Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines.

CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting-cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naïve CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the respiratory tract.

Practice Patterns and Performance in U.S. Fracture Liaison Programs: An Analysis of >32,000 Patients from the Own the Bone Program.

BACKGROUND: We are not aware of any previous investigation assessing a national cohort of patients enrolled in a fracture liaison service (FLS) program in an open health-care system to ascertain prevalent practice patterns. The objective of this investigation was to determine, in a geographically diverse group of centers in a single FLS program, the percentage of patients for whom anti-osteoporosis treatment was recommended or started as well as to identify associations between patient and fracture variables and the likelihood of treatment being recommended. METHODS: The study utilized the Own the Bone program registry, which included 32,671 unique patient records with the required data. The primary outcome measure was whether a recommendation to start anti-osteoporosis treatment was made to the patient at the time of program enrollment. The associations between patient and fracture variables and the likelihood of having treatment recommended were calculated. RESULTS: Anti-osteoporosis treatment was recommended to 72.8% of patients and was initiated for 12.1%. A sedentary lifestyle and a parent who had sustained a hip fracture increased the likelihood of a treatment recommendation by 10% and 12%, respectively. While patients with a spinal fracture were 11% more likely to have received a treatment recommendation, those with a hip fracture were 2% less likely to have received such a recommendation. Age was not strongly associated with the likelihood of receiving a treatment recommendation but was associated with the initiation of treatment. CONCLUSIONS: Practitioners at sites in the Own the Bone program recommend anti-osteoporosis treatment, at the time of initial evaluation, to about three-quarters of patients who present with a fragility fracture. This is a very strong improvement over previously reported national data. The findings that a hip fracture had the lowest association and age had very little association with the likelihood of recommending treatment were unexpected and perhaps deserve further investigation. CLINICAL RELEVANCE: FLS programs and sites as well as all those who manage patients with a fragility fracture can utilize the information derived from this study to improve practice patterns for the care of these patients.