Both the inactivated influenza vaccine and LAIV can be used to reduce the risk of influenza. LAIV is only approved for use among healthy persons aged 5--49 years. Inactivated influenza vaccine is approved for persons aged >6 months, including those with high-risk conditions (see following sections on inactivated influenza vaccine and live, attenuated influenza vaccine).
Persons at Increased Risk for Complications
Vaccination with inactivated influenza vaccine is recommended for the following persons who are at increased risk for complications from influenza:
In 2000, approximately 73 million persons in the United States were included in one or more of these target groups, including 35 million persons aged >65 years, 12 million adults aged 50--64 years, 18 million adults aged 18--49 years, and 8 million children aged 6 months--17 years with one or more medical conditions that are associated with an increased risk for influenza-related complications (125).
Persons Aged 50--64 Years
Vaccination is recommended for persons aged 50--64 years because this group has an increased prevalence of persons with high-risk conditions. In 2000, approximately 42 million persons in the United States were aged 50--64 years, of whom 12 million (29%) had one or more high-risk medical conditions (125). Influenza vaccine has been recommended for this entire age group to increase the low vaccination rates among persons in this age group with high-risk conditions (see preceding section). Age-based strategies are more successful in increasing vaccine coverage than patient-selection strategies based on medical conditions. Persons aged 50--64 years without high-risk conditions also receive benefit from vaccination in the form of decreased rates of influenza illness, decreased work absenteeism, and decreased need for medical visits and medication, including antibiotics (9--12). Further, 50 years is an age when other preventive services begin and when routine assessment of vaccination and other preventive services has been recommended (126,127).
Persons Who Can Transmit Influenza to Those at High Risk
Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Decreasing transmission of influenza from caregivers and household contacts to persons at high risk might reduce influenza-related deaths among persons at high risk. Evidence from two studies indicates that vaccination of health-care personnel is associated with decreased deaths among nursing home patients (119,120). Health-care workers should be vaccinated against influenza annually. Facilities that employ heath-care workers are strongly encouraged to provide vaccine to workers by using approaches that maximize immunization rates. This will protect health-care workers, their patients, and communities, and will improve prevention, patient safety, and reduce disease burden. Health-care workers' influenza immunization rates should be regularly measured and reported. Although rates of health-care worker vaccination are typically <40%, with moderate effort, organized campaigns can attain higher rates of vaccination among this population (118).
The following groups should be vaccinated:
In addition, because children aged 0--23 months are at increased risk for influenza-related hospitalization (52--54), vaccination is recommended for their household contacts and out-of-home caregivers, particularly for contacts of children aged 0--5 months, because influenza vaccines have not been approved by FDA for use among children aged <6 months (see Healthy Young Children).
Healthy persons aged 5--49 years in these groups who are not contacts of severely immunosuppressed persons (see Live, Attenuated Influenza Vaccine Recommendations) can receive either LAIV or inactivated influenza vaccine. All other persons in this group should receive inactivated influenza vaccine.
Pregnant Women
Influenza-associated excess deaths among pregnant women were documented during the pandemics of 1918--19 and 1957--58 (128--131). Case reports and limited studies also indicate that pregnancy can increase the risk for serious medical complications of influenza (132--136). An increased risk might result from 1) increases in heart rate, stroke volume, and oxygen consumption; 2) decreases in lung capacity; and 3) changes in immunologic function during pregnancy. A study of the effect of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14--20 of gestation to 4.7 during weeks 37--42, in comparison with women who were 1--6 months postpartum (137). Women in their third trimester of pregnancy were hospitalized at a rate (i.e., 250/100,000 pregnant women) comparable with that of nonpregnant women who had high-risk medical conditions. Researchers estimate that an average of 1--2 hospitalizations can be prevented for every 1,000 pregnant women vaccinated.
Because of the increased risk for influenza-related complications, women who will be pregnant during the influenza season should be vaccinated. Vaccination can occur in any trimester. One study of influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine (138).
