Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Influenza Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Further comments regarding influenza immunization Schedule and dosage Route of administration

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Other considerations Selected references

The National Advisory Committee on Immunization (NACI) produces a Statement on Influenza Vaccination each year that contains specific information and recommendations regarding the vaccine to be used in the forthcoming season. It is published in the Canada Communicable Disease Report (CCDR) and is available at www.naci.gc.ca. The reader is referred to the latest annual CCDR statement for a more in-depth discussion of selected topics and for recommendations that have been updated after publication of this edition of the Guide.

Since the publication of the 2002 Canadian Immunization Guide changes include 1) a new recommendation for the immunization of healthy children aged 6-23 months; 2) changes in preparations approved for use in Canada; 3) a new recommendation for contacts capable of transmitting influenza to those at high-risk of influenza-related complications; 4) a new recommendation for the immunization of those directly involved in the culling of poultry infected with avian influenza; 5) a new recommendation on subsequent influenza vaccination of persons known to have developed Guillain-Barré syndrome (GBS) within 8 weeks of a previous influenza vaccination; and 6) a new recommendation for the immunization of those with conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration.

Epidemiology

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 are the most common cause of annual influenza epidemics. 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, depending on the virulence of circulating strains and the susceptibility of the population, which is affected by antigenic changes in the virus, vaccine match and vaccine coverage. People at greatest risk of serious infections, complications, hospitalization and/or death are children aged 6-23 months, 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 infections 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 (referred to as drifts) are common, and the greater the change the less the cross-immunity will be to the previously circulating virus. It is this antigenic variation from one influenza virus subtype to another that is responsible for continued outbreaks of influenza, necessitating annual reformulation and administration of the influenza vaccine.

Since 1997, two influenza A subtypes, H3N2 and H1N1, have been circulating in the human population. Influenza B viruses have evolved into two antigenically distinct lineages since the mid-1980s, represented by B/ Yamagata/16/88-like and B/Victoria/2/87-like viruses. The B/Victoria lineage first re-appeared in 2001 after an absence of more than 10 years in North America, and since that time viruses belonging to the two influenza B lineages have caused outbreaks in different influenza seasons. 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.

Between 1996 and 2005, six of the nine seasons (1997-98, 1998-99, 1999-2000, 2001-02, 2003-04, 2004-05) were predominantly influenza A seasons (84%-99% of laboratory detections being influenza A). Two seasons (1996-97 and 2002-03) were considered mixed seasons (61% and 58% of laboratory detections being influenza A and 39% and 42% being influenza B, respectively), and one season (2000-01) was a predominantly influenza B season (68% of laboratory detections being influenza B). Influenza A is typically associated with greater morbidity and mortality than influenza B and typically affects the elderly, whereas influenza B is more often seen in young children. As well, influenza A/H3N2-like viruses tend to be associated with more severe illness than influenza A/H1N1-like or influenza A/H1N2-like viruses.

In four of the six predominantly influenza A seasons, 41%-46% of laboratory-confirmed influenza cases were in persons 65 years of age and older. In those same seasons, children less than 5 years of age accounted for less than 20% of laboratory-confirmed cases. In the mixed seasons and influenza B season, children less than 5 years of age accounted for 24%-32% of laboratory-confirmed cases, whereas persons 65 years of age and older accounted for 7% to 19% of laboratory-confirmed cases.

Pandemic influenza is usually associated with a major antigenic change (referred to as a shift) and the rapid global spread of influenza A virus with a different H and possibly a different N antigen from strains circulating previously. Canada, like other countries, was affected by the major influenza pandemics that occurred in 1889-90, 1918-19, 1957-58 and 1968-69.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

• Fluviral^® S/F (influenza trivalent split virion), ID Biomedical Corporation
• Influvac™ (influenza vaccine, inactivated, surface antigen), Solvay Pharma Inc.
• Vaxigrip^® (inactivated influenza trivalent types A and B [split virion]), Sanofi Pasteur Ltd.

All three vaccines are sterile suspensions prepared from influenza viruses propagated in chicken embryos. The viruses are inactivated and purified.

Two products (Vaxigrip^® and Fluviral^®) are “split virus” vaccines, which are treated with an organic solvent to remove surface glycoproteins, producing a "split-virus" resulting in reduced vaccine reactogenicity. Influvac^TM is a surface antigen, trivalent, inactivated subunit vaccine.

