ARCHIVED - Canada Communicable Disease Report

 

Volume 35 • ACS-6
October 2009

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Statement on Seasonal Trivalent Inactivated Influenza Vaccine (TIV) for 2009-2010

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization and certain prophylaxis agents. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product leaflet(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s)/leaflet(s) of the Canadian manufacturer(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

IMPORTANT note regarding antiviral guidelines and pandemic vaccine recommendations:

Owing to the increasing complexity of antiviral issues, antiviral recommendations will be developed, updated, approved and posted through a separate national process.

Information related to immunization against the 2009 pandemic influenza A/H1N1 virus is not addressed in this NACI statement but is instead being developed, updated, approved and posted through a separate national process.

Introduction

The purpose of this statement is to review the NACI recommendations for immunization with the seasonal trivalent inactivated influenza vaccine (TIV) for the 2009-2010 season in light of the recent H1N1 pandemic, based on evidence available at this time.

The annual Advisory Committee Statement (ACS) setting out the NACI recommendations for seasonal influenza vaccine is usually published in June or July of each year, and contains the recommended antigenic components of the influenza vaccine for the coming season, surveillance and epidemiology of circulating influenza strains, as well as vaccine-related information, and recommended vaccine recipients. In the spring of 2009, a novel influenza A/H1N1 virus emerged (henceforth referred to in this document as pandemic A/H1N1 or pH1N1), and on June 11, 2009, the World Health Organization (WHO) declared that a pandemic was in progress. The ACS  was already complete at that time, and as the pandemic progressed over the early summer, the Public Health Agency of Canada (PHAC) decided not to publish the NACI ACS that had been prepared without the benefit of the knowledge of the epidemiology and clinical patterns of the 2009 novel influenza virus.

Summary:

After consideration of the evidence currently available, NACI continues to recommend seasonal TIV for the 2009-2010 season.

Immunization programs should focus on those persons 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.

Health care providers may offer the seasonal TIV when it becomes available, since seasonal influenza activity may start as early as November in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic issues (e.g., consideration of the need to deliver the pandemic H1N1 influenza vaccine). Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local medical officers of health. Although vaccination prior to the onset of the influenza season is preferred, vaccine may still be administered up until the end of the season. Health care workers (HCWs) should use every opportunity to give TIV to individuals at risk who have not been immunized during the current season, even after influenza activity has been documented in the community.

Relative risks and benefits of TIV should be discussed prior to vaccination.

In addition, NACI makes the following recommendation for the 2009-2010 season:

Individuals who have been immunized with seasonal influenza vaccine and who are eligible to receive pH1N1 vaccine can be immunized with pH1N1 vaccine as soon as possible. Eligible individuals for whom seasonal TIV is recommended but who have been immunized with pH1N1 vaccine first should subsequently be immunized with seasonal TIV as outlined above. Seasonal TIV and pH1N1 vaccines may be administered concurrently in opposite limbs. If not administered together, there are no timing restrictions on the administration of the subsequent vaccine.

Background

In Canada, two available measures can reduce the impact of influenza: immunoprophylaxis with trivalent inactivated influenza vaccine (TIV) and chemoprophylaxis, or therapy with influenza-specific antiviral drugs. Immunization is the cornerstone of influenza prevention and is the focus of this NACI statement. Antiviral recommendations are no longer within the purview of NACI and are to be developed, updated, approved, and posted through a separate national process.

Influenza A viruses are classified into subtypes on the basis of two surface proteins: hemagglutinin (H) and neuraminidase (N). Three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) are recognized among influenza A viruses that have caused widespread human disease. Currently, the human H3N2 and human H1N1 influenza A subtypes contribute to influenza illness to varying degrees each year. Immunity to the H and N antigens reduces the likelihood of infection and lessens the severity of disease if infection occurs.

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. Viruses of the B/Yamagata lineage accounted for the majority of isolates in most countries between 1990 and 2001. In contrast, viruses belonging to the B/Victoria lineage have not been identified outside of Asia between 1991 and 2001. In March 2001, B/Victoria lineage viruses re-emerged for the first time in a decade in North America (1). Since then, viruses within the B/Yamagata and B/Victoria lineages have variously contributed to influenza illness each year.

TIV is reformulated annually to include standardized amounts of the H protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and one of the two influenza B lineages (Yamagata orVictoria). H-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon age and/or prior antigenic experience with both B lineages(2-8). Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or B lineage. Despite this antigenic drift, cross-protection among strains belonging to the same A subtype or B lineage is expected. Because of antigenic drift in one or more components of TIV, a new vaccine formulation must be considered each year.

National influenza surveillance in the 2008-2009 season (from 24 August 2008 to 29 August 2009)

Laboratory and epidemiologic indicators of activity

National influenza surveillance is coordinated through the Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada (PHAC). The FluWatch program collects data and information from five different sources in order to provide a national picture of influenza activity. The detailed methodology of the FluWatch program has been described elsewhere (9). The information in this statement is based on surveillance data reported up to August 29, 2009.

Nationally, seasonal influenza activity increased across the country from late December 2008 and persisted well into the season until about the end of March 2009. The season was characterized by a mix of both human influenza A subtypes (seasonal H1N1 and H3N2) as well as influenza B activity. Of the 10,043 positive influenza detections reported up to May 9, 2009, 6,261 (62.3%) were influenza A and 3,782 (37.7%) were influenza B. Influenza A was more prevalent in all provinces with the exception of Ontario, where influenza B virus was most common until the pandemic strain emerged.

