Influencing Antibody-Mediated Attenuation of Methamphetamine CNS Distribution through Vaccine Linker Design

Abstract

Active vaccination examining a single hapten engendered with a series of peptidic linkers has resulted in the production of antimethamphetamine antibodies. Given the limited chemical complexity of methamphetamine, the structure of the linker species embedded within the hapten could have a substantial effect on the ultimate efficacy of the resulting vaccines. Herein, we investigate linker effects by generating a series of methamphetamine haptens that harbor a linker with varying amino acid identity, peptide length, and associated carrier protein. Independent changes in each of these parameters were found to result in alterations in both the quantity and quality of the antibodies induced by vaccination. Although it was found that the consequence of the linker design was also dependent on the identity of the carrier protein, we demonstrate overall that the inclusion of a short, structurally simple, amino acid linker benefits the efficacy of a methamphetamine vaccine in limiting brain penetration of the free drug.

Efficacious Vaccine against Heroin Contaminated with Fentanyl

“…Heroin titers increased in vaccination groups containing Her-KLH after a subsequent boost between week 3 and week 5; however, fentanyl titers in the individual Fent-KLH vaccine decreased slightly over time, but exhibited increased antibody affinity by surface plasmon resonance (SPR, Table 2). We have observed this phenomenon for several antidrug vaccines, including a fentanyl vaccine, 7 an oxycodone vaccine, 14 and a methamphetamine vaccine, 8 and this may be the result of a shortened vaccination schedule. 15 Antibody titers detected in the admixture were approximately half the level detected in the individual Her-KLH vaccine, as predicted based on the amount of Her-KLH immunoconjugate employed in each group (Table 1), but antibody affinity remained at similar levels.…”

“…8 Diluted mouse serum IgGs from day 24 (week 3) and 38 (week 5) were incubated with serial dilutions of fentanyl (and analogues), heroin, 6-AM, and morphine and injected into a Biacore 3000 containing a Her-BSA-loaded or Fent-BSA-loaded sensor chip. The ligand, BSA immunoconjugate, was immobilized using NHS, EDC coupling reaction.…”

Enhancing Efficacy and Stability of an Antiheroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality

“…This approach has been preclinically validated for vaccines against nicotine, 6,7 cocaine, 8,9 and methamphetamine. 10,11 For heroin specifically, vaccination efficacy has been repeatedly demonstrated in mice, rats, and nonhuman primates. 12–18 …”

Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity

“…Thus, a theophylline hapten (THEO, 9 ) and two amphetamine haptens (AMPH, 10; 1-A 1 , 11 ) were generated (Figure 3A and Supplementary Methods). 25 Following formulation and immunization with these haptens, robust titers were observed for THEO-KLH and 1-A 1 -KLH (Figure 3B). While THEO-KLH serum readily bound theophylline and fenethylline but not amphetamine, 1-A 1 -KLH bound amphetamine and fenethylline but not theophylline (Figure 3C).…”