Clinical assessment of a novel simian adenovirus-vectored influenza vaccine designed to induce broadly protective immunity

Lead Research Organisation: University of Oxford
Department Name: The Jenner Institute


The influenza vaccines that are used at present have a number of disadvantages. The vaccines have to be reformulated every year to keep up with changes in the viruses that are circulating, and people have to be revaccinated every year. About one year in 20, the virus that is circulating changes after the vaccine formulation for that year has been decided, and then the vaccine does not work well. At best the trivalent inactivated vaccine (TIV) has an efficacy of 60 % in adults aged under 65 years, and lower than that in older people who are the main group targeted for vaccination.

At the Jenner Institute we have tested a new type of influenza vaccine using a live virus vaccine, similar to the smallpox vaccine, which has been attenuated to prevent it from causing disease and make it very safe to use. Our first clinical trials with this new vaccine MVA-NP+M1 showed that it was very effective at boosting T cell immune responses to influenza, and that in a small study, fewer vaccinated than non-vaccinated volunteers who were then exposed to influenza virus developed symptoms of influenza infection. Importantly, the vaccine was very immunogenic in older volunteers, which is not the case with TIV.

We now wish to conduct clinical trials with a different viral vectored influenza vaccine, this one based on an attenuated adenovirus, since in clinical trials of vaccines against other diseases this type of vaccine was even more immunogenic and the immune responses lasted for longer after vaccination.

The first ever clinical trials of this new vaccine, ChAdOx1 NP+M1, have already started, in a small study designed to work out the best dose to use. We are now applying for funding to do two trials with this new vaccine. The first will be in healthy volunteers aged 18 to 50 years. Half of them will receive ChAdOx1 NP+M1, and half will receive MVA-NP+M1, so that we can compare the immunogenicity of the two vaccines. Later, they will all receive a second vaccination with the vaccine that they did not receive the first time, so that we can see the effect of giving first one vaccine and then the other, as this is expected to produce the strongest and most durable response.

The second trial will be in volunteers aged over 50 years who will receive a single dose of ChAdOx1 NP+M1 to determine immunogenicity in older people. After these studies have been completed, we will be able to design much larger studies to find out how effective the vaccine is at preventing people from becoming ill with influenza

Technical Summary

A vaccine against influenza that induced protective T cell responses against conserved internal antigens could provide lasting immunity against not only human seasonal influenza, but also other subtypes currently found in avian species or swine which threaten to cause a new influenza pandemic. Adenoviruses are the ideal vector for such a vaccine as they induce broad, potent and well-maintained T cell responses after a single vaccination, so could be used to confer broad immunity rapidly. They can also boost pre-existing T cell responses acquired by prior exposure to influenza that have since declined to non-protective levels in adults or the elderly. We have constructed a replication-deficient simian adenovirus-vectored vaccine expressing conserved influenza antigens, completed manufacture in preparation for clinical trials, and will conduct a dose-escalation during Q2-Q3 2012.

The first clinical study proposed here will test vaccination with the new simian adenovirus-vectored vaccine and the existing MVA-vectored vaccine in a crossover design that allows comparison of the two vaccines as well as heterologous prime-boost immunisation with two different boosting intervals. A second clinical trial will test safety and immunogenicity of the adenovirus-vectored vaccine in volunteers aged over 50 years.

The MVA-vectored vaccine has already been shown to provide protection against infection in an influenza Phase IIa challenge study, and comparing the two vaccines at the same time in the same population will provide a clear understanding of the relative immunogenicity of the vaccines. At the completion of the study, sufficient information will have been gathered to enable efficacy testing of the adenovirus vectored vaccine to proceed, either as a Phase IIa influenza challenge study or a Phase IIb field efficacy study, leading to Phase III studies and licensure if successful.

