In an unexpected twist, during the 1997-98 flu season when the study took
place, the predominant circulating flu virus was A/Sydney. Since this
strain had not emerged as an upcoming threat when the vaccine was made, the
vaccine was not designed to protect against it. Yet the nasal spray vaccine
proved 86 percent effective against A/Sydney. In addition, none of the
children became infected with the three strains of influenza the vaccine was
specifically designed to prevent.
"This study gave us an unanticipated opportunity to test how well this
vaccine works against a variant virus, an influenza strain that had
undergone so-called 'antigenic drift,'" says Linda Lambert, Ph.D., influenza
program officer at NIAID. "Virus proteins important to disease development,"
she explains, "had undergone minor, spontaneous changes. Still, the vaccine
performed remarkably well in this 'natural experiment.'"
The double-blind, placebo-controlled trial enrolled 1,358 children between 2
and 7 years old. These children had entered the vaccine study during the
1996-97 flu season and returned for a single revaccination during the
1997-98 flu season. Each participant received either the nasal spray
vaccine, FluMist(tm), or placebo, matching what they had received the
previous year. Those who got FluMist(tm) experienced no serious side
effects related to vaccination.
Of the 71 cases of influenza seen in the study children, 66 were caused by
A/Sydney. Only 15 of the A/Sydney cases occurred among the 917 children who
got FluMist(tm). These 15 children had significantly milder disease
symptoms -- shorter duration of fever, fewer cases of influenza-related
middle-ear infections, and no lower respiratory tract disease -- than did
the 51 placebo recipients who developed A/Sydney flu. All five cases of
non-A/Sydney flu occurred among the 441 children in the placebo group.
The first-year study results -- which showed an overall efficacy of 93
percent during the 1996-97 flu season when the circulating influenza strains
were well-matched to the vaccine -- were published in The New England
Journal of Medicine in May 1998.
"In the second year of this study, the safety and efficacy results were very
similar to those seen in year one," says Robert Belshe, M.D., study chair
and director of the Center for Vaccine Development at Saint Louis
University. "The overall protection rate for the two-year period was 92
percent. The additional data on cross-protection against A/Sydney and
significant reduction in disease severity among the vaccinees are extremely
important new pieces of information from year two." The second-year data
also found that the vaccine provided 94 percent protection against
influenza-related middle-ear infections, or otitis media. Otitis media is
the most common illness in young children requiring a doctor visit. Since
the licensed flu vaccine was not included in the study, no head-to-head
comparison between it and FluMist(tm) can be made.
The trial took place at 10 clinical sites nationwide, including six Vaccine
and Treatment Evaluation Units funded by NIAID and four sites funded by the
vaccine manufacturer, Aviron.
An estimated 35 to 50 million Americans come down with influenza each flu
season, which typically lasts from November to March. Children are two to
three times more likely than adults to become ill with flu, and children
frequently spread the virus to others. Although most people recover from
the illness, influenza's deadly potential among vulnerable populations is
often underestimated, and at least 20,000 people in the United States die
from influenza and its complications each year.
NIAID has supported the development of this "cold-adapted" live virus
influenza vaccine concept for nearly 25 years. Early work by researchers in
NIAID's Laboratory of Infectious Diseases and their colleagues at the
University of Michigan paved the way. They developed weakened influenza
viruses that could stimulate immunity in the cooler nasal passages but could
not cause disease in the warmer temperatures of the lower airways. Simpler
versions of FluMist(tm) were tested by NIAID-supported researchers in
smaller trials. Then in 1995,
Aviron entered into a Cooperative Research and Development Agreement with
NIAID for development of an advanced version of the vaccine into a
Aviron is a biopharmaceutical company based in Mountain View, CA, focused on
the development of live virus vaccines to prevent disease.
NIAID is a component of the National Institute of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses such
as HIV disease and other sexually transmitted diseases, tuberculosis,
malaria, asthma and allergies. NIH is an agency of the U.S. Department of
Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at www.niaid.nih.gov.
RB Belshe, et al. Efficacy of vaccination with live attenuated,
cold-adapted, trivalent, intranasal influenza virus vaccine against a
variant (A/Sydney) not contained in the vaccine. J Pediatrics 136:168-75
K Subbarao. As good as the real thing. J Pediatrics 136:139-41 (2000).