Breaking methamphetamine's grip

To help overcome the destructive brain chemistry of drug addiction, scientists are developing vaccines that block drugs from generating a high or even reverse an overdose. Researchers have now created a vaccine that cultivates a potent immune response against methamphetamine. Rodents given the vaccine didn’t become as hyperactive after a dose of methamphetamine as those that weren’t immunized against the stimulant (J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem.6b00084).

Compared with the pathogens vaccines tend to target, methamphetamine is a relatively small molecule. “Getting an immune response against a small molecule is way different than getting a response against HIV or Zika,” says Kim D. Janda of Scripps Research Institute. The immune system typically ignores them. To convince the body to build an army of antibodies that can bind to and neutralize a small molecule, scientists can link the molecule to larger carriers, such as proteins, to draw the immune system’s attention and provoke it into striking back.

In a previous study, Janda’s group developed a methamphetamine vaccine based on this principle but got only a so-so immune response in the mice (J. Am. Chem. Soc. 2011, DOI: 10.1021/ja108807j). For the current study, “we’ve gone about it with a more systematic approach,” Janda says, by optimizing the linker molecule and carrier protein to maximize the immune response. A larger immune response should mean more antibodies to bind methamphetamine and sequester the drug in the body, keeping it from reaching its target organ, the brain, and preventing a high. In addition, the tighter the antibodies bind methamphetamine, the better they should be at defanging the drug.

The researchers tested two toxins modified for safe use in vaccines—diphtheria toxoid and tetanus toxoid—as carrier proteins. They synthesized 12 compounds consisting of methamphetamine and a linker molecule, and then conjugated the chemical to the proteins. The researchers tested each of the resulting vaccines by injecting them into mice and measuring how much antibody the mice produced and how tightly the antibodies bound to methamphetamine. The best vaccine using diphtheria toxoid generated antibodies that bound strongly to methamphetamine but stimulated disappointingly low concentrations of antibody. A vaccine using tetanus toxoid—and a change to the adjuvant, an additive in many vaccines that enhances immune response—increased antibody concentration sixfold, though with some loss in affinity for methamphetamine.

The researchers then checked how well this leading vaccine protected mice against the effects of methamphetamine by using video to track their movements. When given methamphetamine, a stimulant, mice typically increase their activity level. Vaccinated mice moved around about a third as much in the 90 minutes after getting a 2 mg/kg dose of methamphetamine as those given carrier protein alone.

Janda spells out some very clever things he’s done to modify the structure of methamphetamine to trick the body into recognizing these vaccines with high affinity,” says Phil Skolnick of the National Institute on Drug Abuse. He cautions, however, “they are very far away from human trials. This is a start.”

Janda plans to continue to optimize the vaccines, he says. “We’re still trying to increase concentration and affinity to give ourselves the best chance of having something successful.”