It turns out that an innocuous segment of the V. cholerae toxin--the B subunit--binds readily to a molecule on M cells that ushers foreign material into those cells. By fusing antigens from other pathogens to this subunit, it should be possible to improve the uptake of antigens by M cells and to enhance immune responses to the added antigens. The B subunit also tends to associate with copies of itself, forming a doughnut-shaped, five-membered ring with a hole in the middle. These features raise the prospect of producing a multicomponent vaccine that brings several different antigens to M cells at once--thus potentially fulfulling an urgent need for a single vaccine that can protect against multiple diseases simultaneously.
Researchers are also grappling with the reality that plants sometimes grow poorly when they start producing large amounts of a foreign protein. One solution would be to equip plants with regulatory elements that cause antigen genes to turn on--that is, give rise to the encoded antigens--only at selected times (such as after a plant is nearly fully grown or is exposed to some outside activator molecule) or only in its edible regions. This work is progressing.
Further, each type of plant poses its own challenges. Potatoes are ideal in many ways because they can be propagated from "eyes" and can be stored for long periods without refrigeration. But potatoes usually have to be cooked to be palatable, and heating can denature proteins. Indeed, as is true of tobacco plants, potatoes were not initially intended to be used as vaccine vehicles; they were studied because they were easy to manipulate. Surprisingly, though, many species of potatoes are actually eaten raw in SouthAmerica. Also, contrary to expectations, cooking of potatoes does not always destroy the full complement of antigen. So potatoes may have more practical merit than most of us expected.
Bananas need no cooking and are grown widely in developing nations, but banana trees take a few years to mature, and the fruit spoils fairly rapidly after ripening. Tomatoes grow more quickly and are cultivated broadly, but they, too, may rot readily. Inexpensive methods of preserving these foods--such as freeze-drying--might overcome the spoilage problem. Among the other foods under consideration are lettuce, carrots, peanuts, rice, wheat, corn and soybeans.
In another concern, scientists need to be sure that vaccines meant to enhance immune responses do not backfire and suppress immunity instead. Research into a phenomenon called oral tolerance has shown that ingesting certain proteins can at times cause the body to shut down its responses to those proteins. To determine safe, effective doses and feeding schedules for edible vaccines, manufacturers will need to gain a better handle on the manipulations that influence whether an orally delivered antigen will stimulate or depress immunity.
A final issue worth studying is whether food vaccines ingested by mothers can indirectly vaccinate their babies. In theory, a mother could eat a banana or two and thus trigger production of antibodies that would travel to her fetus via the placenta or to her infant via breast milk. We have shown that this strategy is effective for protecting against rotavirus infection in mouse pups.
Nonscientific challenges accompany the technical ones. Not many pharmaceutical manufacturers are eager to support research for products targeted primarily to markets outside the lucrative West. International aid organizations and some national governments and philanthropies are striving to fill the gap, but the effort to develop edible vaccines remains underfunded.
In addition, edible vaccines fall under the increasingly unpopular rubric of "genetically modified" plants. A British company (Axis Genetics) that was supporting studies of edible vaccines failed; one of its leaders lays at least part of the blame on investor worry about companies involved with genetically engineered foods. I hope, however, that these vaccines will avoid serious controversy, because they are intended to save lives and would probably be planted over much less acreage than other food plants (if they are raised outside of greenhouses at all). Also, as drugs, they would be subjected to closer scrutiny by regulatory bodies.