IL-1ß as mucosal vaccine adjuvant: the specific induction of tissue-resident memory T cells improves the heterosubtypic immunity against influenza A viruses.

A universal influenza vaccine must provide protection against antigenically divergent influenza viruses either through broadly neutralizing antibodies or cross-reactive T cells. Here, intranasal immunizations with recombinant adenoviral vectors (rAd) encoding hemagglutinin (HA) and nucleoprotein (NP) in combination with rAd-Interleukin-(IL)-1ß or rAd-IL-18 were evaluated for their efficacy in BALB/c mice. Mucosal delivery of rAd-IL-1ß enhanced HA-specific antibody responses including strain-specific neutralizing antibodies. Nevertheless, the beneficial effects on the local T cell responses were much more impressive reflected by increased numbers of CD103+CD69+ tissue-resident memory T cells (TRM). This increased immunogenicity translated into superior protection against infections with homologous and heterologous strains including H1N1, pH1N1, H3N2, and H7N7. Inhibition of the egress of circulating T cells out of the lymph nodes during the heterologous infection had no impact on the degree of protection underscoring the unique potential of TRM for the local containment of mucosal infections. The local co-expression of IL-1ß and antigen lead to the activation of critical checkpoints in the formation of TRM including activation of epithelial cells, expression of chemokines and adhesion molecules, recruitment of lung-derived CD103+ DCs, and finally local TRM imprinting. Given the importance of TRM-mediated protection at mucosal barriers, this study has major implications for vaccine development.

Barriers to HIV Cure.

Since the beginning of the epidemic, more than 70 million people have been infected with human immunodeficiency virus (HIV) and about 38 million have died from acquired immune deficiency syndrome (AIDS)-related illnesses. While the discovery of highly active antiretroviral therapy (HAART) in the mid 90's has saved millions of lives, a complete eradication of HIV is still not possible as HIV can persist for decades in a small reservoir of latently infected cells. Once reactivated, these latently infected cells can actively produce viral particles. Recent studies suggest that several sanctuaries exist within infected individuals where HIV can remain undetected by the immune system. These cellular, anatomical and microanatomical viral reservoirs represent a major obstacle for the eradication of HIV. Here we review recent findings on potential sanctuaries of HIV and address potential avenues to overcome these immunological barriers.

Codon-optimization of the hemagglutinin gene from the novel swine origin H1N1 influenza virus has differential effects on CD4(+) T-cell responses and immune effector mechanisms following DNA electroporation in mice.

DNA electroporation is a powerful vaccine strategy that could be rapidly adapted to address emerging viruses. We therefore compared cellular and humoral immune responses in mice vaccinated with DNA expression plasmids encoding either the wildtype or a codon-optimized sequence of hemagglutinin from the novel swine origin H1N1 influenza virus. While expression of HA from the wildtype sequence was hardly detectable, the H1N1 hemagglutinin was well expressed from the codon-optimized sequence. Despite poor expression of the wildtype sequence, both plasmids induced similar levels of CD4(+) T-cell responses. However, CD8(+) T-cell and antibody responses were substantially higher after immunization with the codon-optimized DNA vaccine. Thus, efficient induction of immune effector mechanisms against HA of the novel H1N1 influenza virus requires codon-optimization of the DNA vaccines. Since DNA vaccines and several viral vector vaccines employ the same cellular RNA-Polymerase II dependent expression pathway, the poor expression levels from wildtype HA sequences might also limit the induction of immune effector mechanisms by such viral vector vaccines.