Nasal Spray Vaccine Prevents Both the Flu and Flu-Related Earaches

National Institute of Allergy and, Infectious DiseasesEMBARGOED FOR RELEASE, Wednesday, May 13, 1998, 5:00 PM Eastern Time, Laurie K. Doepel, [email protected]

A vaccine sprayed as a fine mist into children's nostrils is highly effective at preventing both the flu and flu-related ear infections, according to results of a nationwide study published in the May 14 issue of The New England Journal of Medicine. The vaccine provided 93 percent protection against the flu and, unexpectedly, 98 percent protection against a common complication of the flu, otitis media.

"These data suggest a promising new approach to potentially reducing the burden of flu and flu-related illness among children," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which funded the study. Children experience the highest incidence of influenza disease, two to 10 times that seen in adults, and are a common source of its spread.

The Phase 3 trial enrolled 1,602 children in 10 clinical sites across the nation: six NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs) and four other clinical sites funded by the vaccine manufacturer, Aviron (Mountain View, Calif.). The VTEUs are part of a network of university-based sites that conduct clinical research on new and improved vaccines against major childhood and adult diseases.

"The routine use of this vaccine in children would result in a substantial reduction not only in the flu but also in febrile otitis media [ear infection with fever] and the consequent use of antibiotics," says study chair Robert B. Belshe, M.D., director of the Center for Vaccine Development and of the VTEU at Saint Louis University School of Medicine.

Although bacteria are the most common type of infectious agent implicated in ear infections, the triggering event usually is infection with a respiratory virus, such as influenza, which can lead to a build-up of fluid in the middle ear where bacteria can collect. "By preventing flu-related otitis media, we can inhibit the overuse of antibiotics and thereby reduce the risk of having new antibiotic-resistant strains of bacteria emerge," says Dominick Iacuzio, Ph.D., influenza program officer for NIAID.

The children in the study ranged from 1 to 6 years old. By random assignment, approximately two-thirds of them received the nasal spray vaccine, known as FluMist(TM), and one-third a placebo.

FluMist(TM) is made from live but weakened influenza viruses adapted to grow only at cooler temperatures, such as those found in the nasal passages. These cold-adapted viruses stimulate mucosal immunity in the nose but do not grow in the warmer environment of the lower respiratory tract. The vaccine is being developed under a cooperative research agreement between NIAID and Aviron.

The trial began late in the summer of 1996, before that fall's flu season. The 1,314 children who entered the study earliest were enrolled in the group to receive two doses of vaccine or placebo; the other 288 children received a single dose. The trial was originally planned for two years. However, the first flu season was severe, and enough cases occurred, that the investigators could stop the study early and evaluate the results after just one year. A summary of the most important findings was released last summer, but details of the efficacy data not available then are in the just-published report, and findings on ear infections also are presented for the first time.

Overall, the vaccine proved 93 percent effective against influenza in the children in the study. Only 14 of 1,070 (1 percent) children who received FluMist? developed culture-confirmed influenza compared with 95 of 532 (18 percent) of children who received placebo. Both one dose and two doses of FluMist? were effective (89 and 94 percent, respectively).

None of the vaccinated children who got the flu had more than one influenza A infection, while six of the 95 children in the placebo group who became sick had two distinct culture-positive influenza A and B illnesses, resulting in a total of 101 illnesses among them. FluMist? was efficacious against both strains of influenza circulating during the 1996-97 season, A/H3N2 and B.

Of added significance, only one of the 14 children in the vaccine group who came down with influenza also developed an associated ear infection: a 98 percent protection rate against otitis media. Twenty cases of flu-related earaches occurred among the 95 placebo recipients who developed the flu.

In addition, during the study period, the incidence of ear infection with fever of any cause was 30 percent lower in the vaccinated group compared with the placebo group. Fever sometimes, but not always, accompanies an earache.

Overall, FluMist? was safe and well tolerated by the volunteers, who, according to the investigators, much preferred the spray to a shot.

In the fall of 1997, the investigators revaccinated all the children in the study with a single dose of the vaccine or placebo, according to which preparation they originally received. The vaccine had been modified to contain influenza strains expected to circulate during the 1997-98 season: A/Wuhan/359/95-like (H3N2) and B/Beijing/184/93-like, both of which were in the 1996-97 vaccine, and one new strain, A/Bayern/07/95-like (H1N1). The children have been followed for a second influenza season to test the efficacy of revaccination. Results from this follow-up phase are expected later this summer.

