December 14, 2007 (Potomac, Maryland) -- "The T-cell vaccine concept is hanging by a thread right now. You need to decide whether or not to cut that thread or strengthen it into a rope," Cornell University researcher John Moore, PhD, told a special meeting of the National Institute of Allergy and Infectious Diseases AIDS Vaccine Research Subcommittee this week.
The meeting was called to review the findings of the STEP trial of Merck's HIV vaccine and the effect that might have on the proposed PAVE 100 vaccine trial. The Merck trial was halted in September when it became clear that those who received the vaccine were becoming infected at higher rates than those who received placebo. Initiation of the PAVE 100 trial, supported by the National Institutes of Health Vaccine Research Center (VRC), is on hold pending review and possible modifications to the protocol.
STEP was a phase 2B test-of-concept trial with the principal goals of prevention of infection or better control of infection with a lower viral set point in those who became infected, explained Michael N. Robertson, MD, Merck's principal investigator on the trial.
The 3000 participants were randomly assigned in a 1:1 ratio to receive placebo or a vaccine using an adenovirus 5 vector (Ad5) with HIV-1 clade B optimized gag, pol, and nef at 0, 1, and 6 months. Overall, 19 patients who received the vaccine became infected with HIV compared with 11 who received the placebo, and the trial was stopped.
In trying to understand why this occurred, Dr. Robertson noted confounding factors that may have contributed to the outcome. Some 56% of participants were enrolled in North America and Australia and were more likely to have low levels of Ad5 antibodies and be circumcised. Participants from South America and the Caribbean were more likely to have high levels of Ad5 antibodies and be uncircumcised.
Dr. Robertson said that circumcision appears to play a protective role, but he cautioned against reaching premature conclusions. The researchers have not completed analysis on the presence of herpes zoster infection, which is known to significantly increase the risk of acquisition, or of human leukocyte antigen types, which affect disease progression and possible acquisition.
Jay Berzofsky, MD, PhD, chief of the vaccine branch at the National Cancer Institute, suggested that the level of Ad5 antibodies "might be affecting the way the vaccine is taken up and processed and could potentially lead to an immune response against the vaccine component that skews more toward a Th2 type of immune response and a greater chance of infection." He suggested looking at cytokine profiles and immunoglobulin isotypes — evidence for some shift in the Th/Th2 balance.
Dr. Robertson said that persons who are negative for Ad5 antibodies at baseline develop those antibodies after the first inoculation. He did not know whether the replication defective vector used in the trial generated the same functional response as natural infection. The researchers are going to examine adeno-specific T-cell responses to the vaccine in those patients who are naive and who have either low or high Ad5 antibody levels.
Dr. Moore suggested that the naturally occurring Ad5 antibody titers might be a surrogate "that is tracking correlates of susceptibility; the higher the antibody titer to Ad5, the less likely you are to be infected at common risk." In the AIDSVAX trials, individuals with the highest titers were less likely to be infected.
Lawrence Corey, MD, a researcher at the University of Washington and principal investigator of the HIV Vaccine Trials Network, suggested that future trials stratify participants by Ad5 antibody titers, separating them into 2 groups with titers more or less than 18, which is the limit of detection of the current assay, because that is the breakpoint where one begins to see differences in response.
M. Juliana McElrath, MD, PhD, from the University of Washington, reviewed laboratory data on response to the vaccine at week 30, 4 weeks after administration of the final inoculums. There were no differences in T-cell activation or chemokine (C-C motif) receptor 5 expression between the groups. However, "the magnitude of responses in the male with high Ad5 titer (>200) are beginning to creep down, in contrast to those with the low Ad5 titer (<200)."
Dr. McElrath said the T-cell response in long-term nonprogressors is as much as a log higher and broader than what was seen in this trial but she said she hesitated to make that comparison because the studies have used different peptides and reagents, and so any numbers may not correlate well with what is really occurring.
David Watkins, PhD, from the Wisconsin Regional Primate Research Center, was "struck by the paucity of CD8-specific responses induced by the Ad5 vaccine in humans. In the Merck study, an average of 3 epitope-specific responses are being induced. If you do the same studies in nonhuman primates, almost all of the animals are making 10 epitope-specific responses. The numbers are far greater."
Given the great variability of a natural HIV challenge, "I think the breadth is a real problem." In macaques, most respond with 5 epitope-specific responses to gag alone; Dr. Watkins said that he does not understand what the difference is. "Maybe in humans, it is prior exposure to Ad5, and when you vaccinate in that setting, your first response is a massive CD8 response that drowns out the response to the overreading frame that you've put into that virus."
Dr. Watkins said the response in macaques is stronger and broader, which likely is key to containing viral escape of the highly unstable and variable virus, adding that heterologous challenges are very different.
A central question at the meeting was whether the PAVE 100 vaccine trial is sufficiently different from the STEP trial to support it going forward, even though it also uses an Ad5 vector.
