Pre-clinical development of a simian adenovirus vectored respiratory syncytial virus (RSV) vaccine
Lead Research Organisation:
THE PIRBRIGHT INSTITUTE
Department Name: UNLISTED
Abstract
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Technical Summary
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
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
Planned Impact
unavailable
Organisations
People |
ORCID iD |
| Geraldine Taylor (Principal Investigator) |
Publications
Pierantoni A
(2015)
Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates.
in Molecular therapy. Methods & clinical development
Taylor G
(2015)
Efficacy of a virus-vectored vaccine against human and bovine respiratory syncytial virus infections.
in Science translational medicine
| 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 | 09/2015 |
| End | 09/2017 |
| Title | Novel Prime-Boosting Regimens Involving Immunogenic Polypeptides Encoded by Polynucleotides |
| Description | The present invention relates to administration regimens which are particularly suited for vaccine composition comprising polynucleotides which encode immunogenic polypeptides. Said administration regimens involve the repeated administration of a vaccine composition and enhance the immune response against the immunogenic polypeptide. |
| IP Reference | 20180256704 |
| Protection | Patent application published |
| Year Protection Granted | 2017 |
| Licensed | Yes |
| Impact | The IP had been licensed to GSK. The PanAd-RSV prime/MVA-RSV boost vaccine is in clinical trials. See links to references below: https://stm.sciencemag.org/content/7/300/300ra126 https://www.ncbi.nlm.nih.gov/pubmed/26510727 https://www.ncbi.nlm.nih.gov/pubmed/30742894 NOVEL PRIME-BOOSTING REGIMENS INVOLVING IMMUNOGENIC POLYPEPTIDES ENCODED BY POLYNUCLEOTIDES Publication number: 20150209420 Abstract: The present invention relates to administration regimens which are particularly suited for vaccine composition comprising polynucleotides which encode immunogenic polypeptides. Said administration regimens involve, the repeated administration of a vaccine composition and enhance the immune response against the immunogenic polypeptide. Type: Application Filed: July 5, 2013 Publication date: July 30, 2015 Inventors: Alfredo Nicosia, Ricardo Cortese, Alessandra Vitelli |
| Title | Genetically-modified chimpanzee adenovirus and MVA-vectored respiratory syncytial virus vaccine safely boosts humoral and cellular immunity in healthy older adults |
| Description | The safety and immunogenicity of a single dose of MVA-RSV given by intra-muscular (IM) injection (n = 6), two doses of IM PanAd3-RSV given 4-weeks apart (n = 6), IM PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), intra-nasal (IN) spray of PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), or no vaccine (n = 6) were evaluated in adults 60 to 75 years of age. Safety measures included all adverse events within one week of vaccination and blood monitoring. Immunogenicity measures included serum antibody responses (RSV- and PanAd3-neutralising antibody titres measured by plaque-reduction neutralisation and SEAP assays, respectively), peripheral B-cell immune responses (frequencies of F-specific IgG and IgA antibody secreting cells and memory B-cells by ex vivo and cultured dual-colour ELISpot assays respectively), and peripheral RSV-specific T-cell immune responses (frequencies of IFN?-producing T-cells by ex vivo ELISpot and CD4+/CD8+/Tfh-like cell frequencies by ICS/FACS assay). The vaccines were safe and well tolerated. Compared with each individual baseline immunity the mean fold-changes in serum RSV-neutralising antibody, appearance and magnitude of F-specific IgG and IgA ASCs and expansion of CD4+/CD8+ IFN?-producing T-cells in peripheral circulation were comparable to the results seen from younger healthy adults who received the same vaccine combination and dose. There were little/no IgA memory B-cell responses in younger and older adults. Expansion of IFN?-producing T-cells was most marked in older adults following IM prime, with balanced CD4+ and CD8+ T cell responses. The RSV-specific immune responses to vaccination did not appear to be attenuated in the presence of PanAd3 (vector) neutralising antibody. The trial was sponsored by ReiThera Srl (formerly Okairos Srl), which was acquired by GlaxoSmithKline Biologicals SA during the trial. The trial was funded by ReiThera Srl and the NIHR Oxford Biomedical Research Centre, Oxford, and with salary support for Charles Sande and Paul Klenerman (WT 109665MA) from the Wellcome Trust. PK and AP are NIHR Senior Fellows. |
| Type | Therapeutic Intervention - Vaccines |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2015 |
| Development Status | Closed |
| Clinical Trial? | Yes |
| Impact | The results of the trial were published in: https://pubmed.ncbi.nlm.nih.gov/30742894-novel-genetically-modified-chimpanzee-adenovirus-and-mva-vectored-respiratory-syncytial-virus-vaccine-safely-boosts-humoral-and-cellular-immunity-in-healthy-older-adults/ |
| URL | https://clinicaltrials.gov/show/NCT01805921 |
| 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 |
| 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 |