The Role of Vaccination in the Prevention of Influenza

Release Date:  December 1, 2007

Expiration Date: December 31, 2009 

FACULTY:

Jay H. Bauman, PharmD
President, Scientific and Technical
Evaluation of Pharmaceuticals, Inc.
Raleigh, North Carolina

Allyn Bandell, PharmD
Director, Medical Sciences
MedImmune, Inc.
Gaithersburg, Maryland

FACULTY DISCLOSURE STATEMENTS:

Dr. Bauman has received financial support for analytical services provided to MedImmune, Inc.
Dr. Bandell is an employee of MedImmune, Inc. U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To review the antigenic characterization of the influenza virus, note differences between antigenic drift and antigenic shift, review clinical guidelines for influenza immunization in select patient groups, identify various vaccine formulations, and highlight the efficacy and safety of vaccination among high-risk groups.

OBJECTIVES:  

After reading this article, the participant should be able to:

1. Identify the various types and subtypes of influenza viruses, note the major clinical differences among them, and understand the clinical significance of antigenic drift and antigenic shift.*
2. Describe the differences in immunogenicity between live and inactivated influenza vaccines and how this may translate to differences in clinical response in select patient groups.*
3. Understand the various patient groups identified as being at high-risk of complications and/or hospitalization and note differences in clinical response to influenza immunization based on patient age.*
4. Describe various roles of the pharmacist in influenza immunization programs.*

* Also applies to pharmacy technicians.

Influenza epidemics occur yearly in the United States, typically beginning in the late fall or winter and concluding during the spring.¹ During the 2006-2007 season, influenza circulated at epidemic levels for 14 weeks and peaked during February, the month most frequently associated with peak activity over the past 31 influenza seasons.^1,2 According to estimates from the Centers for Disease Control and Prevention (CDC), influenza has been historically responsible for approximately 36,000 deaths and 226,000 hospitalizations annually.^3,4 However, this varies from year to year based on viral virulence and duration of circulation. All age groups are targets for illness�about 10% to 20% of the general population and 40% or more of young children can become infected in a given year.^5-7 Complications, hospitalizations, and death are most common in elderly patients 65 or older, followed by young children and in/USPExams/105669/dividuals with any medical condition that places them at high risk.^3,8,9 Infants and otherwise healthy children younger than five are at higher risk of hospitalization than older children. Those younger than two have the highest rate of hospitalization among all pediatric age groups, which approaches that of the at-risk elderly.^10,11

A recent analysis of the impact of influenza on associated medical and indirect costs projected that annual influenza epidemics resulted in an average of 610,000 life-years lost, 3.1 million hospitalized days, 31.4 million outpatient visits, direct medical costs of $10.4 billion, and lost earnings totaling $16.3 billion.¹² The total economic burden was calculated to be $87.1 billion.¹² The findings illustrate the enormous economic and social impact of influenza on society despite vaccination efforts.

Annual immunization against influenza is the most effective strategy for reducing the effects of disease, yet not all members of the population for whom vaccination is recommended are immunized. Pharmacists have played an important role in influenza immunization programs over the past 15 years and, with a potential pandemic on the horizon, can seize an ongoing opportunity to have greater impact on the burden of disease. The following discussion will review current recommendations and strategies for influenza immunization, contrast clinical and safety data for different commercially available influenza vaccines, and emphasize potential opportunities for pharmacists in the delivery of care related to influenza immunization.

Description of Influenza Virus and Antigenic Characterization

There are three types of influenza viruses�A, B, and C�all of which are members of the Orthomyxoviridae family and can be distinguished from each other according to antigenic differences between their matrix and nucleoproteins, host range, and ability to cause significant disease in humans.¹³ The A and B viruses contain two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) and are responsible for severe disease in humans.¹⁴ The HA antigen is the main determinant of virulence and facilitates entry of the virus into cells, whereas the NA antigen facilitates the release of newly produced viral cells. Antibodies against HA act to neutralize the virus and are protective against illness, whereas antibodies against NA can reduce the severity of disease. Influenza A viruses are further classified into subtypes based on the surface antigens. In total, there are 16 HA subtypes (designated H1-H16) and nine NA subtypes (designated N1-N9) of influenza A viruses, of which only three H subtypes (H1, H2, and H3) and two N subtypes (N1 and N2) have currently established disease lineages in humans (i.e., H1N1, H2N2, and H3N2). There have also been rare reports of sporadic outbreaks of H7N7, H7N2, and H9N2 viruses; extremely virulent avian H5N1 viruses have also been identified.² Although there are no subtypes of influenza B, the virus has two distinct genetic lineages�Yamagata and Victoria. As a family, influenza strains are described and named according to the antigenic type of the nucleoprotein core (A or B), geographical location of initial isolation, strain serial number, year of isolation, and subtype with all designations separated by a slash mark.

