Vaccine-Preventable Diseases

Influenza

Influenza is caused by influenza A and B viruses and occurs in Canada every year, generally during late fall and the winter months. Influenza A viruses, which periodically undergo antigenic changes, are the most common cause of epidemic influenza. Outbreaks of influenza B are generally more localized and in any one year may be restricted to one region of the country. An association between influenza outbreaks, especially those caused by type B virus, and cases of the rare, but serious, Reye syndrome has been noted.

The annual incidence of influenza varies widely, and it is difficult to predict the impact of a particular virus strain on disease during an inter-pandemic period. People at greatest risk of serious disease and death are those with chronic medical conditions (especially cardiopulmonary diseases) and the elderly. Although many other respiratory viruses can cause influenza-like illness during the year, influenza virus is usually the predominant cause of serious respiratory disease in a community. Influenza A viruses are classified into subtypes based on their hemagglutinin (H) and neuraminidase (N) antigens. Recently circulating strains have possessed one of three H and one of two N antigens, and the subtypes are designated accordingly (e.g., H3N2, H1N1). Antibodies to these antigens, particularly to H antigen, can protect an individual against a virus carrying the same antigen. During inter-pandemic periods, minor H antigen changes ("drift") are common, and the greater the change the less will be the cross-immunity to the new strain conferred by the previously circulating virus. It is this antigenic variation from one influenza virus subtype to another that is responsible for continued outbreaks of influenza and that necessitates annual reformulation and administration of the influenza vaccine. The antigens of influenza B viruses are much more stable than those of influenza A viruses and, although antigenic variation does occur, it is less frequent.

Pandemic influenza is usually associated with a major antigenic change or "shift" and the rapid global spread of influenza A virus with a different H and often a different N antigen from strains circulating previously. Canada, like other countries, has been affected by major influenza pandemics, e.g., in 1889-90, 1918-19, 1957-58 and 1968-69.

Influenza Vaccine

Three influenza vaccines are licensed for use in Canada, two produced by Aventis Pasteur (Fluzone® and Vaxigrip®) and one by Shire Biologics (Fluviral S/F®). All three are sterile suspensions prepared from influenza viruses propagated in chicken embryos. The virus is inactivated, purified and treated with an organic solvent to remove surface glycoproteins, producing a "split-virus" preparation that is intended to reduce vaccine reactogenicity. One dose (0.5 mL) of vaccine contains 15 µg of hemagglutinin of each of three antigens. The antigens are selected from two strains of influenza A and one strain of influenza B. The virus strains chosen for inclusion in influenza vaccine are reviewed annually to ensure that they include antigens that are expected to provide the best protection during the following winter. All three licensed vaccines use thimerosal (0.01%) as a preservative. Gelatin (0.05%) is used as a stabilizer in Fluzone®. Vaxigrip® may contain undetectable traces of neomycin, used during production.

Influenza vaccines derived from tissue culture and live attenuated vaccines are in development, but at the time of printing of this book they are not licensed in Canada.

Efficacy and Immunogenicity

Repeated annual administration of influenza vaccine has not been demonstrated to impair the immune responsiveness of the recipient.

The effectiveness of influenza vaccine varies, depending upon the age and immunocompetence of the vaccine recipient, the endpoint studied, the incidence of infection, and the degree of similarity ("match") between the vaccine viral strain and the circulating viral strain during influenza season. With a good match, influenza vaccination has been shown to prevent influenza illness in approximately 70% to 90% of healthy children and adults, whereas a vaccine efficacy of 30% to 60% has been demonstrated when there are significant antigenic differences between circulating andvaccine viral strains. During 8 of the past 10 years, there has been a good to excellentmatch between the predominant seasonal viral strain and the chosen vaccine strain. A double-blind placebo controlled trial involving people > 60 years of age demonstrated vaccine efficacy of 58% in the prevention of laboratory-proven influenza illness. Pooled estimates from a meta-analysis of 20 cohort studies of influenza vaccine among the elderly demonstrated 56% effectiveness in preventing respiratory illness, 50% in preventing hospitalization for pneumonia and 68% in preventing death. Among residents of long-term care facilities, effectiveness in preventing influenza illness may be relatively low (30% to 40%), but vaccination may be 50% to 60% effective in preventing hospitalization and pneumonia, and up to 85% to 95% in preventing death.

