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Fentanyl is a major contributor to the devastating increase in overdose deaths from substance use disorders (SUD). A vaccine targeting fentanyl could be a powerful immunotherapeutic. Here, we evaluated adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens. We tested adjuvants derived from the heat-labile toxin of E. coli including dmLT and LTA1 by intramuscular, sublingual or intranasal delivery. Our results show anti-fentanyl serum antibodies and antibody secreting cells in the bone-marrow after vaccination with highest levels observed with an adjuvant (alum, dmLT, or LTA1). Vaccine adjuvanted with LTA1 or dmLT elicited the highest levels of anti-fentanyl antibodies, whereas alum achieved highest levels against the carrier protein. Vaccination with sublingual dmLT or intranasal LTA1 provided the most robust blockade of fentanyl-induced analgesia and CNS penetration correlating strongly to anti-FEN IgA. In conclusion, this study demonstrates dmLT or LTA1 adjuvant as well as mucosal delivery may be attractive strategies for improving the efficacy of vaccines against SUD.

IntroductionThe objective of this study was to determine the burden of influenza disease in patients with or without diabetes in a population of American adults to understand the benefits of seasonal vaccination.Research design and methodsWe performed a retrospective cohort study using electronic medical records totaling 1,117,263 from two Louisiana healthcare providers spanning January 2012 through December 2017. Adults 18 years or older with two or more records within the study period were included. The primary outcome quantified was influenza-related diagnosis during inpatient (IP) or emergency room (ER) visits and risk reduction with the timing of immunization.ResultsInfluenza-related IP or ER visits totaled 0.0122–0.0169 events per person within the 2013–2016 influenza seasons. Subjects with diabetes had a 5.6-fold more frequent influenza diagnosis for IP or ER visits than in subjects without diabetes or 3.7-fold more frequent when adjusted for demographics. Early immunization reduced the risk of influenza healthcare utilization by 66% for subjects with diabetes or 67% for subjects without diabetes when compared with later vaccination for the 2013–2016 influenza seasons. Older age and female sex were associated with a higher incidence of influenza, but not a significant change in risk reduction from vaccination.ConclusionsThe risk for influenza-related healthcare utilization was 3.7-fold higher if patients had diabetes during 2013–2016 influenza seasons. Early immunization provides a significant benefit to adults irrespective of a diabetes diagnosis. All adults, but particularly patients with diabetes, should be encouraged to get the influenza vaccine at the start of the influenza season.

•Formulations and thermal stress uniquely alter dmLT biochemical stability.•Biochemical stability poorly predicts immunity in mouse dmLT vaccine models.•Delivery route and antigen impact vaccine outcomes more than dmLT stability.•Biochemical and immunity testing are needed for vaccine formulation optimization. A key aspect to vaccine efficacy is formulation stability. Biochemical evaluations provide information on optimal compositions or thermal stability but are routinely validated by ex vivo analysis and not efficacy in animal models. Here we assessed formulations identified to improve or reduce stability of the mucosal adjuvant dmLT being investigated in polio and enterotoxigenic E. coli (ETEC) clinical vaccines. We observed biochemical changes to dmLT protein with formulation or thermal stress, including aggregation or subunit dissociation or alternatively resistance against these changes with specific buffer compositions. However, upon injection or mucosal vaccination with ETEC fimbriae adhesin proteins or inactivated polio virus, experimental findings indicated immunization route and co-administered antigen impacted vaccine immunogenicity more so than dmLT formulation stability (or instability). These results indicate the importance of both biochemical and vaccine-derived immunity assessment in formulation optimization. In addition, these studies have implications for use of dmLT in clinical settings and for delivery in resource poor settings.