Overall, the attenuated live-virus vaccine provided 93 percent
protection against influenza in this population. Only 1 percent of
1,070 children who received the vaccine developed culture-confirmed
influenza during last year's flu season versus 18 percent of 532
children the same age who received placebo.
"The initial results from this trial are very exciting," comments
Anthony S. Fauci, M.D., director of NIAID. "An influenza vaccine
given in a nasal spray would be easier to administer and more
acceptable than an injection, especially to children. Such a vaccine
could have a significant impact on public health."
Each year, between 35 and 50 million Americans contract
influenza, and more than 20,000 people die. In addition to work days
lost, an estimated $4.6 billion is spent annually on direct medical
costs related to influenza.
The Phase 3, double-blind trial was conducted at 10
geographically diverse sites nationwide, including six Vaccine and
Treatment Evaluation Units (VTEUs) supported by NIAID and four
sites supported by Aviron.
The study enrolled 1,602 children from 15 months to 6 years
old. Approximately two-thirds received the intranasal, cold-adapted
influenza vaccine and one-third received a placebo. Following their
vaccinations, the children were monitored for flu symptoms during the
1996-1997 influenza season. The vaccine protected children from
influenza caused by both the A and B strains of the virus circulating
last year. The findings were highly consistent with data from many
previous studies of the vaccine and its components, according to the
"This is the largest well-controlled field trial of any influenza
vaccine in this age group," comments Robert B. Belshe, M.D., study
chair and director of the Center for Vaccine Development and of the
VTEU at Saint Louis University in Missouri. "We targeted this trial to
healthy young children because they experience the highest
incidence of influenza disease and often spread the virus to others."
The attack rate in children is two to ten times that seen in adults.
"By age 5, most children will have had two or three cases of the flu," says
According to Dr. Belshe, it also is important to do an efficacy
trial in a group that is not already being protected through
Although more than 90 percent of influenza-associated deaths occur
in people age 65 or older, many elderly people are immunized yearly
with the currently licensed injectable vaccine based on "killed" or
In the current study, each child was assigned at random to
receive either the intranasal vaccine or placebo. (Currently, the
inactivated flu vaccine is not routinely given to healthy children.)
The 1,314 children enrolled into the study between mid-August and mid-
October 1996 received two doses, spaced about two months apart.
The 288 children who entered the study later received a single dose.
A dose comprised two tiny squirts (0.25 milliliter per nostril) of spray
containing the vaccine or a placebo. Both one and two doses were
efficacious against strains circulating last year.
Beginning the first evening after the vaccination and
continuing for 10 days, the parent or guardian monitored the child
daily for possible side effects, fever and flu-like symptoms, recording
them on a diary card. Starting on the eleventh day, the study site
began calling the parent or guardian once every two to three weeks
until influenza struck the site's community. Once an influenza
outbreak was confirmed, the investigators called more often to
determine if the child had flu-like symptoms. Those who had
symptoms were visited at home or returned to the study site to have
throat swabs taken for culture confirmation of influenza.
Overall, the vaccine was safe and well-tolerated by the
volunteers who, according to the investigators, much preferred the
spray to a shot.
The trial began late last summer in anticipation of the flu
season. The investigators originally planned to evaluate the efficacy
data after two years. However, enough influenza cases occurred in
the study population during the 1996-1997 flu season to unblind the
study data and evaluate the vaccine's efficacy after one year.
This fall, the investigators plan to revaccinate all the children
in the study with a single dose of the intranasal vaccine or placebo,
according to their original blinded treatment assignment, and follow
them for a second influenza season to test the efficacy of
revaccination. The vaccine will contain flu strains expected to be
circulating during the 1997-1998 flu season: two in last year's
vaccine (A/Wuhan/359/95-like [H3N2] and B/Beijing/184/93-like) and
one new one (A/Bayern/07/95-like [H1N1]).
This fall Aviron also plans to initiate a large trial in healthy
working adults to determine whether the trivalent intranasal vaccine
reduces health care costs and absenteeism due to influenza disease.
Also planned is a study of the vaccine in children with asthma, and a
trial of the nasal vaccine co-administered with the current inactivated
flu vaccine in elderly people.
The results presented here summarize the most important
findings from the priority analysis of the data. The investigators plan
to present additional information in appropriate scientific meetings
Based on the findings from this Phase 3 study and other data,
Aviron expects to file an application with the Food and Drug
Administration (FDA) next summer to license the trivalent cold-adapted
intranasal flu vaccine for use in children and in healthy
adults. Pending FDA approval, the company intends to make the
vaccine available by prescription in the United States for vaccination
campaigns in the fall of 1999.
The 10 sites that participated in the study and the principal
investigators are listed below. The six NIAID-supported Vaccine and
Treatment Evaluation Units are:
Saint Louis University School of Medicine, St. Louis, Missouri
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,
Ken Zangwill, M.D.
University of Maryland at Baltimore, Baltimore, Maryland
James King, M.D./Karen Kotloff, M.D.
