Epic disaster in HIV vaccine world

I can think of at least two 'worst nightmares' for vaccine designers.

  1. Your vaccine looked super in animal models and such... but it turns out to be directly harmful to people.  And not 'some' people.  All people.
  2. Your vaccine actually does the opposite of what you want it to do-- instead of preventing the disease, it makes people more prone to the disease.

That second one is a nightmare come to life for a group of HIV-1 scientists:

Extended follow-up confirms early vaccine-enhanced risk of HIV acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus HIV vaccine (Step study)

The "Step Study" was an HIV-1 vaccine trial that was stopped in 2009, because it appeared that people in the *vaccine* arm of the study group were getting infected at a *higher* rate than the people in the placebo arm.  For real.

This paper is an analysis of that data, and data infection rates  18 months after the study was stopped.  They stratified their data by who had preexisting antibodies to the virus in the vaccine, Ad5, and for some reason, by whether or not the person was circumcised.

Right after the trial was stopped, these groups had the following hazard ratios vs placebo:

Uncircumcised, Ad5+: 4.18

Uncircumcised, Ad5-: 2.66

Circumcised, Ad5+: 1.98

Circumcised, Ad5-: 0.38

4.18  Holy freaking crap.

But heres the good news! *creepy Stepford Wife forced smile* Whatever the really, really bad effect of this vaccine was inducing, it fades with time!

After all follow-up, these groups had the following hazard ratios vs placebo:

Uncircumcised, Ad5+: 1.58

Uncircumcised, Ad5-: 2.35

Circumcised, Ad5+: 1.61

Circumcised, Ad5-: 0.97

Its obvious to even the most casual observer that stopping HIV-1, making an HIV-1 vaccine is really, really difficult.  And because its so difficult, we are needing to try new things that have never been tried before, for any virus, or any other disease-- like utilizing Ad5 vectors.  When you are trying revolutionary, new approaches... sometimes there are disasters.  When you are trying to fly to the moon, occasionally a shuttle blows up .  *This* shuttle blew up with almost 2000 people on board.  All we can do is try to learn everything we can from the disaster, so it never happens again.

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Sadder still is that this increase in susceptibility was predicted to happen long before it was observed in these trials (at least 2003) and has been previously observed in vaccination attempts against the related FIV and EIAV =(....(references below, although please do correct me if they are too dated and more recent data refuted them).

"The Trojan exosome hypothesis." Proc Natl Acad Sci U S A. 2003 September 16; 100(19): 10592–10597.

"Possible immunoenhancement of persistent viremia by feline leukemia virus envelope glycoprotein vaccines in challenge-exposure situations where whole inactivated virus vaccines were protective." Vet Immunol Immunopathol. 1986

"Efficacy of inactivated whole-virus and subunit vaccines in preventing infection and disease caused by equine infectious anemia virus." J Virol. 1992

"Enhancement of feline immunodeficiency virus infection after immunization with envelope glycoprotein subunit vaccines." J Virol. 1995

"Enhancement of EIAV replication and disease by Immunization with a baculovirus-expressed recombinant envelope surface glycoprotein." Virology. 1994

By Poodle Stomper (not verified) on 31 May 2012 #permalink

This is something that is to be expected in something still in trial stage, and human trials are a necessary thing for advancing medicine. I'm for advancing medicine so I'm for this.

However, I do have one question to ask. When this sort of backfiring happens, do the people behind the study have any sort of "emergency treatment" fund to help these people deal with this? This isn't a matter of them not know the possible consequences when they signed up, but a simple matter of basic humanitarian aid. It seems to me that that should be a basic responsibility in these events. That's all I'm saying.

By Dark Jaguar (not verified) on 31 May 2012 #permalink

Disaster may be overstatement.
Look how much the HR estimates changed. It's cause they had so few events. Even now with 172 of 1836 men infected, and HR=1.4, p=.03 for the main planned analysis, I'm only about 50% sure that they harmed anyone, much less that the shuttle blew up. I would agree with the very boring thought that this particular vaccine doesn't need further testing.
Now show us your posterior. I'm not that informed so it should be of more interest than mine.

Thanks Poodle Stomper. I'll hold my tongue a bit longer next time.

@Poodle Stomper (#1)
It is certainly true that enhancement of infection by antibodies has long been known (as you cite), and indeed, concerns about such enhancing antibodies have dogged the HIV-vaccine field since the 80's. However, such antibodies are, as far as I am aware, invariably directed at the viral receptor protein, i.e. Env for HIV. The STEP vaccine was a mixture of non-replicating adenovirus vectors expressing the HIV genes coding for Gag, Pol and Nef. There was therefore no reason to expect the development of enhancing antibodies with this vaccine. What the STEP trial showed was that recipients with a pre-existing immunity to the adenoviral vector were more susceptible to infection. One hypothesis (much disputed) is that the vaccine activated the pre-existing adenovirus-specific memory T-cells and this provided a greater reservoir of target cells for HIV (HIV loves activated T-cells) and therefore enhanced susceptibility to infection. One could argue that this scenario should have been expected, but hindsight is 20/20 vision, I guess.