Ongoing changes in viral antigens (i.e., �antigenic drift�) occur when the replication of viral RNA, an error-prone process due to the lack of proofreading mechanisms, gradually results in the accumulation of point mutations within the antibody-binding sites of the proteins.¹⁵ Depending on the nature of the mutation, the new viruses may be either partially recognized or not recognized at all by antibodies against previous virus strains. Drift occurs in both influenza A and B viruses, although it appears at the greatest rate with the H3 subtype. As a result of the emergence of frequent antigenic variants through antigenic drift, the composition of influenza vaccines (i.e., three strains comprised of one H1N1, one H3N2, and one B type) must be updated yearly in order to achieve optimal protection (TABLE 1). When a virus has drifted significantly in a given season, a vaccine mismatch can occur as evidenced in five of the past 10 influenza seasons (TABLE 2). As a result, the recommended virus strains contained in the vaccine may not afford adequate protection against illness from the drifted virus strain and an epidemic can ensue.

Table 1
Recommended Composition of Influenza Vaccines Since the 2000/2001 Influenza Season
Season	H1N1 Component	H3N2 Component	B Component
2007/2008	A/Solomon Islands/3/2006-like	A/Wisconsin/67/2005-like	B/Malaysia/2506/2004-like
2006/2007	A/New Caledonia/20/99-like	A/Wisconsin/67/2005-like	B/Malaysia/2506/2004-like
2005/2006	A/New Caledonia/20/99-like	A/California/7/2004-like	B/Shanghai/361/2002-like
2004/2005	A/New Caledonia/20/99-like	A/Fujian/411/2002-like	B/Shanghai/361/2002-like
2003/2004	A/New Caledonia/20/99-like	A/Moscow/10/99-like*	B/Hong Kong/330/2001-like�
2002/2003	A/New Caledonia/20/99-like	A/Moscow/10/99-like*	B/Hong Kong/330/2001-like�
2001/2002	A/New Caledonia/20/99-like	A/Moscow/10/99-like*	B/Sichuan/379/99-like�
2000/2001	A/New Caledonia/20/99-like	A/Moscow/10/99-like*	B/Beijing/184/93-like�
* Manufacturers may use A/Panama/2007/99. � Manufacturers may use B/Hong Kong/1434/2002. � Manufacturers may use either B/Johannesburg/5/99, B/Victoria/504/2000, or B/Guangdong/120/2000. � Manufacturers may use B/Yamanashi/166/98. Source: www.cdc.gov/flu/weekly/fluactivity.htm.

A more significant, abrupt influenza epidemic can occur when a new virus strain is introduced into the human population through a process known as �antigenic shift.� This occurs exclusively among influenza A viruses.¹⁵ Antigenic shift results under the following circumstances: either a circulating human virus exchanges gene segments with an animal virus via genetic reassortment/co-infection in the human respiratory tract, an avian virus is transmitted directly to humans without an intermediate step, or a virus that circulated previously in humans reappears.^16-18 Antigenic shifts occur less frequently than antigenic drifts but have the potential to cause a pandemic if the virus is easily transmitted among humans in the absence of previous human exposure. Shifts are thought to occur every 10 to 20 years (TABLE 3) beginning in the U.S. during summer or early fall and are characterized by a large increase in mortality.⁷ Pandemics occur worldwide and can start in any season.