One dose (0.5 mL) of influenza vaccine contains 15 µg of hemagglutinin of each of three antigens. The antigens are selected from one strain of influenza A/H3N2, one strain of influenza A/H1N1 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 influenza season. The antigenic match between the vaccine strains recommended by the World Health Organization and subsequent circulating epidemic strains was appropriate during 12 of the 15 (80%) influenza seasons between 1982-1983 and 1996-1997.

As of 2005, Vaxigrip^® and Fluviral^® contain thimerosal, which is used as a preservative. Influvac™ does not contain thimerosal. Vaxigrip^® may contain undetectable traces of neomycin, used during production. At this time, influenza vaccines derived from tissue culture and live attenuated viruses are not approved for use in Canada.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

Intramuscular administration of inactivated influenza vaccine results in the production of circulating IgG antibody to the viral hemagglutinin as well as a cytotoxic T lymphocyte response. Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. Anti-hemagglutinin serum antibody is a predictor of total protection (acquisition of infection) and partial protection (disease after infection). The production and persistence of antibody after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immunodeficiency states. Humoral antibody levels, which correlate with vaccine protection, are generally achieved 2 weeks after immunization, and immunity usually lasts less than 1 year. However, antibody levels in the elderly may fall below protective levels in 4 months or less. Data are not available at this time to support the administration of a second dose of influenza vaccine in elderly individuals within the same influenza season in order to boost immunity.

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

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 strains and the circulating viral strain(s) during the 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 and vaccine viral strains.

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% effective in preventing death.

Recommended usage

As is the case with other vaccines, recommendations for usage may change over time as new research becomes available. Recommended recipients for the influenza vaccine at the time of this publication are outlined below, but for up-to-date information, the reader is referred to the annual Statement on Influenza Vaccination published in the CCDR and at www.naci.gc.ca.

Recommended recipients (see Table 6)

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 children and adults should be encouraged to receive the vaccine.

People at high risk of influenza-related complications

• Adults and children with selected chronic health conditions. These include cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis and asthma), diabetes mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression (due to underlying disease and/or therapy), renal disease, anemia and hemoglobinopathy, as well as conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration. This category includes children and adolescents (age 6 months to 18 years) with conditions treated for long periods with acetylsalicylic acid (because of the potential increased risk of Reye syndrome associated with influenza). Pregnant women with any of these co-morbidities are also at increased risk of the complications of influenza and should be immunized.
• People of any age who are residents of nursing homes and other chronic care facilities.
• People ≥ 65 years of age.
• Healthy children aged 6-23 months.

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. These individuals include the following:

• Health care workers (HCWs) and other care providers in facilities and community settings who, through their activities, are potentially capable of transmitting influenza to those at high risk of influenza complications. This group includes regular visitors, emergency response workers, those who have contact with residents of continuing care facilities or residences, and those who provide home care for persons in high-risk groups. NACI considers the provision of influenza vaccination for these HCWs to be an essential component of the standard of care for influenza prevention for the protection of their patients. HCWs who have direct patient contact should consider it their responsibility to provide the highest standard of care, which includes undergoing annual influenza vaccination. In the absence of contraindications, refusal of HCWs who have direct patient contact to be immunized against influenza implies failure in their duty of care to patients.
• Household contacts (adults and children) of people at high risk of influenza complications. This group includes household contacts of children < 6 months of age (who are at high risk of complications from influenza but for whom there is no available effective vaccine) and of children aged 6-23 months whether or not they have been immunized. Pregnant women should be immunized in their third trimester if they are expected to deliver during influenza season, as they will become household contacts of their newborn.
• Those providing regular child care to children under 24 months of age, whether in or out of the home.
• Those who provide services within closed or relatively closed settings to persons at high risk (e.g., crew on cruise ships).

People who provide essential community services

Vaccination for these individuals should be encouraged in order to minimize the disruption of routine activities during annual epidemics. Employers and their employees should consider yearly influenza immunization for healthy working adults as this has been shown to decrease work absenteeism from respiratory and other illnesses.

People in direct contact with avian influenza-infected poultry during culling operations

These individuals may be at increased risk of avian influenza infection because of exposure during the culling operation. The theoretical rationale is that it may prevent the infection of these individuals with human influenza strains and thus reduce the potential for human-avian reassortment of genes should they become coinfected with avian influenza. Please refer to the current Statement on Influenza Vaccination in the Canada Communicable Disease Report and at www.naci.gc.ca for further information.

