Skip to Content

Making Needles Needless

Vaccines of the future are going to come in a remarkable array of forms: nasil sprays, nose drops, flavored liquids, skin patches, even fried food.
September 1, 1998

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.”

A Bouncer at the Door

The chief target of noninjected vaccines is the body’s vast expanse of mucosal membranes. Combined, mucous cells cover an area equal to about one and one-half tennis courts, lining the respiratory and gastrointestinal tracts, urinary and genital passages-even the eyelids. Mucosal immunity is the body’s front line of defense, since 90 percent of infections start at mucosal sites. Such common infections as pneumonia, sore throats, flu, diarrheal diseases, ulcers and sexually transmitted diseases all begin at mucosal surfaces.

Mucosal immunization prompts the immune system to produce two types of antibodies in different regions of the body: powerful IgA antibodies at mucosal surfaces, and IgG antibodies in the bloodstream. In contrast, injected vaccines trigger only IgG antibodies in the blood. By eliciting the IgA response, mucosal vaccines protect the body against invading pathogens before they reach and damage internal organs. The protection of an IgG-inducing injected vaccine only kicks in after an infection starts.

A mucosal vaccine could take a number of different forms. Nasal sprays, nose or eye drops, capsules, liquids and rectal or vaginal suppositories are all possible vehicles for vaccination-some clearly more practical and palatable than others. Fortunately, says David Burt, vice president of research at Montreal-based Intellivax International Inc., “the mucosal immune system is interconnected,” so vaccines applied at a convenient mucosal site protect other areas of the body as well.

A Shot in the Nose

One of the first vaccines to make it into patients’ nostrils will probably be FluMist, a nasal spray aimed at influenza viruses. Both children and healthy adults may soon get their annual flu “shots” from this syringe-like device with an aerosol sprayer where the needle ought to be. The device delivers a live, but weakened, influenza virus that only grows at the cooler temperatures of the nasal passages. There, the vaccine primes the mucosal immune system to stop disease-causing flu viruses before they can take hold in the nose and upper airways.

FluMist has done well in clinical trials-it provides 93 percent protection against the flu in children, with mild side effects (runny nose or sore throat) that last a day or so. But the new vaccine might also have another-and more positive-side effect. It reduces the rate of flu-related ear infections by 98 percent. Ear infections send American children to the pediatrician more than 31 million times each year, and most of those kids receive antibiotics; vaccinating children against influenza could make a dent in this overuse of antibiotics and the resulting rise of drug-resistant bacteria.

Aviron, the California company that is developing FluMist, applied for FDA approval for the nasal flu shot this summer. The company hopes to make FluMist available in time for the 1999 flu season.

Down the Gullet

Another obvious route for noninjectable vaccines is-down the hatch. But oral vaccines face tough obstacles. They must survive the harsh environment of the stomach and intestines. In addition, the digestive tract sees a lot of “immunological challenges from food,” says Peter Nara, president of the International Society for Vaccines and director of R&D at the Maryland start-up Biological Mimetics. As a result, the lining of the tract tends to overlook immune stimuli such as vaccines. Any vaccine operating there is “working against City Hall,” according to Nara.

Despite these hurdles, new vaccines against diseases as disparate as typhoid fever and stomach cancer will soon be swallowed. One of the first will most likely be RotaShield, developed to protect young children from the severe diarrhea caused by rotaviruses. Nearly 1 million children die yearly from rotavirus infections in developing countries, and its oral form may make RotaShield easier to distribute in those regions. In the United States, 3 million cases of rotaviral diarrhea account annually for 500,000 doctor visits, 100,000 hospitalizations and 100 deaths, costing the health care system $1.4 billion in direct and indirect costs.
Albert Kapikian and his colleagues began tinkering with the oral rotavirus vaccine in 1980. “We never even considered the possibility of an injected route,” says Kapikian, head of the epidemiology section of the Laboratory of Infectious Diseases, part of the National Institute of Allergy and Infectious Diseases. Making an oral vaccine for an intestinal virus “was a natural way to go.”

To save the vaccine from destruction in the stomach’s acidic environment, children in early studies drank milk (an acid-neutralizer) a half-hour before vaccination. In its final form, the vaccine is freeze-dried, then mixed with a small amount of a salty buffer that protects it. In the gut, the virus multiplies long enough to generate protective mucosal antibodies-the only side effect is a mild, brief fever. “The proof is in the pudding-or the protection-which has been excellent,” says Kapikian; the vaccine reduces the incidence of severe rotaviral diarrhea by up to 90 percent. Licensed by Wyeth-Ayerst Laboratories, RotaShield is awaiting FDA approval. The vaccine, which will be recommended for all children at 2, 4 and 6 months of age, has already gained the endorsement of the Centers for Disease Control, the American Academy of Pediatrics, and the WHO.