Table 2
Antigenic Characterization of Mismatched Vaccine and Epidemic Strains of Influenza Over the Past 10 Years in the U.S.
Influenza Season	Mismatched Influenza Type	Vaccine Strain	Mismatched �Drifted� Strain	% Drifted in Mismatched Type	Ratio of the Drifted Strain/All Strains Antigenically Characterized
2005/2006	B	B/Shanghai	B/Victoria	81	26
2004/2005	A/H3	A/Wyoming	A/California	78	51
2003/2004	A/H3	A/Panama	A/Fujian	89	82
2000/2001	B	B/Beijing	B/Sichuan	89	40
1997/1998	A/H3	A/Wuhan	A/Sydney	81	77
Source: www.cdc.gov/flu/weekly/fluactivity.htm.

Vaccine Supply and Distribution

The selection and manufacture of influenza vaccines is a long and tedious process and extends eight months or longer. The production process is currently not very flexible, and disruptions in influenza vaccine supply have occurred in at least four of the past seven seasons. Demand for vaccine during the 2006-2007 influenza season was greatest during the months of September and October but the number of doses released into the supply chain varied weekly and did not peak until December. Manufacture of vaccine was impacted by the difficulty in growing the H3N2 strain, and some providers did not have adequate supply of vaccine to meet peak demand. More than 120 million doses of influenza were manufactured for the 2006-2007 influenza season, but due to the mild season and distribution issues almost 20 million doses went unused and were discarded.^1,2 The CDC projects that at least 132 million doses�50 million doses produced by Sanofi Pasteur, 40 million doses produced by Novartis Vaccines, 30 to 35 million doses produced by GlaxoSmithKline, and up to 7 million doses produced by MedImmune�will be manufactured for the 2007-2008 season.^1,2 The most significant potential solution to supply issues concerns the introduction of newer production methods utilizing cell-based and reverse genetic technologies.^19,20 They have the potential to reduce production timelines and result in purer products.

Influenza Vaccine Formulations and Immunogenicity

Six influenza virus vaccines are approved in the U.S. and will be available for the 2007-2008 influenza season�five are trivalent, inactivated vaccines (TIV) for intramuscular use and one is a trivalent live, attenuated influenza vaccine (LAIV) given by intranasal administration (TABLE 4).¹ TIV formulations have been available in the U.S. for more than 60 years, whereas the process for the production of LAIV was identified in 1960. During the production of TIV, three influenza virus strains are independently grown in chicken eggs and inactivated/killed prior to combination into a final formulation.

The production of LAIV differs from TIV in several aspects. For the creation of LAIV, a influenza A virus (A/Ann Arbor/6/60 [H2N2]) in primary chicken kidney tissue cultures was subjected to gradually lower temperatures until the viruses adapted to multiply at 25�C, a temperature suboptimal for normal growth of influenza.²¹ The resultant genetic changes were responsible for attenuation of the master donor viruses (MDV), which develop characteristics of cold adaption (ca), attenuation (att), and temperature sensitivity (ts). A contemporary wild-type virus that expresses the normal surface HA and NA glycoproteins is cultured simultaneously with a MDV. Due to the segmented nature of the influenza genome, a genetic 6-2 reassortant can be identified, resulting from the six genes from the MDV and the HA and NA genes from the virulent wild-type virus. Although the final product is comprised of live, attenuated viruses, LAIV will multiply in the colder temperatures of the nasal passages but not in the lungs. As such, vaccination will not produce clinical disease in patients.

Multiple mechanisms are involved in the natural immune response to influenza.²² Naturally acquired infection stimulates long-lived protection against future infection in healthy subjects by the production of antibodies and activation of other immune cells: serum antibodies and antibodies present at the mucosal surface of the respiratory tract; influenza-specific cytotoxic T-cells, which play a role in recovery from illness; and interferons, which are involved in protection from illness during the early stage of natural infection. Secretory immunoglobulin A (SIgA) protects the upper respiratory tract and serum IgG provides protection of the lower respiratory tract.¹³ A comparison of immunity following natural infection with that following TIV reveals that both stimulate hemagglutinin inhibitory (HAI) antibodies against wild-type species, but the protection associated with natural infection is broader and longer lasting.²³ Influenza-specific IgG antibodies dominate the serum antibody response following the administration of TIV but low concentrations of IgM and IgA antibodies are also detected.¹³