From May 9 to August 29, pandemic A (H1N1) 2009 dominated, with a total of 6,676 pandemic influenza A (H1N1) 2009 detections reported. Of all the 23,369 influenza isolates typed from August 24, 2008 to August 29, 2009, 83.3% (19,467) were influenza A and were 13.7% (3,902) were influenza B. It should be noted that influenza testing levels increased substantially after April 23, 2009, which heavily influences the comparison of numbers of laboratory-confirmed cases before and after the arrival of the pandemic (H1N1) 2009 strain.

From September 1, 2008 to August 28, 2009 the National Microbiology Laboratory (NML) antigenically characterized 1,298 influenza viruses received from sentinel public health and hospital laboratories across Canada: 260 (20%) were antigenically similar to A/Brisbane/59/2007 (H1N1); 172 (13%) were A/Brisbane/10/2007 (H3N2)-like; 379 (29%) were B/Malaysia/2506/2004 (Victoria lineage)-like; 180 (14%) were B/Brisbane/60/2008-like; and 11 (1%) were B/Florida/4/2006 (Yamagata lineage)-like. While there was a good match with the influenza A components included in the 2008-2009 influenza vaccine - (A/Brisbane/59/2007(H1N1) and A/Brisbane/10/2007 (H3N2) - included in the 2008-2009 influenza vaccine), the same was not true for the influenza B component. B/Malaysia/2506/2004-like and B/Brisbane/60/2008-like were the predominant circulating B strains, but they did not match the B component that was included in the 2008-2009 vaccine, which was B/Florida/04/2006. B/Brisbane/60/2008-like is the recommended influenza B component for the 2009-2010 seasonal vaccine. Of the 1,298 influenza isolates that were subtyped, 296 (23%) were the A/California/07/2009 (H1N1) pandemic strain.

Weekly influenza-like illness (ILI) consultation rates for the non-pandemic season (before May 2009) remained within or below baseline levels since the beginning of the season, and peaked in week 9 (early March) to about 48 consultations for ILI per 1,000 patient visits, which was still within the expected range. The median number of ILI consultations during the influenza season was 16 per 1,000 patient visits. The highest ILI consultation rates were reported in children 0 to 4 years of age, at 39 ILI consultations per 1,000 patient visits. However, once the pandemic strain began circulating in Canada, a highly synchronized epidemic ensued with a shape and pattern typical of average influenza epidemics in Canada. A peak value of 41 ILI per consultations per 1,000 patient visits was seen for weeks 23 and 24 (June 13 and June 20).

Of the 296 outbreaks of influenza or ILI that were reported, 128 (43.2%) occurred in long-term care facilities (LTCFs), 13 (4.4%) in hospitals, 144 (48.76%) in schools, and 11 (3.7%) in other facilities. The number of outbreaks reported in LTCFs over the last five seasons ranged from 142 in 2005-2006 to 847 in 2004-2005. Once the pandemic influenza A was established, there were an additional 73 outbreaks reported, with 22 (30.1%) in LTCFs, 9 (12.3%) in hospitals, 24 (32.9%) in schools, and 18 (24.7%) in other categories.

Widespread influenza activity was reported 26 times in 10 regions in 5 provinces (British Columbia, Alberta, Manitoba, Quebec and Newfoundland and Labrador) since the start of the season, with the most activity occurring in British Columbia (55%). The majority of widespread activity was reported between late January and late April 2009 (weeks 4 and 18). Only two widespread levels were reported during the pandemic phase.

A total of 398 influenza-associated pediatric hospitalizations were reported through the Immunization Monitoring Program ACTive (IMPACT) network from October 26, 2009 to April 25, 2009. 54.3% of these hospitalizations were due to seasonal influenza A. Influenza A and B were about equally distributed among hospitalized cases prior to the onset of pandemic cases (54.3% for influenza A, 45.7% for influenza B). Two influenza-associated pediatric deaths were reported through IMPACT during that period in Canada. One was due to influenza A, the other due to influenza B. Over the last four seasons, between 370 and 492 (mean = 407) laboratory-confirmed paediatric hospitalizations and between two and five deaths (mean = 3) were reported in Canada each season.

In comparison, a total of three hundred and sixty-seven pediatric hospitalizations were reported through the IMPACT network from April 26, 2009 to August 29, 2009. 99.5% of these hospitalizations have been due to influenza A and 95.1% of these influenza A hospitalizations have been due to pandemic (H1N1) 2009. Four influenza-associated pediatric deaths due to pandemic (H1N1) 2009 were reported through IMPACT during that period in Canada.

While the spectrum of clinical illness, risk factors for complicated outcomes, and morbidity and mortality associated with the pH1N1 influenza virus is not yet fully characterized, the following features have been observed based on information available to 14 October 2009:

  • Similarities between pH1N1 and seasonal influenza in terms of groups at risk of severe outcomes have been noted in Canadians, including: children less than 2 years of age, pregnant women and persons with co-morbidities.(10) In contrast to seasonal influenza, pH1N1 influenza has caused significant morbidity in adults under 65 years of age.
  • In a multi-centre observational study of 168 critically ill confirmed or probable cases of pH1N1 admitted to Canadian intensive care units (ICUs), the mean age of patients was 32.3 ± 21.4 years, 113 patients (67.3%) were female, 50 patients (29.8%) were children, and 43 patients (25.6%) were Aboriginal persons. Co-morbidities were present in 91% of these ICU patients at presentation (most commonly chronic lung disease, obesity, hypertension) and 7% were pregnant (11)
  • In some case series in the United States, obesity (defined as body mass index [BMI] ≥30) or morbid obesity (BMI ≥40) has been noted among hospitalized patients with pH1N1 virus infection (12;13). However, the majority of these patients had other underlying medical risk factors. Studies examining whether obesity is an independent risk factor for severe infection are in progress.
  • In Canada, morbidity (as measured by hospitalization and ICU admission) and mortality due to pH1N1 has been higher in Aboriginal persons than in non-Aboriginal persons. It is currently not clear to what extent various host factors (comorbidities, population age structure, nutritional status, concomitant pregnancy, etc) and environmental factors (housing characteristics including air quality and crowding, access to health services, etc) may contribute to the risk of exposure to pH1N1 and the risk of development of illness, illness severity, and death due to this virus in Aboriginal Canadians.
  • Compared to seasonal influenza, persons 65 years of age and older appear to have lower rates of laboratory-confirmed pH1N1 illness, which may be due to immunity from exposure to related variants of influenza in the past through immunization or infection (14).  However, seniors admitted to hospital with pH1N1 influenza infection do have a higher risk of complications than younger individuals. Because of the relative rarity of infection in those 65 years of age and older, hospitalization rates overall are lower than those for younger age groups (10;15).

