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AJN, American Journal of Nursing:
doi: 10.1097/01.NAJ.0000361490.52718.cf
Feature Articles

Influenza Vaccination with a Live Attenuated Vaccine

Michael, Michele PhD, CRNP; Helm, Elizabeth MSN, CPNP; Graafeiland, Brigit Van DNP, CPNP; Malinoski, Frank MD, PhD; Bauman, Jay PharmD

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Author Information

Michele Michael is a program director in advanced practice pediatrics, Elizabeth Helm is a clinical instructor, and Brigit Van Graafeiland is an assistant professor at the University of Maryland School of Nursing, Baltimore, MD. Frank Malinoski is a senior vice president at MedImmune, Gaithersburg, MD, the manufacturer of FluMist, the product discussed in this article. Jay Bauman is president of Scientific and Technical Evaluation of Pharmaceuticals, Raleigh, NC, and a former employee of MedImmune and serves currently as an advisor to and provides medical writing support to the company; he was paid by MedImmune for his work on this and other manuscripts on the company's products. Michael, Helm, and VanGraafeil consulted MedImmune in the writing of this article; MedImmune reviewed the content prior to submission and made changes to several drafts but did not pay those three authors for their work. MedImmune also reviewed the article and made changes during the editing process.

Contact author: Michele Michael, michael@son.umaryland.edu.

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Abstract

Influenza is a highly contagious, acute respiratory illness with a long history of outbreaks dating back several centuries. Although immunization is an effective means of protection against influenza, vaccination rates have been suboptimal, especially among certain high-risk groups, including children and health care personnel. This article reviews basic information about influenza and immunization, discusses the relevance of children as vectors of disease, and highlights current information on FluMist, an intranasally administered, live attenuated influenza vaccine, including studies of its use compared with trivalent inactivated vaccine and in children.

Influenza outbreaks of variable severity occur each year in the United States, usually beginning in late fall or winter and ending in the spring.1 Influenza circulates at epidemic levels for three to four months, with activity often peaking in February, but sometimes as late as May. Influenza epidemics are responsible for almost 40,000 deaths and 230,000 hospitalizations annually.2, 3 In young children, the incidence of illness can be even greater: in an early study, Glezen found the incidence of influenza in children to range from 30% to 50%, second only to the elderly.4 Although few studies have examined the direct and indirect costs of influenza, the total economic burden has been calculated to be $87.1 billion, a staggering amount given that influenza can be prevented through vaccination.5

Figure. A two-year-o...
Figure. A two-year-o...
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Children are especially vulnerable and are major vectors for spreading the virus. The Centers for Disease Control and Prevention (CDC) recommends influenza vaccination for all children between six months and 18 years of age. Nonetheless, vaccination rates among children are low. As Glezen concludes in a recent article, "vaccine coverage has not improved since 1997."6 However, health care providers can play an important role in encouraging parents to protect their children against influenza.

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BACKGROUND

Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. These viruses spread from person to person through large-particle droplets from sneezes or coughs or through direct contact with an infected patient or contaminated surface. After transmission, incubation typically lasts from one to four days.7 Children tend to shed the virus several days before the onset of illness and can be infectious for seven days or more after symptoms appear. The illness is characterized by an abrupt appearance of signs and symptoms, including fever, malaise, sore throat, cough, rhinitis, and myalgia. Cough and fever occur in almost all cases. Mild complications include dehydration, sinusitis, and otitis media in children. Influenza can also lead to more serious complications such as bacterial pneumonia and worsening of chronic conditions such as congestive heart failure, asthma, or diabetes. In the majority of patients, signs and symptoms subside within seven days, although cough and malaise may linger for two weeks or longer.

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Classifying Influenza Strains

What's in a name?

Influenza strains are described and named according to standard nomenclature. The designation includes the nucleoprotein core (A or B), geographical location of initial isolation, strain serial number, year of isolation, and—for influenza A viruses—the subtype: for example, A/Solomon Islands/3/ 2006 (H1N1).

Influenza A viruses are classified into subtypes based on the surface antigens. Sixteen HA subtypes (H1 to H16) and nine NA subtypes (N1 to N9) of influenza A viruses have been identified. Of these, only three H subtypes (H1, H2, and H3) and two N subtypes (N1 and N2) have established disease lineages in humans. Influenza B viruses are not divided into subtypes.

There are three types of influenza viruses—A, B, and C—but only types A and B cause significant illness in humans. Each type contains two main surface proteins: hemagglutinin (HA) and neuraminidase (NA).7 The HA antigen enables the virus to enter into cells, while the NA antigen facilitates cell-to-cell transmission. Prior exposure to an influenza virus with similar HA or NA antigens usually results in the development of antibodies that can lessen illness severity. But if either antigen has changed significantly, few if any preexisting antibodies will be of use. Such a virus may infect more people and cause higher rates of morbidity and mortality.