Vaccine Veggies

As knowledge of the mucosal immune system was emerging, so were the genetic engineering tools that enable researchers to insert vaccine molecules into plants. The next logical step was to investigate whether food plants carrying vaccines could immunize the digestive tract. “The tools and knowledge converged that naturally led us down this path,” according to William Langridge, a molecular biologist at California’s Loma Linda School of Medicine.

Langridge converted the plebeian potato into a cholera vaccine by adding genes for cholera toxin. In mice that ate the raw potatoes, the toxin bound cells in the gut and triggered the production of antibodies against cholera. To make the potatoes more appealing, Langridge boiled small cubes of his special spuds until soft-surprisingly, at least half the vaccine remained active. Flash cooking methods, like deep fat frying, may preserve more vaccine, he suspects. (Imagine getting your vaccination from a bag of chips or a plate of fries.) Langridge’s experiments have sparked interest from biotechnology companies, but it’s too early in negotiations to identify them, he says.

Potatoes are a dietary staple in Peru, Bolivia and India-countries where cholera causes dehydrating diarrhea and death-so the potato is a “good target plant,” Langridge says. He calculated that eating one boiled potato weekly for a month should protect against cholera. Booster spuds may be needed if protection falls. “Food plants move us closer to achieving a low-cost, convenient, effective and safe strategy for prevention of infectious enteric (intestinal) diseases,” says Langridge. When grown locally in developing countries, edible vaccines could circumvent problems of transportation and refrigeration that hamper effective vaccination programs.

While researchers from Cornell University’s Boyce Thompson Institute for Plant Research (BTI) have also experimented with potato-based vaccines, they now are turning their attention to plants more commonly eaten raw. “Potatoes were the proof-of-concept crop,” says Cornell researcher Hugh Mason, “but bananas and tomatoes look more promising for human consumption.”

In June, BTI announced a research and license agreement with Axis Genetics, a biopharmaceutical firm in Cambridge, England. Axis will back BTI’s edible vaccine research for three years, in return for exclusive use of BTI technology.

Back to the Band-Aid

Perhaps the most remarkable vaccines in early development are those that cross the skin-as injections do-but without a needle. Several groups, including the Iomai Corp. in Washington, D.C., are working on a painless way to tackle this traditional route. Iomai researchers added cholera toxin to diphtheria and tetanus vaccines and rubbed it on the skin of shaved mice. The combination activates Langerhans cells in the skin, some of the mightiest of known immune cells. The mice built up blood antibodies against both diphtheria and tetanus.

The process, known as transcutaneous immunization, “could be particularly useful given the large surface area of the skin and its potent immune cells,” says Gregory Glenn, scientific director of Iomai. Eventually, the immune-stimulating concoction could be incorporated into bandages or patches. Instead of leaving the doctor’s office with a Band-Aid over a vaccination stab wound, a patient could go home wearing the vaccine itself. “It’s an exciting possibility, but we have a tremendous amount to learn,” remarks University of Maryland’s Edelman. For example, researchers don’t even know just how the vaccine crosses the skin. Studies to test the new method in humans are just starting.

Keep Reading

Most Popular

Large language models can do jaw-dropping things. But nobody knows exactly why.

And that's a problem. Figuring it out is one of the biggest scientific puzzles of our time and a crucial step towards controlling more powerful future models.

The problem with plug-in hybrids? Their drivers.

Plug-in hybrids are often sold as a transition to EVs, but new data from Europe shows we’re still underestimating the emissions they produce.

Google DeepMind’s new generative model makes Super Mario–like games from scratch

Genie learns how to control games by watching hours and hours of video. It could help train next-gen robots too.

How scientists traced a mysterious covid case back to six toilets

When wastewater surveillance turns into a hunt for a single infected individual, the ethics get tricky.

Stay connected

Illustration by Rose Wong

Get the latest updates from
MIT Technology Review

Discover special offers, top stories, upcoming events, and more.

Thank you for submitting your email!

Explore more newsletters

It looks like something went wrong.

We’re having trouble saving your preferences. Try refreshing this page and updating them one more time. If you continue to get this message, reach out to us at with a list of newsletters you’d like to receive.