Antiviral resistance

Details of antiviral resistance patterns of circulating influenza strains performed by the routine surveillance program at the National Microbiology Laboratory (NML) are reported by the FLuWatch program. As noted earlier, recommendations for antiviral use for prevention of influenza will be published separately and will be developed, updated, approved and posted through a separate national process. A brief summary of antiviral resistance for the 2008-2009 season is provided here.

By week 34 (ending August 29, 2009), the NML had tested 1,074 influenza A isolates (396 H3N2, 319 H1N1 and 359 pandemic H1N1) for amantadine resistance. While all A/H3N2 isolates and all pandemic H1N1 (pH1N1) isolates were resistant to amantadine, all seasonal A/H1N1 were sensitive.The proportion of influenza A(H3N2) virus isolates that is resistant to amantadine has been very high in two of the three previous seasons (91.5% in 2005-2006 and 99.6% in 2007-2008).

The NML tested 1,597 influenza isolates (319 A/H1N1, 194 A/H3N2, 573 B and 511 pH1N1) for oseltamivir (Tamiflu®) resistance. All of the pH1N1, A/H3N2, and B isolates were sensitive; however, all but one of the seasonal A/H1N1 isolates were resistant to oseltamivir.

All 1,291 influenza isolates (267 pH1N1, 256 A/H1N1, 190 A/H3N2 and 578 B) tested for zanamivir resistance to date have been sensitive to zanamivir.

For up-to-date information on influenza epidemiology and activity, see http://www.phac-aspc.gc.ca/fluwatch/index-eng.php. For additional information on pH1N1 epidemiology, please refer to the Guidance Document on the Use of Inactivated Pandemic Influenza A(H1N1) 2009 Monovalent Vaccine.

International influenza surveillance

Europe

In Europe, the seasonal epidemic came to an end at week 22. Consultation rates for ILI and/or ARI rose above baseline levels as of week 49/2008 in most western and central European countries, and high seasonal influenza intensity was reported in 15 countries after week 51/2008. Generally, the highest consultation rates have been in the 0-4 year and 5-14 year age groups, but Ireland, the UK, Norway, and Romania have reported their highest ILI consultation rates in the 15-64 year age group. Influenza A (83%) has been the dominant seasonal virus type circulating in Europe, mostly characterized antigenically and/or genetically as A (H3N2) (68% of the strains characterized). Of the influenza B viruses that were characterized, the majority were B/Victoria lineage (26% of total viruses characterized). Unlike the B/Victoria lineage viruses, the A viruses circulating were similar to the strains included in the 2008/2009 Northern Hemisphere influenza vaccine: A (H1N1), A (H3N2)(16).

United States: September 2008 to August 2009

Influenza activity in the U.S. remained low until January, peaked in mid-February, and decreased thereafter until the third week of April. Up to mid-March, seasonal influenza A (H1N1) was the predominant strain, and followed by influenza B thereafter. Based on a sample of 1,137 isolates that were antigenically characterized, 64% were seasonal influenza A H1N1 subtype, 9% were influenza A (H3N2) subtype, and 27% were influenza type B viruses. All influenza A(H1) viruses were related to the influenza A(H1N1) component of the 2008-2009 influenza vaccine (A/Brisbane/59/2007) and all influenza A (H3) viruses were related to the A(H3N2) vaccine component (A/Brisbane/10/2007). Of the B viruses tested, only 17% belonged to the B/Yamagata lineage and were related to the vaccine strain (B/Florida/04/2006) (17).

Pandemic influenza A (H1N1) virus infections were first identified in the U.S. in April 2009; activity peaked during May and June and declined during July and early August. Since May 3, the majority of influenza viruses identified have been pandemic H1N1 influenza A viruses. All of the pH1N1 viruses characterized at the Centers for Disease Control (CDC) have been related antigenically to the reference strain chosen for the influenza A (pH1N1) monovalent vaccine: A/California/7/2009(H1N1). The majority of pH1N1 2009 viruses are susceptible to oseltamivir: however, nine cases of oseltamivir resistance were confirmed in the U.S. (18).

Avian influenza

From 1 September, 2008 to 31 August, 2009, 47 human cases of influenza A(H5N1) leading to 19 deaths were confirmed in Cambodia, China, Egypt, Indonesia and Vietnam. The largest number of cases reported were from Egypt (n=34), and the largest number of deaths reported were from Egypt (n=5) and China (n=5). Many of these people had visited live bird markets or had had contact with sick or dead poultry. From 2003 to August 31, 2009, a total of 440 human cases and 262 deaths have been confirmed from 15 countries (19). To date, there has been no evidence of sustained human-to-human transmission due to avian influenza(20).

