FluMist: the new intranasal influenza vaccine

September 2003

In June, the FDA granted approval for widespread use to the first live viral influenza immunization – FluMist (MedImune, Wyeth). FluMist is administered intranasally, and thus allows for an alternative route of administration for immunization against influenza infection, an attribute that may be beneficial for children.

FluMist is a live trivalent vaccine. Influenza strains included in FluMist are those recommended by the U.S. Public Health Service for the 2003-2004 season and are similar to the included strains of the injectable, killed vaccine. These strains (A/New Caledonia [H1N1], A/Panama [H3N2], and B/Hong Kong) are cold-adapted, temperature-sensitive, and attenuated. This implies that the included viral strains replicate well at 25°C and do not replicate well at 37°C to 39°C (dissimilar from wild-type influenza virus), and by being attenuated, do not cause classic influenza-like illness. The vaccine strains replicate in the nasopharynx after intranasal administration, resulting in protective immunity.

Large impact of flu

The availability of another option for immunization against influenza disease is important because of the large impact influenza has on morbidity of children and adults in the United States. Although deaths due to influenza are mostly seen in adults, spreading disease to contacts, and morbidity are important considerations in the pediatric population. Rates of infection with influenza virus are highest among children — and children are the most important spreaders of infection.

People at increased risk of disease complications, hospitalization and death include adults 65 years of age and older, adults and children with certain underlying medical conditions and young, otherwise healthy children. Because of this, the 2003 recommendations for influenza control by the Advisory Committee on Immunization Practices (ACIP) of the CDC call for encouraging the immunization of healthy children 6 to 23 months of age. Hospitalization rates for influenza disease among children are highest in the first year of life, with rates comparable to adults 65 years of age and older.

Studies of the Tennessee Medicaid population over a 20-year period (1973 to 1993) revealed that healthy children aged 6 to 35 months were hospitalized secondary to influenza infection at rates similar to children 3 to 14 years of age with high-risk predisposing factors. Because no influenza vaccine is indicated for children less than 6 months of age, immunizing household contacts and out-of-home caregivers are recommended to limit influenza infection in this vulnerable population.

Clinical studies

The package insert for the vaccine describes clinical studies that evaluated 4,719 children 5 to 17 years of age administered vaccine in randomized trials. Efficacy studies include two published randomized, double-blind, placebo-controlled trials. Belshe (1998) and colleagues conducted a multicenter, double-blind, placebo-controlled trial of intranasally administered live influenza virus vaccine during the 1996-1997 influenza season. Healthy children age 15 to 71 months were enrolled.

Influenza illness was defined as symptomatic illness and isolation of wild-type influenza virus upon culture. Children randomized to vaccine received either one (n5189) or two (n5849) doses. The primary efficacy endpoint was the first episode of influenza for children who became ill 28 days or more after the first vaccine dose or at any time after the second dose. Overall, the vaccine was highly efficacious — 93% against culture-confirmed influenza (89% efficacy for one dose, 94% efficacy for two doses). The vaccine was efficacious toward both influenza strains circulating during the 1996-1997 season (A/H3N2, B) and matched the strains included in the vaccine.

Of the few vaccinated children who developed influenza illness, overall they were less ill than children receiving placebo who developed influenza illness, for vaccine recipients had less fever (P<0.05), and fewer developed febrile otitis media (P<0.05). Adverse effects associated with vaccine administration were relatively mild. Rhinorrhea or nasal congestion occurred more frequently among vaccine recipients (after dose one) on days two, three, eight and nine as compared with placebo recipients (P<0.05). Both fever (mean 38.2°C) and decreased activity occurred more frequently on day two as compared with placebo recipients (P<0.05), after dose one. There were no differences in adverse effects among vaccine and placebo recipients after dose two, which implies that the above adverse effects were associated with vaccine viral replication.

The study was continued through the following influenza season of 1997-1998 and evaluated revaccination of children with the live intranasal vaccine (Belshe 2000). The primary endpoint was the first episode of culture-confirmed influenza illness occurring after revaccination. Nine hundred and seventeen children (aged 26 to 85 months) continued through year two and were revaccinated.

