Location May Make a Difference in Flu Vaccinations

by Kayt Sukel

November 6, 2008

In many areas of medicine, how effective a treatment is depends on whether it is directly applied to the area of injury or infection. For example, bandaging the shoulder when your wrist is broken may not provide the relief desired.

The importance of location may also prove true for preventive measures. Delivering an influenza (flu) vaccine deep into the lung may not only increase the body’s immune response to the vaccine but may do so at a far lower dosage, suggests a study by scientists at the University of Melbourne, published in the Sept. 24 issue of Mucosal Immunology.

Importance of vaccination

More than 200,000 people are hospitalized each year with flu symptoms and 36,000 people die from complications related to the flu, according to the U.S. Centers for Disease Control and Prevention in Atlanta. Many of these cases could be prevented if the person had been given that year’s influenza vaccine (a vaccination that contains three flu viruses experts believe will be in high circulation during a given year), the CDC reports. Once inoculated, the body produces an immune response in the form of antibodies to provide immunity to those strains.

“The majority of vaccines that we have are really 98-percent-plus effective,” says Peter Palese, an immunization expert at the Mount Sinai School of Medicine. “The one exception is the flu vaccine. Its efficacy can depend on the strain being used and the age of the person vaccinated. So there the efficacy is just not as high as we’d like to see.”

The flu can be most deadly in young children, pregnant women and elderly people. Researchers are looking for ways to improve immune response specifically in those populations.

“It’s important to say that the flu vaccination works quite well,” says Philip Sutton, a researcher at the University of Melbourne’s Centre for Animal Biotechnology. “But we are looking to see if there might be room for improvement.”

Tapping into the mucosal immune response

Flu vaccines are available in two forms. The so-called “flu shot,” a subcutaneous injection containing killed virus, is available for people over 6 months of age. A nasal spray version that contains live but weakened flu viruses is approved only for healthy people between 2 and 49 years old. Some studies suggest that the mist variety is more effective than the shot because it acts upon the interior of the nose, a mucosal site.

Many immunologists now say that the mucosal surfaces in the body, including those in the intestines, mouth, nose, throat, and anal and urogenital tracts, share a powerful, integrated immune system. And, they say, these sites produce robust immune responses when vaccinations are directly delivered to them, a phenomenon they call the mucosal immune response.

“The immune system is developed to respond at the site of infection,” Sutton says. “So in the case of a lung infection, like the flu, when you inject a vaccine in the arm, it may not be as good as one that is directly delivered to the site of [future] infection.”

To test this idea, Sutton and colleagues, in collaboration with CSL Ltd., an Australian biotechnology company, experimented with sheep to see if a vaccine transported straight to the lung would trigger a stronger immune response.

Sutton’s group compared sheep that were given the traditional injected vaccination to those that received a dose directly to the deep lung via a bronchoscope. They did this several times, reducing the amount of antigen, or killed flu virus, that the bronchoscope group received until it stopped showing as good a response as the injected group.

“We got a superior response when the vaccine was delivered to the lung, where the virus infects,” says Sutton. “But we also saw a space reduction effect, where we were able to reduce the amount of antigen by a factor of 375 and still see it produce a response.”

That means that, if people respond to deep lung vaccinations as well as these sheep did, physicians could potentially vaccinate 375 people with the same amount of antigen currently used in one dose of the injected flu vaccine. Sutton says that could have real implications in the event of a flu pandemic. It is difficult to make the vaccine in a short amount of time, so stretching the amount on hand could make a big difference.

Implications for HIV, other research

The next step is to determine if the same effect is true in humans. Sutton hopes that clinical trials can start soon. The difficulty is how to safely and comfortably administer the vaccine to the deep lung. “That’s where the technological challenge will lie,” says Sutton. It is possible that an inhaler-like device might do the trick, he says. That also would need to be proved in clinical trials.

But just as important, Sutton says, is that scientists now understand a bit more about the mechanisms behind the mucosal immune response and how we might harness them for future vaccines.

Barton Haynes, director of the Duke Human Vaccine Institute, is working on a potential HIV vaccine and says this idea of injection location being important to the effectiveness of the vaccine has strong implications for the development of an HIV vaccine.

“With HIV, sexual transmission occurs at the genitals, a mucosal site,” he says. “Clearly sites do matter.” Understanding more about the mucosal immune response would help researchers in their search for a vaccine that would produce the long-lived antibody response needed to prevent HIV, Haynes says. He encourages scientists to take a step back to more basic science.

“It’s extremely difficult to make vaccines for many diseases,” he says. “We can vaccinate against one strain of influenza, not all. We can’t make a broadly effective malaria vaccine and we have major problems with tuberculosis and HIV.

“We need to go back to the bench, to really go back and tease apart how the immune system works, the antibody and cellular responses, so that we can harness what’s needed to make a truly effective vaccine for these more difficult diseases.”