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 [1,2]. 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 [3,4]. 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 [4-6]. 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 [7-9]. 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 © Korean Vaccine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. K O R E A N V A C C I N E S O C I E T Y