July 30, 2020

Heavy' heroin vaccine provides hope for addiction treatment Replacing key hydrogen atoms in the experimental vaccine with heavy hydrogen mysteriously improved results in animals, leading to follow-up studies.

July 30, 2020

LA JOLLA, CA Chemists at Scripps Research have reported a promising but mysterious finding in experiments with a potential vaccine that is meant to combat heroin addiction.

In the heroin-mimicking molecule at the heart of the vaccine, the researchers replaced several hydrogen atoms with atoms of a heavier form of hydrogen called deuterium, and found that the new vaccine was significantly improved at eliciting anti-heroin antibodies and blunting heroin's behavioral effects in rodents.

The discovery, reported in the Journal of the American Chemical Society, appears to increase the chances that researchers will be able to develop a clinically effective heroin vaccine. It also suggests the possibility that deuterating other vaccines in this way may be a broadly applicable method for boosting their effectiveness although precisely why this alteration works is still unknown.

I just had a hunch there wasn't anything in the vaccine literature to indicate that it would work, says study senior author Kim Janda, PhD, Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research.

Janda and his laboratory in the past three decades has helped pioneer the development of vaccines against a number of notorious drugs of abuse including opioids, cocaine, and methamphetamine. These vaccines are meant to prime the immune system to make antibodies that attack drug molecules as soon as they reach the bloodstream. The idea is that by stopping the drug molecules from reaching the brain, the vaccine would keep a user from experiencing a high from a drug, while also deterring possible overdose.

A heroin vaccine has been seen as a particularly powerful public health tool, given the ongoing epidemic of deaths from heroin and synthetic opioids a toll that exceeded 70,000 in the United States last year. Scientists have warned in recent months that the COVID-19 pandemic may be making the opioid crisis even worse, by disrupting treatment and other interventions. However, current efforts to develop a heroin vaccine for clinical use have been slowed by the fact that the vaccine's induced antibody response doesn't block heroin's effects sufficiently.

Heavy heroin

Janda's hunch was that a molecule called deuterium might provide the needed boost in effectiveness. Deuterium is a naturally occurring and stable variant, or isotope, of hydrogen. Seawater, for example, contains one deuterium atom for every 6,000 or so atoms of ordinary hydrogen. Whereas ordinary hydrogen consists of a positively charged proton and a negatively charged electron, deuterium has those plus a neutron. That makes it slightly bulkier and heavier than its much more common cousin, even though it has essentially the same chemical properties.

In the study, Janda and colleagues started with an experimental heroin vaccine they developed and tested several years ago, then chemically replaced six hydrogen atoms with deuterium atoms at one end of the heroin-mimicking part of the vaccine molecule which is attached at the other end to a carrier protein.

Working in rodents, the scientists found that the heavy heroin vaccine elicited significantly higher antibody levels compared to the non-deuterated vaccine. Tests also showed that the antibodies generated by the heavy heroin vaccine could bind to heroin, and to its most important brain-affecting breakdown product in the blood, at least as well as and mostly better than antibodies generated by the non-deuterated heroin vaccine.

Behavioral tests on the mice indicated that those who had received the heavy heroin vaccine were markedly less affected by heroin when injected with it, compared with the mice who had received the non-deuterated vaccine.

Janda and colleagues still don't know how the deuteration of the vaccine, which should have only subtle effects on its physical properties, boosts its ability to elicit an antibody response. They note, though, that deuteration has been shown for other drugs to slow their breakdown in the blood by enzymes. If this is occurring with the heavy heroin vaccine, it may allow the vaccine to be processed by the immune system for longer periods and thus elicit a better antibody response.

The researchers are following up with further studies, including comparisons of the standard and deuterated forms of the heroin vaccine in monkeys.

This is a technique that potentially can be used to resurrect not just our heroin vaccine but also other vaccines that have shown marginal effectiveness, Janda says.

The co-authors of the paper, Enhancement of a Heroin Vaccine Through Hapten Deuteration, were Tyson Belz, Paul Bremer, Bin Zhou, Beverly Ellis, Lisa Eubanks, and Kim Janda, all of Scripps Research during the study.

Support for the research was provided by the National Institutes of Health (UH3DA041146).

Chemistry Janda, Kim

LINK:	https://www.scripps.edu/news-and-events/press-room/2020/20200730-janda...
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