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Feature Article

Nov/Dec 2000, Volume 3, No.9, pp. 57–58, 61-62.

Shielding Against Flu Epidemics

By John K. Borchardt

opening artManaging modern influenza vaccines is often as much an administrative art as a science.

Hippocrates first described influenza in 412 B.C. The first well-documented global epidemic of influenza-like disease occurred in 1580. Since that time, 31 possible influenza pandemics have been documented, with three occurring in the 20th century—in 1918, 1957, and 1968. The most devastating of the 20th-century influenza pandemics killed more than 20 million people worldwide between 1918 and 1920.

Influenza activity typically peaks during December through March in temperate regions of the Northern Hemisphere and May through August in temperate regions of the Southern Hemisphere. In tropical regions, influenza typically circulates year-round. Last year, U.S. influenza activity increased in mid-December and peaked between the weeks ending Dec. 25, 1999, and Jan. 15, 2000. The proportion of deaths attributed to pneumonia and influenza reported by 122 cities exceeded the epidemic threshold for 22 consecutive weeks, beginning the week ending Nov. 27, 1999, through the week ending April 22, 2000.

Influenza, or “flu”, is responsible for approximately 20,000 deaths and 110,000 hospitalizations annually in the United States. Influenza viruses cause disease in all age groups. Although children have the highest infection rates, rates of serious illness and death are highest among people older than 65 and people of any age with medical conditions, such as asthma, that place them at high risk for complications from influenza.

The most effective way to reduce the impact of influenza is to vaccinate people at high risk for complications shortly before the influenza season each year. In the United States, influenza outbreaks occur nearly every winter and peak between late December and early March; therefore, the optimal vaccination time is between early October and mid-November. Vaccine generally becomes available in August or September; however, in some years, it might not be available in some locations until later in the fall.

The two types of influenza
The two types of influenza viruses (Myxovirus influenzae) that cause epidemic human disease are influenza A and B. (There is also a type C, but it is endemic and causes only sporadic cases.) Influenza A viruses are categorized into subtypes based on two surface antigens: hemagglutinin and neuraminidase.

Influenza B viruses are not categorized into subtypes. Influenza A and B viruses are further separated into groups on the basis of antigenic characteristics. New influenza virus variants result from frequent antigenic changes that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses.

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Children have the highest infection rates for influenza viruses.

Types and subtypes
These rapid genetic changes are the reason that one or more new virus strains are usually incorporated into each year’s influenza vaccine. Since 1977, influenza A(H1N1) viruses, influenza A(H3N2) viruses, and influenza B viruses have been in global circulation. A person’s immunity to the surface antigens, especially hemagglutinin, reduces the likelihood of infection and the severity of disease if infection occurs.

An antibody against one influenza virus type or subtype, however, confers little or no protection against another virus type or subtype; thus, an unvaccinated individual can succumb to the disease more than once in a given flu season.

The influenza incubation period is one to four days, with an average of two days. Persons can be infectious starting the day before symptoms begin through about five days after illness onset. Children can be infectious for a longer period. Uncomplicated influenza is characterized by the abrupt onset of fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis. Typically, the illness runs its course after several days; however, cough and malaise can persist for two or more weeks. In some people, influenza can exacerbate underlying medical conditions such as pulmonary or cardiac disease or lead to secondary bacterial pneumonia or primary influenza viral pneumonia.

The flu vaccine and its benefits
Although drugs are becoming available to treat influenza, the disease vaccines remain the primary method for preventing influenza and its complications. And the main option for vaccines remains those made from inactivated (killed) virus. When vaccine and epidemic strains are well-matched, achieving high vaccination rates, particularly in nursing home, day care, school, and health care environments, can reduce the risk of outbreaks by inducing widespread immunity.

Influenza vaccine contains two type A and one type B influenza virus strains. These represent the influenza viruses likely to circulate in the United States in the upcoming winter (see the next section). The vaccine is made from highly purified, chicken-egg-grown viruses that have been made noninfectious by adding a surfactant to disrupt the virus particle. Whole-virus, subvirion, and purified-surface-antigen preparations are available.