Interesting. Abbie/BigSteve, quick question about the potential increased risk issue. Antibodies would also tag HIV in a manner that would pretty specifically target them to macrophages & DCs (via Fc receptors). Since macrophages are thought to be the first cell types infected, and DC's are thought to act as viral carriers, this seems like a plausible mechanisms that explains the apparent increase in infection rate in a fashion more consistent with what is known about HIV infection (or, perhaps, with what I know of HIV infection - which, admittedly, isn't a lot).

Similar things have happened in the past - dengue fever vaccines have been plagued with the issue that anti-DV antibodies direct DV to macrophages. This greatly inhances the infectivity of DV for macs and monocytes.

Thanks for the info Steve! I wasn't aware that it was thought that only the env could increase susceptibility to infection. Do you know if this is the first time this has been seen in human HIV vaccine trials?

Hopefully whatever the cause was will be figured out.

By Poodle Stomper (not verified) on 01 Jun 2012 #permalink

You are, of course, completely correct in stating that one (if not the major) mechanism of antibody-enhanced infection would be an increased uptake by monocytes and DCs via viral Env-antibody-Fc receptor bridging. However, as I mentioned above, the STEP vaccine did not induce any Env-specific antibodies, so there would be nothing floating around that could form the first link in the chain, so to speak. Enhanced infection and disease in the SIV/macaque model for AIDS was actually dramatically demonstrated in a 2004 paper by Staprans et al (PNAS, 101,13026) in which macaques immunised with a recombinant varicella-zoster virus vector expressing Env had, in contrast to the hoped-for outcome, higher virus loads and more rapid progression to disease after challenge with SIV. The actual mechanism remains unclear, however. Luckily, human trials involving Env-based vaccines haven't shown this effect so far.

@Poodle Stomper
I am unaware of any other HIV vaccines that have shown enhancement in humans. Of course, most have shown no effect at all, unfortunately. The one 'positive' clinical trial (the RV144 Thai trial) showed a very, very slight beneficial effect, but I am personally rather skeptical that the effect was actually a biological protection rather than a mere statistical fluke.


You might want to take a look at this hypothesis proposing that T cell allorecognition in vertebrates is a natural innate immune response that protects them against viruses carrying MHC antigens, which might have significant implications for HIV vaccine development:

The astounding MHC allelic diversity in vertebrates, particularly in humans who have several hundred alleles, and the strong anti-MHC allogeneic cytotoxic response are among the most debated and enigmatic issues in immunology. The integrative model presented in these papers offers a plausible evolutionary and molecular explanation for these phenomena. Moreover, it might help with understanding the epidemiology and the dynamics of viral transmission, and it could lead to new approaches in developing vaccines against HIV and other enveloped viruses that carry MHC antigens.

According to this new model, enveloped viruses such as HIV incorporate host ‘self’ MHC antigens on the surface of their viral particles in order to evade immune recognition. In an adaptive response, the vertebrates have diversified their MHC alleles and evolved a strong T-cell innate, cytotoxic immune response against MHC antigens carried by infectious viruses. Based on this model, the T cell allorecognition in vertebrates is a natural, innate immune response, which completely changes the current paradigm and has overarching implications in Immunology. Indeed, during the last half of century, time in which Immunology developed into a modern science, thousands of research findings, models, ideas, and concepts on the interaction of T cells with the MHC proteins have been adjusted to fit the paradigm that T cell allogeneic immune response is artificial, transplantation-associated phenomenon, not a natural innate process.

The new model predicts that transmission of viruses, such as HIV, between individuals with identical or similar MHC alleles occurs at a higher rate than that between individuals with different MHC alleles, which generates the selecting force leading an increase in MHC allelic diversity and the selection of a strong anti-MHC allogeneic cytotoxic response. Among hundreds of studies addressing the correlates of HIV-1 transmission, only a few have attempted to correlate the risk for heterosexual or mother-child HIV-1 transmission with the concordance or disparity of the HLA antigens. However, the results of these few field studies clearly show that HLA concordance is a strong predictor of transmission, just as predicted by the model. In fact, each additional Class I alleles concordance correlated with a stepwise increase in the risk for mother-child HIV-1 transmission, and the HLA concordance was the strongest predictor of transmission, even surpassing the viral load.

If correct, as the current evidence indicate, this new paradigm could have a significant impact in both basic and applied immunology. Of immediate interest would be development of new vaccine strategies. Interestingly, after it was fortuitously revealed, two decades ago, that a control group of macaques immunized with uninfected human cells were protected from SIV grown in analogous cells, the idea of using MHC alloimmunization as a vaccine strategy was considered. However, in absence of a supporting conceptual and evolutionary platform, this idea lost momentum. Although the high percentage of circulating alloreative T cells in humans can sustain a relatively strong innate immune response, which might explain the relatively inefficient HIV-1 transmission in natural settings, MHC alloimmunization might enhance this protection or even abolish natural HIV-1 transmission
Considering the disappointing results of the implemented HIV-1 vaccine field trials, and the genuine call for new ideas and approaches by the AIDS medical and research community, it would make sense to consider MHC alloimmunization as a vaccine approach.

