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Dec 21 2011

Canadian-made HIV vaccine headed to human trials!

And I damn well want every syringe to be stamped “Made In Canada”. The FDA has approved a 40-person trial of a vaccine against the human immunodeficiency virus developed by Dr. Chil-Yong Kang of the University of Western Ontario.

“FDA approval for human clinical trials is an extremely significant milestone for our vaccine, which has the potential to save the lives of millions of people around the world by preventing HIV infection,” said Kang.There have been three clinical trials for an HIV vaccine in the past using live viruses that failed.There have been three clinical trials for an HIV vaccine in the past using live viruses that failed. (Apichart Weerawong/Associated Press)

He said there have been three clinical trials for an HIV vaccine in the past using live viruses. “None of the researchers in the past have used this approach,” he says of his use of a killed virus.

The vaccine, SAV001, will now have to undergo three phases of human clinical trials;

Phase 1. Beginning in January 2012, this phase will involve 30 HIV-positive people on whom safety will be retested.
Phase 2. This phase will examine immune responses in humans and will involve 600 HIV-negative people who are at high risk of contracting the AIDS virus.
Phase 3. This phase will determine the efficacy of the vaccine and will involve 6,000 HIV-negative volunteers at high risk of contracting the virus.

The only cynical thing I have to say about this is that phase 4 is “profit!” Otherwise, the university’s financial backer Sumagen will not make a return on investment. Sigh. Damn capitalism.

And a slight worry: I wonder how they classify people as being “at high risk”. I’m guessing sex workers and gays will get the nod, even if the specific individuals aren’t at any particularly high risk. I wonder if doctors who risk infection by dealing with blood every day will be included in the trials, or not, because they’re “too valuable to society”? I suppose if they volunteer, they volunteer. Just something to look out for in this otherwise promising bit of news. And ultimately, the vaccine will protect not just the common folk, but more specifically those at high risk, who might otherwise be used as human guinea pigs in this trial.

Outside of all that, holy fucking shit we may have found the vaccine against HIV! That’s huge!

21 comments

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  1. 1
    VeritasKnight

    If it works, can you say “Nobel Prize”?

    Hopefully, it works, it works well, and we can start immunizing the people of Africa and Asia where the AIDS epidemic is truly an epidemic.

  2. 2
    Gregory in Seattle

    I hope you are not holding your breath on any of this :-)

    I’m on the Community Advisory Board for the Seattle HIV Vaccine Trials Unit. It is very likely that this vaccine will be tested here, as the Fred Hutchenson Research Center here is one of the coordinators of HIV research in the US.

    One of the big, BIG problem with using a whole virus is that the process that converts living viruses into dead viruses is not 100% effect: in any given batch, you do have live viruses. This is not an issue with normal viruses, because the body will fight it off. HIV, however, is a retrovirus. Let me explain.

    Normal viruses infect a cell and take over the cell’s machinery. Internal structures are dismantled for spare parts to create new viruses. In a matter of hours, the cell falls apart, spewing hundreds of thousands of new viruses out to infect other cells.

    Retroviruses infect a cell and write themselves into the cell’s DNA. In effect, they reprogram the cell to create new viruses for them. A single cell can be infected with multiple retroviruses, either the same or different, each infection producing its own viruses. Unless the cell realizes something is going wrong and self destructs, it will live out its full span, churning out more and more agents of destruction. The T-cells that HIV infects are among the longest lived in the human body, with life spans in the 30 to 50 year range. That is why HIV infection is (for now, at least) incurable.

    So the reason why no one has been willing to try a whole virus HIV vaccine before is because a single living virus, out of the millions that get injected, is all that is necessary to give someone an incurable, progressive, terminal disease.

    This is why the testing protocol starts with people already infected with HIV. I expect that the whole virus is identifiably different in some way, which will allow researchers to distinguish between it and other strains. Almost certainly, the people in the Phase 1 trial will not be on any of the meds that suppress the virus.

    If the study passes to the Phase 2 trial — and honestly, I wouldn’t hold my breath — you are going to have a very difficult time finding volunteers. Right now, we have a lot of trouble even though there is no way one can get HIV from the engineered vaccines being tested now: telling someone that they may very well get HIV from this vaccine is going to be a very, very tough sell. Worse, once this becomes well known, it is going to be much harder finding participants for other studies.

    And Jason, “high risk” is defined precisely in the trials protocols, but is typically determined by means of a behavior survey that looks at the number of sex partners in a given time period, the type of sexual activities they engage in, and how conscientiously the person uses safer sex procedures. Answers are assigned a score, and the protocol will accept people at or above a threshold.