Healthy Young Children
Studies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation (51--53,139,140). The increased rates of hospitalization are comparable with rates for other groups considered at high risk for influenza-related complications. However, the interpretation of these findings has been confounded by co-circulation of respiratory syncytial viruses, which are a cause of serious respiratory viral illness among children and which frequently circulate during the same time as influenza viruses (141--143). Two recent studies have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children who do not have high-risk conditions (52,53). Both studies reported that otherwise healthy children aged <2 years, and possibly children aged 2--4 years, are at increased risk for influenza-related hospitalization compared with older healthy children (Table 1). Among the Tennessee Medicaid population during 1973--1993, healthy children aged 6 months--<3 years had rates of influenza-associated hospitalization comparable with or higher than rates among children aged 3--14 years with high-risk conditions (Table 1) (52,54). Another Tennessee study reported a hospitalization rate per year of 3--4/1,000 healthy children aged <2 years for laboratory-confirmed influenza (32).
Because children aged 6--23 months are at substantially increased risk for influenza-related hospitalizations, ACIP recommends vaccination of all children in this age group (144). ACIP continues to recommend influenza vaccination of persons aged >6 months who have high-risk medical conditions.
The current inactivated influenza vaccine is not approved by FDA for use among children aged <6 months, the pediatric group at greatest risk for influenza-related complications (52). Vaccinating their household contacts and out-of-home caregivers might decrease the probability of influenza infection among these children.
Beginning in March 2003, the group of children eligible for influenza vaccine coverage under the Vaccines for Children (VFC) program was expanded to include all VFC-eligible children aged 6--23 months and VFC-eligible children aged 2--18 years who are household contacts of children aged 0--23 months (145).
Persons Infected with HIV
Limited information is available regarding the frequency and severity of influenza illness or the benefits of influenza vaccination among persons with HIV infection (146,147). However, a retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than during the peri-influenza periods. The risk for hospitalization was higher for HIV-infected women than for women with other well-recognized high-risk conditions, including chronic heart and lung diseases (148). Another study estimated that the risk for influenza-related death was 9.4--14.6/10,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.09--0.10/10,000 among all persons aged 25--54 years and 6.4--7.0/10,000 among persons aged >65 years (149). Other reports indicate that influenza symptoms might be prolonged and the risk for complications from influenza increased for certain HIV-infected persons (150--152).
Influenza vaccination has been demonstrated to produce substantial antibody titers against influenza among vaccinated HIV-infected persons who have minimal AIDS-related symptoms and high CD4+ T-lymphocyte cell counts (153--156). A limited, randomized, placebo-controlled trial determined that influenza vaccine was highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIV-infected persons with a mean of 400 CD4+ T-lymphocyte cells/mm3; a limited number of persons with CD4+ T-lymphocyte cell counts of <200 were included in that study (147). A nonrandomized study among HIV-infected persons determined that influenza vaccination was most effective among persons with >100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL (152). Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, influenza vaccine might not induce protective antibody titers (155,156); a second dose of vaccine does not improve the immune response in these persons (156,157).
One study determined that HIV RNA (ribonucleic acid) levels increased transiently in one HIV-infected person after influenza infection (158). Studies have demonstrated a transient (i.e., 2--4 week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (155,159). Other studies using similar laboratory techniques have not documented a substantial increase in the replication of HIV (160--163). Deterioration of CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIV-infected persons after influenza vaccination compared with unvaccinated persons (156,164). Limited information is available concerning the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza infection or influenza vaccination (146,165). Because influenza can result in serious illness, and because influenza vaccination can result in the production of protective antibody titers, vaccination will benefit HIV-infected persons, including HIV-infected pregnant women.
Breastfeeding Mothers
Influenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect the immune response and is not a contraindication for vaccination.
