Drug addiction vaccines show encouraging efficacy in pre-clinical studies, yet translation to the clinic has been slowed by the variability of serum antibody concentrations reported in immunized subjects. Establishing early markers of vaccine immunogenicity would help predict efficacy, accelerate screening of vaccine designs, and individualize vaccine design selection in clinical settings. The overall hypothesis of this study i that clinically significant responses to drug addiction vaccines (drug hapten-protein conjugate) can be predicted from the number of hapten-specific B cells in naive (unimmunized) and immunized subjects. Specifically oxycodone (OXY)-specific B cells will be compared between different OXY vaccines and will correlate with OXY-specific serum antibodies and OXY distribution before and after immunization with OXY vaccines in rodents. A recently developed strategy detects rare antigen-specific B cells in naive and immunized subjects. Antigen-specific B cells are selected from the total B cell repertoire present in an unimmunized or immunized host by a fluorescent antigen-based enrichment method and then characterized by flow cytometry. This method can be adapted to drug conjugate vaccines by conjugating drug haptens to a fluorescent carrier protein used to detect hapten-specific B cells. Our lab has developed two OXY vaccines showing a range of effects in reducing brain distribution and behavioral effects of OXY, one of the most commonly abused prescription opioids. These vaccines will be used to test if OXY-specific B cells can be used to explain variability between structurally different vaccines and individual variability between subjects after immunization. We will test the hypotheses that: 1) the numbers of pre- and post-immunization OXY-specific B cells will be higher for the more efficient OXY vaccine in both mice and rats 2) the numbers of pre- and post- immunization OXY-specific B cells will correlate with OXY-specific serum antibody titers and with the effect of immunization on OXY distribution to the brain in rats. This will be tested by:
aim 1 A) characterizing the time course of OXY-specific B cell and OXY-specific antibody responses to two OXY vaccines in mice to determine B cell responses;
aim 1 B) assessing the same method in a second species (rats);
aim 2 A) correlating pre- immunization na?ve OXY-specific B cells to OXY-specific antibody titers and their effects on OXY distribution to the brain in rats, and aim 2B) correlating early post- immunization activated OXY-specific B cells to OXY- specific serum antibody titers and their effects on OXY distribution to brain in rats PUBLIC HEALTH SIGNIFICANCE. Prescription drug abuse is the fastest-growing drug problem in the US, with oxycodone and oxymorphone among the most abused. Drug addiction vaccines offer a promising advantage to current pharmacotherapies to treat dependence. Early screening of immunogenicity will enable individualized treatment by matching the vaccine to patient and rapid treatment adjustment. This approach could be expanded to other drug-conjugate vaccines.
Prescription drug abuse is the fastest-growing drug problem in the US, with oxycodone and oxymorphone among the most abused. Drug addiction vaccines offer a promising advantage to current pharmacotherapies to treat dependence. Early screening of immunogenicity will enable individualized treatment by matching the vaccine to patient and rapid treatment adjustment. This approach could be expanded to other drug-conjugate vaccines.
|Laudenbach, M; Tucker, A M; Runyon, S P et al. (2015) The frequency of early-activated hapten-specific B cell subsets predicts the efficacy of vaccines for nicotine dependence. Vaccine 33:6332-9|
|Laudenbach, Megan; Baruffaldi, Federico; Vervacke, Jeffrey S et al. (2015) The frequency of naive and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse. J Immunol 194:5926-36|
|Pravetoni, Marco; Vervacke, Jeffrey S; Distefano, Mark D et al. (2014) Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats. PLoS One 9:e96547|
|Taylor, J J; Laudenbach, M; Tucker, A M et al. (2014) Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse. J Immunol Methods 405:74-86|