    With human testing only now having been approved, it will be at least a year before the protocols are formalized and the informed consent documents are finalized. Then two to five years for the phase 1 trial, including time needed to analyze the data after the testing itself is concluded. If — and only if — the results show promise, it will take another year or so formalize and finalize the phase 2 trial and another two to five years before they can begin planning for a phase 3 trial. And this all assumes that the trials give excellent results the first time through: it is very common for trials to be redone before review boards will allow them to proceed to the next phase of testing. Maybe too many participants dropped out during the study, or data was outside statistical tolerances, or there was some kind of lab contamination, or maybe they just decide they need more data before they can continue.

    I’ve seen a lot of vaccines that looked promising in animal testing never make it out of phase 1. This is exciting news, but really, not something worth getting worked up about yet.

  3. 3
    Jason Thibeault

    Hi Gregory,

    Thanks for taking time to provide all that excellent and balancing information. I really do appreciate it, and I apologize if I seemed more excited than the news actually merits.

    I do have to correct you on one point though, which may not have been in the CBC report I linked but is apparently in the Chronicle Herald coverage — evidently the vaccine approved for testing is a genetically-modified version of the virus engineered to be non-pathogenic. It’s then killed via radiation and chemical processes (I expect through normal means) just as a whole-virus vaccine would.

    So the virus that’s inactivated isn’t capable of performing the retrovirus activities that make it dangerous, but it’s close enough to the whole virus that it triggers strong immune responses that will hopefully confer immunity to the real thing. I understand a problem of other partial-virus vaccines is that they didn’t produce strong immune responses.

    While I am reserving judgment of this as being “THE vaccine”, I am still every shred as hopeful as the last sentence of my original write-up implies.

  4. 4
    Gregory in Seattle

    I looked at the article from the Herald News, and read this:

    To make the vaccine, the researchers start by altering the genetic makeup of the human immunodeficiency virus to make it non-pathogenic — in other words, incapable of causing disease —then further inactivate it with chemicals and radiation.

    It seems to me that they are starting with ordinary live HIV and putting it through three ringers rather than the usual two. That would certainly explain the caution in the described testing protocols, and as far as I know this is type of approach has not yet been tried. It could be a very promising breakthrough, if only to open up a new avenue of research. Still, I’ve seen far too many promising vaccines fail for this news to elicit anything more than piqued curiosity.

  5. 5
    Alecthar

    Gregory, in #2 you indicate that you think it’s likely that the HIV+ participants in Phase I of this study would be required to cease their medication.

    It seems to me that this would be tremendously unethical. My understanding is that a Phase I trial is intended not to determine efficacy, but rather to evaluate the safety of a treatment. With that in mind, what possible benefit could be gained in this phase that would compensate for the cessation of potentially life-saving medication?

  6. 6
    julian

    Crap. I’m giddy like a cold-fusion believer right now. While I understand how iffy any success is… Christ, I hope this works.

  7. 7
    Gregory in Seattle

    @Alecthar #5 – My apologies if I wasn’t clear. The subjects in the phase 1 trial will almost certainly be HIV+ volunteers who have not started drug therapy. Typically, therapy does not not start until the CD4 count has dropped below 400, and that can take several years after initial infection.

    I see two reasons why they would need HIV+ people not on meds. First, they want people who are already HIV+ for the reason I gave upthread: if their preparation is not 100% effective each and every time, folks getting the vaccine will become infected with HIV. If they already have HIV, then the ethical problems are substantially diminished.

    Second, anti-retroviral meds suppress the life cycle of the virus. The point of phase 1 seems to be to make sure that their preparation is 100% effective. If people are already taking viral suppressants, there would be no way to tell whether or not the vaccine caused an infection which would make the phase 1 trials useless.

    I expect the reason for using high-risk volunteers in phases 2 and 3 are likewise to mitigate the ethical concerns. Being HIV-, they have a “clean slate” to look for HIV antibodies, which would show that the vaccine is having the desired effect. But being high risk, if a person does get infected from the vaccine, there is a paper trail establishing that the person was willfully and knowingly engaging in high risk behaviors and already stood a strong risk of getting HIV which will limit the potential liability to the researchers and the trial sponsors. I would be very, very interested in seeing what they put into the informed consent documents for those studies.

  8. 8
    Alecthar

    @Gregory: Thanks for clarifying. That makes much more sense to me now. I too am interested in the ethical issues involved in this study, perhaps moreso than the study itself.

  9. 9
    canadiansteve

    @gregory: Thanks for the additional information. I think there is a lot of reason to not to overhype the chances of sucess here, but I am hopeful they are at least making progress on development. I remain eternally optimistic that we will eventually find a vaccine, even if this one isn’t it.

  10. 10
    Gregory in Seattle

    @canadiansteve #9 – Hope is always good: that is why I’m as involved as I can be in the research.