Travelers
The risk for exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year. In the temperate regions of the Southern Hemisphere, the majority of influenza activity occurs during April--September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups (e.g., on cruise ships) that include persons from areas of the world where influenza viruses are circulating (166,167). Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to
No information is available regarding the benefits of revaccinating persons before summer travel who were already vaccinated in the preceding fall. Persons at high risk who receive the previous season's vaccine before travel should be revaccinated with the current vaccine the following fall or winter. Persons aged >50 years and others at high risk should consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks for influenza and the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza.
General Population
In addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered to children >6 months), depending on vaccine availability (see Influenza Vaccine Supply). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.
Both inactivated influenza vaccine and LAIV are available to reduce the risk of influenza infection and illness. However, the vaccines also differ in key ways.
Major Similarities
LAIV and inactivated influenza vaccine contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one A (H1N1) virus, and one B virus. Each year, one or more virus strains might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. Viruses for both vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza infection.
Major Differences
Inactivated influenza vaccine contains killed viruses, whereas LAIV contains attenuated viruses still capable of replication. LAIV is administered intranasally by sprayer, whereas inactivated influenza vaccine is administered intramuscularly by injection. LAIV is more expensive than inactivated influenza vaccine. LAIV is approved for use only among healthy persons aged 5--49 years; inactivated influenza vaccine is approved for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions.
Persons Who Should Not Be Vaccinated with Inactivated Influenza Vaccine
Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Prophylactic use of antiviral agents is an option for preventing influenza among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications from influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information regarding vaccine components is located in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.
Dosage
Dosage recommendations vary according to age group . Among previously unvaccinated children aged <9 years, 2 doses administered >1 month apart are recommended for satisfactory antibody responses. If possible, the second dose should be administered before December. If a child aged <9 years receiving vaccine for the first time does not receive a second dose of vaccine within the same season, only 1 dose of vaccine should be administered the following season. Two doses are not required at that time. Among adults, studies have indicated limited or no improvement in antibody response when a second dose is administered during the same season (168--170). Even when the current influenza vaccine contains one or more antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines during the year after vaccination (171,172). Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season.
Route
The intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle. A needle length >1 inch can be considered for these age groups because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children (173).
Infants and young children should be vaccinated in the anterolateral aspect of the thigh (64). ACIP recommends a needle length of 7/8--1 inch for children aged <12 months for intramuscular vaccination into the anterolateral thigh. When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8--1.25 inches is recommended (64).
Side Effects and Adverse Reactions
When educating patients regarding potential side effects, clinicians should emphasize that 1) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and 2) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination.
Local Reactions
In placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%--64% of patients) that lasts <2 days (12,174--176). These local reactions typically are mild and rarely interfere with the person's ability to conduct usual daily activities. One blinded, randomized, cross-over study among 1,952 adults and children with asthma, demonstrated that only body aches were reported more frequently after inactivated influenza vaccine (25.1%) than placebo-injection (20.8%) (177). One study (79) reported 20%--28% of children with asthma aged 9 months--18 years with local pain and swelling and another study (77) reported 23% of children aged 6 months--4 years with chronic heart or lung disease had local reactions. A different study (76) reported no difference in local reactions among 53 children aged 6 months--6 years with high-risk medical conditions or among 305 healthy children aged 3--12 years in a placebo-controlled trial of inactivated influenza vaccine. In a study of 12 children aged 5--32 months, no substantial local or systemic reactions were noted (178).
Systemic Reactions
Fever, malaise, myalgia, and other systemic symptoms can occur after vaccination with inactivated vaccine and most often affect persons who have had no prior exposure to the influenza virus antigens in the vaccine (e.g., young children) (179,180). These reactions begin 6--12 hours after vaccination and can persist for 1--2 days. Recent placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (12,174--176).
