Vector did not kill HIV trial

New findings have disproved a leading explanation for why an experimental HIV vaccine made subjects more susceptible to the virus, reopening the door for further HIV vaccine efforts based on similar principles. Human Immunodeficiency VirusImage: NIAIDThe Merck-funded STEP study, which used an adenoviral vector to deliver an HIV vaccine candidate, was halted in 2007 after the data suggested the vaccine increased the risk of HIV infection. Researchers thought the effect might be due to an immune

By | July 20, 2009

New findings have disproved a leading explanation for why an experimental HIV vaccine made subjects more susceptible to the virus, reopening the door for further HIV vaccine efforts based on similar principles.

Human Immunodeficiency Virus
Image: NIAID
The Merck-funded STEP study, which used an adenoviral vector to deliver an HIV vaccine candidate, was halted in 2007 after the data suggested the vaccine increased the risk of HIV infection. Researchers thought the effect might be due to an immune reaction to the viral vector, but two studies published online in Nature Medicine today show this is not the case. "Both of these papers show that's not a possible explanation," said molecular immunologist linkurl:David Weiner;http://www.med.upenn.edu/camb/faculty/gt/weiner.html of the University of Pennsylvania, who was not involved in the research. "Overall this is a positive and optimistic message for the field," said immunologist linkurl:Dan Barouch,;http://www.hms.harvard.edu/dms/virology/fac/Barouch.html chief of Harvard University's Division of Vaccine Research and the lead author of one of the studies. "Other vaccine vectors can and should be further pursued in clinical trials." Individuals who have previously been exposed to adenovirus serotype 5 (Ad5) -- a common cold virus -- have more Ad5-specific antibodies in their blood; that is, they are Ad5 seropositive. Analysis of the trial suggested that Ad5-seropositive subjects contracted HIV at a higher rate when they received the vaccine as opposed to the placebo. Researchers hypothesized that Ad5-seropositive individuals might be more sensitive to the Ad5 vector, and consequently, could "mount a more rapid, larger immune response," explained molecular biologist linkurl:Alan Bernstein,;http://www.hivvaccineenterprise.org/about/index.aspx executive director of Global HIV Vaccine Enterprise, who was not involved in the research. Because HIV attacks activated T cells, increased T-cell counts would provide more plentiful targets for HIV infection, and could thereby explain the boost in susceptibility. The current studies analyzed frozen blood samples from two different precursor trials to the STEP study, and in both cases, the research teams disproved the idea that prior exposure to the Ad5 vector equated to higher T-cell counts. In the study led by Barouch, approximately 90% of subjects had Ad5-specific T cells prior to vaccination, but very few had Ad5-specific antibodies. This demonstrated that the two measures of immunity -- Ad5-specific antibodies and Ad5-specific T cells -- are not correlated, meaning that that Ad5 seropositivity cannot be used to predict levels of Ad5-specific T cells prior to vaccination. Furthermore, while all subjects showed an expansion of Ad5-specific T cells after vaccination -- a typical immune response to the viral vector -- this effect was not greater in Ad5-seropositive individuals. Just the opposite, Barouch's team found 2-3 fold more Ad5-specific T cells in Ad5-seronegative subjects, suggesting that Ad5 seropositivity did not raise the T cell count. Finally, using intracellular cytokine staining to identify individual cells, immunologist linkurl:Michael Betts;http://www.med.upenn.edu/micro/faculty/betts.html of the University of Pennsylvania School of Medicine and his colleagues found in the second study that the T cells produced post-vaccination did not differ in the types of cytokines they secreted. This suggested there were no functional differences in the T cells produced by seropositive and seronegative individuals. "The two papers really biologically have shown that there's no relationship between adenovirus 5 seropositivity and increased acquisition [of HIV]," said Bernstein. "[This] result really rules out the possibility that it was the vaccine itself, and the fact that we used Adeno5, that was somehow increasing susceptibility to acquiring [HIV] in those volunteers." As for what caused the increase in HIV susceptibility in the STEP study, "that's the $64 million question," Weiner said. One important next step is to look at these same immune response measures in the body's mucosal tissues instead of blood. For one thing, "90% of all memory T cells are found in intestinal mucosa," said Betts. "In primary HIV infection, the vast majority of all viral replication takes place in the gut because that's where the majority of T cells are." Furthermore, "that's where the infection occurs," added molecular biologist linkurl:Nelson Michael;http://www.hivresearch.org/about/director-bio.html of the Walter Reed Army Institute of Research. "The fact that you don't see [a difference in T cell] activation in the blood may not necessarily mean that you wouldn't have seen [differences in] activated T cells [in the mucosal tissues of the genitalia]." Alternatively, there may not be a correlation between Ad5 seropositivity and HIV infection after all. In addition to the Ad5 seropositive individuals, uncircumcised men who received the STEP study vaccine also contracted HIV at a higher rate than those receiving the placebo. "Circumcision and Ad5 seropositivity were both factors," Michael explained, "but [they] confounded one another." With more data rolling in from the now-unblinded STEP study subjects, he said, it appears that "the effect of Ad5 [seropositivity] washes out when you control for circumcision." Whatever the reason for the unexpected results, the STEP study and its aftermath were "an important lesson for this field," said Bernstein. "The mistake was thinking the trial failed because the candidate failed. We shouldn't mix up the two. The trial will be a success if we learn something from it, [and] I think that's turning out to be the case."
**__Related stories:__***linkurl:New wrinkle for HIV vaccine;http://www.the-scientist.com/blog/display/55478/
[25th February 2009]*linkurl:HIV vaccine research: crisis of faith?;http://www.the-scientist.com/blog/display/54607/
[24th April 2008]*linkurl:HIV vaccine trials stopped;http://www.the-scientist.com/blog/display/53633/
[25th September 2007]