Most vaccinated children and young adults develop high post-vaccination hemagglutination-inhibition antibody titers. These antibody titers are protective against illness caused by strains similar to those in the vaccine. The effectiveness of influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. When the antigenic match between vaccine and circulating viruses is close, influenza vaccine prevents illness in 70–90% of healthy persons younger than 65.

The elderly and people with certain chronic diseases, such as heart disease, asthma, and diabetes, might develop lower postvaccination antibody titers than healthy adults and remain susceptible to influenza-related upper respiratory tract infection. For these individuals, the vaccine still can be effective in preventing secondary complications and reducing the risk of influenza-related hospitalization and death. Among older persons who do not live in nursing homes or similar chronic-care facilities, influenza vaccine is 30–70% effective in preventing hospitalization for pneumonia and influenza. Among elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and deaths. In this population, the vaccine can be 50–60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death, even though the effectiveness in preventing influenza illness often ranges from 30 to 40%.

The decision process
A World Health Organization (WHO) network for influenza surveillance and control is composed of 110 national influenza centers in 82 countries, and 4 WHO Collaborating Centers for Virus Reference and Research on Influenza in Australia, Japan, the United Kingdom, and the United States (Centers for Disease Control and Prevention [CDC] in Atlanta). The network allows WHO to monitor influenza activity in all regions of the world. The national influenza centers send virus isolates and information to WHO Collaborating Centers for immediate strain identification. On the basis of the identified influenza virus strains, WHO recommends viral strains that should be included in the influenza vaccine for the approaching flu season. All WHO recommendations are published in WHO’s Weekly Epidemiological Record and communicated to public health authorities and influenza vaccine manufacturers. The timing of the recommendations is critical to allow sufficient time for companies to produce the vaccine before the new influenza season starts.

WHO made its recommendation for the composition of the 2000–2001 trivalent influenza vaccine for the Northern Hemisphere on Feb. 16, 2000, after an annual conference by influenza experts at WHO’s Geneva headquarters. WHO recommended that the trivalent influenza vaccine prepared for the 2000–2001 season include A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Beijing/184/93-like antigens. National control authorities in each country approve the specific influenza vaccines used in their countries. National health authorities are responsible for recommendations about the use of the vaccine.

Scientists at the U.S. FDA make the actual recommendation for the composition of each flu season’s vaccine on the basis of antigenic and molecular analyses of recently isolated influenza viruses, epidemiologic data, and postvaccination serologic studies in humans provided by the CDC and WHO. Typically, the FDA’s Vaccines and Related Biologic Products Advisory Committee (VRBPAC) determines its recommended influenza vaccine composition within days of the WHO decision and communicates it to vaccine manufacturers.

For the 2000–2001 U.S. trivalent influenza vaccine, VRBPAC specified that U.S. manufacturers use the antigenically equivalent A/Panama/2007/99 (H3N2) virus instead of the A/Moscow/10/99 (H3N2)-like antigen recommended by WHO. For the WHO-recommended B/Beijing/184/93-like antigen, they will use the antigenically equivalent B/Yamanashi/166/98 virus. These antigenically equivalent viruses will be used because of their better growth properties and because they are representative of currently circulating A(H3N2) and B viruses. U.S. virus manufacturers will also use the A/New Caledonia/20/99-like (H1N1) virus.

Influenza type B viruses were isolated sporadically in the United States and worldwide and were antigenically similar to the 1999–2000 vaccine strain B/Beijing/184/93 and to the widely used equivalent vaccine strain B/Yamanashi/166/98. Therefore,
Further Information
WHO Website, epidemiological information: www.who.int/emc/diseases/flu/index.html.

FluNet, geographic information:. http://oms2.b3e.jussieu.fr/flunet/.

Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC: www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.