Further comments regarding influenza immunization

Immunization of healthy persons aged 2-64 years

Individuals in this age group should be encouraged to receive the vaccine, even if they are not in one of the aforementioned priority groups. In an analysis of randomized controlled trials of inactivated influenza vaccine among healthy adults, Demicheli et al. estimated vaccine efficacy to be 24% in preventing influenza-like illness (ILI) and 68% in preventing laboratory-confirmed influenza infections. Depending on whether infection was defined by serology or culture, in trials of inactivated trivalent influenza vaccine in children aged 2-5 years vaccine efficacy was estimated to be 31%-83%. Fifteen randomized controlled trials of healthy individuals aged 6 months to 19 years conducted over a period during which the recommended vaccine was both well matched and not well matched with circulating viral strains showed a relative risk reduction associated with influenza vaccination ranging from 0% to 93%.

Table 6. Recommended Recipients of Influenza Vaccine

Travellers

People with selected chronic medical conditions should be immunized (see Table 6). Healthy persons should be encouraged to receive vaccine. Vaccines prepared specifically against strains that are predicted to circulate in the southern hemisphere are not currently available in Canada. For further information on advising travellers about influenza prevention the Committee to Advise on Tropical Medicine and Travel (CATMAT) statement should be consulted: http://www.phac-aspc.gc.ca/tmp-pmv/catmat-ccmtmv/index.html.

Immunization during pregnancy and during lactation

Influenza vaccination is recommended for pregnant and breast-feeding women who are characterized by any of the conditions listed under Recommended Recipients above, in particular those who have co-morbidities or who are close contacts of high-risk persons. Pregnant women with any of the selected chronic conditions putting them at high risk of the complications associated with influenza are a priority for immunization. Influenza vaccine is safe for pregnant women at all stages of pregnancy and for breast-feeding mothers.

Immunization of pregnant women has the advantage of potentially protecting the fetus through transplacental antibody passage or through breast milk. Among healthy pregnant women, the morbidity and mortality associated with influenza is increased during pandemics.

Healthy women who will be pregnant during influenza season and who wish to avoid morbidity associated with influenza should be encouraged to be vaccinated during any trimester of pregnancy. Pregnant women should be immunized in their third trimester if they are expected to deliver during influenza season, as they will become household contacts of their newborn.

Schedule and dosage

The recommended dosage schedule and type of influenza vaccine are presented in Table 7. Influenza vaccines in Canada are available as a split-virus (chemically disrupted) and an inactivated subunit preparation. Each 0.5 mL of vaccine contains 15 µg of hemagglutinin of each vaccine strain.

Previously unvaccinated children < 9 years of age require two doses of the split-virus influenza vaccine, with an interval of 4 weeks. The second dose of influenza vaccine is not needed if the child has received one or more doses of vaccine during a previous influenza season.

The subunit vaccine is currently approved for use only in those 18 years of age and older.

There are no data suggesting that administration of a second dose of influenza vaccine in the same influenza season in elderly individuals or other individuals who may have an altered immune response will boost immunity.

Immunization with currently available influenza vaccines is not recommended for infants < 6 months of age.

Table 7. Recommended Influenza Vaccine Dosage, by Age

Route of administration

The vaccine should be administered intramuscularly. The deltoid muscle is the recommended site in adults and children ≥ 12 months of age. The anterolateral thigh is the recommended site in infants under 12 months of age.

Serologic testing

There is no indication for pre- or post-immunization serology.

Storage requirements

Influenza vaccine should be stored at a temperature between +2° C and +8° C and should not be frozen.

Simultaneous administration of other vaccines

Influenza vaccine may be given at the same time as other vaccines. The same limb may be used if necessary, but different sites on the limb should be chosen. A separate needle and syringe must be 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, in contrast to influenza vaccine, is not given annually.

Adverse reactions

Influenza immunization cannot cause influenza because the vaccine does not contain live virus. Soreness at the injection site lasting up to 2 days occurs in 10%-72% of patients but rarely interferes with normal activities. Fever, malaise and myalgia may occur within 6 to 12 hours after vaccination and last 1 to 2 days, especially in those receiving vaccine for the first time. Prophylactic acetaminophen may decrease the frequency of some side effects in adults. Healthy adults receiving the split-virus vaccine have shown no increase in the frequency of fever or other systemic symptoms compared with those receiving placebo.