The immune response following administration of LAIV involves the production of multiple immune components�interferons and cytotoxic T-cells�and closely mimics that following natural infection. A primary response to LAIV is characterized by peak concentrations in serum IgA and IgM two weeks after vaccination, a rise in serum IgG four to 12 weeks postvaccination that can persist for one year or longer, and an increase in secretory IgA, which peaks two to 11 weeks following vaccination.¹³ As a result, LAIV may produce broader protection in patients than TIV during epidemics in which circulating influenza strains do not match those contained in the vaccine.²⁴

Table 4
Approved Influenza Vaccines for the 2007-2008 Influenza Season
Vaccine	Trade Name	Manufacturer	How Supplied	Thimerosal Content (mcg Hg/ 0.5 mL dose)	Approved Age Group	Number of Doses to Be Administered	Route of Administration
TIV	Fluzone	Sanofi Pasteur	0.25-mL prefilled syringe 0.5-mL prefilled syring 0.5-mL vial 5.0-mL multidose vial	0 0 0 25	6-35 months =36 months =36 months =6 months	One or two* One or two* One or two* One or two*	Intramuscular
TIV	Fluvirin	Novartis Vaccines	5.0-mL multidose vial	24.5	=4 years	One or two*	Intramuscular
TIV	Fluarix	GlaxoSmithKline	0.5-mL prefilled syringe	<1.0	=18 years	One	Intramuscular
TIV	FluLaval	GlaxoSmithKline	5.0-mL multidose vial	25	=18 years	One	Intramuscular
TIV	Afluria	CSL Biotherapies	0.5-mL prefilled syringe 5.0-mL multidose vial	0 24.5	=18 years	One	Intramuscular
LAIV	FluMist	MedImmune	0.2-mL sprayer	0	2-49 years	One or two�	Intranasal
TIV: trivalent inactivated vaccine; LAIV: live, attenuated influenza vaccine. * Two doses administered at least one month apart are recommended for children aged 6 months to 8 years who are receiving TIV for the first time. Those who received only one dose in their first year of vaccination should receive two doses in the following year. � Two doses administered at least six weeks apart are recommended for children aged 2 to 8 who are receiving LAIV for the first time. Those who received only one dose in their first year of vaccination should receive two doses in the following year. Source: Reference 1.

ACIP Guidelines for Vaccinations
of Select Patient Populations

The CDC�s Advisory Committee on Immunization Practices (ACIP) develops recommendations annually regarding the immunization of select patient groups. Specific guidelines may be changed each year, as well as composition of the influenza vaccine, and are influenced by the availability of new epidemiological and clinical data. Recent changes have included expanded recommendations for children six months to five years of age and reflect the severity of disease in this patient population.²⁵ The most current recommendations for influenza immunization were made available in July 2007 and are highlighted in TABLE 5.¹

Timing of Injection: Based on current ACIP recommendations, more than 200 million people are prime candidates for influenza vaccination during the 2007-2008 season.¹ As the onset and duration of influenza seasons vary from year-to-year, it is difficult to determine the optimal time to vaccinate select patient populations. Nevertheless, the ACIP does provide guidance on timing of vaccination.¹ These recommendations, however, may be impacted by vaccine availability.

Timing of influenza vaccination is especially critical for the elderly, as the immunological response to vacci-nation is reduced as one ages, and young children, for whom two doses are recommended.²⁶ Vaccination of elderly patients during September may not result in a robust response, thereby rendering them susceptible to infection during the latter months of the season. Compliance with the two-dose regimen in children younger than nine is less than 50%, and the administration of only one dose of TIV has resulted in suboptimal protection against infection compared with the two-dose schedule.^27-30 Limited clinical results following only one dose of LAIV in healthy young children suggest similar efficacy to the two-dose schedule during a matched year.^31,32 As the second dose should be given four to six weeks after the first, the earlier the initial dose is given the greater the likelihood of compliance to this regimen.²⁷

