Vaccination against cocaine: Incremental advance

Oct 06 2009 Published by under Cocaine, Drug Abuse Science, Opiates

I last broached the topic of immunization against drug use some time ago and I concentrated more on the ethical implications of vaccinating. I was being ever so slightly disingenuous because the current state of progress is not such that we need to consider such questions as:

Would you recommend it broad-spectrum for all children much like MMR?
Would you recommend parents be permitted to subject their drug abusing teen against his or her will?
Allow the courts to mandate inoculation?
Suppose it were made a condition of employment?

ResearchBlogging.org This post was chosen as an Editor's Selection for ResearchBlogging.orgA recent paper by Martell and colleagues provides a nice opportunity to review the promise and limitations of immunopharmacotherapy for drugs of abuse. The rationale for such studies is pretty easy to grasp, although at present the results fall short of the lasting immunity you associate with childhood vaccines and even the seasonal flu shot. Drugs of abuse are molecules that do not generate any immune response because they are too small. The starting rationale is that if you create a drug mimic and attach it to something that will attract the attention of the immune system you might be able to generate antibodies that recognize the target drug.


The earliest attempts at this that I can locate are from the mid-late 1970s. The investigators tried to raise anti-morphine antibodies in monkeys who were trained to self-administer heroin, IV. With either active immunization or passive immunization (isolate the antibodies from one monkey for administration in recipient monkey) the authors were able to show increased self-administration of drug. This is precisely what you'd expect if the drug molecules were being bound to antibody in the blood (sequestered) and prevented from entering the brain, thus lowering the effective dose where it counts.
From what I can tell the topic was dropped for a good while until a paper from Carrera and colleagues in 1995 showed that active immunization against cocaine in rats could reduce locomotor stimulation and the induction of repetitive stereotyped behavior (stereotypy) because of reduced cocaine entry to the brain. This sparked a renewed interest and a bunch of papers. Preclinical results were promising and we now have human clinical trials for nicotine and cocaine vaccination ongoing. The main topic for today is a paper describing the outcome of one of these human trials.

Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients: A Randomized, Double-blind, Placebo-Controlled Efficacy Trial Bridget A. Martell, MD, MA; Frank M. Orson, MD; James Poling, PhD; Ellen Mitchell, RN; Roger D. Rossen, MD; Tracie Gardner, PhD; Thomas R. Kosten, MD. Arch Gen Psychiatry. 2009;66(10):1116-1123

