Challenges in the development of T-cell-based universal influenza vaccines.

An influenza virus infection generates humoral and cellular immunity that provides protection against reinfection if it does not subvert an infected host. The efficacy of current influenza vaccines depends on humoral immunity directed at surface glycoproteins, such as hemagglutinin and neuraminidase. The antibody-mediated protection is effective against homologous strains but not against heterologous strains with serologically distinct surface proteins. The highly mutagenic properties of influenza viral RNA polymerase and immunologic pressure from the host result in strains with antigenic drifts mainly in those glycoproteins, which reduce or eliminate a vaccine's efficacy. Thus, vaccine formulations must be updated annually through surveillance of strains that will most likely be prevalent in the subsequent flu season. However, as demonstrated by previous epidemics and pandemics, there have been years in which flu vaccines were ineffective owing to discrepancies between the strains used to create the vaccines and the strains that ended up circulating or the emergence of a new strain as a result of antigenic drift and accumulated mutations or antigenic shift by genetic reassortment between different viral subtypes. Moreover, it takes several months to isolate and amplify new strains and create vaccines against them. These limitations of current vaccines spur the need to develop new vaccines capable of protecting against a broad range of influenza strains.

Such broadly protective “universal influenza vaccines” are based on the phenomenon of heterosubtypic immunity, wherein host immune responses to highly conserved epitopes across several influenza subtypes confer protection against heterosubtypic challenge. In animal models, it has been shown that heterosubtypic immunity could be mediated by T cells, specifically CD8+ T cells and CD4+ T cells [12]. The heterosubtypic T cells are cross-reactive to conserved peptides, predominantly those of internal viral proteins such as polymerase-binding protein (PB) 1, matrix 1 (M1), and nucleoprotein (NP). CD8+ T cells are thought to be the primary effectors of heterosubtypic immunity owing to their cytotoxic effects against virus-infected cells and antiviral suppressor function. In contrast, the role of CD4+ T cells in mediating heterosubtypic immunity is less clear, but it is an increasing focus of attention [34]. Recent studies suggest that heterosubtypic CD4+ T cells mediate cross-protection through various mechanisms, including direct cytolytic activity and interactions with B cells or CD8+ T cells [456]. In humans, recognition by CD4+ T cells and CD8+ T cells of conserved epitopes in internal proteins was shown to correlate with protection against influenza infection [789]. Regarding protection against influenza, lung resident memory T cells (TRM), which are present locally in the airways or parenchyma of the respiratory tract, are receiving increasing attention. Recent studies have shown that lung TRM cells have superior protective capacity as compared to circulating memory CD8+ T cells [1011]. Lung TRM cells have also been found in humans, and it has been suggested that they can respond to influenza infection [1213]. However, a direct connection between TRM cells and reduced disease severity in humans remains to be made.

Overall, recent studies strongly suggest that T-cell–based vaccines could be a promising strategy for a “universal influenza vaccine.” However, there are some challenges facing development of a T-cell–based universal influenza vaccine. One is generation of durable antigen-specific memory responses in the respiratory tract. Regarding this, previous studies have shown that several factors such as dendritic cells in the respiratory tract, antigen persistence in the lungs, and antigen delivery routes might be associated with generation of long-lasting TRM cells in the lungs [141516]. Another challenge lies in developing vaccines that provide sufficient coverage to individuals with diverse HLA haplotypes, which presents the need to examine T-cell responses in the context of ethnicity. There are also concerns about inflammatory pathologies which could be promoted and/or exacerbated by vaccine-induced T cells. In addition, the correlation between vaccine-induced T-cell responses and protection is difficult to measure quantitatively in humans, which presents another barrier to developing T-cell–based influenza vaccines. Despite these obstacles, it is expected that our growing understanding of the mediators of heterosubtypic immunity and technological advancements related to vaccine design will expedite the development of T-cell–based, broad-acting, new influenza vaccines.