Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats.

Marco Pravetoni,Mark D. Distefano,Ashli M. Tucker,Paul R. Pentel,Megan Laudenbach,Jeffrey S. Vervacke,Valerie A. Ferro

doi:10.1371/journal.pone.0096547

Marco Pravetoni, Mark D. Distefano + Show 5 more

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https://doi.org/10.1371/journal.pone.0096547

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Abstract

Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund’s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations.

Highlights

Drug addiction is a worldwide public health concern [1]
The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, known to induce strong Th1 responses, was not as effective as alum suggesting that responses to 6OXY-native keyhole limpet hemocyanin (nKLH) and 6OXY-tetanus toxoid (TT) may depend on Th2 activation
TT has been successfully used as a carrier for heroin conjugate vaccines [24,25] and this study extended its use to vaccines against prescription opioids

Summary

Introduction

Drug addiction is a worldwide public health concern [1]. Abuse of prescription opioid analgesics is highly prevalent in the USA with oxycodone and hydrocodone being amongst the most commonly abused drugs in people over 12 years of age [2]. In the USA, overdose is the leading cause of death after prison release, with prescription opioids (oxycodone and hydrocodone) being the most common substances involved [3]. To address this problem, vaccination against drugs of abuse may offer a complementary treatment strategy to current addiction therapies. Addiction vaccines are made by conjugating the target drug to a larger immunogenic carrier peptide or protein of bacterial, viral or other foreign origin and by the use of adjuvants to increase immunogenicity. Drugs of abuse are not immunogenic on their own due to their small size, and the larger carrier is thought to provide signaling for T cell-dependent B cell activation [4]. Vaccine efficacy is limited by the ability of generating high levels of high affinity drug-specific serum antibodies that reduce drug distribution to the brain and block drug-induced behavioral effects

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