Comments

Avatar of: Richard Jefferys

Richard Jefferys

Posts: 3

July 21, 2009

The writer of this piece should contact Susan Buchbinder to ensure that Dr. Michael's interpretation of the circumcision data is correct. I've seen Dr. Buchbinder present the data fairly recently and she clearly stated that the independent enhancing effect of receipt of the vaccine was not eliminated by these analyses. Rather, they show that the effect was largest and statistically significant in the uncircumcised men with pre-existing antibodies to Ad5. The Nature Medicine papers show that one particular hypothesis about the role of Ad5-specific CD4 T cells has not borne out, but they do not absolve the vector from enhancing the risk of HIV acquisition among vaccine recipients in the trial.
Avatar of: anonymous poster

anonymous poster

Posts: 9

July 26, 2009

I always believed that the Ad 5 vector was not at fault. This has substantially been been upheld!
Avatar of: Richard Jefferys

Richard Jefferys

Posts: 3

July 29, 2009

Regrettably, that isn't the case. Susan Buchbinder's most recent presentation showed that the enhancement effect has waned over time, which only adds to the evidence that the vector was responsible. Email Dan Barouch and ask him directly. This article is flat-out wrong.
Avatar of: ROULETTE Wm. SMITH

ROULETTE Wm. SMITH

Posts: 10

August 2, 2009

Adenovirus-associated vectors have been used in several vaccine trials and gene therapy trials. Sadly, I know of no research reports that investigate and rule-out a likely etiology; to wit, autovirulence. I first reported autovirulence as a general (and, indeed, widespread) phenomenon and process in 1982 and in multiple subsequent reports. I have not seen any serious and thoroughgoing studies of the process to date. Any notion that the immune system is a culprit entirely misses the point!

Popular Now

  1. Running on Empty
    Features Running on Empty

    Regularly taking breaks from eating—for hours or days—can trigger changes both expected, such as in metabolic dynamics and inflammation, and surprising, as in immune system function and cancer progression.

  2. Athletes’ Microbiomes Differ from Nonathletes
  3. Mutation Linked to Longer Life Span in Men
  4. Gut Feeling
    Daily News Gut Feeling

    Sensory cells of the mouse intestine let the brain know if certain compounds are present by speaking directly to gut neurons via serotonin.

AAAS