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Insight & Intelligence : Aug 6, 2012
Why The AIDS Vaccine Remains Elusive
Virus’ variability and ability to integrate with host DNA are two major hurdles.!--h2>
The Cold War arms race is a great metaphor for how the AIDS virus infects people, says Barton Haynes, M.D., director of the Duke Human Vaccine Institute at Duke University School of Medicine. While the Cold War is history, the quest for a vaccine against HIV continues—an often-elusive goal that now offers some glimmers of hope.
Just as the U.S. and USSR built bigger and bigger bombs against each other a generation ago, so HIV touches off antibodies that kill most of their target virus, then induce an escape virus that infects the patient. That in turn touches off another round of antibody deployment followed by escape virus. After two to three years, 85% of patients with chronic AIDS experience poor or non-neutralizing antibody response.
The other 15% develop broadly neutralizing antibodies—which researchers hope can someday be induced in others with HIV through a vaccine.
Discovering how that happens will be the goal of two new Centers for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID), one of which will be led by Dr. Haynes at Duke. Last month, NIH’s National Institute of Allergy and Infectious Diseases (NIAID) awarded $31 million in first-year funding, and possibly $186 million or more over seven years for CHAVI-ID.
“The new grant is to now define virus evolution and antibody evolution in a whole series of patients, to understand what happens on the virus side when broadly neutralizing antibodies develop on the antibody side—when the arms race goes in the right direction, if you will,” Dr. Haynes told GEN. “Embedded in those virus sequences and structures are, essentially, a prototype vaccine at least in that person that induced the right kind of antibodies.”
By pulling out those virus sequences and envelopes and structures, he said, “We’ll be, number-one, looking to see how common the patterns are for what induces the right kinds of broadly neutralizing antibodies from patient to patient.
“Secondly, we’ll be actually making those envelopes and testing them in nonhuman primates, and hopefully eventually soon in Phase I trials, to see if we can recreate that induction of broadly neutralizing antibodies in the context of a vaccine and its adjuvant,” Dr. Haynes added.
Dr. Haynes was among speakers assessing progress, and challenges toward an HIV vaccine at the recent XIX International AIDS Conference (AIDS 2012), where several conference speakers delivered surprisingly upbeat assessments of the state of AIDS research: “We are on scientifically solid ground when we say we can end the HIV/AIDS pandemic,” NIAID Director Anthony S. Fauci, M.D., declared at a plenary session.
Since the first AIDS cases emerged in 1981, only three major HIV vaccine candidates have completed efficacy clinical trials. Robert Gallo, M.D., a co-discoverer of HIV and director of the Institute of Human Virology (IHV) of the University of Maryland School of Medicine, told GEN. VaxGen’s AIDSVAX likely failed due to type-specific antibodies and perhaps inadequate antibody titans, while V520, a candidate of NIAID’s Vaccine Research Center and Merck, failed and even increased the number of infected patients—likely due to use as a vector of an adenovirus strain already exposed to a sizeable percentage of people from earlier infections.
Most successful was the RV144 Thai vaccine trial of 2009, which saw just 31.2% of patients protected through the combination of Sanofi’s ALVAC-HIV and AIDSVAX. Dr. Haynes led a consortium that in April published in The New England Journal of Medicine a follow-up study to RV144. Binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins may have contributed to protection against infection, while high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies, the group found.
One hurdle to developing an AIDS vaccine is the virus’ variability.
“We really need immune responses, which don’t block just one virus or one small family of viruses, but are reactive against the epidemic. And we now have quite a number of them. And more are being discovered all the time.” C. Richter (Rick) King, Ph.D., vp of vaccine design for the AIDS Vaccine Design & Development Laboratory of the International AIDS Vaccine Initiative, told GEN.
“All of us are pretty excited about the fact that there’s a new day here in this area, which just wasn’t the case five years ago,” Dr. King said. “The field of broadly neutralizing antibodies has really picked up and invigorated the vaccine design area.”
Dr. Gallo told GEN that while broadly neutralizing antibodies have shown promise in some people with HIV, researchers don’t yet know what antigen can induce them, or how to make them last long enough to be truly effective against the virus.
“I believe if you have perfect neutralizing antibodies, and they’re high-titer and they last, that’s one way that we should have a successful vaccine. But let’s keep our minds open. There may be more than one way to get a home run,” Dr. Gallo said. “There are antibodies with other biologic activity, like antibody-dependent cellular cytotoxicity or ADCC. There are antibodies with other biologic activity.
Dr. Gallo’s IHV and a spinout company, Profectus Biosciences, are collaborating with Sanofi and the U.S. Military HIV Research Program (MHRP) in developing a DNA-based vaccine candidate that encodes a full-length, single-chain fusion protein targeting co-receptor CCR5. The vaccine candidate is designed to induce antibodies to CD4-induced (CD4i) epitopes on the protein gp120. The collaboration last year won $23.4 million toward preclinical and Phase I/II trials from sources including the Bill & Melinda Gates Foundation, MHRP, and NIH.
Another hurdle to an HIV vaccine is the retrovirus’ ability to integrate with host DNA.
“That means you need something with long-lasting antibodies or boosts that will keep those antibodies at reasonably high levels, because you can’t afford a situation like polio, which is in your gut till it reaches your brain, giving you time to clear it out. You can’t wait those two weeks or three weeks,” Dr. Gallo said.
How long until an AIDS vaccine finally emerges?
“Anybody who gives you an answer to that is telling you fantasies, deliberately or unconsciously,” Dr. Gallo said.
Added Dr. Haynes: “We have directions to move now, and we have hypotheses to test, and we understand what the problem is. The field is going to be working as hard as possible to translate it to vaccine candidates as quickly as possible. That’s about all I can say.”
Dr. King told GEN that researchers are “probably somewhere in the range of 10 years away from a deployed vaccine, and it could be longer.”
“The detection of broadly neutralizing antibodies or another effective immune response can come in relatively early clinical trials, sometimes even in the safety trial. We might expect to begin to see those kinds of results in much less time, maybe four to five years,” he added. “I’m fairly optimistic that we’ll know we’re on a good path by about that point.”
Until then, investigators and officials must master a difficult balancing act: They must temper hopes raised among people with HIV by scientific progress, often amplified by giddy researchers, ambitious activists or simplistic news reports, with caution about how far off a safe and effective AIDS vaccine remains.
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