The second year of this study differed from the first year in that the predominant circulating wild influenza virus strain differed from the strains contained in the intranasal vaccine. In year two the influenza viral strain A/Sydney/5/97 caused 66/71 cases of influenza illness. However, the efficacy of the vaccine remained high – 86% (95% CI 75-92). Of the few vaccinated children who developed influenza illness, their symptoms were milder than ill children who received placebo. Fever was shorter in vaccinated children as compared with children receiving placebo (2.1 days vs. 4.9 days, P<0.05). Overall, vaccine efficacy was 92% over two years. Revaccination with the live intranasal vaccine in year two was well tolerated. There were no differences in rhinorrhea, fever, decreased activity, or other adverse effects between vaccine and placebo recipients in year two. This contrasts with year one in which vaccine recipients were more likely to experience rhinorrhea, fever or decreased activity.

Dosing and administration

FluMist is indicated for active immunization for the prevention of influenza disease in children 5 to 17 years of age and in adults 18 to 49. Despite the inclusion of children younger than 60 months in the above studies, additional safety studies in children 1 to 17 years of age found increased rates of asthma or reactive airways disease in children 12 to 59 months of age after dose one (unpublished data provided in the package labeling). Because of this, FluMist is not indicated in children younger than 60 months.

The vaccine should not be administered concurrently with other vaccines. In clinical studies, patients were not given other live viral vaccines within one month of the vaccine administration, nor within two weeks of inactivated vaccines.

FluMist is contraindicated in children or adults with a history of hypersensitivity reactions to chicken eggs, as the vaccine is produced with chick kidney cells. Other contraindications include children and adolescents receiving aspirin or salicylates and immunocompromised children or adults. Children 5 to 8 years of age should receive two doses of vaccine, approximately 60 days apart. Children 9 years and older should receive only one dose. The vaccine is available as a single-dose (0.5 ml) nasal sprayer. The vaccine is stored at 5°F and under and should be thawed prior to use. Upon application into each naris, a fine mist deposits primarily into the nose and nasopharynx. Each nasal applicator includes a dose-divider clip, which allows approximately one-half of the dose (0.25 ml) to be deposited into each naris. The vaccine does not contain any preservatives, including thimerosal. The cost of one dose of FluMist is approximately $50.

For the upcoming influenza season many clinicians, parents, and children will be able to choose between an injection and an intranasal application for immunization against influenza disease. Although the inactivated vaccine and FluMist have not been directly compared in a clinical trial, the efficacy of both dosage forms has been shown and is likely similar. However, some important differences exist. FluMist is a live viral, attenuated vaccine, and as such should not be administered to children with underlying immunodeficiencies. The inactivated vaccine may be given to children with immunosuppressive disorders, although its administration should occur after immunosuppressive therapy has been completed. The vaccine is indicated for children aged 5 years and above, whereas inactivated vaccine may be administered to infants 6 months and older. This may prevent more widespread immunization against influenza in the pediatric population at significant risk for illness complications and hospitalization — 6 to 23 month olds.

Route of administration

A difference between these vaccines that may be most important to children is the route of administration. It is quite likely that many children will prefer intranasal application of a vaccine instead of an injection. The inactivated influenza vaccine continues to be underused in both children and adults, and it is known that vaccination is the most effective means of reducing the adverse effects of influenza disease. Logistical issues, including the availability of personnel properly trained in administering an injectable dosage form, may be reduced with the availability of a nasally administered influenza vaccine. Increasing the use of influenza vaccine in children will likely benefit adults as well, as children are known to be among the most important spreaders of influenza virus. Some experts have expressed concerns with the use of FluMist, including the genetic stability of the live viral strains contained in it, the replication of the virus in the respiratory tract and the risk of secondary infections, and the potential risk of inadvertent administration of the vaccine to immunocompromised children.

Because FluMist is a new vaccine product, it is especially important for health care providers to report suspected adverse effects to the Department of Health and Human Services. This can be accomplished through the Vaccine Adverse Event Reporting System (800-822-7967, www.vaers.org). It is incumbent upon pediatric clinicians to familiarize themselves with FluMist as well as the current recommendations for influenza prevention, including the use of all available influenza vaccine products.

For more information:

• Belshe RB. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza A virus vaccine in children. N Engl J Med. 1998;338:1405-12
• Belshe RB. 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. 2000;136:168-75
• Subbarao K. As good as the real thing. J Pediatrics. 2000;136:139-41
• CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2003;52 (No.RR-8):1-34
• Neuzil KM. The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatrics. 2000;137:856-64