By David N. Leff
What would you think of a prizefight in which one boxer went into the ring with one arm tied behind his back?
That¿s what your immune system is up against when it comes to designing vaccines against high-powered viruses, such as HIV, and many cancers. It has two arms ¿ humoral and cellular ¿ but both don¿t land punches at once. The humoral glove packs a wallop in the form of neutralizing antibodies, which go after infectious protein antigens. The cellular glove¿s punch consists of killer T cells, which can potentially knock out antigen-targeted viruses and tumor cells.
Now an unexpected contender is warming up to step into the vaccine ring, and take on the champs. It¿s none other than Saccharomyces cerevisiae ¿ the yeast that makes bread rise and beer ferment. It¿s been doing this job for millennia, ever since the human race discovered agriculture.
Now immunologists have another gig for yeast ¿ freeing up the immune-system glove that handcuffs the cellular arm, and turning those killer T cells loose.
Research immunologist Cara Wilson, at the University of Colorado in Denver, explained: ¿We were interested in looking at the mechanism by which this yeast might work. The yeast cell has a wall around itself that¿s covered with sugars. Our immune system has adapted so that its dendritic cells identify certain sugars as foreign, and can generate a strong immune response to them. Most attenuated viral vaccines,¿ she pointed out, ¿rely on a cellular immune response. Not many protein-based vaccines could generate such a reaction.¿
Wilson is senior author of a paper in the current issue of Nature Medicine, for May 2001. It bears the title: ¿Whole recombinant yeast vaccine activates dendritic cells and elicits protective cell-mediated immunity.¿ The article¿s corresponding author is clinical immunologist Richard Duke, a tenured professor at the university.
¿We have, for the first time ever,¿ Wilson told BioWorld Today, ¿used recombinant yeast ¿ which is essentially baker¿s or brewer¿s yeast ¿ as a vehicle, to carry HIV genes that are nonreplicating, not infectious, and use that as a vaccine.¿
Yeast: A Natural Expression System
¿Duke and another co-author, Alex Franzusoff,¿ Wilson continued, ¿have now formed a company here in Denver, called GlobeImmune Inc. They first came up with the idea to use yeast as a vaccine because they were working with it to express other proteins. It¿s very common to use yeast as an expression system. So they decided to try it to generate an immune response in a mouse model.
¿As we reported,¿ she went on, ¿inside the yeast wall, we¿ve encapsulated the HIV or the foreign tumor vaccine protein, so that like a Trojan horse it¿s carried into the cell marked for infection. And as a byproduct of this recognition of the yeast cell wall, a strong immune response is generated against that foreign protein that we¿ve put in there. One of the unique aspects of this vaccine,¿ Wilson added, ¿is that it truly is protein based, but generates killer T-cell activity.¿
In one vaccine format, the team used the HIV gp160 envelope protein as its antigenic target. ¿We did most of those studies in vivo in a mouse model,¿ Wilson recounted, ¿and showed that we could generate a strong cellular immune response when immunizing animals with the whole recombinant HIV-expressing yeast, and that both T-cell types ¿ cytolytic and helper are stimulated. We haven¿t done studies showing that the vaccine directly targets dendritic cells in vivo. What we have done in vivo shows that we can generate an immune response.¿
While the Denver team is focused mainly on generating vaccines that produce cellular responses, it also is investigating ways to enhance the humoral arm.
¿We think this vaccine is unique,¿ Wilson observed, ¿not only because it¿s a protein vaccine that stimulates a cell-mediated response, but also because it shows that it will be safe. Even SCID mice have not had any ill effects with this vaccine. Yeast,¿ she concluded, ¿is something that people are exposed to all the time.¿
Duke, GlobeImmune¿s founder and CEO, is working hard to put that vaccine safety factor to the test in human HIV and tumor patients. ¿Our lead candidate,¿ he told BioWorld Today, ¿is a yeast vaccine expressing the HIV gag protein. This is an epitope in the virus that is less subject to mutation than the other proteins are. It seems to be a dominant target for cytotoxic T cells in patients.
¿We engineered a yeast to go after that gag protein,¿ he recounted. ¿That¿s growing up yeast the way you do with beer. At the end you throw the beer part away and keep the yeast. We just resuspended it in an injectable carrier, and injected the whole construct.¿
Into Africa: Cheap, Easy-To-Use AIDS Vaccine
Duke went on: ¿A liter worth of yeast, we calculated, is around 10,000 human units ¿ probably the cheapest and easiest vaccine to make. I just presented this data at the International AIDS Vaccine Conference in Puerto Rico last week. For Africa it would be a real boon. Those countries could make the vaccine themselves; they wouldn¿t need any help, beyond the engineering. But once they had the vaccine made, then growing it and giving it would be no problem. No purification beyond having clean cultures.
¿The version we¿ll probably use here in the U.S.,¿ Duke said, ¿is the live version frozen until use. But we have done an early trial looking at a lyophilized vaccine, which is essentially the same baker¿s yeast you buy at the store. So you¿d only have to reconstitute it and inject it directly.
¿What we have to do ourselves at the company,¿ Duke observed, ¿is get this thing into clinical trials, in order to be able to push it forward. We have not yet had a pre-IND meeting with FDA. We¿re looking to schedule that for late August, early September, hopefully moving toward an IND by the end of this year. We foresee Phase I clinical trials in the first part of 2002, with completion between 12 and 24 months ¿ just to establish the safety and the immunogenicity. The patient studies would be run through the NIH-sponsored AIDS Clinical Trial Group. We are going to make the vaccine ourselves.¿