Broad and effective protection against influenza achieved by viral vectored vaccines

Seasonal influenza vaccines are widely used, requiring annual revaccination, but vaccine effectiveness has been low in recent years, especially in older adults who are more likely to experience severe or fatal disease. In the event of an influenza pandemic, a new vaccine will be required, but will not become available in significant quantities until several months after the pandemic starts. At the Jenner Institute at Oxford University we have been working on the development of novel influenza vaccines that will be effective against both seasonal and pandemic influenza viruses, including in older adults, and one of the vaccines is now in a phase II clinical trial. We are now preparing to test further improvements to the vaccine.
The first version of the vaccine includes only internal antigens of the influenza virus and boosts T cell responses to them. Multiple studies have demonstrated protection against both seasonal and pandemic influenza in people who have high T cell responses to these antigens, and we have demonstrated that we can boost responses, including in older adults, by vaccination. We will now include a further antigen into the vaccines, to induce antibodies against neuraminidase, which is a protein found on the surface of the influenza virus and is less variable that haemagglutinin which is the major antigen in licensed vaccines.
We will also test different routes of vaccine administration. Licensed influenza vaccines are given to adults by intramuscular injection, and are known to increase antibodies to influenza haemagglutinin in the blood. However the virus infects the respiratory tract, and it may be possible to improve protection by delivering the vaccines to the respiratory tract also. The new vaccines will be tested in pigs which have already been exposed to influenza virus, to mimic the effect of vaccinating humans. We will study the induction of immune responses to both the internal antigens and neuraminidase, as well as testing for differences in vaccine efficacy after intramuscular, upper respiratory tract or lower respiratory tract immunisation.
Viral vectored influenza vaccines expressing internal antigens have been tested in humans and shown to be safe, and to significantly boost T cell responses. Adding a further antigen and changing the route of vaccine administration may prove highly beneficial in improving vaccine efficacy.

Currently licensed influenza vaccines offer very low levels of protection despite annual review and updating of the vaccine
composition. In adults over 65 years there has been little to no detectable protection despite annual revaccination. However
it is known that T cell responses to conserved influenza antigens acquired by infection with influenza virus offer protection
against symptomatic disease upon re-infection. We have demonstrated that these immune responses can be boosted by
intramuscular vaccination by viral vectors expressing influenza nucleoprotein (NP) and matrix protein 1 (M1) in humans,
and that the responses are protective against influenza challenge in small animals. We now propose to extend this work in
a preclinical study in which we will include a third antigen, the external glycoprotein neuraminidase (NA), as well as NP and
M1. Recent research has underlined the role of anti-NA antibodies in protection against influenza disease in humans.
Additionally we will determine how the route of vaccination affects vaccine efficacy in mice and in pigs, which are a better
model of human disease. Natural exposure to influenza virus results in tissue resident memory T cells in the lung, and
whereas intramuscular immunisation of humans has been shown to boost these responses in the blood, the effect on
memory responses in the lungs is not known, and cannot be studied directly in humans. We will pre-expose pigs to
influenza virus in the respiratory tract, and then study the effect of different vaccination routes on humoral and cellular
immunity to influenza virus, and on protective efficacy of vaccination. The results (vaccine efficacy, correlates of protection,
degree of correlation between immune responses in blood and lung, possible improvement in efficacy by including NA as
well as NP+M1) will inform future vaccine design and future clinical trial design.

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. 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, as well as examining the impact of route of vaccination of vaccine efficacy.
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.