International seasonal influenza immunization programs

Current information (as of October 14, 2009) on the planned seasonal influenza immunization programs for 2009-2010 in the Northern Hemisphere is as follows:

  • Most countries in the Northern Hemisphere (e.g. the U.K., European Union) are planning seasonal influenza immunization programs as in previous years, in addition to a pH1N1 immunization campaign.
  • In the United States, the timing of immunization programs will be based on vaccine availability of the seasonal and pandemic vaccines; simultaneous administration of seasonal and novel pH1N1 vaccination is permissible if different anatomic sites are used (21).
  • Sweden has postponed its seasonal influenza immunization program, which usually begins in mid-October, and may co-administer seasonal influenza vaccine with dose 2 of the pH1N1 vaccine in December or January (22).

Recommendations for the 2009-2010 seasonal influenza vaccine

(Please note: Information related to immunization against the 2009 pandemic influenza A/H1N1 virus is not addressed in this NACI statement but is instead being developed, updated, approved, and posted through a separate national process.)

General considerations

The national goal of the seasonal influenza immunization program in Canada is to prevent serious illness caused by influenza and its complications, including death(23). In keeping with this, NACI recommends that immunization priority for seasonal TIV be given to those persons 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, influenza vaccine is encouraged for all Canadians who have no contraindication.

The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year's vaccine. The World Health Organization (WHO) recommends that the trivalent vaccine for the 2009-2010 season in the Northern Hemisphere contain A/Brisbane/59/2007(H1N1)-like, A/Brisbane/10/2007(H3N2)-like, and B/Brisbane/60/2008(Victoria lineage)-like antigens(5). Vaccine producers may use antigenically equivalent strains because of their growth properties.

All manufacturers of influenza vaccines in Canada have confirmed to the Biologics and Genetic Therapies Directorate of Health Canada that the vaccines to be marketed in Canada for the 2009-2010 influenza season contain the above three WHO-recommended antigenic strains.

Several characteristics of the trivalent influenza vaccine recommended for 2009-2010 should be noted. First, only the B component has changed from 2008-2009. Second, despite similar names, the three components of TIV for 2009-2010 are not antigenically related. Finally, it should be noted that the B/Brisbane/60/2008-like virus belongs to the B/Victoria lineage whereas the 2008-2009 B vaccine component belonged to the B/Yamagata lineage.

Annual immunization against influenza is recommended for optimal protection. Because of antigenic drift in one or more of the predominant influenza viruses, a new TIV formulation—updated yearly with the most current circulating strains—provides optimal protection against new infections. Protective antibody levels are generally achieved 2 weeks following immunization. Although initial antibody response may be lower to some influenza vaccine components among elderly recipients, a recent literature review identified no evidence for subsequent antibody decline that was any more rapid in the elderly than in younger age groups(24).

Health care providers may offer the seasonal TIV when it becomes available, since seasonal influenza activity may start as early as November in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing and intensity), opportune moments for vaccination, as well as programmatic issues (e.g., consideration of the need to deliver the pandemic H1N1 influenza vaccine). Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local medical officers of health. Although vaccination before the onset of the influenza season is preferred, vaccine may still be administered up until the end of the season. Health care workers (HCWs) should use every opportunity to give TIV to individuals at risk who have not been immunized during the current season, even after influenza activity has been documented in the community.

Relative risks and benefits of TIV should be discussed prior to vaccination.

In addition, NACI makes the following recommendation for the 2009-2010 season:

Individuals who have been immunized with seasonal influenza vaccine and who are eligible to receive pH1N1 vaccine can be immunized with pH1N1 vaccine as soon as possible. Eligible individuals for whom seasonal TIV is recommended, who have been immunized with pH1N1 vaccine first, should subsequently be immunized with seasonal TIV as outlined above. Seasonal TIV and pH1N1 vaccines may be administered concurrently in opposite limbs. Recommendations on the use of the pandemic vaccine for the 2009-2010 season will be published separately by the Public Health Agency of Canada.

Recommended recipients

Current influenza vaccines approved for use in Canada are immunogenic, safe, and associated with minimal side effects (see below, Adverse reactions and Contraindications and precautions). Influenza vaccine may be administered to anyone ≥6 months of age without contraindications.

To reduce the morbidity and mortality associated with influenza, 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. These groups remain the priority for influenza vaccination programs in Canada. However, significant illness and associated societal costs also occur with seasonal influenza in people who may not be considered at high risk of complications (i.e., healthy people aged 2 to 64 years).

Table 1. Recommended recipients of seasonal influenza vaccine

People at high risk of influenza-related complications or those more likely to require hospitalization

  • Adults (including pregnant women) and children with the following chronic health conditions:
    • 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 or hemoglobinopathy;
    • conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration; or
    • children and adolescents with conditions treated for long periods with acetylsalicylic acid.
  • People of any age who are residents of nursing homes and other chronic care facilities.
  • People ≥65 years of age.
  • Healthy children 6 to 23 months of age.
  • Healthy pregnant women; (the risk of influenza-related hospitalization increases with length of gestation, i.e., it is higher in the third than in the second trimester).

People capable of transmitting influenza to those at high risk

  • Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk of influenza complications.
  • Household contacts (adults and children) of individuals at high risk of influenza-related complications (whether or not the individual at high risk has been immunized):
    • household contacts of individuals at high risk, as listed in the section above;
    • household contacts of infants <6 months of age who are at high risk of complications from influenza but for whom influenza vaccine is not approved; and
    • members of a household expecting a newborn during the influenza season.
  • Those providing regular child care to children <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 a ship).

Others

  • People who provide essential community services.
  • People in direct contact during culling operations with poultry infected with avian influenza.

Note: Healthy persons aged 2 to 64 years without contraindication are also encouraged to receive influenza vaccine even if they are not in one of the aforementioned priority groups.

