Influenza virus infections represent a significant public health problem. In the United States alone, 10,000 to 40,000 excess deaths are attributed to its complications annually.1 The groups at highest risk include the elderly and those with chronic illnesses, particularly chronic pulmonary or cardiac diseases. The economic costs attributable to influenza are estimated to be in the billions of dollars annually in the United States.2 Therefore, the development of strategies to prevent influenza infection or illness has been vigorously undertaken during the past six decades. This article is directed toward two key preventive agents: inactivated influenza vaccines administered parenterally and live attenuated influenza vaccines administered intranasally.
INACTIVATED INFLUENZA VACCINE
A formalin-inactivated whole virus influenza vaccine was first used experimentally during World War II. Then and now) the vaccine virus was grown in chick embryo allantoic fluid and inactivated with formalin. However, several key refinements have been introduced over the years to improve this vaccine. Zonal grathent centrifugation has removed reactogenic contaminants. Treatment of the virus with solvents (split vaccine) or detergents (subunit vaccine) has resulted in a vaccine with fewer adverse reactions when compared with the whole virus vaccine.3
During the past two decades, licensed influenza vaccines have contained two influenza A strains (HlNl and H3N2) and one influenza B strain. Each spring, decisions are made as to which strains to include in the vaccine for the upcoming influenza season. Strain recommendations are made by the Centers for Disease Control and Prevention in consultation with scientists at the Food and Drug Administration and National Institutes of Health, and are based on worldwide influenza surveillance information provided to the World Health Organization. Strain selection is generally completed by March and vaccine is usually available by September or October.
The incidence and severity of reactions to parenteral inactivated influenza vaccine are proportional to the dose of antigen used. Split or subunit vaccines have fewer side effects than whole virus vaccine and are therefore recommended for children.
Local reactions to parenteral inactivated vaccine include erythema, pain, or tenderness at the injection site and occur in approximately 25% to 50% of these immunizations. Induration is less frequent and rarely incapacitating. Fever appears in approximately 8% to 50% of vaccinated children and may be associated with other systemic symptoms such as myalgia, arthralgia, headache, and malaise, but not respiratory symptoms.4
Severe, immediate hypersensitivity reactions have been rare. Although the vaccine is grown in eggs, most individuals with "egg allergy" can be safely immunized.5 Reports of neurologic complications such as Guillain-Barré syndrome exist, but recent studies suggest that not more than one *additional case of Guillain-Barré syndrome per million individuals vaccinated has been associated with the use of influenza vaccine in recent years.6
In healthy children and adults, the licensed influenza vaccine should reduce the incidence of clinical influenza illness by approximately 60% to 90%.7·8 This estimate assumes that the circulating wild type influenza virus is homologous to one of the vaccine strains. Investigations into the medical and economic impact of parenteral inactivated influenza vaccine have been favorable, particularly for high-risk adult populations.9·10 Inactivated vaccine has also been a costeffective protective measure against illness and absenteeism from work in healthy adults.11 Finally, mass vaccination of school children with inactivated influenza vaccine has been associated with a reduction of influenza-like illness in unvaccinated individuals who were in close proximity to the vaccinated cohort.12 Parenteral inactivated influenza vaccine is less efficacious in the elderly or when circulating influenza strains are not closely matched to the vaccine strains.
Serum antibody induced by inactivated influenza vaccine peaks between 2 and 4 months after vaccination but wanes quickly thereafter, with antibody levels falling to near baseline before the next influenza season.13 Annual vaccinations are therefore necessary because of the duration of protective immunity and the antigenie shift and drift of influenza A viruses (see the article by Subbarao and Bridges in this issue for more information).
Indications for Use
Most healthy individuals recover from influenza illness without intervention. However, there is substantial morbidity and mortality in the elderly and those with chronic diseases, especially diseases of the pulmonary or cardiovascular systems. Specific recommendations regarding target groups for annual vaccination from the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention14 are presented in Table 1.