Gary Nabel, MD, PhD, director of the VRC, the sponsor of the trial, argued that it is. He said the first 3 injections (0, 1, and 2 months) are DNA primes using 6 plasmid constructs; gag, pol, and nef, plus env from clade A, B, and C virus. The Ad5 boost is used only at 6 months compared with its use at all 3 time points in the STEP trial. He said this both boosts and broadens the response. "It is qualitatively different," he stated.
The VRC's Richard Koup, MD, said the DNA induces the CD4 response, and the Ad5 boost results in a 5- to 10-fold increase in CD8 response. "Polyfunctionality, in both CD4 and CD8, [is] associated with long-term nonprogressive HIV infection and vaccine-mediated control of SHIV infection.... The quality of the T-cell response you get with DNA/Ad vs adenovirus alone gives you much more polyfunctional T-cells. They make more cytokine on a per-cell basis; the interferon-gamma production is about 20-fold greater."
Jerald C. Sadoff, MD, president of the Aeras Global TB Vaccine Foundation, mentioned the fact that a higher elispot count -- in the thousands -- correlates with protection in primates compared with the count seen in humans, which is around a hundred. Dan H. Barouch, MD, PHD, from Brigham and Women's Hospital, said it is more than just a count; there are 3 key differences: the magnitude of the response, the quality of the response, and the breadth of response.
Dr. Nabel said the STEP Ad5 vector contains a single deletion (E1) to make it replication incompetent, whereas the PAVE 100 Ad5 vector contains a triple deletion (E1, E3, E4), and "there may be an advantage to that." Ad5 does not replicate in nonhuman primates, so it will be difficult to answer questions concerning the vector, prior exposure, and effect of antibodies except through human trials.
There was a general consensus among the committee that the PAVE 100 trial is sufficiently different to allow it to move forward, although several persons voiced skepticism or reservations.
Dr. Wright was "not entirely convinced it is sufficiently different." He noted that 20% to 30% of the vaccinees in early-phase trials are not generating a response to the vaccine, and that those who do respond are generating only an average of 3 CD8 epitope-specific responses.
Dr. Koup countered that the STEP and PAVE 100 studies used different epitope mapping techniques, and that he was hesitant to compare those numbers. He said, "I know we've missed epitopes" mapping with 15 mers. Going down to 9 mers, he noted, they picked up epitopes for each of the 3 clades in the construct.
Dr. Sadoff expressed frustration that for the last 2 meetings, he has been asking for head-to-head data between STEP and PAVE, "same methods, same lab, to see what the true differences are in an immunological sense," so that real comparisons can be made between them, but this has not been done.
Bruce Walker, MD, from the Partners AIDS Research Center, was concerned about the breadth, magnitude, and specificity of the responses. Studies have shown that the response to gag is the one that influences viral load the most, in terms of disease progression. He noted, "It's hard for me to say stop the trial, based on those theoretical concerns.... I'm not exuberantly enthusiastic."
Dr. Moore was conflicted as to whether the PAVE 100 study should move forward or not. If it does, he urged that it be done as an experiment, noting, "you do that by doing the quickest, most efficient experiment to test the concept of [whether] a T-cell vaccine, which is strongly immunogenic, [can] protect."
Given the results from the STEP trial, maybe gay men are not the right population in which to conduct this trial, said William Snow, founder of the AIDS Vaccine Advocacy Coalition.
Dr. Sadoff concurred. "The risk of infection by heterosexual transmission is lower than [for men who have sex with men (MSM)]." It may be that a vaccine might be able to protect against a small amount of virus but not a larger amount. He said part of the reason that trials are being conducted in MSM is because they are more willing to volunteer for a trial, but, "when you make decisions for operational reasons rather than scientific reasons, that's where you're going to have problems."
At the same time, there was concern that it would be difficult, if not impossible, to enroll sufficient numbers of high-risk women in the United States to get meaningful results. Enrolling women in developing countries will add the confounding factor of higher levels of Ad5 antibodies, and enrolling men in those settings will entail having to offer circumcision, now that it has proved to be efficacious. In addition, the increased availability of therapy in those countries will affect the incidence of transmission. All of these factors will add to the size, duration, complexity, and cost of conducting trials.
Dr. Sadoff said, "We don't have correlates of immunity, we don't have an animal model, we have no way to go forward except in clinical trials in order to validate some of those preclinical methods. The mechanism of action may or may not be important, but what is important is whether or not a vaccine that induces cellular immune responses is able to protect. That is the critical question."
He added, "I don't think it is a prudent development pattern to wait until we figure out the mechanism of why this particular trial went bad, when people are suffering from the disease."
Medscape Medical News © 2007 Medscape
Cite this: Bob Roehr. Future of HIV Vaccine Research Remains Uncertain - Medscape - Dec 14, 2007.