Pre-clinical development of an influenza vaccine to induce broad protection through multiple immune mechanisms

There is an overwhelming need for a universal influenza vaccine to protect against the next influenza pandemic as well as providing improved protection against seasonal influenza. Vaccines that are currently in use are not as effective as we would like them to be even in years when the composition of the vaccines is a good match for the influenza viruses that are circulating and causing illness in the same influenza season. Approximately one year in every 20 there is a poor match, as has happened in 2014-15, and as a result twice as many older adults have required hospital treatment for influenza in the US compared to last year, with an unusually high number of deaths in children also being reported. Research is being conducted into making vaccines that will work against all influenza viruses. The two most advanced approaches both rely on targeting conserved regions of the virus; inducing antibodies against the haemagglutinin stem, or T cells recognizing the internal antigens nucleoprotein (NP) and matrix protein 1 (M1). Oxford has taken the lead in clinical development of T cell boosting vaccines; Mount Sinai has been at the forefront of anti-stem antibody research. A single immunization with MVA-NP+M1 boosts T cell responses in young and older adults, and a current clinical study using both MVA and ChAdOx1 to express NP+M1 has shown increased duration of strong T cell responses following immunization, which will be important to maintain protective immunity. Mount Sinai have been able to achieve protective antibody titres against HA stem after two immunisations, but different versions of the chimeric HA (cHA) molecule must be delivered with each immunization.
We now propose to collaborate to produce vaccines which employ both mechanisms of immunity (antibodies and T cells) in order to produce the ultimate universal influenza vaccine. We will produce and test replication-deficient viral vectors (simian adenovirus ChAdOx1 and Modified Vaccinia virus Ankara MVA) expressing both a cHA molecule derived from a group 2 influenza A virus and the NP+M1 fusion protein that has been used in clinical trials. Using a different version of cHA in each viral vector will allow us to induce protective antibody responses against HA stem at the same time as boosting and maintaining protective T cell responses against NP and M1. We will also test the use of recombinant cHA protein to boost anti-stem antibodies.
We will conduct immunogencity and efficacy testing in mice and ferrets, and produce pre-GMP vaccine and/or cell banks suitable for cGMP manufacture and clinical testing. This will allow us to pregress to clinical trials very soon after the completion of this pre-clinical study.

There is an overwhelming need for a universal influenza vaccine to protect against the next influenza pandemic as well as providing improved protection against seasonal influenza. The two most advanced approaches both rely on targeting conserved regions of the virus; inducing antibodies against the haemagglutinin stem, or T cells recognizing the internal antigens nucleoprotein (NP) and matrix protein 1 (M1). Oxford has taken the lead in clinical development of T cell boosting vaccines; Mount Sinai has been at the forefront of anti-stem antibody research. A single immunization with MVA-NP+M1 boosts T cell responses in young and older adults, and a current clinical study using both MVA and ChAdOx1 to express NP+M1 has shown increased duration of strong T cell responses following immunization, which will be important to maintain protective immunity. Mount Sinai have been able to achieve protective antibody titres against HA stem after two immunisations, but different versions of the chimeric HA (cHA) molecule must be delivered with each immunization.
We now propose to collaborate to produce vaccines which employ both mechanisms of immunity in order to produce the ultimate universal influenza vaccine. We will produce and test replication-deficient viral vectors (simian adenovirus ChAdOx1 and Modified Vaccinia virus Ankara MVA) expressing both a cHA molecule derived from a group 2 influenza A virus and the NP+M1 fusion protein that has been used in clinical trials. Using a different version of cHA in each viral vector will allow us to induce protective antibody responses against HA stem at the same time as boosting and maintaining protective T cell responses against NP and M1. We will also test the use of recombinant cHA protein to boost anti-stem antibodies.
We will conduct immunogencity and efficacy testing in mice and ferrets, and produce pre-GMP vaccine and/or cell banks suitable for cGMP manufacture and clinical testing.

Influenza vaccines have changed little for many decades, and while there have been substantial benefits to public health from using the vaccines, there are some aspects that could be significantly improved. The vaccines need frequent changes in composition 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, as is the case this year. Efficacy is always reduced in older adults, and a new pandemic requires a new vaccine. It takes six months to produce the new vaccine after the new pandemic virus has been identified. 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 as low as 1 or 2% 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 pre-clinical vaccine development studies proposed here will go a long way to adding to our understanding. We will explore means of boosting cross-reactive immune responses to multiple antigens via both antibody and T cell responses at the same time, and test protection against influenza challenge in the ferret model.
The study will have an impact on commercial vaccine producers. There will be 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. This should be possible within three to five years.
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.
Staff working on the study will gain experience in vaccine development, working as part of a highly skilled multi-disciplinary team at a leading research centre.