February 5, 2013
Therapeutic Vaccines: Escaping the 'Viral Escape'
by Benjamin Ryan
Their future clouded by past failures, therapeutic vaccines find new promise as a potential adjunct to cure therapies. But skeptics doubt if they will ever work.
With a checkered past, marred by decades of missteps, dead ends, controversies and a repeated need to change the direction of research, the quest for a therapeutic HIV vaccine is charting a slow but dogged path. Working under the theory that priming the body’s natural immune response could help people with HIV fight the virus, this effort has sharpened its focus in recent years—in particular as the excitement around the potential for a cure has surged and recent research has suggested that vaccines may prove a vital adjunct to cure therapies for people living with HIV.
A small clinical trial conducted in Spain recently achieved a “proof of concept” of a therapeutic vaccine. Publishing their findings in Science Translational Medicine, researchers modified HIV-positive participants’ dendritic cells—the immune cells that prompt CD4s to fight pathogens and which carry the virus to CD4s—to better fight the virus. The vaccine was able to lower what’s known as the plasma viral load set point in study participants for several months. However, eventually all the participants’ viral load set points rose again.
Promising results from the relatively sparse number of other research studies have proved as elusive. And skeptics express doubt that a therapeutic vaccine will ever be possible, thanks to unavoidable truths about the relationship between HIV and the immune system.
Therapeutic vaccine investigators report that funders shy away from vaccine research of any kind, all too aware of the grand, billion dollar failures of preventative vaccines if nothing else.
Kevin Fisher, policy director at AVAC: Global Advocacy for HIV Prevention, whose team recently conducted a survey of therapeutic vaccine researchers, says, “I’ve heard from researchers in our interviews that people would not put ‘therapeutic vaccine’ in their [research grant] application, because it’s just a kiss of death.”
A key foil in the attempt to design a therapeutic vaccine is what’s known as “viral escape.” During the first few weeks of infection with HIV, the body mounts an immune response. But, as with treatment failure on antiretrovirals, mutated viruses that escape the immune response quickly thrive and then become the predominant viral population in the body. (In the language of microbiology, CD8 T-cells are unable to recognize the mutated epitopes in HIV molecules.)
The consequence of this evasion for therapeutic vaccine research has been that fueling the body’s immune response only turns up the heat on a line of defense that is relatively ineffective. In fact, this process of viral escape likely contributes to the development of the viral reservoir, the prime target of cure therapies.
“If the virus has escaped, the virus has escaped. And there’s nothing you can do to make the immune system recognize it,” said Daniel Douek, MD, PhD, chief of the human immunology section at the Vaccine Research Center at the National Institutes of Health (NIH) in Bethesda, Maryland, who is a vocal skeptic about therapeutic vaccines’ potential for success.
Richard A. Koup, MD, the chief of the immunology laboratory at the vaccine research center at the National Institute of Allergy and Infectious Diseases at the NIH, recently conducted an as-yet unpublished study in which he and his team injected various HIV genes into HIV-positive subjects. This prompted an increased immune response to the virus, but no change in viral load or in the latent reservoir. Koup speculates that the immune response may not have been strong enough, but also that viral escape precluded any success from such an attempt.
“If the virus had escaped,” Koup says, “all that we’d done is expand an immune response that the virus had already escaped from.” Which is to say that boosting the immune response is of no use when it can’t actually recognize and target the virus.
“I felt an obligation to test this in HIV-infected individuals,” says Koup, who professes value in research whether it succeeds or fails—the findings can at the very least inform future studies and redirect efforts away from avenues lacking promise. “But,” he adds, “I don’t have a lot of faith that vaccinating people who are already infected is going to do much.
“The definition of insanity is doing the same thing over and over and expecting a different result,” he says. “And I think that the therapeutic vaccine industry or group is in many ways stuck in this rut.”
Others have argued that inoculating someone with a therapeutic vaccine during those first crucial weeks after infection could pre-empt the viral escape. However, considering the scant number of people who are diagnosed so soon after infection—and that HIV tests don’t screen for the virus but for antibodies that take a few weeks to develop after infection—this approach is largely impractical.
But therapeutic vaccines may be of use elsewhere: as a component of a broader cure therapy. A major study conducted by Robert F. Siliciano, MD, PhD, a professor at Johns Hopkins Howard Hughes Medical Institute published in Immunity, showed that purging the viral reservoirs fails to actually kill the virus. Instead, CD8 cells must deliver the fatal blow; however, most people with HIV lack CD8 cells with the capacity to do so.
Enter the therapeutic vaccine, which could prime the CD8 cells to either clear the virus entirely, which is known as a “sterilizing cure,” or to successfully control the virus without the need for daily ARVs, known as a “functional cure.”
“It’s going to be essential to have both an effective latency-reversing strategy and therapeutic vaccination,” Siliciano says. “Neither one alone is going to work.”
Siliciano challenges the skepticism of those who believe that viral escape precludes any hope of developing a therapeutic vaccine. He points to long-established research showing that the course of HIV disease throughout untreated infection would be much worse without the immune response, indicating that the immune system is still controlling a smaller population of unescaped virus. He speculates that vaccine-primed immune cells would recognize at least some of these HIV epitopes that haven’t mutated.
Hans-Peter Kiem, MD, who is researching genetic and cellular therapies for HIV at the Fred Hutchinson Cancer Research Center in Seattle, offers a potential way around the viral escape roadblock. After transplanting blood stem cells and immune cells that have been genetically modified to control HIV, these cells would then become the dominant force in the body, and would be more receptive to the addition of a vaccine.
Harriet L. Robinson, PhD, is the chief scientific officer of GeoVax in Atlanta, which is currently working on a vaccine that instructs the body to create HIV-fighting antibodies as which also elicits CD4 cells that can recognize and kill HIV-infected cells. She remains optimistic about the potential to combine drugs and vaccines to better control or possibly cure the virus.
“People never dreamt that we could control infections the way we can,” she says, referring to the dark days of the AIDS epidemic before the advent of ARVs in the mid-1990s, “At this point a lot of people don’t believe we can actually eradicate an infection But that doesn’t mean that within the next 20 years we won’t have figured out how to do it, with a combination of drugs and vaccine.
“You just have to persevere,” she says.
Search: HIV, AIDS, therapeutic vaccines, Science Translational Medicine, Kevin Fisher, AVAC: Global Advocacy for HIV Prevention, CD8 T-cells, CD4 cells, Daniel Douek, Vaccine Research Center, National Institutes of Health, NIH, Richard A. Koup, MD, National Institute of Allergy and Infectious Diseases, viral escape, Robert F. Siliciano, Johns Hopkins Howard Hughes Medical Institute, Hans-Peter Kiem, Fred Hutchinson Cancer Research Center, Harriet L. Robinson, GeoVax, sterilizing cure, functional cure, antiretrovirals, ARVs.
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