University of Rochester School of Medicine and Dentistry,
Rochester, New York
John Treanor, M.D.
The four Aviron-supported sites are:
Kentucky Pediatric Research, Inc., Bardstown, Kentucky
Stan L. Block, M.D.
Pittsburgh Pediatric Research, Pittsburgh, Pennsylvania
Keith Reisinger, M.D., M.P.H./Mark Blatter, M.D.
University of Virginia, Charlottesville, Virginia
Frederick Hayden, M.D.
Vanderbilt University, Nashville, Tennessee.
William C. Gruber, M.D.
For the study, the EMMES Corporation (Potomac, Md.) served
as the Data Coordinating and Analysis Center, and IRBD-Rostrum
Global (Irvine, Calif.) as the Contract Research Organization
monitoring all the clinical sites.
Background on the Vaccine
"This product has a long history," comments John La
Montagne, Ph.D., director of NIAID's extramural Division of
Microbiology and Infectious Diseases, "and NIAID has supported
research on the cold-adapted vaccine since 1976. It's 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."
The cold-adapted influenza vaccine was developed and
refined over the past decades by H. F. Maassab, Ph.D., at the
University of Michigan School of Public Health; NIAID researchers
Brian Murphy, M.D., and Robert Chanock, M.D.; Aviron; and their
clinical and laboratory collaborators across the country.
"A major advantage of the cold-adapted 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 vaccine, stimulates mucosal as
well as systemic immunity.
The cold-adapted influenza vaccine contains internal flu
proteins from master strains of influenza A and B viruses that grow at
cooler temperatures. These are combined with the surface proteins,
hemagglutinin and neuraminidase, found on contemporary circulating
Another company studied simpler forms of the vaccine in
collaboration with NIAID from 1989 to 1993 before discontinuing the
project. In 1995, Aviron licensed the vaccine from the University of
Michigan and entered into a Cooperative Research and Development
Agreement (CRADA) with NIAID for its development into a
The cold-adapted influenza virus vaccine used in the study is
trivalent (CAIV-T), containing two different influenza A strains and one
influenza B strain, like the currently licensed injectable flu vaccine.
This is the first time a trivalent cold-adapted intranasal flu
vaccine has been tested in such a large U.S. field trial. Last year,
NIAID-funded investigators reported that the trivalent vaccine
demonstrated 85 percent protection against influenza in a trial with 92
healthy adults directly exposed to influenza in a challenge efficacy
Earlier Phase 1 and 2 trials conducted under the NIAID/Aviron
CRADA in 240 adults and 240 children had confirmed the safety of a
trivalent formulation and defined the dose for the current trial.
Earlier NIAID-supported studies had shown that cold-adapted intranasal
vaccines containing only one or two influenza strains were safe, well-
tolerated and immunogenic in more than 7,000 people ranging in age
from 2 months to 103 years old.
"In the face of the next probable serious influenza pandemic,"
comments Dominick Iacuzio, Ph.D., influenza program officer at
NIAID, "a live-attenuated flu vaccine would provide an effective new
tool to combat the disease's spread."
Background on Influenza
Influenza, an acute respiratory infection, is caused by a variety
of flu viruses. The viruses spread from person to person via airborne
droplets of respiratory fluids, especially after an infected individual
sneezes or coughs. Flu viruses generally enter the body through the
mucous membranes of the eyes, nose or mouth.
Prominent symptoms include headache, chills and a dry
cough, which are followed rapidly by body aches, malaise and fever.
Typically, the fever starts declining on the second or third day of the
illness as upper respiratory symptoms--nasal congestion and sore
throat--become more noticeable.
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.
Complications such as pneumonia generally result from secondary
bacterial infections in the lower respiratory tract. In addition, a
neurologic disease known as Reye's syndrome sometimes develops
in a small number of children and adolescents who are recovering
from flu. The syndrome is associated with the use of aspirin, which
often is contained in medications for relieving the pain or fever of
Outbreaks of flu usually begin abruptly. As the disease
spreads through communities, the number of cases peaks in about
three weeks and subsides after another three or four weeks. Twenty
to 50 percent of a population may be affected, with the highest
incidence in children. In a typical flu season, 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. Individuals 9 years and older need
one shot each flu season; previously unvaccinated younger children
also need one-month booster shots. The currently licensed flu shot is
between 70 and 90 percent effective at preventing disease in people
under age 65.
The economic costs of influenza are huge. A severe influenza
epidemic including more than 172,000 hospitalizations would cost at
least $12 billion in medical costs and lost productivity.
NIAID is a component of the National Institutes of Health
(NIH). NIAID conducts and supports research to prevent, diagnose
and treat illnesses such as AIDS and other infectious diseases,
asthma and allergies. NIAID has a major responsibility within the
federal government for developing vaccines to control and prevent
infectious and immunologic diseases. NIH is an agency of the U.S.
Department of Health and Human Services.
Aviron, an emerging biopharmaceutical company based in
Mountain View, Calif., develops vaccines to prevent a wide range of
viral infections that affect the general population.