People at high risk of influenza-related complications or those more likely to require hospitalization

  • Adults (including pregnant women) and children with the following chronic health conditions. A number of chronic health conditions are associated with increased risk of influenza-related complications and/or lead to exacerbation of the chronic disease. These conditions especially include cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis and asthma) but also diabetes mellitus and other metabolic diseases; cancer; immunodeficiency and immunosuppression (due to underlying disease and/or therapy); renal disease; anemia or hemoglobinopathy; and conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration. This category includes children and adolescents (aged 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.
  • People of any age who are residents of nursing homes and other chronic care facilities. Such residents often have one or more chronic medical condition and live in institutional environments that may facilitate spread of the disease.
  • People ≥65 years of age. Admissions attributable to influenza in this age group are estimated at 125 to 228 per 100,000 healthy persons(25), and death rates increase with age(26).
  • Healthy children 6 to 23 months of age. Children in this age group are at increased risk of influenza-associated hospitalization compared with healthy older children and young adults. Hospitalization is most frequent in those <2 years of age with rates estimated in a variety of North American studies to be from 90 to 1,000 admissions per 100,000 healthy children(27;28). Risk is greatest in the very young. These rates of hospitalization are similar to or greater than those of persons ≥65 years of age, although comparisons based on days of hospitalization and other severity indicators are not available and differences in the methods and setting for estimating influenza-attributable rates must also be taken into account. Influenza immunization of older children is efficacious(29-31), but few trials have specifically included children 6 to 23 months of age.

    NACI recognizes that both the number of studies and the number of participants in trials of influenza vaccine in children of this age are limited, that there are unanswered questions (for example, the uncertain efficacy of vaccine in unprimed children who have not had experience with the vaccine or infection and who receive a lower dose per injection than older children), and that there is uncertainty about the cost-effectiveness of routine immunization programs in this age group(32;33). NACI strongly encourages further research regarding these issues. However, on the basis of existing data indicating a high rate of influenza-associated hospitalization in healthy children <24 months, NACI recommends the inclusion of children 6 to 23 months of age among high-priority recipients of influenza vaccine.
  • Pregnant women. Women with the chronic health conditions indicated in Table 1 have a high risk of complications associated with influenza and are recommended by NACI as a high-priority group for immunization at any stage of pregnancy(34).

    Several studies have described influenza-related risk in healthy pregnant women and summary reviews are available(35-41). Since surrogate outcomes for influenza (e.g., hospitalization for ILI and respiratory or cardiopulmonary outcomes) rather than laboratory-confirmed influenza have been reported, it is difficult to know the true influenza-attributable risk. In some studies, it is also difficult to assess the contribution of underlying co-morbidities, since these are not always presented separately. More evaluation of the impact of seasonal influenza on the healthy pregnant woman and her fetus would be helpful.

    All studies that have stratified analysis according to gestational age show that influenza-related risk is not evenly distributed across all trimesters of pregnancy(42-44). In these studies, the rate of influenza-related hospitalization is not significantly increased during the first trimester of healthy pregnancy, but rather, increases later in pregnancy and is highest in the third trimester(42-44). In Neuzil et al.'s frequently cited 1997 publication spanning almost twenty influenza seasons, the risk of cardiopulmonary hospitalization during the influenza season rose significantly above the non-pregnant rate only beyond twenty-one weeks' gestation(42). Both Dodds et al. (Canada) and Neuzil et al. (US) reported excess influenza-related hospitalization rates of 40 and 100 per 100,000 women-months respectively in the third trimester, comparable to non-pregnant adults with co-morbidities(42;43). Differences in the methods and settings for estimating influenza-attributable rates should be taken into account in making these comparisons.

    The most robust epidemiologic evidence for increased influenza-related fatality in pregnancy comes from the major antigenic shifts of the 1918 and, to a lesser extent, the 1957 pandemics. Increased maternal mortality during subsequent antigenic shifts in 1968 and 1976 has not been described. With the exception of case reports and a single ecologic study in a single season in Great Britain(45), epidemiologic evidence has not shown increased maternal mortality associated with seasonal influenza (35;42;46-49).

    The antibody response to TIV in pregnant women is not expected to differ from that of non-pregnant individuals. Transplacental passage of maternal antibody is hypothesized to potentially protect the newborn. Several observational studies have assessed this epidemiologically with mixed results based on non-specific outcomes such as acute respiratory illness(35;50-52). In September 2008, Zaman et al. published the first randomized controlled trial (RCT) to assess effectiveness of influenza vaccine administered in the third trimester of pregnancy(53). In this study, 340 pregnant women in Bangladesh were randomized to receive either TIV or pneumococcal polysaccharide vaccine in the third trimester. A total of 300 mothers were followed from two weeks after antenatal immunization to delivery, and 316 were followed from delivery until their infants were 24 weeks of age. During the prolonged tropical influenza season described, TIV effectiveness against respiratory illness with fever was 36% (95% CI 4%-57%) in mothers and 29% (95% CI 7%-46%) in their infants. Vaccine efficacy against laboratory-confirmed influenza in the infants of immunized mothers followed for six months was 63% (95% CI 5%-85%). This study provides the first RCT evidence for mother/infant protection from TIV administered in pregnancy. The extent to which these results may be extrapolated to seasons with a different mix of virus strains and vaccine components, to temperate rather than tropical activity, and to different household/infant care or breastfeeding patterns warrants further evaluation.

    Passive surveillance has not identified concern related to serious adverse events following influenza immunization in pregnant women. Active studies to date have not shown evidence of harm to the mother or fetus associated with influenza immunization(38), but cumulative sample size to date has been small, especially during the first trimester (50;51;54-58). Further systematic evaluation would thus be informative.

