Tolerability and Safety of Sublingual Immunotherapy in Patients with Tree Pollen Allergy in Daily Practice-An Open, Prospective, Non-Interventional Study.

To investigate the tolerability and safety of two sublingual tree pollen extracts approved in 2018, a non-interventional study (NIS) was performed. This NIS was an 8-month observational study conducted at 84 sites throughout Germany. Study participants received either a sublingual liquid allergen extract of birch pollen (SBPE) or a liquid allergen extract consisting of a mixture of birch, hazel, and alder tree pollen (STPE). Data from 432 patients were analyzed for the occurrence of adverse events and patient compliance. At least one local reaction occurred in 69 (22.2%) patients, whereas systemic reactions were only observed in 27 (6.3%) patients. STPE-treated patients developed systemic reactions more frequently than SBPE-treated patients (SBPE: 9 (4.3%) vs. STPE: 18 (8.0%)). Only one patient developed a systemic grade III reaction. Severe systemic grade IV reactions were not observed. A total of 348 (98.6%) of the patients who completed all visits were satisfied or very satisfied with the sublingual immunotherapy (SLIT), and 322 (71%) patients completed all visits. Both investigated products were well tolerated by the patients and demonstrated a good safety profile. AEs were observed less frequently than in the preceding clinical phase III trial, and no new safety concerns were identified.

Efficient Induction of Cytotoxic T Cells by Viral Vector Vaccination Requires STING-Dependent DC Functions.

Modified Vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus and currently under investigation as a promising vaccine vector against infectious diseases and cancer. MVA acquired mutations in host range and immunomodulatory genes, rendering the virus deficient for replication in most mammalian cells. MVA has a high safety profile and induces robust immune responses. However, the role of innate immune triggers for the induction of cytotoxic T cell responses after vaccination is incompletely understood. Stimulator of interferon genes (STING) is an adaptor protein which integrates signaling downstream of several DNA sensors and therefore mediates the induction of type I interferons and other cytokines or chemokines in response to various dsDNA viruses. Since the type I interferon response was entirely STING-dependent during MVA infection, we studied the effect of STING on primary and secondary cytotoxic T cell responses and memory T cell formation after MVA vaccination in STING KO mice. Moreover, we analyzed the impact of STING on the maturation of bone marrow-derived dendritic cells (BMDCs) and their functionality as antigen presenting cells for cytotoxic T cells during MVA infection in vitro. Our results show that STING has an impact on the antigen processing and presentation capacity of conventionel DCs and played a crucial role for DC maturation and type I interferon production. Importantly, STING was required for the induction of efficient cytotoxic T cell responses in vivo, since we observed significantly decreased short-lived effector and effector memory T cell responses after priming in STING KO mice. These findings indicate that STING probably integrates innate immune signaling downstream of different DNA sensors in DCs and shapes the cytotoxic T cell response via the DC maturation phenotype which strongly depends on type I interferons in this infection model. Understanding the detailed functions of innate immune triggers during MVA infection will contribute to the optimized design of MVA-based vaccines.

Advantages and Limitations of Integrated Flagellin Adjuvants for HIV-Based Nanoparticle B-Cell Vaccines.

The great advantage of virus-like particle (VLP) nano-vaccines is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter viral proteins in their natural conformation. "Wild-type" viral nanoparticles can be further genetically or biochemically functionalized with biomolecules (antigens and adjuvants). Flagellin is a potent inducer of innate immunity and it has demonstrated adjuvant effectiveness due to its affinity for toll-like receptor 5 (TLR5). In contrast to most TLR ligands, flagellin is a protein and can induce an immune response against itself. To avoid side-effects, we incorporated a less inflammatory and less immunogenic form of flagellin as an adjuvant into HIV-based nanoparticle B-cell-targeting vaccines that display either the HIV-1 envelope protein (Env) or a model antigen, hen egg lysozyme (HEL). While flagellin significantly enhanced HEL-specific IgG responses, anti-Env antibody responses were suppressed. We demonstrated that flagellin did not activate B-cells directly in vitro, but might compete for CD4+ T-cell help in vivo. Therefore, we hypothesize that in the context of VLP-based B-cell nano-vaccines, flagellin serves as an antigen itself and may outcompete a less immunogenic antigen with its antibody response. In contrast, in combination with a strong immunogen, the adjuvant activity of flagellin may dominate over its immunogenicity.