

Bovine respiratory syncytial virus (BRSV) is associated bovine respiratory disease complex, a major problem for the cattle industry, and is closely related to human RSV (HRSV). It results in considerable morbidity and mortality in calves worldwide. Efficacy of current vaccines is limited because they are compromised by maternal antibodies in calves. This proposal will exploit of a combination of novel technologies to generate new BRSV vaccines. We will bring together world-renowned expertise in paramyxovirus reverse genetics, structure-based vaccine antigen design, and vaccine development to generate a new generation of BRSV vaccines designed to circumvent the limitations of current vaccines. This will include the use of Sendai virus (SeV) and parainfluenza virus type 5 (PIV5) as vectors for BRSV vaccine antigens. As neither of these viruses is found in cattle and there is no known cross-reactivity with bovine antibodies, problems associated with maternal antibodies will be circumvented. Use of SeV and PIV5 will facilitate development of a prime/boost vaccine regimen, which will circumvent virus vector-specific immunity induced by the 1st vaccine administration, as both viruses are antigenically distinct. We will develop both replication competent and incompetent viruses for both SeV and PIV5. Replication-incompetent SeV and PIV5 vectors will address safety concerns related to environmental dissemination of recombinant viruses. We will exploit novel structure-based vaccine design to generate the most highly immunogenic BRSV antigen, based on a BRSV pre-fusion stable F protein. Precedence for this was demonstrated for a HRSV pre-fusion F protein, which was many fold superior to native F as a vaccine antigen. We will bring these complementary but disparate elements together to develop novel BRSV vaccines and vaccine regimens and test their efficacy in calves. These vaccines-natural host systems will also serve as the basis for design of effective HRSV vaccines.

This proposal focuses on the generation of novel bovine respiratory syncytial virus (BRSV) vaccine candidates. BRSV is a respiratory virus associated bovine respiratory disease complex, which is a major problem for the cattle industry and is closely related to human RSV (HRSV) in terms of virus structure and associated clinical disease. It results in considerable morbidity and mortality in cattle, and particularly young calves, worldwide. Efficacy of current vaccines is limited and there is a major need for a much more effective vaccine. The immunogenicity of current vaccines is compromised by the presence of maternal antibodies. This current proposal will target the exploitation of a combination of novel technologies to generate novel BRSV vaccines. Specifically, we will bring together world-renowned expertise in paramyxovirus reverse genetics, structure-based vaccine antigen design, and vaccine development to generate a new generation of BRSV vaccines that we are confident will circumvent many of the limitations of current vaccines. This will include the use of Sendai virus (SeV) and parainfluenza virus type 5 (PIV5) as vectors to deliver BRSV vaccine antigens. As neither of these viruses is found in cattle and there is no known cross-reactivity with bovine antibodies, problems associated with the presence of maternal antibodies will be circumvented. The use of SeV and PIV5 will facilitate development of a prime/boost vaccine regimen, which will circumvent virus vector-specific immunity induced by the 1st vaccine administration, as both viruses are antigenically distinct. Such a regimen is likely to maximize immune responses to the BRSV antigen. We will develop both replication competent and incompetent viruses for both SeV and PIV5. Our cumulative data, both published and unpublished, confirms that both replication competent viruses are independently highly efficient vectors for human RSV vaccine antigens in animal models. The development of replication-incompetent SeV and PIV5 viral vectors will address some safety concerns related to environmental dissemination of recombinant viruses, and will involve the generation of novel rescue technologies for both viruses. We will exploit novel state-of-the-art structure-based vaccine design to generate the most highly immunogenic BRSV antigen, based on the use of a pre-fusion stable F protein construct. Precedence for this was demonstrated for a human RSV pre-fusion F-based vaccine, which was shown to be many fold superior to native F as a vaccine antigen (Science. 2013 342(6158):592-8; McLellan JS et al,Science. 2013 May 31;340(6136):1113-7). Finally, we will bring all of these complementary but disparate elements together to develop novel BRSV vaccines and vaccine regimens and test their efficacy in the final host target for the use of these vaccines, i.e., calves.
Therefore, reasonable outcomes of this project will include:
- novel rescue technologies for replication incompetent SeV and PIV5 vectors;
- novel BRSV vaccines based on replication competent and incompetent SeV and PIV5 vectors expressing BRSV pre-fusion F;
- a novel vaccine regimen to induce efficient protective immunity against BRSV, even in the presence of maternal antibodies;
- a novel BRSV vaccine and regimen with sufficient data to justify commercial development.
- in view of the considerable similarities between BRSV and HRSV, both virologically and clinically, the data derived from this study will likely inform future vaccine strategies for HRSV.
As such, this project is likely to have a considerable impact on UK industry, both biotech and agricultural, and increase the reputation of the UK as a world leader in vaccine design and technologies that directly impact on society.