By Claudiu Bandea (not verified) on 07 Jun 2012 #permalink

What if the basic paradigm is upside down and viruses in virgin wilderness, which unfortunately no longer exists, are not pathogens at all but the means of transferring genes horizontally, as well as being a toolbox of viruses, HIV and some cancer viruses such as RAS included, whose role is inducing modifications in the way cells behave.

Viruses in the concrete jungle, which is the very antithesis of wilderness, are analogous to weeds, and like weeds have also undergone a range of mutations that make them more infectious and virulent in the transition from wilderness to the concrete jungle as well as infecting a larger range of species.

In this model a variety of viruses in wilderness form collaborative, synergistic relationships just as plants do in wilderness. There would be no such thing as single viral infections as with plagues. Same with plants, no one plant, as a weed, taking over and destroying everything else.

One huge oversight in Darwinian evolutionary theory is how does immune suppression against newly emerging body structures take place precisely at the same time of said emergence to prevent an 'auto immune' attack. Something that does this would have to be totally resistant itself to destruction by the immune system.

Enter HIV, but a different HIV than what is infecting people in a poor state of health relative to the animal in the wild, persistently stressed, eating foods out of season, no longer entrained into natural light and temperature cycled ETCETERA.

It infects differently to that of blood to blood transfer ie T4 cell trophic. It is dendritic cell trophic, these cells apparently having a small number of CD4 receptors on them and a special viral compartment in which the virus undergoes modification with various inputs to become MACROPHAGE trophic. Similar thing here to finally become T4 cell trophic. By this time it has undergone a huge range of inputs relative to the genetic makeup of it's host

Doesn't having MHC-2 receptors on the virus mean that it is mimicking an APC and epitope therein.? Where does one go from here as it would be a vastly complicated process. Heresy maybe, but might just be the answer.

By paul hill (not verified) on 08 Jul 2012 #permalink

Hello, is anybody there? All to busy cooking up vaccines are we, even if it's a total waste of time? Am I alone in this jungle?

By paul hill (not verified) on 09 Jul 2012 #permalink


What if toadstools were actually made of chocolate? Wouldn't that be wonderful? What-if can be a fun game to play, but it has to work within the framework of reality.

The problem with your idea is that it requires teleology - that is, some guiding principle ensuring viruses behave themselves. There is no such thing in evolution - the only "guiding principle" in evolution is that what works, works. For viruses, hijacking cells to produce lots and lots of little babby viruses works well - they don't need to help the host at all (although it's somewhat detrimental to them if they kill the host too quickly). So, they don't.

As for your immune system question - i.e. why doesn't the immune system destroy newly emerging structures - it stems from a lack of understanding of how the immune system works. In the fetus, the immune system (and in particular self vs. non-self recognition) doesn't develop until quite late in gestation. Once it does develop, how does it decide what is self and what is non-self? Easy - everything that's already there is "self", and everything that enters from that point on is "non-self".

That's how chimeras form. Add cells from a different individual before the cut-off date, and they'll happily coexist forever after. This happens naturally fairly regularly, and with species where multiple embryos share one placenta things can get really quite haphazard - fertile female monkeys with genetically male ovaries have been documented. It even works with quite distantly related species.

Anyway, the point is that there is no "huge oversight in Darwinian evolutionary theory" here. The problem you're trying to address simply doesn't exist - by the time the immune system develops, any novel structures are already part of the "self".

Are toadstools REALLY made of chocolate? As to viruses. If they had some sort of organelles, metabolic machinery, methods of propulsion etc. ie were LIVING things then I'd have to agree that they'd have to be real sneaky. But they are not. As to cellular defenses such as interferon, these are simply the cells way of modulating the degree of 'infection' in this virgin wilderness hypothesis.

As to immune recognition,what you are articulating is fine for a Darwinist . I'm not. I'm a Larmaskist and evolution takes place in the adult organism via very welled behaved cancers. Some cancer cells express MHC-2 receptors containing an epitope of a new protein they have evolved. They have an extra receptor, CD86 from memory, that matches one on, I was going to say a T8 killer cell, but that would mean an MHC-1 on the cancer cell.

This is from memory at a Cancer conference I attended years ago. Anyway this extra receptor binds to one on the immune cell and activates apoptosis in it, thereby blinding the immune system to the shape of the epitope. If this is an internal protein only in the cancer cell, it would be antigenic with necrotic cell death with whole proteins being released from the burst cell.

I think you'd have to agree that there must be a paucity of information on Larmarkist evolution as it is heresy and NOT researched except by Ted Steele immunologist at Uni of Woolongong NSW Aust.

Anyway, thanks for the first intelligent comment I've had since being on Science Blogs. It's been very informative. (I'm only grovelling so you don't rip into me.) Have a gander at what I've had to endure on these links.



By paul hill (not verified) on 09 Jul 2012 #permalink