Table 5
Target Groups for Vaccination: Recommendations for the 2007-2008 Influenza Season
General Considerations Annual vaccination is recommended for all persons, including school-aged children, who wish to reduce the likelihood of illness due to influenza or of transmitting influenza to others Any child older than six months may be vaccinated. Immunization is recommended for women who are breastfeeding and who are contacts of infants or children 59 months or younger Any traveler who wants to reduce the risk for influenza should consider vaccination at least two weeks prior to departure. Travelers should keep in mind that influenza activity typically occurs in the Southern Hemisphere during April to September Persons at Risk for Medical Complications or More Likely to Require Medical Care Vaccination with TIV is recommended for the following persons who are at increased risk for severe complications from influenza, or at higher risk for influenza-associated clinic, emergency department, or hospital visits: All children six to 59 months of age All persons aged 50 or older Children and adolescents (aged six months to 18 years) who are receiving long-term aspirin therapy and who therefore might be at risk for developing Reye�s syndrome following infection Women who will be pregnant during the influenza season Adults and children who have chronic pulmonary, cardiovascular (except hypertension), renal, hepatic, hematological, or metabolic disorders (including diabetes) Adults and children who have immunosuppression (including that caused by medications or HIV) Adults and children who have any condition that can compromise respiratory function or the handling of respiratory secretions, or that can increase the risk for aspiration (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) Residents of nursing home and other chronic-care facilities							Persons Who Live with or Care for Persons at High Risk for Influenza-Related Complications Vaccination is recommended for the following persons to prevent transmission to high-risk in/USPExams/105669/dividuals: Health care personnel Healthy household contacts (including children) and caregivers of children 59 months or younger and adults 50 years or older, with emphasis on vaccinating contacts younger than six months Healthy household contacts (including children) and caregivers of in/USPExams/105669/dividuals with medical conditions (including immunocompromised states) that put them at higher risk for severe complications form influenza Persons Who Should Not Be Vaccinated Contraindications to influenza vaccine vary according to type of vaccine administered. The following patient types should not be vaccinated: TIV Anyone known to have an anaphylactic hypersensitivity to eggs or to other components of the vaccine Persons with moderate-to-severe acute febrile illness should not be vaccinated until their symptoms abate The occurrence of Guillain-Barr� syndrome (GBS) within six weeks following a previous dose of vaccine is considered to be a precaution for further use of TIV LAIV Anyone known to have an anaphylactic hypersensitivity to eggs or to other components of the vaccine Persons younger than two or older than 50, due to lack of substantial data in these age groups Persons with any of the following underlying medical conditions: asthma, reactive airways disease or other chronic disorders of the pulmonary or cardiovascular systems, diabetes, renal dysfunction, hemoglobinopathies, immunodeficiency diseases, or immunosuppressed states Children or adolescents receiving aspirin or other salicylates Persons with a history of GBS Pregnant women
Source: Adapted from Reference 1.

Safety and Efficacy of Immunization in Select Populations
Assessment of clinical differences between influenza vaccines is impacted by the outcome measure being studied, immunogenic response to in/USPExams/105669/dividual formulations, comparative age and health status of those being studied, and the extent of match between the strains contained in the vaccines and those circulating in the community.¹ Outcome measures can be /USPExams/105669/divided into vaccine efficacy (i.e., ability to prevent laboratory-confirmed infection in a controlled setting) or vaccine effectiveness (i.e., ability to prevent clinically significant influenza-like illness [ILI]). Effectiveness may also include other variables such as prevention of medically attended acute respiratory illness (MAARI), hospitalizations, or death.

Effectiveness of Vaccination in Children: Children have long been known as vectors for spread of influenza, and high attack rates among school-aged children significantly impacts their quality of life as well as that of their family members and others in the community.³³ Three analyses have recently been published on the efficacy of influenza vaccines in healthy children.^34-36 In these reports, randomized clinical trials of TIV and LAIV published through May 2005 were considered for evaluation. Although numerically higher efficacy rates for culture- and laboratory-confirmed influenza were reported in children given LAIV, there was no clear evidence favoring one vaccine over the other in children two and older. It is interesting to note that there is a paucity of data in children six months to 23 months of age and data that were available for review showed no significant differences in efficacy between TIV and placebo.³⁶

Since these analyses were published, additional data have been reported on the safety and effectiveness of influenza vaccines in young children. Retrospective studies on the safety of TIV in children six to 23 months of age demonstrated few medically-attended adverse events, none of which were serious, prompting the authors to conclude that universal vaccination of children in this age range is not associated with any untoward safety risks.^37,38