Less information from published studies is available for children, compared with adults. However, in a randomized cross-over study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group (177). An analysis of 215,600 children aged <18 years and 8,476 children aged 6--23 months enrolled in one of five health maintenance organizations reported no increase in biologically plausible medically attended events during the 2 weeks after inactivated influenza vaccination, compared with control periods 3--4 weeks before and after vaccination (181). In a study of 791 healthy children (68), postvaccination fever was noted among 11.5% of children aged 1--5 years, 4.6% among children aged 6--10 years, and 5.1% among children aged 11--15 years. Among children with high-risk medical conditions, one study of 52 children aged 6 months--4 years reported fever among 27% and irritability and insomnia among 25% (77); and a study among 33 children aged 6--18 months reported that one child had irritability and one had a fever and seizure after vaccination (182). No placebo comparison was made in these studies. However, in pediatric trials of A/New Jersey/76 swine influenza vaccine, no difference was reported between placebo and split-virus vaccine groups in febrile reactions after injection, although the vaccine was associated with mild local tenderness or erythema (76).
Limited data regarding potential adverse events after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). During January 1, 1991--January 23, 2003, VAERS received 1,072 reports of adverse events among children aged <18 years, including 174 reports of adverse events among children aged 6--23 months. The number of influenza vaccine doses received by children during this time period is unknown. The most frequently reported events among children were fever, injection-site reactions, and rash (unpublished data, CDC, 2003). Because of the limitations of spontaneous reporting systems, determining causality for specific types of adverse events, with the exception of injection-site reactions, is usually not possible by using VAERS data alone.
Health-care professionals should promptly report all clinically significant adverse events after influenza vaccination of children to VAERS, even if the health-care professional is not certain that the vaccine caused the event. The Institute of Medicine has specifically recommended reporting of potential neurologic complications (e.g., demyelinating disorders such as Guillain-Barré [GBS] syndrome), although no evidence exists of a causal relationship between influenza vaccine and neurologic disorders in children.
Immediate --- presumably allergic --- reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination (183). These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have had hives or swelling of the lips or tongue, or who have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses to egg protein, might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies (184--186).
Hypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (187,188). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions (187).
Guillain-Barré Syndrome
The 1976 swine influenza vaccine was associated with an increased frequency of GBS (189,190). Among persons who received the swine influenza vaccine in 1976, the rate of GBS was <10 cases/1 million persons vaccinated. The risk for influenza vaccine-associated GBS is higher among persons aged >25 years than persons <25 years (189). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual incidence of 10--20 cases/1 million adults (191). More definitive data probably will require using other methodologies (e.g., laboratory studies of the pathophysiology of GBS).
During three of four influenza seasons studied during 1977--1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies (192--194). However, in a study of the 1992--93 and 1993--94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0--2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated. The combined number of GBS cases peaked 2 weeks after vaccination (195). Thus, investigations to date indicate no substantial increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and that, if influenza vaccine does pose a risk, it is probably slightly more than one additional case/1 million persons vaccinated. Cases of GBS after influenza infection have been reported, but no epidemiologic studies have documented such an association (196,197). Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni, as well as upper respiratory tract infections are associated with GBS (191,198--200).
Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately 1 additional case/1 million persons vaccinated is substantially less than the risk for severe influenza, which can be prevented by vaccination among all age groups, especially persons aged >65 years and those who have medical indications for influenza vaccination (see Hospitalizations and Deaths from Influenza). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing vaccine-associated GBS. The average case fatality ratio for GBS is 6% and increases with age (191,201). No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated.
The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (192,202). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown; therefore, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is prudent. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination.
Background
Description and Action Mechanisms. LAIVs have been in development since the 1960s in the United States, where they have been evaluated as mono-, bi-, and trivalent formulations (203--207). The LAIV licensed for use in the United States beginning in 2003 is produced by MedImmune, Inc. (Gaithersburg, Maryland; http://www.medimmune.com) and marketed under the name FluMist™. It is a live, trivalent, intranasally administered vaccine that is
In animal studies, LAIV viruses replicate in the mucosa of the nasopharynx, inducing protective immunity against viruses included in the vaccine, but replicate inefficiently in the lower airways or lungs.
