-from Epidemiological Bulletin, Vol. 22 No. 3, September 2001-

Influenza: Basic Epidemiological Aspects for the Development of Vaccines

The Disease
Influenza (the “flu”) is one of the most notorious human ailments. First described by Hippocrates in 412 BC, it is one of the oldest and most common human diseases, affecting large portions of the world population in seasonal epidemics each year. While the symptoms of the flu are often mild in nature, the ever-changing influenza virus can lead to deadly pandemics. Surveillance and vaccine preparation - two important activities of influenza control - are therefore indispensable to prevent its potentially deadly effects.

Influenza virus
Influenza viruses are classified as A, B and C. Influenza A and B are the two types that cause epidemic human disease. Influenza A viruses are further categorized into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). The development of antigenic variants through a process called antigenic drift is the virologic basis for seasonal flu epidemics.

Clinical Signs and Symptoms
Influenza viruses are spread from person-to-person primarily through the coughing and sneezing of infected persons. The incubation period for influenza is 1-4 days, with an average of 2 days. Persons can be infectious starting with the first symptoms through approximately 5 days after illness onset; children can be infectious for a longer period. Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis). It typically resolves after several days for most persons, although cough and malaise can persist for more than 2 weeks. In some persons, the disease can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a co-infection with other viral or bacterial pathogens.

Epidemiology of Influenza
In the temperate and cold climates, the flu usually causes winter epidemics: December-March in the Northern Hemisphere; June-September in the Southern Hemisphere. In tropical and subtropical areas, influenza epidemics can occur either twice a year or even throughout the year. As mentioned before, these seasonal epidemics occur due to antigenic drift.

More rarely, major antigenic changes occur in the viruses that can cause pandemics (worldwide outbreaks of an influenza virus subtype to which the human population has no protection). The most severe infectious disease disaster of the 20th century was the “Spanish” influenza pandemic of 1918, which killed more than 40 million persons worldwide. Other more recent pandemics were the 1957 “Asian” flu and the 1968 “”Hong-Kong” flu.

Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone. The reported sensitivity and specificity of clinical definitions for influenza-like illness that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively, compared with viral culture. Sensitivity and predictive value of clinical definitions can vary, depending on the degree of cocirculation of other respiratory pathogens and the level of influenza activity. For these reasons and because the influenza strains identified during one season are useful to help define the influenza strains to be recommended for the next season, virologic surveillance is the most important element of influenza surveillance. The recommended case definition of influenza is presented in Box 1.

Groups at highest risk
Although influenza viruses cause disease among all age groups, severe complications and death are highest among the elderly and among persons of any age suffering from chronic respiratory and cardiac conditions. The main tool for prevention of influenza is the yearly vaccination of persons at high risk with the inactivated influenza vaccine. According to the United States Centers for Disease Control and Prevention (CDC)’s Advisory Committee on Immunization Practices (ACIP), the primary target groups recommended for annual vaccination in the U.S. are a) groups that are at increased risk for influenza-related complications: persons aged 65 years or older, residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions; adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma; adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications); children and teenagers (aged 6 months to 18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye syndrome after influenza; and women who will be in the second or third trimester of pregnancy during the influenza season; b) the group aged 50-64 years because this group has an elevated prevalence of certain chronic medical conditions; and c) persons who live with or care for persons at high risk (e.g., health-care workers and household members who have frequent contact with persons at high risk and can transmit influenza infections to these persons at high risk). Vaccination of these high-risk groups has shown to be among the most cost-effective interventions in public health.

The ACIP recommendations described above have been the basis for influenza vaccination recommendations in most countries where this vaccine is provided. Depending on their epidemiologic characteristics, some countries may consider the vaccination of other high risk groups, including indigenous communities living in isolation. However, financial or logistic limitations can constrain some countries to limit the recommendations to the groups at highest risk or to those high-risk groups easier to identify.

Work absenteeism due to influenza could be a problem among otherwise healthy adults. Although this and other low-risk groups can also benefit from vaccination, C. Bridges and others, in a two years cost analysis of influenza vaccination in a work setting found that, from a public health perspective, there were no savings when giving the flu shot to healthy adults.

Flu vaccine
A person’s immunity to the surface antigens reduces the likelihood of infection and severity of disease if infection occurs. Antibody against one influenza virus type or subtype confers limited or no protection against another influenza virus type or subtype. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Antigenic drift is the reason for the incorporation of one or more new strains in each year’s influenza vaccine. It is also the basis for the recommendation of yearly influenza vaccination.

