Search

The neuraminidase (NA) is an abundant antigen at the surface of influenza virions. Recent studies have highlighted the immune-protective potential of NA against influenza and defined anti-NA antibodies as an independent correlate of protection. Even though NA head domain changes at a slightly slower pace than hemagglutinin (HA), NA is still subject to antigenic drift, and therefore an NA-based influenza vaccine antigen may have to be updated regularly and thus repeatedly administered. NA is a tetrameric type II membrane protein, which readily dissociates into dimers and monomers when expressed in a soluble form. By using a tetramerizing zipper, such as the tetrabrachion (TB) from Staphylothermus marinus, it is possible to stabilize soluble NA in its active tetrameric conformation, an imperative for the optimal induction of protective NA inhibitory antibodies. The impact of repetitive immunizations with TB-stabilized antigens on the immunogenicity of soluble TB-stabilized NA is unknown. We demonstrate that TB is immunogenic in mice. Interestingly, preexisting anti-TB antibodies enhance the anti-NA antibody response induced by immunization with TB-stabilized NA. This immune-enhancing effect was transferable by serum and operated independently of activating Fcγ receptors. We also demonstrate that priming with TB-stabilized NA antigens, enhances the NA inhibitory antibody responses against a heterosubtypic TB-stabilized NA. These findings have implications for the clinical development of oligomeric vaccine antigens that are stabilized by a heterologous oligomerizing domain., (© 2022. The Author(s).)

Annual administration and reformulation of influenza vaccines is required for protection against seasonal infections. However, the induction of strong and long-lasting T cells is critical to reach broad and potentially lifelong antiviral immunity. The NLRP3 inflammasome and its product interleukin-1β (IL-1β) are pivotal mediators of cellular immune responses to influenza, yet, overactivation of these systems leads to side effects, which hamper clinical applications. Here, we present a bypass around these toxicities by targeting the activity of IL-1β to CD8 + T cells. Using this approach, we demonstrate safe inclusion of IL-1β as an adjuvant in vaccination strategies, leading to full protection of mice against a high influenza virus challenge dose by raising potent T cell responses. In conclusion, this paper proposes a class of IL-1β-based vaccine adjuvants and also provides further insight in the mechanics of cellular immune responses driven by IL-1β., Competing Interests: Competing interestsFinancial interests: N.K. and J.T. are affiliated with Orionis Biosciences Inc. as scientific advisor and/or employee and hold equity interests in Orionis Biosciences Inc. N.K., J.T., S.G., F.P., and G.U. are inventors on the following patent applications related to the work presented in this paper: WO/2015/007542: Targeted modified IL-1 family members. Applicants: VIB VZW, Universiteit Gent, Centre National de la Recherche Scientifique, Université Montpellier, Centre Hospitalier Regional Universitaire de Montpellier. Inventors: J.T., S.G., F.P., and G.U. This patent application describes IL-1β mutants with reduced bioactivity that can be activated by targeting as demonstrated in this paper for IL-1β Q148G. WO/2017/134306: CD8 binding agents. Applicants: Orionis Biosciences Inc., VIB VZW, Universiteit Gent. Inventors: J.T., Anje Cauwels, N.K., and S.G. This patent application describes sdAbs that bind CD8 and that can be used to target mutant IL-1β to CTLs as demonstrated in this paper. The authors have no other, nonfinancial, competing interests to declare., (© The Author(s) 2020.)