How influenza changes. Influenza viruses continually change. Two processes can occur: antigenic drift and antigenic shift.

Antigenic drift is an ongoing process that occurs in both influenza A and B viruses when mutations occur within the HA or the NA genes.8 Depending on the extent of the mutation, the resultant viruses may be either partially recognized or unrecognized by previously developed antibodies. If an antigen drifts significantly in a given season, the current vaccine may not provide adequate protection against disease (when this occurs, there is said to be a "mismatch" between the vaccine and the circulating virus). This is why seasonal influenza vaccines must be updated annually.1

Antigenic shift presents a more significant health risk and occurs exclusively in influenza A viruses.8 Treanor defines antigenic shift as a change resulting "from the replacement of hemagglutinin and sometimes the neuraminidase with novel subtypes that have not been present in human viruses for a long time." Unlike antigenic drift, antigenic shift is uncommon and unpredictable. It can result in the introduction of a new virus strain and can cause pandemics, worldwide outbreaks of severe disease that often materialize without warning.

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VACCINATING CHILDREN

Epidemiologic studies have shown that during the early stages of annual epidemics, most influenza cases are detected in children five to 19 years of age. As an epidemic progresses, the proportion of infected school-age children declines and the number of infected preschool children and adults increases.9 Several field-based regional studies, funded by MedImmune, the manufacturer of FluMist, an intranasal live attenuated influenza (LAIV) vaccine, have recently been conducted to determine the effects of vaccination of young children on the incidence of "medically attended acute respiratory illness" and influenza-like illness during epidemics.10-13 In general, these studies found that vaccination of elementary school-age children can reduce overall illness from influenza.

Each year the CDC publishes recommendations for influenza; recent revisions highlight the growing recognition of the role of school-age children in its spread.14 The CDC expanded its guidelines by adding recommendations for vaccination of children two to five years of age as well as their household contacts and out-of-home caregivers. In February 2008 the CDC's Advisory Committee on Immunization Practices (ACIP) voted to recommend annual influenza vaccination of all school-age children through 18 years of age.15

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FluMist A (H1N1)

An intranasally administered vaccine against the pandemic (H1N1) 2009 virus will be available next year.

MedImmune, the manufacturer of influenza virus vaccine live, intranasal (FluMist) was awarded a $90 million government contract over the summer to produce a vaccine in the fight against the pandemic (H1N1) 2009 virus. According to a press release, MedImmune is making progress: "it may be able to manufacture approximately 200 million bulk doses of FluMist A (H1N1) and fill approximately 40 million doses into nasal sprayers by March 2010." For more, visit http://www.medimmune.com/h1n1.asp.

Joy Jacobson

managing editor

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THE LIVE, ATTENUATED INFLUENZA VACCINE (LAIV)

Six influenza virus vaccines—five trivalent inactivated vaccines (TIVs) and one LAIV—are approved for use in the United States for the 2009–2010 influenza season. TIV formulations, which consist of inactivated or "killed" influenza viruses, are given by intramuscular injection. These have been available in the United States for more than 60 years. The LAIV formulation, administered by intranasal spray, has been available in the United States since 2003 and is marketed as FluMist.

The efficacy of LAIV in children has been established in several trials.16-19 It has been demonstrated to help prevent influenza during matched and mismatched years; following one- and two-dose regimens in previously unvaccinated children; over multiple seasons; and relative to TIV. Children vaccinated with LAIV also had significantly fewer episodes of febrile otitis media.20

Independent analyses of efficacy trials of TIV and LAIV have revealed that children who received LAIV had fewer cases of culture-confirmed influenza illness than those who received TIV.21, 22 The efficacy rates observed with LAIV may be the result of the induction of both mucosal and systemic immune responses or of robust cell-mediated immunity.23, 24

The safety of LAIV in children has been established in numerous clinical trials, postmarketing analyses, and data collected by the Vaccine Adverse Event Reporting System.16, 17, 19, 25-30 LAIV was generally well tolerated in eligible children, with the most common adverse reactions being runny nose or nasal congestion and fever. The vaccine has also been shown to be genetically and phenotypically stable.

Wheezing and asthma. A randomized, double-blind, placebo-controlled safety trial of LAIV was conducted in 9,689 healthy children ages one to 17 years.26 An increased risk of asthma or reactive airway disease in children less than 36 months old was observed. Based on these findings, the original product approval for LAIV excluded use in children less than five years of age. In a subsequent study of children six to 59 months of age designed to compare the safety and effectiveness of LAIV and TIV, the rate of medically significant wheezing occurring within 42 days of vaccination was higher among LAIV recipients.31 But there was no increase in medically significant wheezing for children 24 to 59 months of age. As a result, LAIV is not approved for use in children younger than two years of age.