In addition, Aviron is currently sponsoring several other trials, including one in healthy adults, one in children with asthma and one testing FluMist? in combination with the injected flu vaccine in elderly people with additional risk factors for influenza.

Aviron expects to submit an application to the Food and Drug Administration by mid-1998 to license FluMist? for use in children and healthy adults. Pending FDA approval, the company intends to have the vaccine ready for the fall 1999 flu season.

The 10 sites that participated in the study and the principal investigators included six NIAID-supported VTEUs: Saint Louis University School of Medicine, St. Louis, Mo., Robert B. Belshe, M.D., study chair; Baylor College of Medicine, Houston, Texas, Pedro Piedra, M.D.; Children's Hospital Medical Center, Cincinnati, Ohio, David Bernstein, M.D.; Harbor-UCLA Research and Education Institute, Torrance, Calif., Ken Zangwill, M.D.; University of Maryland Medical Center, Baltimore, Md., James King, M.D./Karen Kotloff, M.D.; and University of Rochester School of Medicine and Dentistry, Rochester, N.Y., John Treanor, M.D. In addition, the group included four sites supported by Aviron: Kentucky Pediatric Research, Inc., Bardstown, Ky., Stan L. Block, M.D.; Pittsburgh Pediatric Research, Pittsburgh, Pa., Keith Reisinger, M.D., M.P.H./Mark Blatter, M.D.; University of Virginia, Charlottesville, Va., Frederick Hayden, M.D.; and Vanderbilt University, Nashville, Tenn., William C. Gruber, M.D.

Besides Drs. Belshe and Iacuzio and the principal investigators at the 10 sites, the other authors of the paper are Paul M. Mendelman, M.D., of Aviron; Mark Wolff, Ph.D., of Emmes Corp., Potomac, Md.; Janet Wittes, Ph.D., of Statistics Collaborative, Washington, D.C.; and Regina Rabinovich, M.D., of NIAID.

Background on Otitis Media

Otitis media is the most common illness for which parents take their children to see a pediatrician. It occurs when fluid from the ear canal, or eustachian tube, collects in the middle ear, the space on the inner side of the eardrum, and becomes infected. The fluid presses on the eardrum, causing an earache. In addition to ear pain, other symptoms can include fever, irritability, sleep disturbances, anorexia and vomiting.

Ear infections are triggered by many infectious agents, including influenza viruses. Influenza viruses irritate the sinuses, causing them to become inflamed. The inflammation makes it more difficult for fluid in the ear to drain. If the fluid backs up into the middle ear space, bacteria or viruses can collect and multiply, causing an infection called otitis media.

Young children are particularly susceptible to ear infections because their eustachian tubes, not yet fully developed, are shorter, wider and straighter than those of adults, making it easier for an infectious agent to reach the middle ear. By age 3, more than 80 percent of children have had at least one episode of otitis media, and nearly half have had three or more episodes. Antibiotics are usually prescribed. In the United States, the annual cost of treating ear infections is between $3 and $4 billion.

Background on Influenza

Influenza is an acute respiratory infection that can be caused by a variety of flu viruses. The virus spreads from person to person via airborne droplets of respiratory fluids, especially after an infected person coughs or sneezes. Flu viruses generally enter the body through the mucous membranes lining the eyes, nose and mouth.

The primary symptoms include headache, chills and a dry cough, followed rapidly by body aches, malaise and fever. Typically, the fever starts dropping on the second or third day of the illness as upper respiratory symptoms, nasal congestion and sore throat become more prominent.

Most people recover from the flu within a week. However, for those at high risk, such as the elderly and people with certain chronic illnesses, flu and its complications can be life threatening. Pneumonia generally results from secondary bacterial infections in the lower respiratory tract. In addition, a neurologic disease known as Reye's syndrome can develop in a small number of children and adolescents recovering from the flu. Reye's syndrome is associated with the use of aspirin, a component of many medications intended to relieve the pain or fever of the flu.

Outbreaks of flu usually begin abruptly. As the disease spreads through a community, the number of cases peaks in about three weeks and subsides three or four weeks later. Twenty to 50 percent of a population may be affected, with the highest incidence in children. Typically, the peak number of cases in children precedes that in adults by about two weeks.

