The opioid use disorder epidemic is ravaging the western society, with high rates of relapse and overdose deaths. Anti-opioid vaccines could reduce long-term opioid (ab)use and the risk of accidental overdose. Current anti-opioid vaccines in pre-clinical development focus on bio-conjugates composed of opioid haptens that are chemically bound to an immunogenic carrier protein in combination with an admixed molecular adjuvant. This approach is sub-optimal on multiple levels. Firstly, this approach is not designed to co-deliver the hapten-protein conjugate with the molecular adjuvant to antigen presenting cells in lymphoid tissue. An alternative approach that does achieve this is expected to yield a vastly improved immune response. Second, random conjugation of haptens to a carrier is a difficult to reproduce process, hence leading to issues regarding manufacturability, but also exposes the hapten motifs in a non-optimal way to the immune system. An alternative approach that is fully defined and exposes hapten motifs in a spherical conformation, similar as the protein motifs on a viral particle surface, is expected to yield vastly improved binding to B cell receptors and hence inducing anti-hapten antibodies with vastly increased affinity. We present an approach inspired by the mRNA lipid nanoparticle (LNP) design that relies on physical entrapment of hapten, immunogen and molecular adjuvant in a single LNP. These LNP contain:<br/>(1) A biologically inactive fentanyl-poly(ethylene glycol)-dialkyl lipid bio-conjugate for multivalent display of fentanyl haptens on the LNP surface. (2) In their interior an ionizable cationic lipid that entraps a peptide that activates antigen specific CD4 T cells. This peptide is the pan HLA DR-binding epitope PADRE, extended by a decaglutamate amino acid sequence to provide the peptide with an overall anionic charge to allow for electrostatic complexation with an ionizable lipid. (3) Also in their interior a molecular adjuvant that activates antigen presenting cells. In our case we made use of an imidazoquinoline TLR7/8 agonist conjugated to a dialkyl lipid to allow for encapsulation in LNP by hydrophobic interaction. In vivo in mouse models we demonstrate the induction of robust fentanyl-specific antibody responses with the isotype strongly depending on LNP composition. In vitro on cell lines, we demonstrate that serum from immunized mice can capture fentanyl and preventing it from binding to the opioid receptor.

Lipid-PEG-fentanyl bio-conjugates as a hapten design for lipid nanoparticle templated anti-fentanyl vaccines

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.