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

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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.