Pre-clinical development of a simian adenovirus vectored respiratory syncytial virus (RSV) vaccine

Respiratory syncytial virus (RSV) causes annual winter outbreaks of respiratory disease, with a peak incidence of severe RSV disease in infants less than 6 months of age. Although nearly all children are infected with RSV by 2 years of age, immunity following natural infection is incomplete and re-infections are common throughout life. In healthy adults, RSV usually causes symptoms similar to those of the common cold. However, diseases can be severe in the elderly and immunocompromised patients. There is currently no effective vaccine and previous attempts at vaccination of infants, using an inactivated virus vaccine, resulted in enhanced respiratory disease following RSV infection. The relatively ineffective immune response induced by RSV infection and the spectre of vaccine-enhanced disease have confounded attempts to develop a safe and effective RSV vaccine. There is currently no anti-viral treatment for RSV, although individuals at high risk of severe disease can be given regular injections of an antibody preparation during the winter months. There is, therefore, a clear need for a safe and effective RSV vaccine. The aim of this project is the preclinical characterization of a viral vectored RSV vaccine that stimulates protective antibody and cellular immune responses. Simian adenovirus vectors, which do not replicate or cause disease in man and which are not neutralized by pre-existing immunity induced by human adenovirus infection will be used either alone, or in a heterologous prime-boost strategy with poxvirus MVA vectors. MVA is an attenuated virus which has been used to safely and successfully vaccinate over 120,000 humans against smallpox. To this end, different chimpanzee adenovirus (AdCh) vectors and an attenuated poxvirus MVA vector expressing RSV antigens will be generated and tested for antigen expression, productivity, genetic stability and immunogenicity in mice. Once the best candidate AdCh-RSV vector has been identified, it will be evaluated for its ability to induce protective immunity against RSV in a mouse and cotton rat model of RSV infection, and also in calves, a natural infection model of RSV. The proposed study will provide Proof of Concept that vaccination with an AdCh-RSV vector protects animals against RSV infection and will lead directly to translation of the findings into clinical trials in man.

RSV is a major cause of respiratory disease in infants worldwide, with a peak incidence of severe disease in infants less than 6 months of age. Repeated infections occur throughout life, and the burden of RSV disease in the elderly is comparable to that of seasonal influenza, while the economic impact of RSV disease in adults is even greater. There is no effective RSV vaccine or anti-viral therapy. Vaccine development has been hampered by the finding that a formalin-inactivated RSV vaccine failed to protect against RSV infection and primed for exacerbated respiratory disease. There is, therefore, a need for a safe and effective RSV vaccine not only to protect infants, but also to boost immunity in adults and the elderly, thereby reducing the circulation of RSV in the community. Ideally, an RSV vaccine should induce rapid, protective T- and B-cell responses, not prime for enhanced disease, and be able to boost immune responses in those whose immunity has declined. To this end, we have generated replication-defective chimpanzee adenovirus (ChAd) vectors, which are not neutralized by pre-existing anti-vector immunity in humans, and an attenuated poxvirus vector, MVA, expressing a string of conserved RSV proteins. Intranasal vaccination with ChAd/RSV, or vaccination by heterologous prime-boost with ChAd/RSV and MVA/RSV, completely protected mice and cotton rats against RSV, and did not prime for exacerbated pulmonary pathology. In this project, we will identify a ChAd/RSV vaccine for clinical application by comparing ChAd/RSV vaccine candidates for genetic stability, productivity, immunogenicity and safety in small animal models. The ability of ChAd/RSV to protect against bovine RSV in calves, a natural host of RSV, the effects of route of vaccination and maternal antibody on vaccine efficacy, and the ability to boost pre-existing immunity will be determined. A vaccine production process in GLP conditions for Phase I clinical trials will also be developed.

The proposed study has the potential to lead to the development of a safe and effective respiratory syncytial virus (RSV) vaccine capable of inducing protection against RSV in infants and also able to boost protective immunity in adults and the elderly. RSV is the major cause of hospitalisation of infants less than 2 years of age throughout the world, causing disease in an estimated 64 million children each year. Furthermore, RSV bronchiolitis in infants is associated with an increased risk of recurrent episodes of wheezing later in life. RSV re-infects healthy individuals throughout life, and the burden of RSV disease in the elderly is comparable to that of seasonal influenza. Furthermore, the economic impact of RSV-related disease in adults is estimated to be greater than that of influenza in relation to numbers of days lost from work. In the UK, an effective RSV vaccine would reduce the annual incidence of hospital admissions attributable to RSV from the current 2% to 3% of all children < 1year old. An RSV vaccine that boosts immunity in the elderly and in adults with underlying pulmonary or cardiac disease will reduce morbidity and mortality ( e.g. >17,000 deaths annually in elderly adults in the USA) due to RSV. An RSV vaccine to boost immunity in hospital staff would reduce the nosocomial spread of RSV, especially in paediatric wards during the winter months, and if deployed to adults would reduce the number of days lost from work, thereby increasing the nation's health and prosperity.