The first step in developing an LAIV was the derivation of two stably attenuated master donor viruses (MDV), one for type A and one for type B influenza viruses. The two MDVs each acquired the cold-adapted, temperature-sensitive, attenuated phenotypes through serial passage in viral culture conducted at progressively lower temperatures. The vaccine viruses in LAIV are reassortant viruses containing genes from these MDVs that confer attenuation, temperature sensitivity, and cold adaptation and genes from the recommended contemporary wild-type influenza viruses, encoding the surface antigens hemagglutinin (HA) and neuraminidase (NA). Thus, MDVs provide the stably attenuated vehicles for presenting influenza HA and NA antigens, to which the protective antibody response is directed, to the immune system. The reassortant vaccine viruses are grown in embryonated hens' eggs. After the vaccine is formulated and inserted into individual sprayers for nasal administration, the vaccine must be stored at --15ºC or colder.
The immunogenicity of the approved LAIV has been assessed in multiple studies (96,208--213), which included approximately 100 children aged 5--17 years, and approximately 300 adults aged 18--49 years. LAIV virus strains replicate primarily in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not completely understood but appear to involve both serum and nasal secretory antibodies. No single laboratory measurement closely correlates with protective immunity induced by LAIV.
Shedding and Transmission of Vaccine Viruses. Available data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses for >2 days after vaccination, although in lower titers than typically occur with shedding of wild-type influenza viruses. Shedding should not be equated with person-to-person transmission of vaccine viruses, although, in rare instances, shed vaccine viruses can be transmitted from vaccinees to nonvaccinated persons.
One unpublished study in a child care center setting assessed transmissibility of vaccine viruses from 98 vaccinated to 99 unvaccinated subjects, all aged 8--36 months. Eighty percent of vaccine recipients shed one or more virus strains, with a mean of 7.6 days' duration (214). One vaccine type influenza type B isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient in the same children's play group. The placebo recipient from whom the influenza type B vaccine virus was isolated did not exhibit symptoms that were different from those experienced by vaccine recipients. The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient in this child care population was 0.58%--2.4%.
One study assessing shedding of vaccine viruses in 20 healthy vaccinated adults aged 18--49 years demonstrated that the majority of shedding occurred within the first 3 days after vaccination, although one subject was noted to shed virus on day 7 after vaccine receipt. No subject shed vaccine viruses >10 days after vaccination. Duration or type of symptoms associated with receipt of LAIV did not correlate with duration of shedding of vaccine viruses. Person-to-person transmission of vaccine viruses was not assessed in this study (215).
Stability of Vaccine Viruses. In clinical trials, viruses shed by vaccine recipients have been phenotypically stable. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (216). Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes.
Using Live, Attenuated Influenza Vaccine
LAIV is an option for vaccination of healthy persons aged 5--49 years, including persons in close contact with groups at high risk and those wanting to avoid influenza. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response, its ease of administration, and the acceptability of an intranasal rather than intramuscular route of administration.
Persons Who Should Not Be Vaccinated with LAIV
The following populations should not be vaccinated with LAIV:
Close Contacts of Persons at High Risk for Complications from Influenza
Close contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk. Use of inactivated influenza vaccine is preferred for vaccinating household members, health-care workers, and others who have close contact with severely immunosuppressed persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunosuppressed person requires care in a protective environment. The rationale for not using LAIV among health-care workers caring for such patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person and cause disease. No preference exists for inactivated influenza vaccine use by health-care workers or other persons who have close contact with persons with lesser degrees of immunosuppression (e.g., persons with diabetes, persons with asthma taking corticosteroids, or persons infected with human immunodeficiency virus), and no preference exists for inactivated influenza vaccine use by health-care workers or other healthy persons aged 5--49 years in close contact with all other groups at high risk.