    There are no trial sites in Canada (right now), but if anyone in interested in learning more about the research, I recommend visiting the HIV Vacine Trials Network website. If you live near any of the cities where trials are being done, you might qualify to participate in one of the current studies; requirements differ, but most studies are recruiting men and women who are HIV- and classed as “low risk.” As explained above, you cannot get HIV from any of the vaccines currently being tested. If you do not qualify for a study, you can ask that your contact info be kept on file in case a new study opens up, or you can get involved in the site’s Community Advisory Board.

  11. 11
    Daniel M.

    I was going to ask the same thing, how do they determine who is “high risk”?

    Don’t knock capitalism, without profit, no one would work to make this stuff, how else would they feed their kids?

    :)

    Otherwise, good post. I’ll keep my eye on this.

  12. 12
    'Tis Himself

    And I damn well want every syringe to be stamped “Made In Canada”.

    So you’re a Rick Mercer fan.

  13. 13
    HFM

    @ #7: I believe the reason they’re using high-risk volunteers is so they can show an effect in a reasonable amount of time. The faster your control group gets HIV, the faster you can tell if your vaccine group is doing any better. (Also, people who are high-risk and know it may be more likely to sign up for an investigational vaccine…but that’s a bonus.)

    I’m cheering them on, of course, but HIV is a notoriously tough vaccine target. (I’m not an immunologist, but as I understand it, the capsule doesn’t have any handles that a human antibody can grab onto…there’s only so much variability that the antibody has access to as it matures, and the few antibodies that are known to bind HIV are significantly more scrambled than that.) This might do it if anything will, though, so here’s to trying.

  14. 14
    Ace of Sevens

    I assume they compensate for this at some point, but it seems the risk/benefit calculations for high risk groups would be different than the usual population. For instance, if you have a vaccine that has a 2% risk of causing AIDS and a 50% chance of preventing it, and your test group has a 5% risk, that would fall to 4.5%, making it appear that the vaccine is somewhat effective, though not a miracle cure. If you applied it to a general population with a .5% risk, you would raise the risk to 2.25%, which is disastrous. Granted, the real numbers would be lower, but it could cause a huge difference in apparent efficacy if one of the concerns in the vaccine may cause HIV.

  15. 15
    Crommunist

    Phase 4 isn’t “profit”. The phases refer to specific stages of a clinical trial. Technically speaking, Phase 4 is post-implementation evaluation. Many drugs don’t undergo this kind of analysis (although it’s what I and the team I work for specializes in). Just FYI.

  16. 16
    Gregory in Seattle

    @HFM #13

    I believe the reason they’re using high-risk volunteers is so they can show an effect in a reasonable amount of time. The faster your control group gets HIV, the faster you can tell if your vaccine group is doing any better.

    That approach would be so unethical as to be illegal under the many national and internaltional laws that govern human medical experimentation. I cannot speak for Canada, but the United States has some particularly tough rules, put in place as a response to the Tuskegee syphilis experiments (where black men infected with syphilis were not told about penicillin, the better to track the disease through its terminal stages) and the nuclear wind tests of the 1950s and 60s (where above-ground nuclear explosions were set off, in part to test the effects of fallout on the people living down wind.) Any experimenter who designed a testing protocol with the goals you propose might get a trial before being thrown in prison for life, never again to see the light of day.

    Again, I cannot speak for Canada specifically, but I believe that every country has a similar process. First, the researchers amass a body of laboratory tests. Then they design testing protocols involving animals, which must be approved by various ethics boards.

    Once they have those results, they must prepare an incredibly detailed protocol for human testing, down to the dimensions of the slides that will be used for visually inspecting samples and the size of the pipettes used to prepare those slides. Then all of the data and the proposed protocol are passed by various boards managed by the originating lab (in this case, the University of Western Ontario.) These boards review the procedures and ethics of how the data was collected.

    If everything passes review, the originating lab allows the researchers to begin the process of getting national approval in the countries where testing will be done. A lot of HIV research is done through the HIV Vaccine Trials Network, linked above, which oversees trials around the world. For the sake of example, lets say that UWO goes to the HVTN. The Network reviews the data and the proposed protocol with their own boards; if everything looks good, the Network consults with the researchers and decides which of the member trials units will run the tests. They then submit the data and protocols to the appropriate federal agencies, who can approve the testing or not. In the United States, where HVTN has 22 trials units, the appropriate federal agency is the Food and Drug Administration. Tests conducted in South Africa, Peru and other countries would need to be reviewed by, and get authorization from, the equivalent government agencies. That seems to be where this vaccine is right now.

    After the tests have been authorized, the trials units are invited to participate. Each unit has its own ethical review board, community advisory board and protocol review board, who look over the proposed protocol and decide if they want to participate. This is where things get tricky: if my CAB in Seattle decides that there are issues with targeted a vulnerable, likely desperate population for risky medical research, or even if the human risk of a whole virus is too high, we can withhold our consent to the trial. That would not be a veto, but our decision will be given a great deal of weight by the unit directors when deciding whether or not to take part.

