Abstract
Due to the high risk of an outbreak of pandemic influenza, the development of a broadly protective universal influenza vaccine is highly warranted. The design of such a vaccine has attracted attention and much focus has been given to nanoparticle-based influenza vaccines which can be administered intranasally. This is particularly interesting since, contrary to injectable vaccines, mucosal vaccines elicit local IgA and lung resident T cell immunity, which have been found to correlate with stronger protection in experimental models of influenza virus infections. Also, studies in human volunteers have indicated that pre-existing CD4+ T cells correlate well to increased resistance against infection. We have previously developed a fusion protein with 3 copies of the ectodomain of matrix protein 2 (M2e), which is one of the most explored conserved influenza A virus antigens for a broadly protective vaccine known today. To improve the protective ability of the self-adjuvanting fusion protein, CTA1-3M2e-DD, we incorporated it into porous maltodextrin nanoparticles (NPLs). This proof-of-principle study demonstrates that the combined vaccine vector given intranasally enhanced immune protection against a live challenge infection and reduced the risk of virus transmission between immunized and unimmunized individuals. Most importantly, immune responses to NPLs that also contained recombinant hemagglutinin (HA) were strongly enhanced in a CTA1-enzyme dependent manner and we achieved broadly protective immunity against a lethal infection with heterosubtypic influenza virus. Immune protection was mediated by enhanced levels of lung resident CD4+ T cells as well as anti-HA and -M2e serum IgG and local IgA antibodies.
Highlights
The quest for a broadly protective influenza vaccine is ongoing
We found that most of the fusion protein CTA1-3M2e-DD (FPM2e) had been bound to the NPLs, as shown by the absence of free FPM2e in the native polyacrylamide gel electrophoresis (PAGE) analysis (Figure 1B, right panel)
It was clear that the immunogenicity of the incorporated HA greatly benefitted from the adjuvant enhancing effects of the HA:FPM2e:NPL vector as anti-HA serum IgG titers were almost 10-fold higher than in HA:NLPs without the FPM2e (Figure 4G). Though, this effect was seen only when the FPM2e was in the same particle as the HA and not when the FPM2e was co-administered in antibodies in serum (H) or IgA antibodies in broncheoalveolar lavage (BAL) (I) were measured by ELISA in Balb/c mice immunized i.n. with FPM2e, FPM2e:NPL or PBS, as indicated, and given as mean log10-titers ± SD of 3 independent experiments giving similar results
Summary
The quest for a broadly protective influenza vaccine is ongoing. Whereas many different strategies have been employed to design a novel vaccine, a common denominator for these has been to identify conserved viral epitopes that could serve as effective vaccine components [1]. Clinical studies have indicated that cell-mediated immune responses, more than antibodies, may be critical for a broadly protective influenza vaccine and, M2e, and several internal structural proteins have been considered for a universal flu vaccine [10, 13]. While both memory CD4+ and CD8+ T cells have been found to correlate with protection against heterosubtypic influenza virus strains, experimental evidence in this regard points to a critical function of lung resident memory T cells for protection [17,18,19,20]. Many researchers have focused efforts on mucosal vaccines, which have been found superior to injectable vaccines at stimulating lung resident memory T cells, concomitant with strong secretory IgA (sIgA) and significant systemic IgG immune responses [22]
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