Recommended Usage

Recommended recipients

Influenza vaccine may be administered to any healthy child, adolescent or adult for whom contraindications are not present. To reduce the morbidity and mortality associated with influenza and the impact of illness in our communities, immunization programs should focus on those at high risk of influenza-related complications, those capable of transmitting influenza to individuals at high risk of complications, and those who provide essential community services. However, significant morbidity and societal costs are also associated with seasonal interpandemic influenza illness and its complications occurring in healthy children and adults. For this reason, healthy adults and their children who wish to protect themselves from influenza should be encouraged to receive the vaccine.

People at high risk for influenza-related complications

•  Adults and children with chronic cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis and asthma) severe enough to require regular medical follow-up or hospital care.

• People of any age who are residents of nursing homes and other chronic care facilities.

• People >= 65 years of age.

• Adults and children with chronic conditions, such as diabetes mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression (due to underlying disease and/or therapy), renal disease, anemia and hemoglobinopathy.

• Children and adolescents (age 6 months to 18 years) with conditions treated for long periods with acetylsalicylic acid. This therapy might increase the risk of Reye syndrome after influenza.

• People at high risk of influenza complications embarking on travel to destinations where the virus is likely to be circulating.

People capable of transmitting influenza to those at high risk of influenza-related complications

People who are potentially capable of transmitting influenza to those at high risk should receive annual immunization, regardless of whether the high-risk person(s) has been immunized.

• Health care workers (HCWs) and other personnel who have significant contact with people in the high-risk groups previously described. The following groups should be immunized: HCWs in long-term care facilities, hospitals, and outpatient settings; employees of long-term care facilities who have patient contact; and those who provide services within relatively closed settings to people at high risk (e.g., providers of home care services, crews on ships that cater to those at high risk).

• Household contacts (including children) of people at high risk who either cannot be immunized or may respond inadequately to immunization.

People who provide essential community services

Immunization may be considered for these individuals in order to minimize the disruption of routine activities in epidemics. Employers and their employees should consider yearly influenza immunization for healthy working adults, as this has been shown to decrease work absenteeism due to respiratory and other illnesses.

Other potential recipients

Immunization of healthy people
Anyone who wishes to protect him/herself from influenza should be encouraged to receive the vaccine, even if that individual is not in one of the aforementioned priority groups. Several studies have suggested that influenza immunization of healthy adults and children may be cost-effective under selected circumstances. Assessment of the potential benefits of influenza immunization in healthy adults and children depends on numerous factors, including seasonal viral virulence and attack rates, the match between vaccine and circulating viral strains, protective immunity in previously infected individuals, vaccine side effects, and the costs of immunization and of influenza-associated morbidity. Among children, the effects of co-circulating viruses such as respiratory syncytial virus must be separated from those of influenza. Policy decisions regarding public funding of influenza vaccine for healthy adults and children depends on modelling of these factors within populations, as well as assessment of health priorities, resources and pragmatic programmatic issues.

Immunization of pregnant women
Influenza vaccine is considered safe for pregnant women at all stages of pregnancy and for breast-feeding mothers. Immunization is recommended for pregnant and breastfeeding women who are characterized by any of the conditions listed under "Recommended Recipients". Any pregnant woman who wishes to decrease her risk of developing influenza may be safely immunized. However, NACI concludes that there is insufficient evidence at this time to recommend a public health program to routinely immunize healthy Canadian women who are pregnant during influenza season.

Schedule and Dosage

The recommended dosage schedule and type of influenza vaccine are presented in the Table. Split-virus vaccines are available in Canada. Previously unvaccinated children < 9 years require two doses of the split-virus influenza vaccine, with an interval of 4 weeks. The second dose is not needed if the child has received one or more doses of vaccine during a previous influenza season.

In infants < 6 months of age, influenza vaccine is less immunogenic than in infants and children aged 6 to 18 months. Therefore, immunization with currently available influenza vaccines is not recommended for infants < 6 months of age.

Route of Administration

The vaccine should be administered intramuscularly. The deltoid muscle is the recommended site in adults and older children, and the anterolateral thigh in infants and young children.

Storage Requirements

Simultaneous Administration of Other Vaccines

Influenza vaccine may be given at the same time as other vaccines, provided different sites and administration sets (needle and syringe) are used.

The target groups for influenza and pneumococcal immunization overlap considerably. Health care providers should take the opportunity to immunize eligible people against pneumococcal disease when influenza vaccine is given. Pneumococcal vaccine, however, is usually given only once, whereas influenza vaccine is given annually.

Adverse Reactions

Allergic responses are rare and are probably a consequence of hypersensitivity to some vaccine component, most likely residual egg protein, which is present in minute quantities.

Rare cases of systemic vasculitis have been reported to occur in individuals within 2 weeks of influenza immunization. Influenza antigens have not been identified in circulating immune complexes or in vessel walls, and a causal relationship has not been proven.

