By Daniel Schneeberger, Checkbiotech

Although a HIV-vaccine would be highly desirable, so far no candidate have shown adequate efficacy when administered alone. However, a subunit vaccine produced in plants could be the solution.

Vaccines present one of the most powerful and cost-effective arms of medicine. Modern medicine’s triumphs against many horrible diseases as polio and smallpox are mainly thanks to vaccines. A vaccine against HIV would be highly desirable as the disease is silently spreading out of control in many parts of the world, infecting as many as five million people last year, while also being responsible for almost every twentieth premature death worldwide. However, the design and development of such vaccines seems to be very challenging.

So far none of the developed vaccine candidates have demonstrated adequate efficacy. “HIV is so complex that any attempt to target one step in its life cycle is doomed to fail,” said Tsafrir Mor, Assistant Professor at the Arizona State University.

A promising strategy to overcome this obstacle could be the combination of multiple vaccines that target different mechanisms of infection. As HIV-infection most commonly occurs through mucosal tissue, such a vaccine cocktail should include a component that engages the mucosal immune system against HIV. With this in mind, Dr. Mor’s team at the Arizona State University, together with Dr. Morgane Bomsel’s laboratory at the Cochin Institute of Molecular Genetics in Paris, France, created a novel vaccine candidate.

Our body is delimited to the environment and therefore protected from outside influences by a layer of different tissues, all summed-up under the generic name “epithelia”. Unfortunately, HIV is able to use a feature of mucosal epithelia, transcytosis, which allows the transport of HIV through mucosal epithelia. Imagine a soap bubble which transports the virus through epithelial cells. In fact, transcytosis works pretty much like this.

The process of transcytosis depends on interactions between a viral protein called gp41 and a specific receptor on the epithelial cell membrane. The scientists fused the corresponding binding site of gp41 to a subunit of cholera toxin in order to ensure mucosal targeting and adequate immunogenicity.

According to the results, published in PNAS, the administration of the vaccine elicited the mucosal immune system to produce antibodies against the above mentioned binding-site of gp41 in mice. Furthermore, it was shown, that those antibodies were effective in preventing transcytosis of HIV-1 ex vivo. The scientists also demonstrated the possibility of plant production in Nicotiana benthamiana, which could permit cheap production.

Needle-free delivery is an important feature of this vaccine candidate as experience has shown that many people in developing countries are very sceptic of taking medication by injection. The compliance is expected to be much better, if the medication can be administered orally.

The development of the specific antibody levels suggests that frequent refreshments of this vaccine candidate may be needed. Although frequent refreshments would involve quite a logistic effort, plant production and oral delivery could make vaccination campaigns with multi-component vaccines feasible one day.

Currently, the scientists are in the middle of pre-clinical testing. The next big challenge is to show, that the vaccine candidate can protect non-human primates from infection with a Virus similar to HIV. If all goes well, the researchers will be able to start phase I/II testing in humans in about a year, according to Dr. Mor. Those trials have to show the safety and immunogenicity of the vaccine.

“Only then (based on success in phase I and II) will a third phase trial commence, in which a large population of volunteers will receive the vaccine and be monitored for incidence of infection over several years,” said Dr. Mor. If those trials show satisfactory safety and efficacy, the vaccine could be approved in five to ten years.

Daniel Schneeberger is a Science Writer for Checkbiotech in Basel, Switzerland, and is currently studying Medicine at the University of Basel. Contact him at daniel.schneeberger@stud.unibas.ch.

Matoba N, Magerus A, Geyer BC, Zhang Y, Muralidharan M, Alfsen A, Arntzen CJ, Bomsel M, Mor TS. Amucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs. Proc Natl Acad Sci 2004 Sep 14;101(37):13584-9.

Abstract available at: www.pnas.org/cgi/content/abstract/101/37/13584

Contact:
Tsafrir Mor
Assistant Professor
School of Life Sciences
Arizona State University
tsafrir.mor@asu.edu.

Dr. Tsafrir Mor’s Homepage
http://sols.asu.edu/index.php .

Homepage of the Department of Cell Biology at the Cochin Institute of Molecular Genetics www.cochin.univ-paris5.fr/recherche/InstitutCochin.htm