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Biomedicine

A New Approach to Combating HIV

High-tech solutions of oil in water could lead to an effective HIV vaccine.

Specialized nanoemulsions–made up of tiny soybean oil droplets suspended in water, studded with bits of pathogenic organisms, and swabbed into the nose–may be the vaccines of the future. Nanoemulsion vaccines, which have previously proved effective against influenza and anthrax, have now been shown to generate immunity to smallpox and HIV in mice.

Deadly droplets: Nanoemulsions of soybean oil droplets (green bubbles) in water serve as the basis for a new approach to nasally administered vaccines–particularly for HIV and smallpox. At approximately 200 nanometers wide, the droplets easily carry antigens through the nasal mucosa and into critical immune cells. The resulting mucosal immunity, which translates to the urogenital tract, could provide a critical barrier against HIV infection. And in an added benefit, the droplets’ high surface tension makes them lethal to nasty pathogens. For example, they kill the vaccinia virus used in smallpox vaccines, rendering nanoemulsion-based smallpox vaccines safer than existing live-virus alternatives.

“There’s a tremendous amount of promise for a number of different diseases,” says Mansoor Amiji, codirector of the Nanomedicine Education and Research Consortium at Northeastern University, who was not involved in the project.

The technology derives from the cosmetic industry, where nanoemulsions were developed to allow skin creams to easily penetrate through pores and down hair shafts. It is this property that makes the vaccines so successful, says James Baker, who has spent the past decade adapting nanoemulsions for use in vaccines. Baker directs the Michigan Nanotechnology Institute for Medicine and Biological Sciences at the University of Michigan.

Each miniscule oil droplet–just 200 nanometers in diameter–bears at its surface either all or part of the pathogen targeted by the vaccine. When the nanoemulsion enters the nose, the droplets burrow down into the mucosal tissue and are taken up by immune cells called dendritic cells. Once introduced to their target in this way, the dendritic cells go about mounting an immune response.

Most vaccines require a so-called adjuvant to stimulate the immune system enough to generate lasting immunity, as the chopped-up or otherwise disabled pathogen itself is not sufficient to do so. But because the nanoemulsion delivers the pathogen directly to dendritic cells, says Baker, immune-stimulating adjuvants are unnecessary.

One key characteristic of these vaccines is that because they are administered through the nose, they produce immunity not just in the bloodstream but also in the mucosal tissues of the nose, mouth, lungs, and urogenital tract. These tissues often provide a first barrier against infection, making nasal vaccines relevant for a wide variety of diseases.

Regarding HIV in particular, recent studies have shown that shortly after infection, the virus replicates extensively in the genital mucosa. A strong mucosal immune response against the virus would prevent such replication, slowing or stopping the virus before it could reach the bloodstream. “The best thing to do is neutralize the virus at entry,” says Baker, “so that your systemic immune response can clear it before it gets a foothold.” In a paper appearing in the February issue of AIDS Research and Human Retroviruses, Baker showed that his nanoemulsion HIV vaccine did produce genital mucosal immunity in mice.

“It’s a point in time where people are reevaluating approaches to HIV vaccines,” says Baker. The failure in human trials of V520, Merck’s experimental HIV vaccine, last September is the most recent in a long series of unsuccessful attempts. Baker believes that his approach–the first nasally administered HIV vaccine, and thus the first to generate mucosal immunity–may reinvigorate the search for a viable HIV vaccine candidate.

While the nanoemulsion HIV vaccine showed promise in Baker’s study, says Amiji, mice are not a good model for HIV infection. The technology must stand up as well to testing in nonhuman primates and eventually humans. Amiji also cautions that the nanoemulsion tactic does not directly address one of the most vexing challenges in creating a vaccination for HIV: the virus’s rapid evolution.

Baker’s vaccine does use an HIV protein that is not as prone to evolution, and therefore takes a similar form in most HIV strains. This may allow the immune system to recognize even highly divergent versions of the virus.

Besides its promise as an HIV vaccine, the new technology also has the potential to radically change the face of smallpox vaccination by obviating the need to use a live virus. While smallpox was eradicated three decades ago, maintaining stockpiles of the vaccine has remained a priority due to concerns about bioterrorism. In 2002, President Bush announced a program to vaccinate certain military personnel and civilian health-care workers against the virus. But concerns remain about the safety of existing vaccines.

All smallpox vaccines employ a virus called vaccinia, which is less deadly than the smallpox virus but similar enough to induce immunity against it. In fending off smallpox infection, the most important component of the immune system is cellular immunity, in which infected cells are identified and destroyed. Since existing vaccines require a live vaccinia virus to produce adequate cellular immunity, adverse effects are common. As a result, many of those targeted by Bush’s program declined the vaccine.

The nanoemulsion–which, thanks to the destructive surface tension of its oil droplets, is an effective antimicrobial solution–actually kills the vaccinia virus. But because it shuttles the dead virus directly to dendritic cells, says Baker, the establishment of cellular immunity is not compromised. In Baker’s experiments, mice given the nanoemulsion smallpox vaccine survived doses of the vaccinia virus that were lethal in unvaccinated mice. The results appear in the February issue of Clinical and Vaccine Immunology.

“We prevent replication entirely, but we maintain the strong immune response that one would get with a live viral infection,” says Baker. “So it’s the best of all worlds.”

These new smallpox and HIV studies further expand the repertoire of diseases amenable to nanoemulsion vaccines, although no such vaccines have yet been used on humans. In earlier work, Baker has shown the technology to be effective for vaccinating against both influenza and anthrax in animal models, and he is currently working with the Bill and Melinda Gates Foundation to develop a new hepatitis B vaccine. Nanoemulsions are uniquely suited to the demands of vaccination in developing countries because the constituent proteins are stabilized, require no needles or costly inhalers, and can survive high temperatures. Baker says that human trials for the nanoemulsion hepatitis B vaccine could begin by the end of this year.

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