Injection Route and TLR9 Agonist Addition Significantly Impact Heroin Vaccine Efficacy

Abstract

Active immunization is an effective means of blocking the pharmacodynamic effects of drugs and holds promise as a treatment for heroin addiction. Previously, we demonstrated the efficacy of our first-generation vaccine in blocking heroin self-administration in rats, however, many vaccine components can be modified to further improve performance. Herein we examine the effects of varying heroin vaccine injection route and adjuvant formulation. Mice immunized via subcutaneous (sc) injection exhibited inferior anti-heroin titers compared to intraperitoneal (ip) and sc/ip coadministration injection routes. Addition of TLR9 agonist cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) to the original alum adjuvant elicited superior antibody titers and opioid affinities compared to alum alone. To thoroughly assess vaccine efficacy, full dose–response curves were generated for heroin-induced analgesia in both hot plate and tail immersion tests. Mice treated with CpG ODN 1826 exhibited greatly shifted dose–response curves (10–13-fold vs unvaccinated controls) while non-CpG ODN vaccine groups did not exhibit the same robust effect (2–7-fold shift for ip and combo, 2–3-fold shift for sc). Our results suggest that CpG ODN 1826 is a highly potent adjuvant, and injection routes should be considered for development of small molecule–protein conjugate vaccines. Lastly, this study has established a new standard for assessing drugs of abuse vaccines, wherein a full dose–response curve should be performed in an appropriate behavioral task.

El estado actual de las vacunas contra las drogas

“…Con esto se obtuvieron mayores títulos de anticuerpos (cuatro veces más de IgG1), con mayor afinidad de unión a los opioides evaluados (27 veces para heroína, nueve veces para 6AM y 12 veces para morfina). El efecto protector de la formulación se incrementó de 10 a 13 veces respecto a los grupos sin vacunar y de dos a siete veces en los vacunados sin el adyuvante (Bremer, Schlosburg, Lively, & Janda, 2014). Estos resultados vuelven a la vacuna muy prometedora para apoyar el tratamiento de la adicción.…”

Biologics to treat substance use disorders: Current status and new directions

“…[44][45][46][47] Yet, it is not fully understood whether immunization against drugs of abuse benefits from T h 2-polarized or more balanced T h 1/T h 2 responses. [44][45][46][47] Immunogen dose and adjuvant choice are known to affect CD4 C T cell clonal expansion, differentiation, and polarization.…”

“…[44][45][46][47] Yet, it is not fully understood whether immunization against drugs of abuse benefits from T h 2-polarized or more balanced T h 1/T h 2 responses. [44][45][46][47] Immunogen dose and adjuvant choice are known to affect CD4 C T cell clonal expansion, differentiation, and polarization. [48][49][50] It is possible that specific polarization patterns in the CD4 C T cell repertoire (T h 1 v. T h 2, or T h 1 v. T fh 48,39,51 ) are associated with increased efficacy of vaccines for SUD.…”

“…46,108 Similarly, addition of phosphorothioated CpG to a heroin vaccine adsorbed on alum enhanced Ab titer, affinity, blockage of opioid-induced antinociception. 45 Combination of CpG and alum also showed preclinical efficacy for vaccines directed against the prescription opioid fentanyl. 109 These data suggest that addition of CpG to alum adjuvant improves the quantity, quality, and function of the post-vaccination Ab response, and that this approach will likely improve other vaccines for SUD.…”

“…42,45 Intradermal immunization with a nicotine vaccine combined with skin illumination by a laser source, which increases the motility of dendritic cells, 110 showed immunogenicity and efficacy comparable to intramuscular immunization with the same vaccine adsorbed on alum, MPLA, and MPLA/CpG. 111 Although translation of new adjuvants is often limited by toxicity, side effects, proprietary restrictions, or regulatory approval, it will be important to test available pre-clinical stage, licensed, and/or non-traditional adjuvants to constantly improve the efficacy of SUD vaccines.…”