The study tested "a cocaine vaccine made by covalently linking succinylnorcocaine to recombinant cholera toxin B-subunit protein,
adsorbed onto aluminum hydroxide adjuvant
" which was administered to 57 individuals (55 completed the immunizations series) who met DSM-IV criteria for opioid and cocaine dependence and were on methadone maintenance for the opioid dependence. An additional 57 similar individuals were given a sham vaccine. The subjects received 5 injections on a 2-week interval for the first 4 and a 4-week interval for the final booster. The reason for the dual-dependence and methadone maintained population was simple. Prior studies show that methadone patients will remain enrolled and keep returning for the necessary length of time whereas cocaine-only patients do not tend to keep coming back for a 20-week study period. Non-compliance with the regimen has a tendency to leave you with uninterpretable results (which apparently is not always a death knell). So for an early attempt, this makes a lot of sense.
The cocaine vaccine and vaccination schedule have been previously demonstrated to produce cocaine-specific antibodies in humans which peak at about the 8-12 week point of the schedule.
The primary outcome measure of this study was a urine sample collected thrice weekly and analyzed for the cocaine metabolite benzoylecgonine. Values were compared between sequential samples to determine if there was evidence of new cocaine use using an established method.
The result of this study was positive in that vaccination resulted in about 45% cocaine-free urine samples compared with about 35% in the placebo group. The effect was apparent from about weeks 10-16 in decent correlation with the antibody response during vaccination/boost and after discontinuation. So far so good.
Martell09-CocVacc-Fig2.png
source
There was a catch, however, which is depicted in Figure 2, reproduced here. The figure shows the antibody response for individuals receiving active vaccine across weeks of the study. What immediately strikes you is the observation that some individuals mounted a robust antibody response and some did not. The authors have a rationale for using a threshold of ever getting above 43 ug/ml as a critical dividing line. The results mentioned above are only for the group that mounted an antibody response above 43 ug/ml, the lower-responders matched the placebo group in terms of the number of cocaine-free urine samples provided.
So this is the current state of technical limitation. The vaccine works for some individuals but not others and I expect the next step is to try to figure out why and/or to predict who will benefit from vaccination. Even for the high-responders the outcome was far from overwhelming, a 10 percentage improvement from 35% to 45% cocaine-free urines isn't exactly eye-popping. So perhaps the next goals are to see whether other anti-cocaine constructs will work (better) in different individuals or if a given individual will respond (or not) to just about any immunogen. To try to get better efficacy. It is also likely that the dirty little secret of vaccines may be playing a major role here. (My next post on this topic will almost certainly be about an adjuvant story.)
I'll end by noting that my personal read on agonist therapy for cocaine dependence is that it is a big fat failure. There has been a lot of research effort, generally funded by NIDA, into dopamine transporter inhibitors that might work as agonist therapy for cocaine. It seems to have been a bust. We need new approaches and this immunopharmacotherapy stuff has potential.
It is quite obviously not a silver bullet solution at present. And when you think about it a bit, it never will be. This is a dose-reduction strategy. People can overcome this by taking more drug, just as was observed with the early heroin self-administration studies I cited at the start of the post. At present I think the target population will be a cocaine-dependent one that is reasonably motivated to stop using cocaine. Getting stuck in the deltoid every 2-4 weeks is pretty aversive. If keeping cocaine users in 6 mo studies is already difficult, a repeated vaccination does not sound universally promising.
If anyone comes up with a vaccine that lasts on the order of a year after one to three injections...well then maybe we can talk about broader applications. Such as your teenager.
Which will make the ethical discussion much more interesting once again.
__
The usual disclaimer applies. I may have in the past conducted, in the present conduct or be actively seeking to conduct research related to this topic. Furthermore, I may have have held, currently hold or be actively seeking to secure grant funding related to this topic. Or maybe I just know people who are working on this stuff. Especially since there is a commercial potential in this case, I encourage you to apply a pinch of "conflicted up the wazoo" salt to your reading of this post since I would rather you overestimate rather than underestimate any COI.

Literature Cited

Bonese KF, Wainer BH, Fitch FW, Rothberg RM, & Schuster CR (1974). Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature, 252 (5485), 708-10 PMID: 4474602
Killian A, Bonese K, Rothberg RM, Wainer BH, & Schuster CR (1978). Effects of passive immunization against morphine on heroin self-administration. Pharmacology, biochemistry, and behavior, 9 (3), 347-52 PMID: 101989
Carrera, M., Ashley, J., Parsons, L., Wirsching, P., Koob, G., & Janda, K. (1995). Suppression of psychoactive effects of cocaine by active immunization Nature, 378 (6558), 727-730 DOI: 10.1038/378727a0
Bridget A. Martell, MD, MA, Frank M. Orson, MD, James Poling, PhD, Ellen Mitchell, RN, Roger D. Rossen, MD, Tracie Gardner, PhD, & Thomas R. Kosten, MD (2009). Cocaine Vaccine for the Treatment of Cocaine
Dependence in Methadone-Maintained Patients: A Randomized, Double-blind, Placebo-Controlled Efficacy Trial ARCH GEN PSYCHIATRY, 66 (10), 1116-1123

11 responses so far

  • matt says:

    you should check out the groups developing cocaine esterase as an enzymatic therapy for cocaine abuse and addiction. probably a better approach than vaccination

  • DrugMonkey says:

    Why is that a better approach?

  • Scicurious says:

    It'd be very interesting to see how the vaccine response correlated with things like "motivation" to take heroin via a progressive ratio schedule, or with initial conditioned place preference for drug. Is it possible, for example, that those who mount a high antibody response are in general less likely to find the drug reinforcing? There's a lot of individual variation in this, correlated with things like receptor levels, etc (well, in some models). It'd be pretty sad if the correlation of the immune response was only in those who probably wouldn't really like the drug in the first place.