If a health-care worker receives LAIV, that worker should refrain from contact with severely immunosuppressed patients as described previously for 7 days after vaccine receipt. Hospital visitors who have received LAIV should refrain from contact with severely immunosuppressed persons for 7 days after vaccination; however, such persons need not be excluded from visitation of patients who are not severely immunosuppressed.
Personnel Who May Administer LAIV
Low-level introduction of vaccine viruses into the environment is likely unavoidable when administering LAIV. The risk of acquiring vaccine viruses from the environment is unknown but likely to be limited. Severely immunosuppressed persons should not administer LAIV. However, other persons at high risk for influenza complications may administer LAIV. These include persons with underlying medical conditions placing them at high risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years.
LAIV Dosage and Administration
LAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV must be stored at --15ºC or colder. LAIV should not be stored in a frost-free freezer (because the temperature might cycle above --15ºC), unless a manufacturer-supplied freezer box is used. LAIV must be thawed before administration. This can be accomplished by holding an individual sprayer in the palm of the hand until thawed, with subsequent immediate administration. Alternatively, the vaccine can be thawed in a refrigerator and stored at 2ºC--8ºC for <24 hours before use. Vaccine should not be refrozen after thawing. LAIV is supplied in a prefilled single-use sprayer containing 0.5 mL of vaccine. Approximately 0.25 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. If the vaccine recipient sneezes after administration, the dose should not be repeated.
LAIV should be administered annually according to the following schedule:
LAIV and Use of Influenza Antiviral Medications
The effect on safety and efficacy of LAIV coadministration with influenza antiviral medications has not been studied. However, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV.
LAIV Storage
LAIV must be stored at --15ºC or colder. LAIV should not be stored in a frost-free freezer because the temperature might cycle above --15ºC, unless a manufacturer-supplied freezer box or other strategy is used. LAIV can be thawed in a refrigerator and stored at 2ºC--8ºC for <24 hours before use. It should not be refrozen after thawing. Additional information is available at Wyeth Product Quality (1-800-411-0086) or at http://www.FluMist.com.
Side Effects and Adverse Reactions
Twenty prelicensure clinical trials assessed the safety of the approved LAIV. In these combined studies, approximately 28,000 doses of the vaccine were administered to >20,000 subjects. A subset of these trials were randomized, placebo-controlled studies in which >4,000 healthy children aged 5--17 years and >2,000 healthy adults aged 18--49 years were vaccinated. The incidence of adverse events possibly complicating influenza (e.g., pneumonia, bronchitis, bronchiolitis, or central nervous system events) was not statistically different among LAIV and placebo recipients aged 5--49 years.
Children. Signs and symptoms reported more often among vaccine recipients than placebo recipients included runny nose or nasal congestion (20%--75%), headache (2%--46%), fever (0%--26%), and vomiting (3%--13%), abdominal pain (2%), and myalgias (0%--21%) (208,211,213,217--219). These symptoms were associated more often with the first dose and were self-limited. In a subset of healthy children aged 60--71 months from one clinical trial (92,93), certain signs and symptoms were reported more often among LAIV recipients after the first dose (n = 214) than placebo recipients (n = 95) (e.g., runny nose, 48.1% versus 44.2%; headache, 17.8% versus 11.6%; vomiting, 4.7% versus 3.2%; myalgias, 6.1% versus 4.2%), but these differences were not statistically significant. Unpublished data from a study including subjects aged 1--17 years indicated an increase in asthma or reactive airways disease in the subset aged 12--59 months. Because of this, LAIV is not approved for use among children aged <60 months.
Adults. Among adults, runny nose or nasal congestion (28%--78%), headache (16%--44%), and sore throat (15%--27%) have been reported more often among vaccine recipients than placebo recipients (94,220,221). In one clinical trial (94), among a subset of healthy adults aged 18--49 years, signs and symptoms reported more frequently among LAIV recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (13.9% versus 10.8%); runny nose (44.5% versus 27.1%); sore throat (27.8% versus 17.1%); chills (8.6% versus 6.0%); and tiredness/weakness (25.7% versus 21.6%).