Planned Impact

Influenza vaccines have changed little for many decades, and while there have been substantial benefits to public health from using them, there are some aspects that could be significantly improved. The vaccines need frequent reformulation to keep up with genetic drift in seasonal influenza strains, but despite that, approximately one year in 20 the vaccine does not match the circulating virus and vaccine efficacy is low. Efficacy is always reduced in older adults.A new pandemic requires a new vaccin, requiring six months to produce the new vaccine after identification of the new pandemic virus. The recent H1N1 pandemic largely resulted in mild disease, and may be viewed as a test run for what might happen in a pandemic caused by a more pathogenic virus. Pandemic-specific vaccines were produced following worldwide co-operation, and were eventually deployed on a wide scale. Had the pandemic resulted in even 1% mortality, disruption to all normal activities, including vaccine production, distribution and use, would have resulted in a very different outcome.
It has been known for many years that not everyone is susceptible to influenza, even at the beginning of a pandemic. We know that some immune responses to influenza are cross-reactive, but we have not known what they are, or how long they last. More information is being gathered but we do not know the relative importance of T cell responses or antibody responses to different conserved regions of the influenza virus. We do not know how to produce a broadly protective immune response by vaccination, we do not know what that immune response comprises of, and we do not know which members of the population are immune to influenza A at any particular time.
The vaccine development studies proposed here will go a long way to adding to our understanding. Initial clinical studies with a novel influenza vaccine designed to boost pre-existing T cell responses have already demonstrated safety, immunogenicity and partial efficacy. By conducting comparative studies with a second vaccine, employing combination regimes and using gene expression studies as well as standard measures of T cell immunogenicity we will gain greater understanding of what protective immune responses to influenza are, and how to induce them by vaccination.
The study will have an impact on commercial vaccine producers, providing opportunities for them to license Intellectual Property and vaccine seed stocks to take one or both vaccines being testing into commercial production. However, once a protective immune response is more fully understood, it will be possible to make an early and rapid assessment of other technologies designed to prime or boost T cell responses to ascertain whether they are likely to be beneficial. A number of small biotech companies are attempting to develop universal influenza vaccines employing peptides to vaccinate with, and inducing low level immune responses. Information on the magnitude and phenotype of T cell response required for protection will define what these peptide-based vaccines will need to achieve, and may prevent unecessary testing of poorly immunogenic vaccines.
The availability of a broadly protective influenza vaccine that is effective in older adults as well as younger ones would have a major impact on public health. If widely deployed, circulation of influenza A viruses could be considerably reduced, and the threat of a new pandemic averted. Seasonal influenza currently results in considerable economic losses which could be avoided. This will require extensive efficacy testing prior to licensure which may take up to 10 years to achieve.
The findings of the study will also be of use in the development of other vaccines, against infectious diseases and cancer.
Clinical and scientific staff working on the study will gain experience in translational medicine and training in GCP, working as part of a highly skilled multi-disciplinary team at a leading research centre.
Description MRC DPFS_DCS
Amount £793,586 (GBP)
Funding ID MR/N006372/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2016 
End 02/2018
Description Combining anti-HA stem antibodies with T cell responses to influenza 
Organisation Icahn School of Medicine at Mount Sinai
Country United States 
Sector Academic/University 
PI Contribution My research team are experts in inducing protective T cell responses against influenza.
Collaborator Contribution Florian Krammer is an expert in inducing antibody responses against the conserved stem regions of influenza haemagglutinin.
Impact New DPFS grant award to the partners in the collaboration to pursue this work.
Start Year 2015
Title A Phase I Study of Candidate Influenza Vaccines MVA-NP+M1 and ChAdOx1 NP+M1 
Description Viral vectored influenza vaccine in Phase I clinical development, funded by an MRC DPFS-DCS award. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Still under assessment. 
Company Name Vaccitech 
Description Vaccitech will develop viral-vectored vaccines originally produced at the University of Oxford, with a focus an influenza and therapeutic vaccines against prostate cancer. 
Year Established 2016 
Impact Nothing yet - the investment was finalised three days ago.
Description ESWI SPI 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I took part in a science policy interface session at the European Science Working Group on Influenza Conference in Riga, Latvia, 2014. I spoke and answered questions on Universal Influenza Vaccines.
Year(s) Of Engagement Activity 2014
Description Public talk for Biomedical Research Centre, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk will take place on 27.11.14
Year(s) Of Engagement Activity 2014