by Fernanda Ferreira
figures by Brad Wierbowski

Every day 140 Americans die from an opioid overdose. To confront the crisis, not only must opioid addiction treatment become more readily available, but new and improved forms of treatment must also be developed. Dr. Carl Alving, whose life work has been to develop an HIV vaccine, never planned on investigating novel systems for treating opioid addiction. But after an intriguing suggestion at a dinner party in 2010, he’s found himself involved in the development of a vaccine to both prevent HIV and help treat heroin addiction.

The Surprising Benefits of Google Stalking

When Dr. Carl Alving’s wife, Barbara, was Director of National Institute of Health’s (NIH) National Center for Research Resources, dinners at their house included doctors, scientists and other institute directors. At one such occasion in 2010, a National Institute on Drug Abuse (NIDA) official approached Dr. Alving with an interesting suggestion. “She had done a Google search on me and discovered I was an adjuvant guy,” Alving explained from his office in Silver Spring, MD. “At the dinner, she suggested that I should make a vaccine against heroin.”

As an ‘adjuvant guy’, Dr. Alving studies important vaccine components (i.e. adjuvants), which help to boost the immune response to a vaccine. Alving’s work at the US Military HIV Research program (MHRP) has led to the development of the Army Liposome Formulation (ALF) family of adjuvants that have now been used in a number of Phase 1 and Phase 2 human trials for vaccines against both infectious diseases and cancers. (If you want to learn more about the phases of human trials, the FDA has a great explainer here).

Alving considered the benefits of developing an anti-heroin vaccine from an HIV perspective: injection drug use, especially when needle sharing occurs, is a direct route for HIV transmission, and was responsible for 8% of new HIV cases in the US in 2015, according to the CDC. Moreover, HIV infection is a major contributor to loss of quality of life in those suffering from opioid abuse.

Initially, Alving decided to maintain his focus exclusively on HIV. “My mission in the army, which has been my direct mission since 2004, is to make a prophylactic vaccine to HIV,” Alving explained. But Alving could not stop thinking about a heroin vaccine. The more he contemplated the intersection between heroin and HIV, the more convinced he became that developing not just an anti-heroin vaccine, but a dual HIV-heroin vaccine was the answer. Such a vaccine would protect heroin users from acquiring HIV and, at the same time, treat the heroin addiction that makes users more prone to acquiring HIV.

“Heroin is a small molecule that by itself can only induce a small immune response,” Alving says. A successful anti-heroin vaccine is one where, following vaccination, our immune system will produce antibodies against heroin. These antibodies will bind to heroin in the blood, keeping heroin from crossing the blood-brain barrier and binding to opioid receptors in the brain. But to create these antibodies, heroin must first be detectable to the immune system. To create a viable vaccine, the small heroin molecule must be placed on a much larger adjuvant that our immune system can actually detect, and thus generate an immune response. “In order to make a heroin vaccine, it’s necessary to put it onto a carrier protein [which binds the heroin molecule to the adjuvant]. I reason that, if the carrier protein is an HIV protein, then this dual vaccine is my mission,” Alving explained excitedly.

A crisis with no end in sight

In terms of health, opioids are considered the most dangerous class of drugs. This diverse group of chemically-related drugs interact with the opioid receptors on nerve cells in the brain. In 2015, 35 million individuals used drugs in this group, such as heroin, synthetic opioids like fentanyl, and a number of prescription pain-relievers like morphine, codeine and oxycodone. Unfortunately, opioid usage is “associated with the risk of fatal and non-fatal overdoses; the risk of acquiring infectious diseases […] through unsafe injecting practices; and the risk of other medical and psychiatric comorbidities”.

The ongoing opioid epidemic in the US is illustrative of the harms of opioid use. According to the Centers for Disease Control and Prevention (CDC), more than 140 Americans die from opioid overdoses each day. Further, the United Nations Office on Drugs and Crime (UNODC), reports that overdose deaths have tripled in the US between 1999 and 2015. This has mostly been driven by opioid use, and in the past year, the rate has increased by 11.4 percent. Currently, the US accounts for approximately one quarter of the drug-related deaths worldwide. As Tom Friedan, the former director of the US Centers for Disease Control and Prevention, wrote in a 2016 editorial: “America is awash in opioids; urgent action is needed.”

The standard treatment for opioid use disorders (OUD) is psychosocial support coupled with medication. These medications, or pharmacotherapies, like naloxone and methadone, help during the withdrawal period, but come with side effects of their own, such as a profound state of unease and the potential for overdose and abuse.

In a 2017 Special Report in the New England Journal of Medicine, Drs. Nora D. Volkow, NIDA Director, and Francis S. Collins, NIH Director, called on science to help develop novel and improved strategies for combating opioid use disorders. One potential strategy they cited was vaccines against opioids, which would generate antibodies that bind to opioids in the blood and prevent them from crossing the blood-brain barrier where they can bind to opioid receptors in the brain (Figure 1).