Safety Among Groups at High Risk from Influenza-Related Morbidity. Until additional data are acquired, persons at high risk for experiencing complications from influenza infection (e.g., immunocompromised patients; patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease; or persons aged >65 years) should not be vaccinated with LAIV. Protection from influenza among these groups should be accomplished by using inactivated influenza vaccine.
Serious Adverse Events. Serious adverse events among healthy children aged 5--17 years or healthy adults aged 18--49 years occurred at a rate of <1%. Surveillance should continue for adverse events that might not have been detected in previous studies. Health-care professionals should promptly report all clinically significant adverse events after LAIV administration to VAERS, as recommended for inactivated influenza vaccine.
When vaccinating children aged 6 months--3 years, health-care providers should use inactivated influenza vaccine that has been approved by FDA for this age group. Inactivated influenza vaccine from Aventis Pasteur, Inc., (FluZone split-virus) is approved for use among persons aged >6 months. Inactivated influenza vaccine from Chiron (Fluvirin) is labeled in the United States for use only among persons aged >4 years because data to demonstrate efficacy among younger persons have not been provided to FDA. Live, attenuated influenza vaccine from MedImmune (FluMist) is approved for use by healthy persons aged 5--49 years.
The annual supply of inactivated influenza vaccine and the timing of its distribution cannot be guaranteed in any year. Information regarding the supply of 2004--05 vaccine might not be available until late summer or early fall 2004. To allow vaccine providers to plan for the upcoming vaccination season, taking into account the yearly possibility of vaccine delays or shortages and the need to ensure vaccination of persons at high risk and their contacts, ACIP recommends that vaccine campaigns conducted in October focus their efforts primarily on persons at increased risk for influenza complications and their contacts, including health-care workers. Campaigns conducted in November and later should continue to vaccinate persons at high risk and their contacts, but also vaccinate other persons who wish to decrease their risk for influenza infection. Vaccination efforts for all groups should continue into December and beyond. CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will make recommendations in the summer preceding the 2004--05 influenza season regarding the need for tiered timing of vaccination of different risk groups.
Vaccination in October and November
The optimal time to vaccinate is usually during October--November. ACIP recommends that vaccine providers focus their vaccination efforts in October and earlier primarily on persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6--23 months), household contacts of persons at high risk (including out-of-home caregivers and household contacts of children aged 0--23 months), and health-care workers. Vaccination of children aged <9 years who are receiving vaccine for the first time should also begin in October or earlier because those persons need a booster dose 1 month after the initial dose. Efforts to vaccinate other persons who wish to decrease their risk for influenza infection should begin in November; however, if such persons request vaccination in October, vaccination should not be deferred. Materials to assist providers in prioritizing early vaccine are available at http://www.cdc.gov/flu/professionals/vaccination/index.htm (see also Travelers in this report).
Timing of Organized Vaccination Campaigns
Persons planning substantial organized vaccination campaigns should consider scheduling these events after mid-October because the availability of vaccine in any location cannot be ensured consistently in early fall. Scheduling campaigns after mid-October will minimize the need for cancellations because vaccine is unavailable. Campaigns conducted before November should focus efforts on vaccination of persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6--23 months), health-care workers, and household contacts of persons at high-risk (including children aged 0--23 months) to the extent feasible.
Vaccination in December and Later
After November, many persons who should or want to receive influenza vaccine remain unvaccinated. In addition, substantial amounts of vaccine have remained unused during three of the past four influenza seasons. To improve vaccine coverage, influenza vaccine should continue to be offered in December and throughout the influenza season as long as vaccine supplies are available, even after influenza activity has been documented in the community. In the United States, seasonal influenza activity can begin to increase as early as October or November, but influenza activity has not reached peak levels in the majority of recent seasons until late December--early March. Therefore, although the timing of influenza activity can vary by region, vaccine administered after November is likely to be beneficial in the majority of influenza seasons. Adults develop peak antibody protection against influenza infection 2 weeks after vaccination (222,223).