    Once the trial units are on board, each unit drafts its own informed consent documents. While IC in the US has become largely boilerplate, each unit has its own variation to accomodate the unique needs and concerns of their local communities. With tests involving whole virus and recruiting HIV+ volunteers, however, very little of the standard text will be useable, so IC for this vaccine will have to be drafted from scratch. That takes time, as all of the review boards and advisory groups need a chance to look over the documents and provide comment. The CAB also has a voice in this, as part of our function is to serve as advocates for trial participants and make sure that all of their rights and protections are clearly laid out, with no hidden gotchas or fine print.

    Then, after all this has passed inspection, the unit needs to start lining up their 30 ducks. Almost certainly, this will be split between several units: it will be a serious challenge to find enough people in one location willing to take part. That is going to be a severe challenge, and if the units cannot get enough volunteers, the test will be delayed or even cancelled. If it is delayed for too long, then it is likely that the review process will have to be restarted at some point. Once a minimum number of volunteers are recruited — the exact number is given in the approved testing protocol — injections will begin.

    So after all that, with so many eyes looking at ethical issues and a very sharp Sword of Damocles hanging over the process, you can bet that the researchers will come up with a much better justification for using high-risk volunteers than just, “We will get our results that much faster.”

  17. 17
    Jason Thibeault

    I’m actually going to post something about the Canadian ethics laws surrounding human testing with reference to the testing in the 1970s of Agent Orange and other pesticides on the residents of CFB Gagetown in New Brunswick. As soon as I get all my ducks in a row. Canada’s not free of such blots on their record. In the case of Agent Orange, it was at the request of the US government, mind you. But we’re not all sunshine and roses here either.

  18. 18
    Gregory in Seattle

    @HFM #13 — Also, keep in mind that efficacy — the basis you offered for using high-risk volunteers — is not tested until phase 3 trials.

    Phase 1 focuses on “Are there any nasty side effects in humans?”, with “Can we get the immune reaction we need?” being the secondary focus. That is why phase 1 trials involve a very small number of volunteers, typically 50 or fewer, who meet very stringent qualifications.

    In phase 2, the foci reverse, with “Can we get the immune reaction we need?” becoming the primary question “Are there any nasty side effects?” a secondary concern. Phase 2 trials will typically have 100 to 200 people, with fewer but still strict qualifications on who can participate.

    Phase 3, the first two questions remain but get pushed aside by “Does the darn thing work?” It is not unusual for phase 3 trials to have thousands of volunteers with fewer restrictions.

    The few HIV vaccines that have reached phase 3 almost always recruit high risk participants, so that would be nothing new. It is very unusual to recruit high risk participants in a phase 2 study, and I have never heard of a vaccine study that recruited HIV+ volunteers at any phase.

    @danielrudolph #14 – Trial participants are compensated for their time, but it is illegal (in the US, at least) to compensate them for anything else. Paying a participant for the risk of getting a vaccine is ethically very shady, and it frequently leads to bad results when people sign up for the income.

    @Crommunist #15 – I’ve never heard of phase 4, but it makes sense. If a vaccine passes its phase 3 trials, the next step is authorization to use; at that point, doctors and clinics start injecting their patients. A drug or vaccine manufacturer would do well to collect follow-up data and monitor safety and efficacy as their product is widely distributed, if only to supply evidence in case there are lawsuits such as the ones that targeted Prozac, Paxil, Vioxx and fen-phen. But since CABs and ERBs are not part of that process, I don’t know anything about them.

  19. 19
    Gregory in Seattle

    @Jason #17 – I would be very interested in seeing the process for Canada. I am also hoping that this vaccine will open some HVTN trials units in your country; the more, the merrier :-)

  20. 20
    999999

    hiv virus is one of retro virus. But hiv virus has no function to correct errors on DNA itself. So that’s one of the greatest barrier by which inventing a vaccine has been failed so far.

    Actually it’s clear that people can’t hear experts’ hopefully positive opinion. Even we should be aware of the reason why the guy is emphasizing “developing countries”.

    phase2&3 should be tested on hiv-negative people. many people of poor countries will get in phase2&3.

    You could buy poor people at low price. But it doesn’t mean that this world first exam will success!

    Plus, it’s also very easy to think that the company need to seek money of any foundations.

    Let’s keep in mind that it’s just first try but not a great white hope of science. Because hiv virus is a maestro of tranform.

    Killed whole virus may not work well.

  21. 21
    999999

    You can get somehow misunderstanding of hiv-virus even so of vaccine.

    However if people used to get the idea of it, it would be a huge disaster.

    plus, hiv-vaccine has another dilemma.
    probability of infection is too much low in case of hiv. So almost 100% prevention is required. contrariwise a killed whole virus vaccine must be killed 100% !!

    .
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    .

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