VRBPAC recommended retaining B/Beijing184/93-like virus protection for the 2000–2001 vaccine. Manufacturers will use the B/Yamanashi/16/98 strain as the 2000–2001 influenza B vaccine component because of its better growth properties and antigenic similarity to B/Beijing184/93-like viruses.

WHO made its recommendations for the composition of vaccines intended for the May to October 2001 period in the Southern Hemisphere in September 2000. Their experts recommended the following strains for inclusion: A/Moscow/10/99 (H3N2)- like virus, A/New Caledonia/20/99 (H1N1)-like virus, and B/Sichavan/379/99-like virus.

Who should be immunized?
For 2000, WHO and the Advisory Committee on Immunization Practices (ACIP) are advocating that the recommended age for universal vaccination be lowered from 65 to 50. The 50–64 age group was added to the universal vaccination recommendation list because one-quarter to one-third of people in this age group have one or more chronic medical conditions that place them at high risk for influenza-related hospitalization and death. Rates of influenza-related excess hospitalization among adults younger than 65 with one or more high-risk conditions have been estimated at 56–635 per 100,000 persons, compared with 13–60 per 100,000 among those without high-risk conditions. Despite the increased risk of severe illness, the CDC estimates that only 40–41% of people age 50–64 with chronic medical conditions and 28–29% of those without high-risk conditions were vaccinated against influenza in 1997.

ACIP reports that targeting this age group should not only protect more high-risk people, but will also result in higher vaccination rates. This strategy also probably help to increase vaccination rates among people without high-risk conditions but for whom annual vaccination is recommended because they live with people at increased risk of influenza-related complications.

For the 2000–2001 influenza season in the United States, lower-than-anticipated production yields for this year’s influenza A(H3N2) vaccine component and other manufacturing problems were encountered. As of September 28, the CDC announced that it expected vaccine amounts “should be approximately what was distributed last year” although “a substantial amount of vaccine will reach providers later than usual.”

ACIP has advised delaying at least some large, organized vaccination campaigns until later in the season as availability of vaccine becomes assured. In previous years, ACIP recommended that organized vaccination campaigns take place during October through mid-November. Normally, these timing recommendations balance several considerations other than availability, including the desirability of administering vaccine before significant seasonal influenza activity has begun but not vaccinating so early that vaccine antibody titers might substantially decrease in some persons, nor so late that the vaccine will have insufficient time to become effective. But given this year’s delays, ACIP recommends that vaccination efforts should first focus on health care workers and people at high risk for complications. It advises that “these efforts should continue into December and later as long as influenza vaccine is available” and that special efforts should also continue into December and later to vaccinate the 50–64 age class and others who are not at high risk.

Potential new vaccines
Intranasally administered, cold-adapted, live attenuated influenza virus vaccines (LAIVs) are being used in Russia and have been under development in the United States since the 1960s. The viruses in these vaccines replicate in the upper respiratory tract and elicit a specific protective immune response. LAIVs have been studied as monovalent, bivalent, and trivalent formulations. LAIVs consist of live but attenuated viruses that induce minimal symptoms and replicate poorly at temperatures in the lower respiratory tract.

Possible advantages of LAIVs include their potential to induce a broad mucosal and systemic immune response, ease of administration, and the acceptability of an intranasal route of administration compared with injectable vaccines. In a five-year study comparing conventional trivalent inactivated vaccine and bivalent LAIVs (administered by nose drops) that used related but different vaccine strains, the two vaccines were found to be approximately equivalent in effectiveness. In a recent study of children age 15–71 months, an intranasally administered trivalent LAIV was 93% effective in preventing culture-positive influenza A(H3N2) and B infections.

In a follow-up study during the 1997–1998 season, the trivalent LAIV was 86% effective in preventing culture-positive influenza in children, despite a poor match between the vaccine’s influenza A(H3N2) component and the predominant circulating influenza A(H3N2) virus. A study conducted among healthy adults during the same season found a 9–24% reduction in febrile respiratory illnesses and a 13–28% reduction in lost workdays. No study has directly compared the efficacy or effectiveness of trivalent inactivated vaccine and trivalent LAIV.

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