A new type of influenza vaccine given in a nasal spray is very effective at preventing the flu in healthy young children, according to results from a large multicenter study supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the biopharmaceutical company Aviron.
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 investigators.
"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 Dr. Belshe.
According to Dr. Belshe, it also is important to do an efficacy trial in a group that is not already being protected through vaccination. 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 inactivated virus.
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 this fall.
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, 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 at Baltimore, Baltimore, Md. James King, M.D./Karen Kotloff, M.D. University of Rochester School of Medicine and Dentistry, Rochester, N.Y. John Treanor, M.D. The four Aviron-supported sites are: 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.
Vanderbilt University, Nashville, Tenn. 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 viruses.
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 commercial product.
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 study.
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 flu.
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.
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