Harnessing the Power of T Cells: The Promising Hope for a Universal Influenza Vaccine

Abstract

Next-generation vaccines that utilize T cells could potentially overcome the limitations of current influenza vaccines that rely on antibodies to provide narrow subtype-specific protection and are prone to antigenic mismatch with circulating strains. Evidence from animal models shows that T cells can provide heterosubtypic protection and are crucial for immune control of influenza virus infections. This has provided hope for the design of a universal vaccine able to prime against diverse influenza virus strains and subtypes. However, multiple hurdles exist for the realisation of a universal T cell vaccine. Overall primary concerns are: extrapolating human clinical studies, seeding durable effective T cell resident memory (Trm), population human leucocyte antigen (HLA) coverage, and the potential for T cell-mediated immune escape. Further comprehensive human clinical data is needed during natural infection to validate the protective role T cells play during infection in the absence of antibodies. Furthermore, fundamental questions still exist regarding the site, longevity and duration, quantity, and phenotype of T cells needed for optimal protection. Standardised experimental methods, and eventually simplified commercial assays, to assess peripheral influenza-specific T cell responses are needed for larger-scale clinical studies of T cells as a correlate of protection against influenza infection. The design and implementation of a T cell-inducing vaccine will require a consensus on the level of protection acceptable in the community, which may not provide sterilizing immunity but could protect the individual from severe disease, reduce the length of infection, and potentially reduce transmission in the community. Therefore, increasing the standard of care potentially offered by T cell vaccines should be considered in the context of pandemic preparedness and zoonotic infections, and in combination with improved antibody vaccine targeting methods. Current pandemic vaccine preparedness measures and ongoing clinical trials under-utilise T cell-inducing vaccines, reflecting the myriad questions that remain about how, when, where, and which T cells are needed to fight influenza virus infection. This review aims to bring together basic fundamentals of T cell biology with human clinical data, which need to be considered for the implementation of a universal vaccine against influenza that harnesses the power of T cells.

Keywords: T cell; influenza virus; universal vaccine.

Figure 1

CD4 and CD8 T cells act in synergy with multiple immune arms for heterologous protection. Effective heterologous immunity against zoonotic influenza (H7N9) viruses requires synergy of multiple immune arms [30,76,78]. Without the recruitment of two or more immune arms, protective immunity is diminished, as modelled on outcomes of infection from H7N9-infected patients. Although multiple arms are likely to be activated at the same time, hospitalized patients clearly demonstrate that different arms had a more prominent role if one arm fails to respond. MAIT: mucosal associated invariant T.

Figure 2

Immune responses stimulated by natural influenza virus infection, current vaccination, and the ideal scenario of a universal vaccine.

Figure 3

Pre-pandemic vaccines in clinical development. (A) Number of vaccines against viruses of pandemic potential in clinical development for human trials. Source from WHO tables on clinical evaluation of Pandemic/potentially pandemic influenza vaccines [193], including those that use adjuvant or are reactive against avian influenza viruses (H5, H7, or H9 subtypes). Vaccines missing input or not defined were excluded. (B) Proportion of total vaccines from (A). * denotes vaccines which are designed to stimulate T cell response.