Guillain-Barré syndrome (GBS) associated with influenza immunization has been observed in a minority of influenza seasons over the last two decades. Apart from the 1976-1977 swine flu season, the risk of GBS associated with influenza immunization is small. In a retrospective study of the 1992-93 and 1993-94 seasons in four U.S. states, the relative risk of GBS occurring within 6 weeks after influenza immunization, adjusted for age and sex, was 1.7 (95% confidence interval 1.0-2.8, p = 0.04), suggesting slightly more than one additional case of GBS per million people vaccinated against influenza. In comparison, the morbidity and mortality associated with influenza are much greater.

In Canada, a study carried out in Ontario and Quebec estimated the background incidence of GBS to be just over 20 cases per million population. A variety of infectious agents, such as Campylobacter jejuni, have been associated with GBS. It is not known whether influenza virus infection itself is associated with GBS, or whether influenza immunization is causally associated with increased risk of recurrent GBS in people with a previous history of this syndrome. Avoiding subsequent influenza immunization of people known to have developed GBS within 6 to 8 weeks of a previous influenza vaccination appears prudent at this time.

Influenza vaccine is not known to predispose to Reye syndrome.

An increased number of influenza vaccine-associated adverse events, primarily characterized by oculorespiratory symptoms, were reported in Canada during the 2000-2001 influenza season. Although the number of these reported adverse events was higher than in the past, conjunctivitis and/or respiratory symptoms following influenza immunization have been reported previously in Canada, the United States and Europe. A case definition for what was called "oculorespiratory syndrome (ORS)" was devised, and enhanced surveillance was initiated. The majority of reported cases of ORS were associated with Fluviral S/F®, one of the three influenza vaccines licensed for use in Canada. The syndrome was noted to be mild and self-resolving within several days.

Electron microscopic studies revealed a higher proportion of unsplit (whole) virus as well as aggregated virus particles in Fluviral S/F® than in other influenza vaccines used in Canada during the 2000-2001 season. The reader is referred to the July 2001 CCDR Annual Statement on Influenza Vaccination for the 2001-2002 Season for more in-depth information and a discussion of potential pathophysiologic mechanisms underlying this syndrome. Subsequent CCDR reports will provide further updates and recommendations, and should be consulted by health care providers. At the time of writing (May 2001), manufacturers are investigating improved methods of virus splitting in the preparation of influenza vaccines. Evidence of a satisfactory safety profile will be required before vaccine licensure. The benefits of influenza immunization in recommended recipients continue to greatly outweigh the risks associated with the vaccine.

Contraindications and Precautions

Influenza vaccine should not be given to people who had an anaphylactic reaction to a previous dose, or those with known anaphylactic hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension and shock. (See Part 1 of the Guide - General Considerations: Anaphylactic Hypersensitivity to Egg and Egg-related Antigens).

Individuals with acute febrile illness should not usually be immunized until their symptoms have abated.

Although influenza immunization can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine.

Strategies for Reducing the Impact of Influenza

Immunization is recognized as the single most effective way of preventing or attenuating influenza for those at high risk of serious illness or death. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% to 91% of residents of long-term care facilities and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually. Studies of HCWs in hospitals and long-term care facilities have shown immunization rates of 26% to 61%.

This low rate of utilization is due both to failure of the health care system to offer the vaccine and to immunization refusal by people who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary. The user is referred to the current annual CCDR Statement on Influenza Vaccination for a discussion of strategies to increase vaccination coverage of target groups, as well as guidelines regarding the prophylactic use of licensed antiviral medication in outbreak settings.  

Selected References

CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2001;50(RR-4):1-44.

Kilbourne ED, Arden NH. Inactivated influenza. In: Plotkin SA, Orenstein WA, eds. Vaccines. Philadelphia: W.B. Saunders, 1999:531-51.

McArthur MA, Simor AE, Campbell B et al. Influenza vaccination in long-term-care facilities: structuring programs for success. Infect Control Hosp Epidemiol 1999;20:499-503.

Nichol KL. Cost-benefit analysis of a strategy to vaccinate healthy working adults against influenza. Arch Intern Med 2001;161:749-59.

McIntosh K, Lieu T. Is it time to give influenza vaccine to healthy infants? N Engl J Med 2000;342(4):275-6.

Potter J, Stott DJ, Roberts MA et al. Influenza vaccination of health-care workers in longterm- care hospitals reduces the mortality of elderly patients. J Infect Dis 1997;175:1-6.