  • David says:

    Nice post, Dr Monkey. Good comprehensive review of a complex paper.
    What would happen if the epitope inciting the response was actually to the part of cocaine that binds the receptor, and if the immune response were carried into the CNS? Isn't there a potential for some very peculiar CNS adverse events here?
    Disclaimer: I work for a drug company on a distantly related topic. This post is my opinion only and doesn't reflect the position of my employer or of any other sane people.

  • DrugMonkey says:

    What would happen if the epitope inciting the response was actually to the part of cocaine that binds the receptor, and if the immune response were carried into the CNS?
    You are asking, more or less, "what if it generates an immune response to dopamine?" I assume. From what I can tell from reading the pre-clinical work*, specificity of the immune response against a single drug compound (and avoiding response to endogenous neurotransmitters) is a big selection factor in moving candidate immunogens forward
    * I failed to emphasize that for each of these vaccines that reaches human trials, there are animal data in the "development pipeline". I put that in quotes because as far as I know much of the preliminary work is from NIH funded scientists, not drug companies
    Is it possible, for example, that those who mount a high antibody response are in general less likely to find the drug reinforcing?
    This trial was in dependent individuals and I imagine this will be the case for some time. As I obliquely mention, the ethics of vaccinating naive populations to prevent future addiction need to be fought out. This will be wrapped up in the question of efficacy for that application which is what you are asking, I think. Personally, I think it is premature to go there if the vaccines don't work particularly well in terms of duration of protection.

  • Klem says:

    What about replacement/maintanence therapy with modafinil, methylphenidate, coca tea, or extended-release cocaine? Is that what you mean by "agonist therapy"?
    Probably the most helpful for cocaine users would be to regulate the purity and dosage of cocaine products, as in the Pure Food and Drug Act of 1906.

  • DrugMonkey says:

    Is that what you mean by "agonist therapy"?
    Yeah, although I was mostly criticizing the programs to purposely construct Dopamine transport inhibitors with various pharmacological properties. My read is that the approaches you mention aren't as successful as methodone for heroin or the patch/gum for nicotine. I could be unduly cynical though.
    Probably the most helpful for cocaine users would be to regulate the purity and dosage of cocaine products
    And are you going to let us in on why that is so? Intranasal would seem to inhabit a middle ground between the ballistic events (IV and PO) and the incremental (and therefore more dose controllable) smoking route.

  • pinus says:

    To me the targets that make the most sense are not the agonists (trying to find a DAT , NET or SERT blocker with hte appropriate profile) but rather to target some of the long term changes in other systems...for example, glutamate systems (Think some of Kalivas' Cystine stuff, or perhaps some of the mglur stuff)

  • Azkyroth says:

    From what I can tell the topic was dropped for a good while until a paper from Carrera and colleagues in 1995 showed that active immunization against cocaine in rats could reduce locomotor stimulation and the induction of repetitive stereotyped behavior (stereotypy) because of reduced cocaine entry to the brain.

    Wouldn't this greatly increase the rate of overdose, since people would need to administer much closer to a lethal dose to get the desired euphoric effects? Or does it also block the mechanism of cocaine's toxicity?

  • DrugMonkey says:

    To answer Azkyroth's question in part, Scicurious has coverage of a paper using the same vaccine up here:
    http://scienceblogs.com/neurotopia/2010/02/immunization_for_addiction_the.php
    That paper reports elevated heart rate and cites a paper showing peripheral regulation of HR by cocaine. This is one of the potential (highly likely imo) drawbacks to this strategy of sequestering drug in the periphery. Depends on many things, of course, but most importantly whether the individual ups the dose and how the kinetics of antibody binding work. The paper Scicurious describes postulates a labile binding relationship as the reason the vaccinated group experienced HR increases for example.

  • [...] -vaccination against drug abuse [...]

Leave a Reply