September 12, 2011

HIV Vaccine : Unnatural Immunity

By Alicia Rose DelGallo, Ivanhoe Health Correspondent

(Ivanhoe Newswire) -- The pandemic still rages as 33.4 million people worldwide live with the human immunodeficiency virus (HIV). Currently no vaccine exists that effectively prevents HIV. However, new improvements, published today by Maraget I. Johnston, Ph.D., and Anthony S. Fauci, M.D., in the New England Journal of Medicine, are taking HIV vaccine development down an innovative path.

Typically, the best way to develop an effective vaccine is to design a candidate that mimics infection, inducing responses similar to those that occur during natural infection. The induced immune response ultimately clears the microbe from the body and leaves the person with protection against reinfection. However, this typical approach does not work with HIV. The body´s natural immune response to HIV infection is completely inadequate. In fact a “natural” response does not occur at all, or it occurs too rarely, is too weak, or is too slow to begin.

When a natural immune system just doesn´t cut it, “unnatural immunity” may be the key. HIV infection does not naturally induce broadly neutralizing antibodies, which according to Dr. James Kublin, director of the HIV Trials Network at Fred Hutchinson Cancer Research Center is an “antibody that prevents the infection and neutralizes the virus to keep it from being infectious.”

The infusion of several broadly neutralizing antibodies completely prevented viral acquisition in nonhuman primate models of AIDS. Therefore, an HIV vaccine that results in the production of broadly neutralizing antibodies before or soon after exposure to HIV is likely to be highly effective.

Inducing these antibodies unnaturally is an important challenge for HIV vaccinologists; and the application of new research tools is helping to guide the design of vaccines that do just that. A recent research focus has been on “structure-based vaccine design”.

More specifically, studies of the crystallographic structure of the HIV- envelope epitope and binding site of a broadly neutralizing antibody are being used to design a vaccine that effectively presents that epitope to the immune system. However, determining how to replicate the three-dimensional structure of the HIV-envelope epitope will be very difficult.

One approach being pursued is scaffolding the epitope onto an exposed portion of a soluble or membrane-associated protein. In other words,

“The vaccine would have pieces of the virus that are built on a larger structure that will make immune responses against HIV that are neutralizing,” Dr. Kublin was quoted as saying.

All potent broadly neutralizing antibodies to date have one or more unusual structural features. These features may result only from years of chronic viral infection. They appear to arise through a complex evolutionary process, termed “somatic hypermutation”, which generates B cells (immune cells that secrete antibodies) that produce antibodies of increasingly higher avidity over time.

It is unknown whether a B cell must undergo a long evolutionary process to produce a broadly neutralizing antibody against HIV, but if so it would be another immense challenge for HIV vaccinologists. Researchers are currently dissecting the steps in this evolutionary process to understand how B cells evolve and design novel vaccines that might accelerate the process.

So what will the future of HIV vaccines look like? Is it possible that the HIV epidemic may be a thing of the past; lumped into a category with the devastating viral pathogens of history such as polio, smallpox, and measles? Researchers say yes.

“With an effective vaccine, yes. We will be able to control the pandemic, if not eradicate it completely,” Dr. Kublin was quoted as saying.

The body is capable of producing potent, broadly neutralizing antibodies; however, it does not do so readily or efficiently. Modern tools of science are enabling researchers to develop HIV vaccines that do better than natural immunity and add to the HIV prevention toolkit.

“The ultimate goal is to have a quick shot in the pharmacy that would not need doctor supervision,” Dr. Kublin was quoted as saying, adding that it is still several years off.

SOURCE: New England Journal of Medicine, phone interview with Dr. James Kublin, held on September 6, 2011