Shedding and potential for secondary transmission. The likelihood of transmission of influenza viruses shed by children after vaccination with LAIV has been determined to be extremely small (0.58% to 2.4%) and has not resulted in clinical influenza illness.32 There appears to be no increased risk of vaccine-virus transmission after immunization with LAIV.32, 33 For secondary virus transmission following vaccination, a defined sequence of events must occur: the vaccinee must shed the vaccine virus in nasal secretions; the quantity of virus shed must be of sufficient quantity to cause clinical symptoms; and the weakened vaccine virus must revert to the wild-type phenotype by losing its attenuated, cold adapted, and temperature-sensitive characteristics and produce clinical disease. In practice, the amount of LAIV virus that is shed is frequently below the infective dose of the virus.32, 34 The likelihood that the shed virus will revert to the wild-type phenotype is very low.35, 36

As a precautionary measure, however, people who receive LAIV should avoid contact with severely immunocompromised subjects who require a protected environment (for example, patients with stem cell transplants) for seven days after vaccination.1

Indications. LAIV is currently indicated for preventing influenza caused by virus subtypes A and B in eligible patients between ages two and 49 years. It's an option for healthy, nonpregnant people, including health care providers and others who have close contact with high-risk people.1, 31 It does not contain thimerosal, a mercury-containing compound.1

Contraindications. LAIV should not be administered to anyone with asthma or to children less than five years of age with recurrent wheezing. It's contraindicated in people with a history of hypersensitivity to eggs, egg proteins, gentamicin, gelatin, or arginine; those who have had life-threatening reactions to previous influenza vaccinations; and children and adolescents who are on aspirin or aspirin-containing agents. Benefits and risks should be carefully weighed in patients who are immunocompromised or in those who have experienced Guillain–Barré syndrome with prior influenza vaccination. (Full prescribing information for FluMist is available at www.medimmune.com/pdf/products/flumist_pi.pdf.)

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THE NURSE'S ROLE IN VACCINATION COMPLIANCE

Nurses are responsible for educating health care providers and parents or legal guardians on the importance of compliance as well as the consequences of inadequate or incomplete immunization. The financial burden related to the hospitalization of a child with influenza generally receives far more attention than the less easily documented indirect costs a family must absorb: lost wages and productivity, employment insecurity, and frequent absences from work pose more than just financial stress. Moreover, rarely addressed are the potential long-term psychosocial effects to the child: lost school days, interrupted development, and impaired relationships.

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PROVIDER EDUCATION

Although influenza vaccination is recommended for health care providers, vaccination rates among this group have been low.1 Indeed, national survey data indicate that in recent years only 42% to 44% of providers were vaccinated.35, 36 Influenza outbreaks in neonatal ICUs and other units have been linked to unvaccinated providers.35-38

Reasons for low vaccination rates include lack of awareness of current vaccination guidelines, concerns about the safety and effectiveness of vaccination, perceived low likelihood of contracting influenza, general avoidance of medications, and fear of needles.39, 40 Willis and Wortley conducted eight focus groups with nurses from Birmingham, Alabama, and Detroit, Michigan, to determine their attitudes about influenza and influenza vaccination.40 Of the four nurse groups from each city, there were two groups each of vaccinated and unvaccinated participants. Compared with their counterparts, unvaccinated nurses tended to be less aware of the rationale for vaccination. Some expressed concern that vaccination with a live virus would cause the disease; others said that vaccination was not necessary because they were not at risk of influenza. Both groups agreed that better education on influenza could inspire them to encourage vaccination among patients.

The following steps may enhance providers' compliance with influenza immunization:

* on-site education programs to provide information and updates from the ACIP.

* use of hospital or practice intranet to address misconceptions surrounding vaccination.

* access to the vaccine on-site, free of charge, while providing coverage of all shifts.

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PARENT EDUCATION

A study of parents of 7,695 children ages 19 to 35 months examined provider influence on parents' decisions to vaccinate their children and about general vaccine safety.38 The study revealed that providers had a significant influence on parents' decisions to vaccinate their children, even those who questioned the safety of vaccines.

Missed vaccination opportunities remain an important reason parents fail to immunize their children.41 In a study of parental attitudes about influenza immunization of healthy children, Daley and colleagues found that barriers to immunization included parents' perceptions that vaccination was risky and that their children had low susceptibility to influenza.42 The study also found that a physician's recommendation was highly correlated with receiving a vaccination.

