We now understand that both influenza A and influenza B viruses have eight genetic segments that encode 10 proteins. Researchers have also elucidated the functions of these proteins. Immunity to influenza in humans is primarily mediated by secretory IgA and serum IgG antibodies directed against the two surface proteins: hemagglutinin and neuraminidase. Hemagglutinin attaches viruses to cells, and neuraminidase is responsible for releasing virus from infected cells. Antibodies directed against these proteins disrupt two key functions of viral replication. Induction of antibodies with standard inactivated influenza vaccine prevents influenza in adults and children. It is estimated that up to 90 million doses of the inactivated vaccine will be used in the United States this year (1). The vaccine has an estimated efficacy of 70% to 90% in adults but is less efficacious in elderly persons because this group may not respond with vigorous antibody responses.

Inactivated influenza vaccine can prevent much of the illness and death caused by influenza. The vaccine is recommended for all persons who are at high risk for serious complications from influenza, including all persons 65 years of age or older and persons of any age who have underlying chronic disease that predisposes them to death from influenza. The latter category includes persons with heart disease, lung disease, chronic renal disease, diabetes, immunosuppression, and severe chronic anemia and residents of nursing homes or other long-term care facilities. To protect persons with underlying medical conditions who are living at home, everyone living at that residence should also be vaccinated. In addition, children who are receiving long-term aspirin therapy should be vaccinated in order to prevent the Reye syndrome, a rare complication of influenza. Physicians and other health care personnel (including medical office staff) who have contacts with these groups should be vaccinated for their own protection and to avoid spread of the infection.

Through worldwide surveillance of influenza, the World Health Organization annually tracks the emergence of new variants of influenza A and influenza B. This surveillance is critically important in providing information to public health authorities and vaccine manufacturers. On the basis of this surveillance, the U.S. Food and Drug Administration annually selects strains that it recommends to manufacturers for inclusion in the inactivated influenza vaccine. In recent years, two types of influenza A—H3N2 and H1N1—and influenza B have circulated; all three are included in the inactivated vaccine. In 9 of the past 10 years, the surveillance system has worked well and the strains recommended for inclusion in the vaccine matched the epidemic strains. In 1997, influenza A/Sydney/H3N2 emerged too late for inclusion in the 1997/1998 vaccine. The inactivated influenza vaccine had little or no efficacy against influenza in adults during that year. Last year (1998/1999), A/Sydney was included in the vaccine; it is also included in this year's (1999/2000) vaccine (1).

The 1999/2000 influenza vaccine contains three antigens: H1N1 (influenza A/Beijing/262/95-like), H3N2 (influenza A/Sydney/5/97-like), and influenza B/Beijing/184/93-like hemagglutinin. Manufacturers in the United States are expected to use B/Yamanashi/166/98 because of its high yield of vaccine antigen and its antigenic similarity to B/Beijing/184/93.

The optimum time to administer influenza vaccine is October to mid-November. This allows at least 2 weeks for antibodies to develop before the circulation of influenza outbreaks in the United States, which are most likely to occur from December through March. If the vaccine is given at the appropriate time, antibody titers will peak in the early winter. Antibody titers can be expected to decline within a few months, particularly in elderly persons. Among elderly persons, who may not respond as vigorously as younger persons, antibody titers may be marginal after influenza vaccine. Therefore, the timing of vaccine administration is important.

Children are believed to be a major vector of influenza in our society because they acquire and disseminate the infection at school and day care centers. Children are more susceptible to influenza and more often develop serious clinical manifestations. Fortunately, children are unlikely to die of influenza. Although inactivated influenza vaccine is approved for use in children, there is some resistance to giving annual injections of inactivated vaccine to this group; thus, it has not generally been a part of routine clinical practice. This policy is being reexamined. Physicians caring for families with both children and at-risk elderly persons should consider vaccinating all household members in an attempt to prevent introduction of influenza into these households.

Three general types of inactivated influenza vaccine are being manufactured: whole inactivated virus (whole-virus vaccine), inactivated virus that has been solubilized into subunits (split-virus vaccine), and purified surface glycoproteins (purified-subunit vaccine). Each of these vaccines is safe and effective in adults. Split-virus or purified-subunit vaccine must be used in children because this group may develop significant febrile reactions to whole inactivated influenza vaccine.

