"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
"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
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
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
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
Aviron, a biopharmaceutical company based in Mountain View, Calif., develops
vaccines to prevent a wide range of viral infections that affect the general
Press releases, fact sheets and other NIAID-related materials are available
via the Internet on NIAID Web site at http://www.niaid.nih.gov.
RB Belshe, et al. The efficacy of live attenuated, cold-adapted, trivalent,
intranasal influenzavirus vaccine in children. The New England Journal of Medicine
ED Barnett. Influenza immunization for children. The New England Journal
of Medicine 358:1459-61 (1998).