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

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

There is no commercial vaccine against RSV, a major cause of respiratory disease in infants and the elderly. A safe and effective RSV vaccine is needed that will not only protect young children, but which will also boost immunity in the elderly.
We have constructed several AdCh/RSV vaccine candidates expressing RSV F, N and M2-1 proteins, which induce complete protection against RSV infection in BALB/c mice and cotton rats, either alone or in a heterologous prime/boost vaccine strategy with MVA/RSV. Importantly, intranasal vaccination did not prime for enhanced pulmonary pathology in either mice or cotton rats, following RSV challenge. However, a transient weight loss was observed in mice. Given the history of RSV vaccine-augmented disease in infants, further studies including ones in a more relevant animal model are required prior to embarking on clinical trials.
The primary objectives of the project are to:
(i) optimise and further evaluate AdCh/RSV vaccine candidates and the AdCh-RSV/MVA-RSV in mice and cotton rats
(ii) evaluate the protective efficacy of the novel AdCh/RSV vaccine in calves, a natural infection model of RSV
(iii) generate pre-GMP material for a rapid implementation of clinical development

Publications

10 25 50
 
Description Human respiratory syncytial virus (HRSV) is a major cause of lower respiratory tract disease in children and the elderly for which there is still no effective vaccine. The spectre of vaccine-enhanced respiratory disease (ERD) and the young age of the main target population, have hindered HRSV vaccine development. PanAd3-RSV is a novel simian adenovirus-vectored vaccine candidate expressing a secreted form of the HRSV F protein and the N and M2-1 proteins of HRSV. Previous studies have shown that PanAd3-RSV has protective efficacy against HRSV infection in mice and cotton rats, and is immunogenic in non-human primates. However, there is uncertainty about the extent to which protection demonstrated in animal models will translate to humans. We have therefore further evaluated the safety, immunogenicity and efficacy of the PanAd3-RSV vaccine, and modified vaccinia Ankara expressing the same HRSV antigen (MVA-RSV), against HRSV in cotton rats and against bovine (B)RSV in young sero-negative calves, a model of a natural RSV infection. Here we show that different homologous and heterologous prime/boost vaccine regimens induced high levels of neutralizing antibodies and protected cotton rats against HRSV infection, and also induced neutralizing antibodies, primed BRSV-specific, IFN?-producing T cells and protected calves against BRSV infection. There was no evidence of enhanced pulmonary pathology in vaccinated cotton rats after HRSV challenge and, importantly, there was no evidence either of enhanced pulmonary pathology or of ERD in vaccinated calves following BRSV challenge. These findings support the continued evaluation of the vectored RSV vaccines in man and show promise as an effective vaccine for calves.
Exploitation Route The vaccine has now been used in phase I clinical trials.
Sectors Agriculture, Food and Drink,Healthcare

 
Description Respiratory Syncytial Virus (RSV) causes annual epidemics of respiratory infection throughout life with young infants and the elderly especially susceptible to developing severe disease. There is only supportive care for severe cases of infection and a monoclonal antibody against RSV F protein as a very expensive preventive measure for high-risk infants. Worldwide, RSV disease in children under the age of 5 years account for 33.8 million lower respiratory infections, 3.4 million hospitalisations and up to 200,000 deaths annually. RSV exposure elicits an immune response capable of protection from severe disease but not from re-infection. 50% of infants suffer at least one RSV re-infection by their second birthday. Moreover, RSV infection in infancy is associated with subsequent wheeze and asthma in later life. Healthy adults can expect a 7-9% annual risk of infection with mild symptomatic disease and severe immune suppression re-establishes a risk to developing severe disease. Immune system senescence and comorbid conditions place the elderly at risk of severe RSV disease, where hospitalisation burden and mortality are comparable to seasonal influenza. The high rate of emergency admissions, lack of universal and cost-effective preventative measures and the magnitude of seasonal disease incidence maintain RSV as a major priority for vaccine development. The demonstration that a novel vaccine based on a chimpanzee adenovirus and modified vaccinia Ankara can protect calves against the closely related bovine RSV infection without enhancement of disease has given confidence to undertake clinical trials in man, which have been funded by Okairos and GSK. Furthermore, the vaccine may also be of value in reducing the economic impact of calf respiratory disease.
First Year Of Impact 2013
Sector Agriculture, Food and Drink,Healthcare
Impact Types Societal,Economic

 
Description Industrial funding
Amount £130,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2015 
End 09/2017
 
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