Two general types of vaccines are being developed to control influenza in the future; live attenuated intranasal viruses and recombinant hemagglutinin vaccine. Live attenuated intranasal vaccine seems to be closest to clinical use. Because of the segmented genetic nature of influenza viruses, the live attenuated vaccine can readily be updated annually so that the hemagglutinin and neuraminidase components can antigenically match those recommended by the Food and Drug Administration for inclusion in the inactivated vaccine. The live attenuated vaccine viruses have been shown to be safe, immunogenic, and highly efficacious in children and adults (2, 3). For elderly persons, the live attenuated vaccine is being considered as an addition to the inactivated vaccine because in this population, the combination of intramuscular trivalent inactivated vaccine plus intranasal live attenuated vaccine seems to be superior to either vaccine alone. Additional research on this combination is under way.

Live attenuated intranasal influenza vaccine is particularly suited for routine use in children and adults younger than 65 years of age. Children readily accept intranasal vaccine spray as opposed to injections. In a recent field trial (2), the vaccine was highly efficacious against influenza A and influenza B. Effectiveness studies in adults indicate that the nasal spray reduces lost work time and decreases health care utilization (3). It is anticipated that the earliest that the live attenuated vaccine will be available for clinical use is the fall of 2000.

Another potentially useful approach has been the use of recombinant DNA technology to produce a recombinant hemagglutinin vaccine. When injected intramuscularly, this vaccine produced fewer adverse reactions than trivalent inactivated vaccine and induced protective immune responses. One trial so far has shown the recombinant vaccine to be efficacious (4).

Amantadine and rimantadine are drugs approved for prevention or treatment of influenza A. These compounds indirectly interrupt the function of hemagglutinin; they block the ion channel M2 protein of influenza A. Interruption of the M2 ion channel appears to interfere with the fusion function of hemagglutinin, a necessary step during viral penetration of host cells. Amantadine and rimantadine are efficacious in preventing influenza A when given daily throughout the exposure interval. When used to treat active influenza A disease, amantadine or rimantadine will shorten the clinical course and accelerate return to normal functioning. The drugs work best if therapy begins within 48 hours of the onset of influenza A.

Adverse reactions to these drugs include central nervous system effects, such as light-headedness and dizziness, and are more common with amantadine than with rimantadine. Because these drugs are commonly used in elderly persons, rimantadine has been the drug of choice. Amantadine and rimantadine are not effective against influenza B virus, and the development of newer, broader-spectrum drugs would be a significant advance in the treatment of influenza.

Influenza A and influenza B each have a surface neuraminidase, and the active enzyme site seems almost identical for both of the viruses. The neuraminidase functions in the virus by cleaving sialic acid residues on the surface of infected cells, thereby allowing new virus particles to be released. Neuraminidase also appears to prevent virus particles from aggregating and may prevent mucus from inactivating the influenza virus. Compounds that interrupt the function of the neuraminidase active enzyme site are now available. These compounds are active against both influenza A and influenza B. Two drugs are expected to be available in the fall of 1999. Zanamivir (Relenza, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina) is an inhaled powder that has been shown to be effective for treating and preventing influenza. The drug shortens the duration of illness and, when used twice daily as powder sprays delivered into the airway, has reduced the clinical manifestations of influenza (3). Oseltamivir (Tamiflu, Roche Pharmaceuticals, Nutley, New Jersey) is an orally administered neuraminidase inhibitor (6) that, when given daily to treat an active infection, has been shown to shorten the clinical manifestations of influenza. When given as daily prevention, both drugs prevented clinical onset of the disease with efficacy of about 60% to 80% (6, 7).

It is expected that zanamivir and oseltamivir will be initially approved for the treatment of influenza A or B in adults. As more experience is gained and additional studies are conducted, the indications of these drugs may be expanded to include prophylaxis for patients who cannot receive the influenza vaccine because of true egg allergy or those who may not respond and are at risk for significant disease (for example, elderly nursing home residents during an outbreak of influenza A or B).

Effective use of zanamivir and oseltamivir will require physicians to be aware of influenza outbreaks in their communities. Generally, influenza activity is widely reported in the lay press, as well as by the Centers for Disease Control and Prevention (see www.cdc.gov/ncidod/diseases/flu/fluvirus.htm for weekly surveillance and information on influenza vaccines). Effective treatment will also depend on rapid case identification and quick intervention. Response to influenza treatment will be best if drug therapy is started within 48 hours of clinical onset (preferably within 30 hours). Rapid initiation of treatment will require an educated public, responsive physicians, and the ability to determine which patients need to be seen and examined and which patients can be safety prescribed medication on the basis of a brief history obtained over the telephone.