Re: NATAP/CROI: Vaccine Problems-calls to 'Step Back'

[Brian Mailman]

> *HIV Vaccine's Mysterious Failure Leads to Call for New Directions
>
> *By Michael Smith, North American Correspondent, MedPage Today
> Published: February 07, 2008
> Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of
> Medicine, Harvard Medical School, Boston.
>
> *note from Jules: *years ago, perhaps in the early years of vaccine
> research, it was obvious to me finding a vaccine would be very difficult
> and I felt not possible. Now, in a controversial oral talk at CROI Ron
> Desrosiers said the effort should step back and search for a new
> direction. In my opinion we should redirect some of the vaccine research
> money and fund the many real live issues suffered by patients here in
> the USA that are underfunded including ADAP, HCV/HIV coinfection, bone
> disease research, and access/education for underserved communities.
>
> BOSTON, Feb. 7 -- There are still no answers to why a potential HIV
> vaccine failed so spectacularly last year in a large clinical trial, and
> researchers are continuing to burrow through the data in a search for clues.
>
> They are focusing on the role of *two possible culprits*. These are
> *circumcision and pre-existing immunity to the adenovirus vector used in
> the vaccine*, according to Susan Buchbinder, M.D., of the San Francisco
> Department of Public Health.
>
> Just how those factors may have left some volunteers who got the vaccine
> more susceptible to HIV, rather than less so, remains unclear, Dr.
> Buchbinder told the Conference on Retroviruses and Opportunistic
> Infections here.
>
> But last year's collapse of the Merck vaccine has left vaccine
> researchers dispirited and some calling for a complete re-examination of
> the enterprise -- including possibly abandoning clinical trials until
> more is known about the virus.
>
> In the wake of the failure -- and that of two earlier vaccines that also
> did not work -- *the National Institute of Allergy and Infectious
> Diseases has scheduled a March 25 "summit" of vaccine researchers to
> re-evaluate vaccine strategy.
>
> "The path forward is not clear,"* said John Mellors, M.D., of the
> University of Pittsburgh, co-chairman of this conference's scientific
> program. "Anyone who talks about a timeline for a vaccine is being silly
> and uninformed."
>
> "We will make progress," Dr. Mellors told reporters, "but the timeline
> of that progress is as cloudy as it ever was."
>
> One thing that is clear, Dr. Mellors said, is that the approach of using
> large clinical trials that last years is too slow, and other
> experimental methods will have to be sought.
>
> The STEP trial -- which tested a vaccine containing the gag, pol, and
> nef genes of the HIV virus, delivered by an inactivated adenovirus-5
> vector -- is a case in point.
>
> The trial itself is being lauded as a model. "Thirty-three months after
> the first patient was vaccinated, we got a clear, definitive answer,"
> Dr. Buchbinder said.
>
> Unfortunately, the answer -- after nearly three years -- was that the
> vaccine did not work and even left some volunteers more susceptible to
> HIV than they would have otherwise been.
>
> As of Oct. 17, 2007, she said, there had been 49 HIV infections in the
> vaccine arm and 33 in the placebo arm, a difference that led to stopping
> the trial and a parallel study conducted in Africa.
>
> All the infections but one were among male volunteers, so the
> researchers have concentrated on the men in attempts to explain the result.
>
> A post hoc analysis of the data showed that for men who were circumcised
> and had low immunity to the vector, the vaccine had essentially no
> effect compared with placebo.
>
> Men who were circumcised and had high immunity to the vector were at
> increased risk of HIV if they got the vaccine, but the increase was not
> statistically significant.
>
> The inverse was also true. Men who were uncircumcised and had low
> immunity to the vector were at increased but not statistically
> significant risk for HIV, Dr. Buchbinder said.
>
> But *men who were uncircumcised and had high immunity had more than four
> times the risk of HIV as did men who got placebo and the difference did
> reach significance. The relative risk in a multivariate model was 4.2,
> with a 95% confidence interval from 1.6 to 11.1.
>
> *The findings are "very surprising and unexplained," she said.
>
> Dr. Buchbinder said she and colleagues are also looking for data on
> other possible factors, including herpes simplex-2 infection, that may
> help explain why there were more infections in the vaccine arm than in
> the placebo arm of the trial.
>
> They are also looking at a range of laboratory and immunological values,
> said Michael Robertson, M.D., of Merck Research Labs in West Point, Pa.,
> although one thing that can be ruled out is a lack of immunological
> effect in the volunteers.
>
> Dr. Robertson said data from the cases and those who were not infected
> show roughly the same immune response. "They appeared to respond as well
> as the main cohort," he said.
>
> He added that the study result is "a very significant finding with broad
> implications for the whole field, but right now we have more questions
> than we have answers."
>
> It's precisely that aspect of the situation that has prompted calls to
> re-think the vaccine strategy.
>
> *"Maybe now is the time to step back" and seek new directions,* said
> Ronald Desrosiers, Ph.D., of the New England Regional Primate Research
> Center, who has been a leader in vaccine studies using non-human primates.
>
> "It really shouldn't be a big surprise that the three [vaccine] efficacy
> trials we've had so far haven't worked, because we're dealing with
> something that's very, very difficult," said Dr. Desrosiers.
>
> Earlier, he had told a plenary audience here that *current vaccine
> trials are essentially futile and added that there is no basis for
> thinking that any of the vaccine candidates in the pipeline "have any
> reasonable hope of being effective."
>
> *Dr. Desrosiers called for *"discovery research" that will generate new
> ideas about how to make a vaccine "rather than a fourth, fifth, or sixth
> efficacy trial."
>
> *He said the March 25 summit "holds promise for re-shaping or
> re-directing where we're headed."
>
> Dr. Buchbinder said the STEP trial was an important study, even though
> the vaccine candidate failed, and may yet provide useful information.
>
> "I don't think it was a mistake to move forward," she said. "We need
> experiments."
>
> The study was sponsored by Merck and the NIH. Drs. Buchbinder, Mellors,
> and Desrosiers reported no conflicts. Dr. Robertson is an employee of Merck.
>
> *Primary source:* Conference on Retroviruses and Opportunistic Infections
> Source reference:
> Robertson M, et al "Efficacy results from the STEP study (Merck V520
> protocol 023/HVTN 502): a phase II test-of-concept trial of the MRKAd5
> HIV-1 Gag/Pol/Nef trivalent vaccine" CROI 2008; Abstract 88LB.
>
> *Additional source:* Conference on Retroviruses and Opportunistic Infections
> Source reference:
> Robertson M, et al "Immunological characterization of subjects from the
> STEP study: A phase IIB test-of-concept trial of the MRKAd5 HIV-1
> Gag/Pol/Nef trivalent vaccine" CROI 2008; Abstract 89LB.

***********************************************************
For AIDS/HIV+ resources, visit the s.s.a.h+ website at :
http://www.webcom.com/benny/ssah/ssah+.html
***********************************************************