Influenza vaccine may be administered to adults and to children 6 months or older. New this year is a recommendation for universal vaccination of all adults 50 years or older. Contacts of high-risk individuals, such as household members and medical caregivers, should also receive inactivated influenza vaccine. A few additional groups have been targeted for annual influenza vaccination both to reduce morbidity and because their absence due to influenza illness would be economically problematic.
The Advisory Committee on Immunization Practices also recommends that immunization be considered by "any person who wishes to reduce the likelihood of becoming ill with influenza."14 In the future, the Advisory Committee on Immunization Practices may recommend universal immunization of very young children because two recent reports indicate that healthy children younger than 2 years are at increased risk of influenza-associated hospitalization when compared with older healthy children.14 Finally, although not specifically recommended by the Advisory Committee on Immunization Practices, parents may wish to vaccinate their younger children so as not to miss work due to their influenza illness.
In a situation of vaccine shortage, which may occur during the 2000-2001 influenza season, priority for immunization should be given to individuals older than 65 years, those with underlying high-risk conditions, and health care workers.
Updated information regarding the annual composition of the influenza vaccine, vaccine availability, and indications for use can be found at the Centers for Disease Control and Prevention influenza website: www.cdc.gov/ncidod / diseases/ flu/ fluvirus.htm.
Target Groups to Receive Annual Trlvalent, Inactivated Influenza Vaccine
Recommendations for Use In Children
Intramuscular injection of the split virus, trivalent, inactivated influenza vaccine should also be given in the fall before the influenza season starts. In young children and infants, the vaccine should be given in the anterolateral thigh, whereas older children can receive it in the deltoid muscle. More than one influenza strain can cause outbreaks during any winter season, and outbreaks can occur as late as March or April. Therefore, it is still advantageous to administer the vaccine throughout the entire winter season to target groups that did not receive it during the previous fall, although the area may have already experienced influenza. Vaccine dosages are given in Table 2. For children 6 months to 9 years old who have never received influenza vaccine, two doses, separated by at least 1 mondi, are recommended. Older children and those previously vaccinated need only one dose. Concurrent administration with other vaccines in separate injections is acceptable.
LIVE ATTENUATED INFLUENZA VACCINE
Shortcomings of parenteral inactivated influenza vaccine include the short duration of induced immunity and die inability to induce a robust local or cellular immune response. However, the main problem is the need for an annual "shot/' which may decrease use in both children and adults. Therefore, alternative vaccine candidates have been sought.
A promising vaccine candidate has been extensively investigated and may soon be considered for licensure. This is the intranasally administered live attenuated influenza vaccine.15 It has been attenuated both by multiple passage in tissue culture and by serially adapting it to cooler temperatures. The resultant vaccine strain is both cold adapted (ie, it grows well at temperatures of 25° to 350C) and temperature sensitive (ie, it grows poorly at temperatures > 370C). These characteristics mean that it replicates well in the cooler upper respiratory tract, but poorly in the lower respiratory tract, which is at core body temperature. This vaccine retains the cold-adapted and temperature-sensitive phenotypes in animals and humans.
Live attenuated influenza vaccine induces both local and systemic antibody production, as well as cellular immune responses when administered intranasally.16'17 In children, nasal replication of the vaccine virus occurs for approximately 1 to 10 days but seems not to be excreted in a high enough concentration in nasal secretions to easily allow transmission.18
The influenza virus has eight gene segments (see the article by Subbarao and Bridges in this issue for additional details). Therefore, it is not technically difficult to produce annual reassortant live attenuated influenza vaccine strains with the two genes coding for the important outer membrane antigens, hemagglutinin and neuraminidase, derived from ,currently circulating wild type influenza virus strains. The remaining six genome segments, including those mat provide the cold-adapted and attenuated phenotype, are derived from master donor attenuated strains.
