Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats

Abstract

Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)4 linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components.

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

“…M-KLH and OXY-KLH produced very high serum antibody concentrations of 0.75 mg/ml, consistent with other reports of heroin and oxycodone vaccine immunogenicity in rats (Anton and Leff, 2006;Pravetoni et al, 2012cPravetoni et al, , 2014aKosten et al, 2013;Raleigh et al, 2013;Jalah et al, 2015), although one report found even higher concentrations of up to 2.8 mg/ml (Stowe et al, 2011). These concentrations are higher than have generally been reported with nicotine or cocaine vaccines using similar linkers and carrier proteins, suggesting that opioid-based haptens are particularly immunogenic, perhaps due to their larger size (Kantak et al, 2000;Keyler et al, 2008;Roiko et al, 2008;Pravetoni et al, 2012a).…”

“…To measure drug-specific serum IgG antibody titers, morphine or oxycodone haptens conjugated to bovine serum albumin were coated on enzyme-linked immunosorbent assay plates at 5 ng/well in carbonate buffer (pH 9.6) and blocked with 1% gelatin (Pravetoni et al, 2012c;Raleigh et al, 2013Raleigh et al, , 2017. Goat anti-rat IgG conjugated to horseradish peroxidase was used as secondary antibodies (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA).…”

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

“…Morphine hapten was synthesized as previously reported (Pravetoni et al, 2012b). Briefly, the C3 position of morphine sulfate was protected with di-tert-butyl carbonate and a tetraglycine (Gly) 4 linker was attached at the C6 to create the hapten M(Gly) 4 (Fig.…”

“…The total number of moles per kilogram of morphine-specific IgG in rats vaccinated with M-KLH was calculated as the product of the reported IgG volume of distribution (131 ml/kg) in rats and the plasma antibody concentration and converted to moles/kg using a molecular weight of 150 kDa for IgG (Bazin-Redureau et al, 1997;Pravetoni et al, 2012b). The corresponding number of drug-binding sites of IgG was twice that number because there are two binding sites per IgG.…”

“…Vaccination with heroin or morphine immunogens can elicit a robust immune response and reduce heroin self-administration and other opioid-related behavioral effects in animals (Bonese et al, 1974;Anton and Leff, 2006;Li et al, 2011;Stowe et al, 2011). These effects are presumably due to the binding of opioids by drug-specific antibodies in blood and reduction of opioid distribution to brain (Pravetoni et al, 2012b). Opioid vaccines have only been studied in animals, but vaccines for cocaine and nicotine have reached phase II-III clinical trials and have shown efficacy in subjects with high antibody responses (Martell et al, 2005;Haney et al, 2010;Hatsukami et al, 2011).…”