Because manufacturers need at least 6 months to prepare a new vaccine, the World Health Organization (WHO) meets every year (usually in March) to recommend the influenza strains to be included in the vaccine for the Northern Hemisphere’s winter (usually December to March). Until 1998, the vaccine recommended for the Northern Hemisphere was used for the Southern Hemisphere winter half a year later. Studies by Regnery, Savy et al. have shown that, for eight out of ten winters analyzed, the vaccine recommended for the Northern Hemisphere did not match the strains that circulated during the following Southern Hemisphere winter. For this reason, since 1998, WHO holds a second yearly meeting (usually in September), to recommend influenza vaccine strains for the Southern Hemisphere. Because of the often-unusual patterns of virus circulation in these areas, deciding the best time for vaccination in tropical and subtropical areas is more challenging and needs to be studied on a case-by-case basis.

The Northern Hemisphere 2001-2002 trivalent vaccine virus strains recommended are A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99(H1N1)-like, and B/Sichuan/379/99-like strains. Although the recommended optimal time period for vaccinating individuals is usually October-November in the Northern Hemisphere, due to delays in the manufacturing and distribution of the vaccine, the ACIP made the following recommendations regarding flu vaccination strategies for the upcoming flu season in the U.S.: For providers: 1) target vaccine available in September and October to those at high risk and health-care workers; and 2) continue vaccination through December and as long as vaccine is available. For the public: 1) if at high risk, seek vaccine in September or October, or as soon as it is available and throughout the season; and 2) if not at high risk, seek vaccine in November or later. The vaccine components recommended for the 2002 Southern Hemisphere’s season are, in this opportunity, the same as those recommended for the 2001-2002 Northern Hemisphere season.

Antiviral agents
The use of influenza-specific antiviral drugs for chemoprophylaxis or treatment of influenza is an important adjunct to vaccination. However, antiviral medications are not a substitute for vaccination. Four currently licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine and rimantadine are chemically-related antiviral drugs effective for treatment and prophylaxis of influenza A but not influenza B viruses. Rimantadine has the advantage of fewer side effects than amantadine. Both drugs are available as generics. Zanamivir and oseltamivir are recently approved neuraminidase inhibitors with activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved for the treatment of uncomplicated influenza infections. Zanamivir is approved for treatment for persons over 7 years of age, and oseltamivir is approved for treatment for persons more than one year old and for prophylaxis of persons over 13. To be effective for treatment, antiviral drugs have to be used within 48 hours of onset of the respiratory symptoms.

Future issues
Live intranasal vaccine
A nasal spray flu vaccine has been shown in clinical tests to prevent influenza in healthy children. It consists of live, attenuated viruses that may have the advantage over the inactivated vaccine of inducing a broad mucosal and systemic immune response, ease of administration, and the acceptability of an intranasal, painless route of administration compared with injectable vaccines.

Although the United States Food and Drug Administration (FDA) has yet to complete its analysis of the product’s safety, live, cold-adapted influenza vaccines such as this one have been in use in the former Soviet Union since the 1960s. It could become available in the United States for the 2002-2003 winter. In a recent study of children aged 15-71 months, an intranasally administered trivalent live, cold-adapted influenza vaccine was 93% effective in preventing culture-positive influenza infections and reduced otitis media among vaccinated children by 30% compared with unvaccinated children. In a follow-up study during the 1997-1998 season, the trivalent live, cold-adapted influenza vaccine was 86% effective in preventing culture-positive influenza among 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 13%-28% reduction in lost work days.

Should young children be recommended for vaccination?
Studies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation. However, the interpretation of these findings has been confounded by cocirculation 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. Recent studies by Izurieta et al and by Neuzel et al have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children under 5 who do not have high-risk conditions. Both studies indicate that otherwise healthy children under 2 years of age are at increased risk for influenza-related hospitalization compared with older healthy children. Because very young healthy children are at increased risk for influenza-related hospitalization, the ACIP is studying the benefits, risks, economic consequences and logistical issues associated with routine immunization of this age group in the U.S.

Source: Prepared by Dr. Hector Izurieta from PAHO's Division of Vaccines and Inmunization (HVP).

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Epidemiological Bulletin, Vol. 22 No. 3, September 2001