Nurses can track the child's immunization status, send reminders for vaccination appointments, and remind parents of the importance of immunization during face-to-face meetings. Currently, there are many nontraditional opportunities to vaccinate children against influenza. The American Academy of Pediatrics recommends that schools, child care centers, and other institutions work with providers to "expand venues for administering vaccine."1 Researchers also advocate including schools in such efforts.11, 41 Other nontraditional sites in which the influenza vaccine is provided include malls, grocery stores, and pharmacies. Educating patients and families will enhance access to care and compliance.

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REFERENCES

1. American Academy of Pediatrics, Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2009–2010. Elk Grove Village, IL; 2009 Jul 16. http://www.cispimmunize.org/ill/Flu/Influenza%20Recommendations.pdf.

2. Thompson WW, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292(11):1333–40.

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4. Glezen WP, et al. Influenza virus infections in infants. Pediatr Infect Dis J 1997;16(11):1065–8.

5. Molinari NA, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 2007;25(27):5086–96.

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7. Cox RJ, et al. Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines. Scand J Immunol 2004;59(1):1–15.

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10. King JC, Jr., et al. A pilot study of the effectiveness of a school-based influenza vaccination program. Pediatrics 2005;116(6):e868–e873.

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15. Centers for Disease Control and Prevention, CDC Division of Media Relations. CDC's advisory committee recommends influenza vaccination for children 6 months through 18 years of age [press release]. 2008 Feb 27. http://www.cdc.gov/media/pressrel/2008/r080227.htm.

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23. Neuzil KM, Griffin MR. Vaccine safety—achieving the proper balance. JAMA 2005;294(21):2763–5.

24. Piedra PA, et al. Trivalent live attenuated intranasal influenza vaccine administered during the 2003–2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children. Pediatrics 2007;120(3):e553–e564.

25. Baxter R, et al. Post marketing evaluation of the safety of live attenuated influenza vaccine (FluMist) [abstract no. 6293.16]. Toronto, ON: Pediatric Academic Societies 2007.

26. Bergen R, et al. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J 2004;23(2):138–44.

27. Izurieta HS, et al. Adverse events reported following live, cold-adapted, intranasal influenza vaccine. JAMA 2005;294(21):2720–5.

28. King JC, Jr., et al. Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children. Pediatr Infect Dis J 2001;20(12):1124–31.

29. Tam JS, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr Infect Dis J 2007;26(7):619–28.

30. Vesikari T, et al. A randomized, double-blind, placebo-controlled trial of the safety, transmissibility and phenotypic stability of a live, attenuated, cold-adapted influenza virus vaccine (CAIV-T) in children attending day care [abstract no. G-450]. Chicago, IL: American Society for Microbiology 2001.

31. MedImmune Vaccines Inc. [Prescribing information]: FluMist influenza virus vaccine live, intranasal 2008. http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM123743.pdf.

32. Talbot TR, et al. Duration of virus shedding after trivalent intranasal live attenuated influenza vaccination in adults. Infect Control Hosp Epidemiol 2005;26(5):494–500.

33. Block SL, et al. Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5–49 years of age. Vaccine 2008;26(38):4940–6.

34. Cosgrove SE, et al. Strategies for use of a limited influenza vaccine supply. JAMA 2005;293(2):229–32.

35. Buonagurio DA, et al. Genetic stability of live, cold-adapted influenza virus components of the FluMist/CAIV-T vaccine throughout the manufacturing process. Vaccine 2006;24(12):2151–60.

36. Buonagurio DA, et al. Genetic and phenotypic stability of cold-adapted influenza viruses in a trivalent vaccine administered to children in a day care setting. Virology 2006;347(2):296–306.

37. Salgado CD, et al. Preventing nosocomial influenza by improving the vaccine acceptance rate of clinicians. Infect Control Hosp Epidemiol 2004;25(11):923–8.

38. Smith PJ, et al. Association between health care providers' influence on parents who have concerns about vaccine safety and vaccination coverage. Pediatrics 2006;118(5):e1287–e1292.

39. Canning HS, et al. Health care worker beliefs about influenza vaccine and reasons for non-vaccination—a cross-sectional survey. J Clin Nurs 2005;14(8):922–5.

40. Willis BC, Wortley P. Nurses' attitudes and beliefs about influenza and the influenza vaccine: a summary of focus groups in Alabama and Michigan. Am J Infect Control 2007;35(1):20–4.

41. Stinchfield PK. Practice-proven interventions to increase vaccination rates and broaden the immunization season. Am J Med 2008;121(7 Suppl 2):S11–21.

42. Daley MF, et al. Influenza among healthy young children: changes in parental attitudes and predictors of immunization during the 2003 to 2004 influenza season. Pediatrics 2006;117(2):e268–e277.

© 2009 Lippincott Williams & Wilkins, Inc.

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