Vaccination Before October
To avoid missed opportunities for vaccination of persons at high risk for serious complications, such persons should be offered vaccine beginning in September during routine health-care visits or during hospitalizations, if vaccine is available. In facilities housing older persons (e.g., nursing homes), vaccination before October typically should be avoided because antibody levels in such persons can begin to decline within a limited time after vaccination (224). In addition, children aged <9 years who have not been previously vaccinated and who need 2 doses before the start of the influenza season can receive their first dose in September or earlier.
Successful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk, use of reminder/recall systems, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (19,225). Using standing orders programs is recommended for long-term--care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies to ensure the administration of recommended vaccinations for adults (226). Standing orders programs for both influenza and pneumococcal vaccination should be conducted under the supervision of a licensed practitioner according to a physician-approved facility or agency policy by health-care personnel trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. The Centers for Medicare and Medicaid Services (CMS) has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term--care facilities, and home health agencies (226). To the extent allowed by local and state law, these facilities and agencies may implement standing orders for influenza and pneumococcal vaccination of Medicare- and Medicaid-eligible patients. Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs as well (20). Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections.
Outpatient Facilities Providing Ongoing Care
Staff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended and who do not have regularly scheduled visits during the fall should be reminded by mail, telephone, or other means of the need for vaccination.
Outpatient Facilities Providing Episodic or Acute Care
Beginning each September, acute health-care facilities (e.g., emergency rooms and walk-in clinics) should offer vaccinations to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility.
Nursing Homes and Other Residential Long-Term--Care Facilities
During October and November each year, vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one time, preceding the influenza season. Residents admitted through March after completion of the facility's vaccination program should be vaccinated at the time of admission.
Acute-Care Hospitals
Persons of all ages (including children) with high-risk conditions and persons aged >50 years who are hospitalized at any time during September--March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. In one study, 39%--46% of adult patients hospitalized during the winter with influenza-related diagnoses had been hospitalized during the preceding autumn (227). Thus, the hospital serves as a setting in which persons at increased risk for subsequent hospitalization can be identified and vaccinated. However, vaccination of persons at high risk during or after their hospitalizations is often not done. In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (228). Using standing orders in hospitals increases vaccination rates among hospitalized persons (229).
Visiting Nurses and Others Providing Home Care to Persons at High Risk
Beginning in September, nursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home, if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination.
Other Facilities Providing Services to Persons Aged >50 Years
Beginning in October, such facilities as assisted living housing, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccination on-site before the influenza season. Staff education should emphasize the need for influenza vaccine.
Health-Care Personnel
Beginning in October each year, health-care facilities should offer influenza vaccinations to all personnel, including night and weekend staff. Particular emphasis should be placed on providing vaccinations to persons who care for members of groups at high risk. Efforts should be made to educate health-care personnel regarding the benefits of vaccination and the potential health consequences of influenza illness for themselves and their patients. All health-care personnel should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (118).
During the 2002--03 season, approximately 95 million doses of influenza vaccine were produced, but 12 million doses went unused and had to be destroyed. During the 2003--04 season, approximately 87 million doses of vaccine were produced. During that season, shortages of vaccine were noted in multiple regions of the United States after an unprecedented demand for vaccine lasted longer into the season than usual, caused in part by increased media attention to influenza. On the basis of early projections, manufacturers anticipate production of 90--100 million doses of vaccine for the 2004--05 season.
Influenza vaccine delivery delays or vaccine shortages remain possible in part because of the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. Steps being taken to address possible future delays or vaccine shortages include identification and implementation of ways to expand the influenza vaccine supply and improvement of targeted delivery of vaccine to groups at high risk when delays or shortages are expected.
ACIP plans to review new vaccination strategies for improving prevention and control of influenza, including the possibility of expanding recommendations for use of influenza vaccines. In addition, strategies for regularly monitoring vaccine effectiveness will be reviewed.