One problematic issue has been recognized. When more than one strain of the vaccine virus is administered simultaneously, one or more of the strains may not be as infectious or immunogenic as when given alone. For example, the serologie response (s* fourfold antibody rise) to the three strains of a trivalent live attenuated influenza vaccine in young children was 92% for the A (H3N2), 88% for the B, and only 16% for the A (HlNl) strain. However, the poor response to the HlNl strain was overcome by a second intranasal dose of the trivalent live attenuated influenza vaccine 1 to 2 months later.19
Administration of Trivalent Influenza Vaccine*
Multiple studies have established the overall safety of intranasally applied, multivalent live attenuated influenza vaccine. Symptoms related to mucosal infection such as nasal stuffiness or rhinorrhea, pharyngitis, and cough can be encountered, but are relatively short-lived and minor. Nasal stuffiness seems to be the most common side effect of live attenuated influenza vaccine, occurring in approximately 30% of children and often peaking the second or third day after vaccination.19 Systemic symptoms such as irritability and decreased activity can occur less often in children and are usually not significantly more frequent than in recipients of placebo.18 Low-grade fever can occur in approximately 7% of recipients.
Intranasal live attenuated influenza vaccine has been given safely to a few children with cystic fibrosis and to individuals with asthma, although it is not clear whether these individuals will be a target population for this vaccine if it is licensed.20'21 Although not an anticipated target population, individuals infected with human immunodeficiency virus (HIV) may inadvertently be exposed to live attenuated influenza vaccine if its use becomes widespread. A few relatively asymptomatic adults infected with HTV have received trivalent live attenuated influenza vaccine without apparent clinical or immunologie consequences, and mis is reassuring.22 A study of the clinical and immunologie safety of trivalent live attenuated influenza vaccine in relatively asymptomatic children infected with HIV is under way.
A 5-year field trial of intranasally applied, bivalent influenza A (HlNl and H3N2) live attenuated influenza vaccine, conducted primarily in healthy adults, revealed efficacy comparable to parenteral trivalent inactivated influenza vaccine in terms of reducing influenza illness.7 The efficacy of bivalent live attenuated influenza vaccine against culture-confirmed influenza illness was 58% to 85% depending on the serotype of influenza A that was circulating during the surveillance winters. Another study involving healthy working adults found that vaccination with intranasal trivalent live attenuated influenza vaccine resulted in significantly fewer febrile illnesses, days of work lost, and days with health care visits, and less use of antibiotics and over-the-counter medications when compared with placebo.23
A separate study involving children 1 to 5 years old demonstrated an impressive efficacy against influenza A (H3N2) (96%) and influenza B (91%) following doses of trivaient live attenuated influenza vaccine, when compared with intranasal placebo. Importantly, this same cohort was given one dose of vaccine (or placebo) the following fall. During the second winter season, trivalent live attenuated influenza vaccine had an efficacy of 86% against culture-proven influenza illness by a circulating A (H3N2) strain that was antigenically different from the vaccine A (H3N2) strain.18 Whether this means that immunity from trivalent live attenuated influenza vaccine is broader than that from parenteral inactivated vaccine is under investigation. This 2-year field trial also demonstrated a reduced severity of culture-proven influenza illness in recipients of live attenuated influenza vaccine versus recipients of placebo. Influenza-associated fever, otitis media, and lower respiratory tract illness was significantly reduced. Antibiotic use was also significantly reduced during the influenza outbreak.
Influenza is an important pathogen deserving of preventive public health efforts. Parenteral inactivated trivalent influenza vaccine is safe and effective and should be administered annually just prior to each influenza season. Target populations and dosage recommendations for children have been described in this article.
Intranasally administered, trivalent live attenuated influenza vaccine appears safe, immunogenic, and efficacious, perhaps even against antigenically distinct influenza strains. It is anticipated that application for licensure of live attenuated influenza vaccine will occur shortly. Target populations have yet to be defined. The public health and economic impact of universal vaccination to healthy children and adults should be investigated.
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19. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl } Med. 1998;338:1405-1412.
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Target Groups to Receive Annual Trlvalent, Inactivated Influenza Vaccine
Administration of Trivalent Influenza Vaccine*