    Serious maternal morbidity (namely hospitalization) during seasonal influenza supports a recommendation for seasonal TIV vaccine for healthy pregnant women since rates of influenza-associated hospitalization increase with length of gestation after the first trimester.

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

People who are potentially capable of transmitting influenza to those at high risk should receive an annual vaccination, regardless of whether the high-risk person has been immunized. Immunization of care providers decreases their own risk of illness, as well as of death and other serious outcomes among the patients for whom they care (59-64). Immunization of care providers and residents is associated with decreased risk of ILI outbreaks(65). Individuals who are more likely to transmit influenza to those at risk of medical complications or hospitalization due to influenza include the following groups:

  • Health care and other care providers in facilities and community settings. This group includes regular visitors, emergency response workers, those who have contact with residents of continuing care facilities or residences, those who provide home care for persons in high-risk groups, and students of related health care services.
  • Household contacts (adults and children) of individuals at high risk of influenza complications, whether or not the individual at high risk has been immunized. These individuals include household contacts of individuals at high risk of influenza-related complications or hospitalization, as listed earlier, household contacts of infants <6 months of age (who are at high risk of complications from influenza but for whom influenza vaccine is not approved) and members of a household expecting a newborn during the influenza season.
  • Those providing regular child care to children <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. crews on ships).

Others

  • 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 due to respiratory and other illnesses.
  • People in direct contact during culling operations involving poultry infected with avian influenza. These individuals may be at increased risk of avian influenza infection because of exposure during the culling operation (66-69). Influenza immunization on a yearly basis for these workers has been recommended in some countries(70) and provinces, based on the theoretical rationale that it may prevent the infection of these individuals with human influenza strains and thus reduce the potential for human-avian re-assortment of genes should such workers become co-infected with avian influenza (71). Direct involvement may be defined as sufficient contact with infected poultry to allow transmission of avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. Those who are immunized with influenza vaccine just before exposure to avian influenza will not produce protective antibodies against the human vaccine strains for approximately fourteen days. For further information on human health issues related to domestic avian influenza outbreaks, see the PHAC guidance at http://www.phac-aspc.gc.ca/publicat/daio-enia/index.html. See also PHAC antiviral guidance to be posted separately.

Further comments regarding influenza immunization

Immunization of healthy persons aged 2 to 64 years. Individuals in this age group are encouraged to receive the vaccine, even if they are not in one of the aforementioned priority groups. Systematic reviews of randomized controlled trials in healthy children and adults show that inactivated influenza vaccine is about 70% to 90% effective in preventing laboratory-confirmed influenza infection (29-31;72;73). A recent meta-analysis of randomized-controlled-trials since 1966 found a vaccine efficacy in young adults of 80% (95% confidence interval [CI] 56% to 91%) against laboratory-confirmed influenza when measured during select seasons of vaccine match and 50% (95% CI 27% to 65%) during select seasons of vaccine mismatch to circulating virus, although the amount of protection conferred is anticipated to vary with the degree of mismatch, the mix of circulating viruses and other factors(73).

In the U.S., the American Academy of Family Physicians and the Advisory Committee on Immunization Practices (ACIP) recommend routine annual influenza vaccination of adults ≥50 years of age. The prevalence of high-risk conditions increases at age 50 years, while the influenza immunization rate among U.S. adults with high-risk chronic medical conditions in this age group has been low. Age-based influenza guidelines may be more successful in reaching individuals with chronic medical conditions; in one analysis, this approach has been considered cost-effective(74).

In 2004, the ACIP in the U.S. recommended annual influenza immunization for children 6 to 23 months of age and their household contacts, and in 2006 extended this to include children 24 to 59 months of age(75;76) on the basis of their increased risk of influenza-related clinic and emergency department visits. In February 2008, the ACIP also recommended annual vaccination for all children aged 5 to 18 years beginning in the 2008-2009 influenza season, if feasible, and no later than during the 2009-2010 influenza season on the basis of:

  1. impact of influenza on school-age children and their household contacts (school absenteeism, antibiotic use, medical visits, parental work loss);
  2. desire to improve coverage for high-risk children;
  3. and potential for indirect protection extended to persons who have close contact with children and for reduced overall transmission within communities, given sufficient vaccination coverage(77). Epidemiologic evidence related to the latter rationale has varied and is mostly ecologic in nature.

Before making recommendations that may influence immunization programs nationally, NACI is committed to careful systematic review of the required and available evidence and interpretation in the context of goals and objectives previously established in Canada by a consensus process(23). As with other new vaccines, this process will be followed in considering population-based indications for expansion of influenza immunization programs. A summary of that analysis in relation to pediatric or other program expansion will be made available when concluded. Until then, NACI continues to encourage influenza vaccine for all Canadians.

  • Travellers. Travellers with a chronic health condition or other factors that would make them recommended recipients of influenza vaccine should be immunized as previously discussed (see Table 1), and healthy persons are also encouraged to receive vaccine as outlined earlier. Vaccine products/formulations prepared specifically for use in the Southern Hemisphere are not currently available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. For further information on advising travellers about influenza prevention, consult the Committee to Advise on Tropical Medicine and Travel (CATMAT) statement(78).

Immunogenicity and efficacy

Intramuscular administration of inactivated influenza vaccine results in the production of circulating IgG antibodies to the viral hemagglutinin and neuraminidase, as well as a more limited cytotoxic T lymphocyte response. Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. The antibody response 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 two weeks after immunization. Because influenza viruses change over time, immunity conferred in one season will not reliably prevent infection by an antigenically drifted strain. For this reason, the antigenic components of the vaccine change each year, and annual immunization is recommended.

