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

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Industrial funding
Amount £130,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2015 
End 09/2017
 
Description Ad-vectored RSV vaccine development 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Evaluation of the immunogenicity and protective efficacy against BRSV of novel adenovirus-vectored human RSV vaccines in calves with maternally-derived serum antibodies. Includes provision of expertise, access to data and facilities and exchange of biological samples.
Collaborator Contribution Provision of novel adenovirus-vectored HRSV vaccine candidates, sample and data analysis
Impact None yet
Start Year 2015
 
Description Change of ownership of Okairos 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Joint discussion on future plans and monitoring of progress
Collaborator Contribution Provision of reagents by GSK GSK undertook some immune assays provision of vaccine candidate
Impact Provision of reagents by GSK GSK undertook some immune assays
Start Year 2013
 
Description Okairos 
Organisation Okairos
Country Italy 
Sector Private 
PI Contribution The pre-clinical evaluation of a novel RSV vaccine developed by Okairos
Collaborator Contribution Development of a novel RSV vaccine and development of vector production processes in GLP conditions
Impact Development of a virus vectored RSV vaccine shown to be safe and effective in calves against bovine RSV, a natural infection model of RSV
Start Year 2010
 
Title Phase 1 clinical trial in RSV sero-positive 2 to 8 year old children 
Description Currently the RSV vaccine program using PanAd3-RSV and/or ChAd155-RSV vectors is being led by the Vaccine Division of the pharmaceutical company GSK. In fact, GSK acquired the chimpanzee adenovirus vaccine platform from Okairos in 2013. A ChAd155 vectored vaccine for RSV, owned by GSK, is currently being tested in a Phase I study in sero-positive children 2-8 y old. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier Not known
Impact None yet 
 
Title RSV vaccine 
Description Pre-clinical evaluation of an RSV vaccine - studies funded by a DPFS grant from the MRC Phase I clinical trials of the RSV vaccine have been undertaken 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier 35082/0003/001-0001
Impact Phase I clinical trials, funded by Okarios and GSK, of the novel RSV vaccine have been undertaken and the vaccine was shown to be safe and immunogenic in adults. RSV is a major cause of pneumonia and bronchiolitis in infants, affecting ~64 million children annually, worldwide. In the UK, 2 to 3% of infants <1 year of age are hospitalised each year due to RSV. Children who experience RSV disease early in life run a high risk of recurrent wheezing and asthma. Although nearly all children are infected with RSV by 2 years of age, immunity following natural infection is incomplete and re-infections are common. The economic impact of RSV in adults and burden of disease in the elderly are comparable to or greater than that of seasonal influenza. There is no effective RSV vaccine or anti-viral therapy, apart from antibody prophylaxis for high risk individuals. An effective RSV vaccine is needed that can be deployed in infants to induce protection against lower respiratory tract disease, and which can be used to boost immunity in adults and the elderly. 
 
Title RSV vaccine 
Description Pre-clinical studies have demonstrated efficacy in small animal models of RSV infection and against bovine RSV infection in calves, a natural host of BRSV. These studies demonstrated that the vaccine was safe and effective in calves without any enhancement of respiratory disease. As a result of this, the vaccine has now undergone phase I clinical trials in Oxford, funded by Okairos and GSK and was shown to be safe and immunogenic (http://bmjopen.bmj.com/content/5/10/e008748.full). 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier 35082/0003/001-0001
Impact None yet 
 
Description Advances for an RSV vaccine 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Interview with a reporter from a Surrey radio station about recent advances in the development of a vaccine to protect against RSV in babies following publication of a paper (http://stm.sciencemag.org/content/7/300/300ra127.short), which was broadcast the next day.
Year(s) Of Engagement Activity 2015
URL http://stm.sciencemag.org/content/7/300/300ra127.short
 
Description Interveiw with local radio 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Radio interview by local radio after a press release
Year(s) Of Engagement Activity 2015
 
Description Jenner Newsletter June 2013 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact "One Health approach to the development of a vaccine against RSV infection in children" Geraldine Taylor

Not known
Year(s) Of Engagement Activity 2013
 
Description Oxford Human & Veterinary Vaccinology course 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Industry/Business
Results and Impact 30 people (post-graduate students, scientsits from academia and industry) attended. Presentations and workshops sparked questions and discussion.

Not known
Year(s) Of Engagement Activity 2012,2013,2014,2015
URL https://www.conted.ox.ac.uk/courses/C900-1