Split-virus influenza vaccines are safe and well tolerated in healthy children. Mild local reactions, primarily soreness at the vaccination site, occur in ≤ 7% of healthy children who are < 3 years of age. Post-vaccination fever may be observed in ≤ 12% of immunized children aged 1 to 5 years.

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

GBS occurred in adults in association with the 1976 swine influenza vaccine, and evidence favours a causal relation between the vaccine and GBS during that season. In an extensive review of studies since 1976, the Institute of Medicine in the United States concluded that the evidence is inadequate to accept or reject a causal relation between GBS in adults and influenza vaccines administered since 1976.

Influenza vaccine is not known to predispose vaccine recipients to Reye syndrome.

During the 2000-2001 influenza season, the Public Health Agency of Canada received an increased number of reports of vaccine-associated symptoms and signs that were subsequently described as oculorespiratory syndrome (ORS). The case definition is as follows: the onset of bilateral red eyes and/or respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) and/or facial swelling occurring within 24 hours of influenza immunization. The pathophysiologic mechanism underlying ORS remains unknown, but it is considered distinct from IgE-mediated allergy.

Since the 2000-2001 influenza season fewer ORS cases have been reported. In the province of Quebec the rate of ORS per 100,000 doses distributed declined from 46.6 in 2000, to 34.2 in 2001, 20.6 in 2002 and down to 9 per 100,000 in 2003. Surveillance for all adverse events following immunization, including ORS, is ongoing.

Contraindications and precautions

Influenza vaccine should not be given to people who had an anaphylactic reaction to a previous dose.

Persons with known IgE-mediated hypersensitivity to eggs, manifested as hives, swelling of the mouth and throat, difficulty breathing, hypotension or shock, should not be routinely vaccinated with influenza vaccine. If egg-allergic individuals are at risk of the complications of influenza they should be evaluated by an allergy specialist, as vaccination might be possible after careful evaluation, skin testing and graded challenge or desensitization. If such an evaluation is not possible, the risk of an allergic reaction to the vaccine must be weighed against the risk of influenza disease.

It is not known whether influenza vaccination is causally associated with increased risk of recurrent GBS in persons with a previous history of GBS. Avoiding subsequent influenza vaccination of persons known to have developed GBS within 8 weeks of a previous influenza vaccination appears prudent at this time.

Individuals with serious, acute febrile illness should not be immunized until their symptoms have abated. Those with mild, non-serious febrile illness (such as mild upper respiratory tract infections) may be given influenza vaccine. Opportunities for immunization should not be lost because of inappropriate deferral of immunization.

Other considerations

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 from influenza infection and related complications. Influenza vaccination 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 that put them at high risk of influenza complications receive the 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 reader is referred to the most up-to-date annual NACI Statement on Influenza Vaccination for a discussion of strategies to increase vaccination coverage of target groups, as well as guidelines regarding prophylactic use of antivirals.

Selected references

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travel, influenza, and prevention. Canada Communicable Disease Report 2005;31(ACS-2):1-8.

Demicheli V, Rivetti D, Deeks JJ et al. Vaccines for preventing influenza in healthy adults (Cochrane Review). In: The Cochrane Library. Chichester: John Wiley and Sons Ltd., 2003:4.

Fukuda K, Levandowski RA, Bridges CB et al. Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA (eds), Vaccines, 4th edition. Saunders: Philadelphia, 2003:339-70

Glezen WP, Alpers M. Maternal immunization. Clinical Infectious Diseases 1999;28(2):219-24.

Institute of Medicine. Immunization safety review: influenza vaccines and neurological complications. URL: <http://www.iom.edu/?id=15639>.

Jefferson T, Smith S, Demicheli V et al. Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review. Lancet 2005;365(9461):773-80.

Langley JM, Faughnan ME. Prevention of influenza in the general population. Canadian Medical Association Journal 2004;171(10):1213-22.

National Advisory Committee on Immunization. Supplementary statement for the 20022003 influenza season: update on oculorespiratory syndrome in association with influenza vaccination. Canada Communicable Disease Report 2002;28(ACS-6):1-8.

Orr P. Influenza vaccination for health care workers: a duty of care. Canadian Journal of Infectious Diseases 2000;11(5):225-26.

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