Because most influenza outbreaks in the United States occur between December and April, public health officials recommend that people be vaccinated in the fall. The currently licensed vaccine is an injected product based on an inactivated influenza virus. The vaccine is recommended for everyone 65 years or older as well as younger people at special risk for complications. More than 90 percent of influenza-related deaths occur in people age 65 or older. Children 9 years and older need one shot each flu season; previously unvaccinated younger children need an additional booster shot. However, despite the fact that the currently licensed flu vaccine is between 70 and 90 percent effective at preventing disease in people under age 65, it is not routinely given to healthy children.

The economic costs of influenza are enormous. Millions of Americans contract the illness each year. Influenza-related deaths, which occur mostly among those over age 65, number more than 20,000 annually. In addition to work days lost, an estimated $4.6 billion is spent each year on influenza-related medical costs. A severe influenza epidemic resulting in more than 172,000 hospitalizations would cost at least $12 billion in medical costs and lost productivity.

Background on Development of the Cold-Adapted Intranasal Influenza Vaccine

NIAID has supported research on the cold-adapted influenza vaccine since the mid-1970s. "This research is an outstanding example of how sustained collaboration between both the extramural and intramural research communities and private industry can make a real contribution to public health," comments John La Montagne, Ph.D., deputy director of NIAID.

Leading the research and development effort for this vaccine during the past few decades have been H.F. Maassab, Ph.D., chair of the department of epidemiology of the University of Michigan School of Public Health; NIAID researchers Brian Murphy, M.D., head of the respiratory viruses section, and Robert Chanock, M.D., chief of the Laboratory of Infectious Diseases; Aviron scientists; and their clinical and laboratory collaborators across the country.

"A major advantage of this vaccine is that it can't grow at warmer temperatures found in the lower respiratory tract," comments Dr. Murphy, "but it grows well in the cooler nasal passages. This allows the vaccine to mimic a natural infection and induce immunity without actually causing disease." Thus, the new vaccine, unlike the currently licensed one, stimulates not only systemic immunity but also mucosal immunity via the upper airways.

Simpler versions of this cold-adapted influenza vaccine containing only one or two influenza strains were studied by another company in collaboration with NIAID from 1989 to 1993, until that company decided to discontinue the project. In 1995, Aviron picked up the ball, licensing the vaccine from the University of Michigan and entering into a Cooperative Research and Development Agreement (CRADA) with NIAID to develop the prototype vaccine into a commercial product.

FluMist? consists of three influenza viruses that have stable cores but changeable coats. Scientists take internal proteins from master strains of influenza A and B viruses that have been adapted to grow at cooler temperatures and combine these internal proteins with surface proteins of currently circulating influenza viruses. These surface proteins, hemagglutinin and neuraminidase, are those proteins recognized by the immune system. Each year, as needed, the surface proteins can be changed to match those of viruses expected to circulate during the upcoming flu season.

Just like the currently licensed injectable flu vaccine, FluMist? contains two different A strains and one B strain. Hence it is called a trivalent, cold-adapted influenza virus vaccine, or CAIV-T.

Although earlier trials had found components of this vaccine to be safe and efficacious, this is the first time that a formulation including all three virus strains found in the injected flu shot had been tested in a large field trial. In 1996, an NIAID-funded efficacy trial found the vaccine to be 85 percent protective against influenza when tested in 92 healthy adults directly exposed to the influenza virus. Earlier Phase 1 and 2 trials conducted under the NIAID/Aviron CRADA in 240 adults and 240 children had confirmed the safety of the three-strain formulation and defined the optimal dose. Other NIAID-supported studies also had shown that cold-adapted intranasal vaccines containing only one or two strains of influenza virus were safe, well tolerated and able to stimulate immune responses in more than 7,000 volunteers from 2 months to 103 years old.

NIAID, part of the National Institutes of Health (NIH), supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.

Aviron, a biopharmaceutical company based in Mountain View, Calif., develops vaccines to prevent a wide range of viral infections that affect the general population.

Press releases, fact sheets and other NIAID-related materials are available via the Internet on NIAID Web site at http://www.niaid.nih.gov.

References: RB Belshe, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. The New England Journal of Medicine 358:1405-12 (1998).

ED Barnett. Influenza immunization for children. The New England Journal of Medicine 358:1459-61 (1998).