From Medscape Medical News
Bob Roehr
May 7, 2010 (Bethesda, Maryland) — HIV vaccine research is diverging from classic vaccinology and its focus on the adaptive immune response, to a field of its own. There has been a shift from protecting against infection to changing the nature of the infection, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), in Bethesda, Maryland, said in his keynote address here at the National Foundation for Infectious Diseases 13th Annual Conference on Vaccine Research.
The principles of classic vaccinology are that "the response to natural infection is the guidepost to the vaccine. . . . The proof of concept is already done for us by the natural response to infection. . . . The vast portion of people spontaneously recover," he said.
"The virus is cleared and eradicated and the person is left with a protective immunity that, in most cases, is complete and lifelong."
But beginning with the gp160 trial in 1987, researchers quickly learned that the principles of classic vaccinology "didn't apply particularly well to HIV. . . . I've been taking care of HIV-infected individuals for almost 29 years and I have never seen anybody eradicate the virus or spontaneously recover," Dr. Fauci said.
"And protective immunity against subsequent infection doesn't appear to occur. That is amazing. You are infected with a microbe and, while you are infected, you get reexposed to the microbe and you get reinfected. That is depressing for vaccinologists."
"There is no proof of concept to help us. We really have to start from scratch," he said. Basic research has been able to generate a few antibodies that are broadly neutralizing to laboratory strains of HIV, but not to wild-type virus, Dr. Fauci noted.
Once these facts began to sink in, the field shifted toward developing a vaccine that would not protect against infection but that might shift the course of disease progression to one that is less lethal, perhaps even benign. The public health goal of reducing transmission might be accomplished by lowering the viral load of those who are infected. "Those attempts, thus far, have not been successful," Dr. Fauci said.
STEP Back
The early stopping of the STEP trial, which was testing an HIV vaccine developed by Merck with the support of NIAID, led the field to another reevaluation. The mix of basic and developmentally oriented research was recalibrated back toward the former.
Then came the Thai study (RV144) "using a pox virus vector and an envelope boost, which, when you looked immunologically, had virtually none of the classical parameters that would predict protection. [Cytotoxic T lymphocytes] were nowhere to be found; neutralizing antibody, nowhere to be found," Dr. Fauci said.
But "for the first time we found a modest, weak, but real signal of prevention of acquisition," he said. "There was no doubt that the Kaplan–Meier curves were separated. We now had a weak signal upon which to build."
The fact that the vaccine had no effect on the viral load of those who became infected confounded the expectations of many, but not Dr. Fauci.
"I think it argues for the dichotomy of effect on acquisition vs the control of chronic viral infection. It is telling us something that perhaps we should have realized a long time ago — an immune response that protects against acquisition might be quite different from the immune response that actually controls chronic virus replication."
"What we have now is a whole new way of looking at things. . . . We really know what is going on and what is needed."
He sees the way forward as building on the empiricism of the RV144 trial while, at the same time, pursuing the fundamental issues of basic research.
Dr. Fauci is not sure that it will be possible to isolate correlates of protection from acquisition from the small number of infections in the Thai trial, "but it certainly will tell us what they are not. And what they aren't is 750 ELISPOTS on an assay. What they aren't is broadly cross-reacting neutralizing antibodies. . . . It may be that they are important, but they are not a requirement."
Different Virus
"As scary and dangerous as HIV infection is, it is a very inefficiently transmitted infection. One of the reasons is that there is a bottleneck to transmission." It has become apparent that "the transmitting virus might be quite different from the chronic replicating virus."
The transmitting virus appears to have a unique hypoglycosylated molecular signature that, surprisingly, appears to be easier to neutralize than variants found later in infection. However, once infection is established, the virus rapidly diversifies with conformational changes and the addition of glycands that can shield antibody binding sites, and the virus evades immune control.
Dr. Fauci pointed to the work of Dennis Burton, showing that "when looking at acquisition, you really need low levels of neutralizing antibody, much lower than you would have predicted" from the study of established infections. "There is a direct correlation between the ease of neutralization of a transmitting virus [and] the virus that has been replicating for years."
He added that "as the quasi-species develops, the virus diverges. The further you are from infection, the more divergent the virus is; the closer you are to the initial infection, the more homogeneous the virus is."
"Once the virus robustly replicates and gets into the lymphoid tissue, for all practical purposes, the ballgame is over for a vaccine. No matter what we do, you don't eradicate the virus. . . . The focus really needs to be on blocking acquisition. That is the end game."
It is why he is focusing on very early events, far earlier than the adaptive immune system is capable of reacting to.
Dr. Fauci indicated that, taken together, the cytotoxic T lymphocyte response will play, at best, a small role in future research toward a preventive vaccine. It might have some role in immunotherapy for HIV disease, but his comments on the effectiveness, tolerability, and cost of available small-molecule drugs create a high bar in moving HIV immunotherapy from basic research into regular clinical practice.
Dr. Fauci has disclosed no relevant financial relationships.
National Foundation for Infectious Diseases (NFID) 13th Annual Conference on Vaccine Research: Session 8. Presented April 27, 2010.
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