Report from the Lab

You’re in: AIDS at 25 Coverage / 25 Years Later: The Vaccine

—New York

By far, the biggest challenge in HIV vaccine development stems from the virus’ structural and functional complexity. The vaccines we have today—against measles, polio, rabies, etc.—were far easier to develop because their targets are simpler and more predictable.

Many different strains of HIV exist worldwide. Viruses within a single strain can differ significantly—this is what gives the virus its complexity. HIV’s coat, or envelope, is covered in “sugars” and can rapidly mutate within an indiv-idual and throughout a population. Finding a way to prime immune systems against such an elusive and diverse target is extremely difficult.

For these reasons, at least in the near term, we know that an effective HIV vaccine is going to be very different from any other vaccine we have today. Aside from the fact that the most common historical approaches to vaccine design (i.e., live attenuated or whole killed virus) are not used due to safety concerns, most licensed vaccines initiate an antibody-mediated immune response, priming cells to produce antibodies to effectively attack the target.

But HIV forces us to take a novel approach because we have not found a way to elicit a broadly neutralizing antibody against it. So until we do, we will focus on priming the body for another type of immune response, a cell-mediated response, which involves the activation of different kinds of immune cells.

We already know that cell-mediated responses are important in controlling viral load in HIV-infected individuals, and we have seen subtle cell-mediated responses in people who have been able to remain uninfected after HIV exposure. We believe that key segments of the virus must remain the same between different worldwide strains in order for it to reproduce efficiently, and that certain cell-mediated responses should be able to detect and attack these segments. As a result, a cell-mediated approach may be helpful in getting past the challenge of the diversity of HIV.

That said, most scientists believe that a fully effective vaccine will require both types of immune responses, antibody-mediated and cell-mediated. Gary J. Nabel, director of the Vaccine Research Center (VRC) at the NIH, calls the broadly neutralizing antibody-approach the “Holy Grail” for HIV vaccine research—and I agree that it would be highly desirable to achieve this in combination with a strong cell-mediated response. But for the time being, we’re making do by pursuing the “slightly less holy” grail, a solely cell-mediated vaccine, because of our difficulties in inducing broadly neutralizing antibodies.

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We have already developed two such vaccine strategies, which are currently in Phase II clinical trials. Three thousand people in the Western hemisphere who are at high risk for HIV are being enrolled to test a Merck vaccine that utilizes an adenovirus (a “cold” virus) as a carrier; a similar study is being planned for southern Africa next year.

In addition, 180 people in the US have been enrolled in another study using a similar vaccine approach developed by Dr. Nabel’s group at the VRC. We are eagerly awaiting the opening of the trial sites in the Caribbean, Brazil and South Africa. Hopefully, this approach will also be moved into expanded testing in high-risk individuals in the next year. Both of these vaccine regimens appear to be tolerated quite well, but we’ll need to wait several more months before any of the important immune response information becomes available.

So while the first licensed vaccine might not be too far off, the ultimate vaccine—one that induces both types of immune responses—is likely to be much further away, and is only liable to arrive once we’ve solved the elusive “antibody puzzle.”

But the good news is, we think our understanding of how to solve the antibody puzzle is progressing. Most scientists feel that there must be critical pieces of the envelope that stay constant—pieces that, if they were to mutate, would not allow the virus to survive and replicate. The key question right now is how we might be able to identify and “get at” these pieces—and then comes the challenge of developing a vaccine that targets them.

Dr. Michael Keefer is the principal investigator of the HIV Vaccine Trials Unit, University of Rochester Medical Center.

Thumbnail Credit: Nicholas Monu

Originally published August 14, 2006


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