Two prospective, randomized, double-blind, placebo-controlled studies examined the safety and efficacy of LAIV given over two seasons in more than 4,000 children ranging from six to younger than 36 months of age.^32,39 Significant efficacy against culture-confirmed influenza among antigenically similar strains was demonstrated for LAIV during the first and second seasons (range 72.9% to 85.4% and 84.3% to 88.7%, respectively), and LAIV was well tolerated with the most frequently observed side effect being runny nose/nasal congestion. A community-based, nonrandomized, open-label field study assessed MAARI and culture-confirmed influenza illness in children five to 18 years of age given LAIV.⁴⁰ Vaccine effectiveness against MAARI was 26% and efficacy was determined to be 56%, which included cross-protection against a drift variant strain. Similar protection against drifted strains has been reported in other trials of LAIV in children.^41-43

Three studies involving more than 12,000 patients assessed the comparative efficacy and safety of LAIV with TIV in otherwise healthy children six to 59 months of age, children six to 71 months of age with recurrent respiratory tract infections, and children six to 17 years of age with a clinical diagnosis of asthma.^44-46 There were significantly fewer cases of culture-confirmed influenza in all studies in patients who received LAIV compared with those who received TIV, and this was consistent for both antigenically similar and, when identified, drifted virus strains. Treatments were similarly well tolerated� runny nose/nasal congestion was more common following administration of LAIV and local injection site reactions were restricted to TIV. The administration of LAIV had previously been associated with an increased risk of asthma/reactive airways disease in children younger than 36 months, but no differences were noted between treatments in the incidence of asthma exacerbations or other symptoms of pulmonary etiology in asthmatic patients.⁴⁶ There was, however, a higher incidence of medically significant wheezing among children less than 24 months who were given LAIV than those given TIV, which was observed within 42 days after the administration of the last dose of vaccine.⁴⁴ Rates of hospitalization for any cause during the 180-day observation period after vaccination were significantly higher among those who received LAIV than among those given TIV. No other significant or unusual untoward effects were observed in these trials or in others specifically designed to monitor the safety of LAIV in young children.^47-49 The greater efficacy observed for LAIV over TIV may be explained by its greater immunogenic potential against matched and mismatched influenza strains.⁵⁰

Effectiveness of Vaccination in the Elderly: Vaccination of those 65 and older is recommended worldwide as this segment of the population is at highest risk for complications, hospitalizations, and death from influenza. While the impact of influenza in this age group is well known, an analysis of the impact of influenza on mortality over 33 seasons indicated that the benefit of vaccination in the elderly may be substantially less than expected.^3,51

A recent review was conducted to evaluate the effects of influenza vaccination in the elderly who resided in long-term care facilities (LTCF) or in the community.⁵² A total of 64 studies comprising 96 datasets were identified that assessed efficacy (i.e., reduction in laboratory-confirmed cases) or effectiveness against ILI (i.e., reduction in symptomatic cases). The following outcomes were analyzed: influenza, ILI, hospital admissions, complications, and death.

The overall effectiveness of TIV against ILI in those in LTCF was 23% during matched seasons, which was not significantly different from no vaccination when matching status was poor or unknown. Efficacy of vaccination against influenza was tested in only seven datasets and was not significant. Well-matched vaccine effectively prevented pneumonia (46%), hospital admissions (45%), and death (42%), whereas those of poor or unknown match did not. During seasons of low viral circulation, TIV prevented ILI (33%), pneumonia (65%), hospital admissions (68%), and influenza-related deaths (71%) but had no effects on influenza in two studies reviewed. Data from more than one million observations from 20 studies of elderly in/USPExams/105669/dividuals residing in the community indicated TIV was not effective against ILI, influenza, or pneumonia. Well-matched vaccines did demonstrate effectiveness against hospital admissions for influenza or pneumonia (26%) and all cause mortality (42%). The elderly who are 65 and older have a significantly diminished antibody response that is reflected in a decrease in the magnitude, onset, and duration of immunity compared with younger adults and forms a logical basis for the reduced efficacy observed in this patient population.^53,54

There are no large, controlled trials that have compared the efficacy of TIV and LAIV in elderly patients, but preliminary data indicate that the combination of TIV and LAIV may be more effective than either given alone.^54-56 Other methods to reduce illness from influenza in the elderly include the administration of higher vaccine doses, development of more immunogenic vaccines by the incorporation of select adjuvants, and widespread vaccination of children who are the main vectors for spread of disease (i.e., herd immunity).²⁶ In general, influenza vaccines are well-tolerated in the elderly.²⁶

