Abstract
Next generation influenza vaccines that target conserved epitopes are becoming a clinical reality but still have challenges to overcome. Universal next generation vaccines are considered a vital tool to combat future pandemic viruses and have the potential to vastly improve long-term protection against seasonal influenza viruses. Key vaccine strategies include HA-stem and T cell activating vaccines; however, they could have unintended effects for virus adaptation as they recognise the virus after cell entry and do not directly block infection. This may lead to immune pressure on residual viruses. The potential for immune escape is already evident, for both the HA stem and T cell epitopes, and mosaic approaches for pre-emptive immune priming may be needed to circumvent key variants. Live attenuated influenza vaccines have not been immunogenic enough to boost T cells in adults with established prior immunity. Therefore, viral vectors or peptide approaches are key to harnessing T cell responses. A plethora of viral vector vaccines and routes of administration may be needed for next generation vaccine strategies that require repeated long-term administration to overcome vector immunity and increase our arsenal against diverse influenza viruses.
Highlights
Seasonal influenza viruses contribute to a substantial disease burden globally and estimated to result in 290,000–650,000 deaths annually, while pandemics can have an even greater impact [1]
Individuals vaccinated with a broadly neutralising HA stem vaccine (Figure 1A,B) may have different levels of efficacy depending on their prior challenge history
Pre-existing immunity in individuals vaccinated by T cell-activating vaccines (Figure 1C,D) may have different outcomes, with previous studies showing pre-existing antibodies may suppress crossreactive T cell responses [37] and pre-existing immunity to one influenza A virus (IAV) subtype could affect responses to novel variants of the same subtype [42]
Summary
Seasonal influenza viruses contribute to a substantial disease burden globally and estimated to result in 290,000–650,000 deaths annually, while pandemics can have an even greater impact [1]. Current influenza vaccination strategies primarily rely on inactivated influenza virus (IIV) vaccines for seasonal protection against IAV by eliciting antibody-mediated protection against the highly mutable surface protein haemagglutinin (HA), as virus neutralization by HA head-specific antibodies can block infection. There are a multitude of varying strategies and methods being used to develop a generation vaccine for IAV pandemic preparedness [7], all of which aim to achieve heterosubtypic immunity to different influenza strains and subtypes in varying ways They may target different outcomes, such as reduction in the number of infections, risk of different disease outcomes after infection (e.g., hospitalisation or death) or propensity to transmit after infection [8,9]. This review explores the interplay of each of these novel vaccine designs with prior immunity, and their potential for enhanced immune pressure and viral evasion due to non-sterilising functions
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