Immunogenicity data for the 2009-2010 TIV for influenza strains recently obtained from respective vaccine manufacturers is summarized below:

  1. FluViral® influenza strains (based on limited clinical study of 55 adult and 55 elderly subjects (79)
    • A/Brisbane /10/2007 (H3N2)-like: met 3/3 EMEA (European Medicines Agency) immunogenicity success criteria for 18-60 year olds and >60 year olds
    • A/Brisbane/59/2007 (H1N1)-like: met 3/3 EMEA immunogenicity success criteria for 18-60 year olds; did not meet any immunogenicity criteria for >60 year olds
    • B/Brisbane/60/2008-like: met 3/3 EMEA immunogenicity success criteria for 18-60 year olds and >60 year olds

      All three strains met the three immunogenicity success criteria for 18-60 year olds, and two strains met all three immunogenicity success criteria for those >60 years of age. While the A/Brisbane/59/2007 (H1N1)-like strain did not meet any immunogenicity success criteria for >60 year olds, the clinical significance is unknown and this strain is not expected to be as prevalent in the 2009-2010 season. Health Canada has approved the use of FluViral®, including in those >60 years of age.
  2. Vaxigrip®(80)
    • A/Brisbane /10/2007 (H3N2)-like: met 3/3 EMEA (European Medicines Agency) immunogenicity success criteria for both 18-60 year olds and >60 year olds
    • A/Brisbane/59/2007 (H1N1)-like: met 3/3 EMEA immunogenicity success criteria for both 18-60 year olds and >60 year olds
    • B/Brisbane/60/2008-like: met 2/3 EMEA immunogenicity success criteria (seroconversion and Geometric Mean Ratio, GMR) in 18-60 year olds and 1/3 EMEA success criterion (GMR) in >60 year olds (using native antigen); however all three criteria were met for both age groups when the HAI method using split antigen for the B strain was used. Vaxigrip® met all three EMEA criteria for influenza A strains for both age groups and at least one EMEA criteria for the influenza B strains for both age groups.

Repeated annual administration of influenza vaccine has not been demonstrated to impair the immune response of the recipient to influenza virus. Multiple studies show that influenza vaccine is efficacious, with higher efficacy demonstrated against laboratory-confirmed influenza than clinically defined outcomes without laboratory confirmation(81). With a good match, influenza vaccination has been shown to prevent influenza illness in approximately 70% to 90% of healthy children and adults (29-31;72;73). Recent meta-analysis identified vaccine efficacy of 50% (95% CI 27% to 65%) during select seasons of vaccine mismatch, although mismatch is a relative term and the amount of cross-protection is expected to vary(73;82;83). Systematic reviews have also demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admission and death in the elderly(84;85) and reduces exacerbations in persons with chronic obstructive pulmonary disease(86). In observational studies, immunization reduces the number of physician visits, hospitalization and death in high-risk persons <65 years of age(87), reduces hospitalizations for cardiac disease and stroke in the elderly(88), and reduces hospitalization and deaths in persons with diabetes mellitus(89). Increasingly, the need for caution has been expressed in the interpretation of observational studies that use non-specific clinical outcomes and that do not take into account differences in functional status or health-related behaviours(90-95). Studies that assess vaccine protection against laboratory-confirmed influenza and its serious complications are needed.

The first time that children <9 years of age receive influenza immunization, a two-dose schedule is required (see Table 2)(96-98).

Allison et al. assessed vaccine effectiveness against outpatient visits for ILI for the period 1 November to 31 December 2003 among children 6 to 21 months of age given two separate-season (fall 2002 + fall 2003) versus two same-season (fall 2003 + fall 2003) doses of TIV (no change in vaccine components between study years). Vaccine effectiveness against ILI of 62% (95% CI 49% to 72%) and 82% (95% CI 77% to 86%) were recorded for the separate-season and same-season schedules, respectively(99). Although significantly different from each other, these vaccine effectiveness estimates are high given the non-specific clinical outcome that was used (ILI) and given that the vaccine was suboptimally matched to a circulating virus in 2003-2004. Results from this study are therefore difficult to interpret in relation to same- versus separate-season scheduling of two-dose immunization.

Englund et al.(7) conducted a randomized study of children 6 to 23 months of age comparing a two-dose TIV schedule given during separate seasons with two doses given during the same season. The authors reported similar immunogenicity whether two doses were given in the same or separate seasons without a change in vaccine formulation between seasons(100). In a non-randomized trial, the same group compared a two-dose TIV schedule in children 6 to 23 months of age during another separate-season (Group 1: fall 2003 + fall 2004) versus same-season (Group 2: fall 2004 + fall 2004) design. Seroprotection rates were not significantly different between the two schedules for the H3N2 (minor vaccine strain change) and H1N1 (no vaccine change) components. However, 27% of healthy infants/toddlers in Group 1 had a seroprotective antibody response to the 2004-2005 influenza B component compared with 86% in Group 2. There was a major antigenic (lineage) change in the B component of the TIV vaccine between the 2003-2004 (B/Victoria) and 2004-2005 (B/Yamagata) vaccine formulations. In a randomized trial involving children 6 to 23 months of age by the same research group and using the same 2003-2004 and 2004-2005 vaccine formulations, similar findings were reported. In the 2007-2008 NACI influenza statement, these immunogenicity data were interpreted in relation to whether doses were given in the same versus separate seasons. Another interpretation, however, is that children 6 to 23 months of age immunized against one B lineage may not be adequately primed to respond to a single dose of the other B lineage. On the basis of the sum total of evidence, NACI gives more weight to the latter interpretation, but further evaluation is required.