Effectiveness of Vaccination in Adults: TIV prevents laboratory-confirmed illness in up to approximately 90% of otherwise healthy adults 18 to 64 years of age when the vaccine matches circulating strains, but efficacy is reduced by 20% to 40% during years of vaccine mismatch.^1,57,58 Vaccination also significantly affects other variables such as days lost from work and consumption of health care resources, even during mismatched years.^1,58 Adults with certain chronic diseases (e.g., asthma, heart disease, diabetes) generally suffer more severe disease, have a muted serum antibody response, and typically have lower rates of response compared with healthy adults.¹ Nevertheless, vaccination of these patients can substantially reduce complications from influenza.⁵⁹

Fewer studies have been conducted with LAIV than with TIV in adults. A randomized, double-blind, placebo-controlled trial conducted during a year of vaccine mismatch in more than 4,000 healthy adults aged 18 to 64 years demonstrated that LAIV significantly reduced the numbers of severe febrile illnesses and febrile upper respiratory tract illnesses, and led to fewer days of illness, less days lost from work, and reduced consumption of health care resources.⁶⁰ LAIV was well tolerated.

Several investigators have reported on the comparative efficacy of LAIV and TIV in adults.^61-63 Efficacy rates were mixed between vaccines: one study favored LAIV, one favored TIV, and similar effectiveness between vaccines was noted in another.^61-63 Until more data become available, the upper age limit of use for LAIV is currently capped at 49; all marketed formulations of TIV are labeled for use in those 18 and older but differ according to minimum age restrictions (TABLE 4).^1,64 Safety data collected through the US Vaccine Adverse Event Reporting System (VAERS) and as part of a phase IV review of medical utilization data from approximately 45,000 patients did not identify any unexpected serious risks following the administration of LAIV.^49,65

General Safety of Influenza Vaccines: Influenza vaccines are contraindicated in in/USPExams/105669/dividuals with known hyper-sensitivity reactions to eggs or egg products, or other components of the influenza vaccine, and should be administered to in/USPExams/105669/dividuals who have a prior history of Guillain-Barr� syndrome only if the benefits outweigh the risks.¹ In addition, LAIV is contraindicated in children and adolescents two to 17 years of age receiving aspirin or aspirin-containing therapy because of the association of Reye�s syndrome with aspirin and wild-type influenza infection.⁶⁴ LAIV should not be administered to any in/USPExams/105669/dividual with severe asthma or active wheezing, and should only be given to children less than five years of age with recurrent wheezing and to immuno-compromised patients if perceived benefits exceed potential risks.⁶⁴ Patients with moderate-to-severe acute febrile illness should not be vaccinated with any influenza formulation until their symptoms have improved.¹

Overall, influenza vaccines are generally well tolerated. The most frequent side effect of vaccination with injectable formulations is soreness at the injection site lasting less than two days, local pain, and swelling.¹ These reactions are typically mild and rarely interfere with daily activities. The most common adverse reactions to LAIV are runny nose or nasal congestion in recipients of all ages, fever greater than 100�F in children two to six years of age, and sore throat in adults.⁶⁴ When observed, these reactions were generally short-lived and were self-limiting. Adverse reactions affecting other organ systems (e.g., gastrointestinal and central nervous systems) have also been reported following the administration of injectable and nasal influenza vaccines.¹

Role of the Pharmacist in Influenza Immunization Programs

History: Pharmacists have been actively involved in the immunization process in some capacity since the mid-1800s when they first distributed smallpox vaccine, and they continued to play a pivotal role in the education of physicians and prospective patients about vaccines during the period surrounding World War I.⁶⁶ Further involvement waned until the advent of the oral polio vaccine in 1962.^66,67

