Abstract
The need for more effective influenza vaccines is highlighted by the emergence of novel influenza strains, which can lead to new pandemics. There is a growing population of susceptible subjects at risk for severe complications of influenza, such as the elderly who are only in part protected by current licensed seasonal vaccines. One strategy for improving seasonal and pandemic vaccines takes advantage of adjuvants to boost and modulate evoked immune responses. In this study, we examined the capacity of the recently described adjuvant cyclic di-adenosine monophosphate (c-di-AMP) to serve as an adjuvant for improved mucosal influenza vaccines, and induce effective protection against influenza H5N1. In detail, c-di-AMP promoted (i) effective local and systemic humoral immune responses, including protective hemagglutination inhibition titers, (ii) effective cellular responses, including multifunctional T cell activity, (iii) induction of long-lasting immunity, and (iv) protection against viral challenge. Furthermore, we demonstrated the dose-sparing capacity of the adjuvant as well as the ability to evoke cross-clade protective immune responses. Overall, our results suggest that c-di-AMP contributes to the generation of a protective cell-mediated immune response required for efficacious vaccination against influenza, which supports the further development of c-di-AMP as an adjuvant for seasonal and pandemic influenza mucosal vaccines.
Highlights
Seasonal and pandemic influenza remain major causes of severe morbidity and mortality worldwide and cause huge economic loss [1]
Epidemic and pandemic outbreaks caused by emerging influenza virus strains, such as the H1N1 of 2009 and the novel avian strains H5N5, H5N8, or H7N9, together with a growing number of high-risk individuals such as elderly or immunosuppressed patients, highlight the need for more effective influenza vaccines
The majority of licensed seasonal vaccines induce humoral responses which correlate with an effective immunity in healthy young adults
Summary
Seasonal and pandemic influenza remain major causes of severe morbidity and mortality worldwide and cause huge economic loss [1]. Most of the licensed seasonal vaccines are administered via parenteral routes; while inducing sufficient systemic immune responses, they fail to promote mucosal immunity [7] This is an important issue considering that the respiratory tract mucosa is the entry portal for influenza viruses. Approval of influenza vaccines in Europe requires demonstration of a protective serological hemagglutination inhibition (HAI) titer above 40, yet other immunologic correlates are important—induction of cellular responses, especially in highrisk groups and effective immune memory [27] In this context, an important aspect of adjuvants is the ability to modulate and potentiate immune responses [17, 18]. Application of the c-di-AMP facilitated dose sparing and cross-clade reactive immune responses against drifted strains, such as A/Anhui/1/2005 (IBCDC-RG6) Together, this supports the further development of c-di-AMP as an adjuvant for seasonal and pandemic influenza mucosal vaccines
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