The jab of the needle is a pain, but it protects us from a multitude of microbes. Children in the United States endure as many as 14 vaccine injections by the time they’re 16. Adults are immunized to ward off influenza and tetanus; travelers arm themselves against cholera, typhoid and other diseases.

Though injection is a time-honored means of delivering the goods, it has significant drawbacks. Injection equipment can quadruple the cost of a single vaccination. Fear of the needle reduces compliance with vaccination schedules in developed countries. In the developing world, reuse of syringes spreads disease, and lack of refrigeration limits the availability of vaccines. Indeed, the severity of these problems recently prompted the World Health Organization (WHO) to declare war on unsafe injections and to urge the development of oral and nasal vaccines.

Injected vaccines reign in part because researchers understand how they work. Introducing a vaccine underneath the skin or into the muscle provokes systemic immunity: Protective antibodies circulate in the blood. Delivering the vaccine orally triggers immunity at moist mucosal surfaces such as those that line the mouth, nose and genital tract, but the process has been far less well understood, says Robert Edelman, associate director of clinical research at the University of Maryland’s Center for Vaccine Development in Baltimore. But when the AIDS epidemic struck in the early 1980s, it forced researchers to begin unraveling the intricacies of mucosal immunity.

In the last five to 10 years, researchers have learned how microbes that enter the body via mucosal surfaces can be blocked by mucosal vaccines. Armed with new knowledge, more than a dozen vaccine technology companies are hoping to render the immunization needle needless and replace it with nasal sprays, nose drops, flavored liquids, skin patches and edible vaccine-laced plants. While some are still testing products in the laboratory, others have already jumped the hurdles of the Food and Drug Administration’s (FDA) approval process. Favored to make it to market first over the next couple of years are an oral vaccine to protect children from rotaviral diarrhea and a nasal spray alternative to the flu shot.

Though each new vaccine comes with a research and development price tag of $50 million to $200 million, the potential payback is enormous. The makers of the rotavirus vaccine, for example, project annual worldwide sales of up to $250 million. Another company estimates that customers could shell out several billion dollars each year for a nasal vaccine against Shigella, a diarrhea-causing bacterium. For his part, Edelman hopes user-friendly delivery systems will improve the rate of childhood immunization at a time when 1 million American children have not had their recommended vaccinations. “Kids have to get so many shots, it cuts down on compliance,” Edelman says. “There’s a need for new delivery systems.”