Figure 1: Heroin is a small molecule that can slip past the immune system. Heroin’s small size also allows it to easily cross the blood-brain barrier to reach the brain, where it binds to opioid receptors on nerve cells causing the user to experience a “high”. In an anti-heroin vaccine, the heroin molecule is attached to a large adjuvant, making it visible to the immune system. B cells, an important member of the immune system, bind to the heroin-adjuvant combo and produce anti-heroin antibodies that are released into the bloodstream where they bind to heroin. Heroin bound by antibodies is too large to cross the blood-brain barrier, keeping it away from the brain and the opioid receptors on nerve cells. As such, an individual vaccinated with an anti-heroin vaccine would not be able to feel a drug “high” even if they used heroin.

Vaccines Against Drug Abuse

Development of the first anti-drug abuse vaccines began in the 1970s when anti-opioid vaccines were tested in rats and primates. In rats, the vaccine generated anti-morphine antibodies that bound to morphine, decreasing the concentration of free morphine in the blood. In primates, the vaccine decreased the amount of self-administered heroin.

Both of these studies are considered proof of principle that anti-drug addiction vaccines work and could potentially become an important tool in the fight against addiction. Based on these results, anti-drug vaccines were developed against nicotine, methamphetamines, and cocaine. Many went on to Phase 2 and 3 trials in humans.

However, the results from these trials, have been disappointing, such as the case of NicVax, an anti-nicotine vaccine developed by Nabi Biotechnologies and GlaxoSmithKline. NicVax has gone through a number of Phase 1 and 2 trials. In 2007, a Phase 2B trial found that when data from all vaccinated subjects were pooled together, the rates of abstinence were similar in the participants who received the anti-nicotine vaccine compared to those that were given a placebo. Interestingly, when study participants were divided depending on the level of anti-nicotine antibodies generated by the vaccine, a difference emerged. Participants with the highest antibody levels were three times more likely to remain abstinent for eight weeks compared to the placebo group.

The NicVax case mirrors the results seen in other anti-drug vaccines: there is a correlation between antibody concentration in the blood and the subjects’ ability to remain abstinent. In the NicVax Phase 2B clinical trial, only a third of the subjects generated an antibody level high enough to block nicotine’s effects. These results beg the question that, with a different more potent adjuvant, could anti-drug vaccines finally become a useful tool in combating addiction?

Employing the Immune Boosting abilities of ALF

“This is one of the reasons NIDA came to me,” Alving explains. “They believe, and I think they’re correct, that one of the reasons why the cocaine and nicotine trials failed was that the adjuvants were not strong enough.” NIDA was interested in collaborating with a laboratory that specializes in adjuvants and Dr. Alving’s lab was an obvious fit; from the top floor of Alving’s research building you can see the NIDA building. “It’s a close relationship and that allows us to go back-and-forth in visits to go over experiments,” Alving says. And, according to him, the collaboration has already begun to demonstrate improved results because, compared to other adjuvants like aluminum salts, ALF is able to induce higher levels of antibodies against heroin.

In a paper published last year, Alving and colleagues presented the first results of their heroin-HIV-2 vaccine, which they call the H2 vaccine. Their vaccine design brings together the ALF adjuvant, a heroin analog called MorHap, and a piece of the HIV-1 envelope protein, called the V2 loop (Figure 2).

Figure 2: The H2 Vaccine Design. To develop a dual heroin-HIV-1 vaccine, Alving and collaborators assembled their three main parts: MorHap, a heroin analog provided by NIDA; the HIV-1 V2-loop; and the ALF liposome as their adjuvant.

The research team then immunized mice with the H2 vaccine and observed that high levels of antibodies were generated against both HIV-1 and heroin. For Alving, the results of the study represent the first major steps towards achieving a dual HIV-heroin vaccine.

While the early results of the H2 vaccine are exciting, Alving warns that an eventual anti-heroin vaccine is not meant to either prevent heroin addiction or be a silver bullet to treat individuals addicted to heroin. The H2 vaccine would target individuals who are using heroin and wish to stop using the drug, which, according to Alving, is the majority of heroin users.

“It has the potential to be a useful means for helping people get off heroin, though they would still have to detoxify in the old way.” Currently used medications, such as methadone, help patients during the withdrawal period by blocking the “high” that users get when taking opioid drugs.  Therefore, methadone works similarly to the proposed H2 vaccine. However, medications come with their own set of side-effects. With methadone, there’s the potential for overdose and abuse, as well as the issue of low treatment adherence. The H2 vaccine would remove these issues, while also protecting individuals suffering from opioid abuse disorder from acquiring HIV.

The dinner that began Alving’s journey towards the H2 vaccine happened in May 2010, exactly seven years before the initial results supporting the potential for a dual HIV-1-heroin vaccine were published. NIDA has since become interested in using the ALF adjuvant to generate vaccines against other drugs, such as nicotine. For Alving, the project is the perfect example of the role of serendipity in science and in generating collaborations. “It was really a very serendipitous meeting that stimulated an idea that led to the beginning of this whole project,” says Alving, proving that one should always Google search one’s fellow dinner guests.

Fernanda Ferreira is a PhD student in the Virology program at Harvard University.

For more information:

A recent SITN article by Mary May about the science behind opioid addiction

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