A major role for pharmacists in immunization delivery was realized in 1994 when the Department of Health and Human Services (DHHS) officially recognized pharmacists had important roles in immunization with respect to the following needs: education, distribution, administration, and registries and tracking systems.⁶⁸ Guidelines for pharmacy-based immunization advocacy were approved soon after by the American Pharmacists Association board of trustees, followed by the American Society of Health-System Pharmacists� guidelines on the pharmacist�s role in immunization, and a formalized training program in pharmacy-based immunization delivery was officially begun in 1996.^69,70 The goals and objectives of the training program are centered around three core principles: advocacy�motivating people to be immunized; facilitation�hosting others who immunize; and, immunization�administration of vaccines. More than 20,000 pharmacists have received immunization training, and as of June 2007, 46 states (with the exception of West Virginia, New York, New Hampshire, and Maine) have passed legislation that allows pharmacists to immunize patients.⁷⁰

Influenza Programs: The literature is replete with reports on the role pharmacists have played in influenza immunization programs.^71-82 In these studies, a pharmacy-driven advocacy program increased vaccine acceptance by at risk patients; elderly patients who resided in states where pharmacists can administer influenza vaccines had higher rates of vaccination than in/USPExams/105669/dividuals who lived in states where this service was not provided; clinic-based pharmacists were able to identify and increase vaccination rates among older patients; and satisfaction with pharmacy-based immunization programs was noted to be well received.^75,76,78,80 Results of these studies clearly show that pharmacist involvement in influenza immunization initiatives increases overall vaccination rates and patients are satisfied with the service they receive.

Potential Opportunities for Pharmacists to Increase Influenza Vaccination Rates

The DHHS has set forth the Healthy People 2010 initiative, a nationwide health promotion and disease prevention program that advocates a 90% immunization rate for all high-risk in/USPExams/105669/dividuals older than 65 and a 60% rate of immunization for high-risk in/USPExams/105669/dividuals from 18 to 64 years of age.⁸³ Coverage data for the 2005-2006 influenza season indicate substantially fewer patients were vaccinated than mandated by the Healthy People 2010 objectives outlined by DHHS. Vaccination rates for selected patient populations were as follows: children six to 23 months of age received one dose (31.9%) and were fully vaccinated (20.6%), otherwise healthy 18 to 49 year olds (18.3%), 18 to 49 year olds with high-risk conditions (30.5%), adults 50 to 64 years (36.6%), and adults 65 and older (69.3%).^84,85

Obstacles to influenza immunization are well known and include patient-, provider-, and clinic-related issues. Strategies to improve immunization rates have included standing orders, physician chart reminders, various educational initiatives, availability of walk-in visits for vaccinations, and patient-direct mailings.^86-88 Pharmacists are uniquely positioned to overcome many of the obstacles to immunization because they are among the most widely available of all health care professionals, they maintain a high level of trust with consumers, and the immunization services offered are valued by clients. Key opportunities for pharmacists to play a role as an advocator, facilitator, or immunizer exist in both hospital, community, and rural settings (TABLE 6).^71,73,81 Clinical pharmacists with practices in institutions and ambulatory care clinics are strategically located to identify and motivate potential immunization candidates through patient profiling systems. Major impact can be realized with young children to increase compliance with the two-dose regimen for those younger than nine, and educational activities can be initiated with health care workers who historically shy away from influenza vacci-nation.⁸⁹ Given the possibility that a pandemic is likely to occur in the near future, pharmacists must increase their role as immunization advocates, be effective risk communicators, and provide up-to-date technical information to dispel disease myths.⁷⁴ An increase in the influenza immunization rate in any of the aforementioned areas will help to fulfill goals of the Healthy People 2010 initiative.

Conclusion

Influenza affects all age groups each year but can be prevented in the majority of patients by the administration of an influenza vaccine. Two types of influenza vaccines are currently available�LAIV and TIV�and both can be differentiated by their method of administration, age restrictions for use, and potential efficacy in select segments of the population. The immune response following LAIV more closely resembles that of natural infection and efficacy has been maintained in children during years of vaccine mismatch. However, there is more clinical experience with TIV and it is recommended for a broader range of patients including those age 50 and older. Each year, the CDC issues recommendations on the vaccination of influenza in different patient populations. Pharmacists have increased their activities in the influenza vaccination process over the past 15 years, as states have passed legislation allowing them to vaccinate patients. With an impending pandemic and an aggressive health initiative proposed for 2010, pharmacists are uniquely positioned to become more involved with influenza vaccination initiatives.

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