NACI thus continues to recommend two doses of TIV for all previously unvaccinated children who are <9 years of age and receiving TIV for the first time. Because they are less likely to have had prior priming exposure to an influenza virus and because they receive a lower per-injection dose of TIV, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children 6 to 23 months of age. While data require further corroboration, recent studies suggest that when there is a major antigenic (B lineage) change in vaccine component (B/Victoria versus B/Yamagata) between sequential seasons, two doses may need to be considered in the second season for children 6 to 23 months of age(6;7). Studies are needed to assess the extent to which this may also apply to older children. Pending further evidence, eligible children <9 years of age who have properly received one or more doses of TIV in the past are recommended to receive one dose per season thereafter. NACI encourages further research in this area, especially with respect to response to the B component.

Vaccine efficacy may be lower in certain populations (e.g. immunocompromised persons, elderly persons) than in healthy adults. However, the possibility of lower efficacy should not prevent immunization in those at high risk of influenza-associated morbidity, since protection is still likely to occur. Influenza vaccination can induce protective antibody levels in a substantial proportion of immunosuppressed adults and children, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients (101-103) Several studies show that administration of a second dose of influenza vaccine in elderly individuals or other individuals who may have an altered immune response does not result in clinically significant antibody boost. (104-109)

Administration of influenza vaccine: dosage and schedule

The recommended dosage schedule and type of influenza vaccine are presented in Table 2. Influenza vaccines in Canada are available as inactivated split-virus or inactivated subunit preparations. Two products (Vaxigrip®, Fluviral S/F®) are split-virus vaccines that are treated with an organic solvent to remove surface glycoproteins, producing a split virus resulting in reduced vaccine reactogenicity. InfluvacTM is a surface antigen, trivalent, inactivated subunit vaccine, which is currently approved for use in persons ≥18 years of age. For all TIV formulations, each 0.5 mL dose of vaccine contains 15 μg of hemagglutinin of each antigen.

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

Influenza 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 between 6 and 12 months of age.

Table 2. Recommended influenza vaccine dosage, by age, for the 2009-2010 season
Age Vaccine type Dosage (mL) Number of doses required
6-35 months split-virus 0.25 1 or 2*
3-8 years split-virus 0.5 1 or 2*
≥9 years split-virus 0.5 1
≥18 years subunit, or split-virus 0.5 1

*Previously unvaccinated children <9 years of age require two doses of the split-virus influenza vaccine, with an interval of 4 weeks. Eligible children <9 years of age who have properly received one or more doses of TIV in the past are recommended to receive one dose per season thereafter. Additional considerations pertaining to the TIV schedule in young children are described in the section entitled Immunogenicity and Efficacy. See above text for details.

Adverse reactions

Influenza vaccination cannot cause influenza because the vaccine does not contain live virus. Soreness at the injection site lasting up to two days is common in adults but rarely interferes with normal activities. Healthy adults receiving the TIV show 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 1 to 5 years of age.

Several influenza vaccines that are currently marketed in Canada contain minute quantities of thimerosal, which is used as a preservative(110;111). Large cohort studies of health databases have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders(112). Similar large-scale studies have not specifically addressed prenatal exposure to thimerosal-containing vaccines in pregnancy. Despite the absence of data indicating any associated risk, influenza vaccine manufacturers in Canada are currently working towards production and marketing of thimerosal-free influenza vaccines. One thimerosal-free influenza vaccine (Influvac™, Solvay Pharma) is already approved and available for persons ≥18 years of age in Canada. (110;111)

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

Guillain-Barré syndrome (GBS) occurred in adults in association with the 1976 swine influenza vaccine, and evidence is consistent with a causal relation between the vaccine and GBS during that season.(113) In an extensive review of studies since 1976, the United States Institute of Medicine concluded that the evidence was inadequate to accept or reject a causal relation between GBS in adults and influenza vaccines administered after the swine influenza vaccine program in 1976.(114)

In a Canadian study, the background incidence of GBS due to any cause was estimated at 2.02 per 100,000 person-years in Ontario and 2.30 per 100,000 person-years in Quebec(115). A variety of infectious agents, including Campylobacter jejuni , cytomegalovirus, Epstein-Barr virus and Mycoplasma pneumoniae, have been associated with GBS(116). A consistent finding in case series is the occurrence of an infection in the six weeks before GBS diagnosis in about two-thirds of patients(116). It is not known whether influenza virus infection itself is associated with GBS. A retrospective review of the 1992-1993 and 1993-1994 U.S. influenza vaccine campaigns found an adjusted relative risk of 1.7 (95% CI 1.0 to 2.8; p = 0.04) for GBS associated with influenza vaccination(117). This is consistent with a more recent Canadian study involving a self-matched case series from the Ontario health care database for the years 1992 to 2004. It found the estimated relative risk of hospitalization for GBS in the period two to seven weeks after influenza vaccination, compared with the period twenty to forty-three weeks after influenza vaccination, to be 1.45 (95% CI 1.05 to 1.99, p = 0.02)(118). These studies suggest that the absolute risk of GBS in the period following vaccination is about one excess case per 1 million vaccinees above the background GBS rate. The potential benefits of influenza vaccine (see Immunogenicity and Efficacy) must be weighed against this low risk.

The Ontario study also looked at the incidence of GBS in the entire Ontario population since 2000, when a universal influenza immunization program was introduced in that province; no statistically significant increase in hospital admissions because of GBS was found. In a recent 2009 publication, authors in the United Kingdom used the self-controlled case series method to investigate the relation of GBS with influenza vaccine and influenza-like illness using cases recorded in the United Kingdom General Practice Research database from 1990-2005. Authors found no evidence of an increased risk of GBS after seasonal influenza vaccine but a greatly increased risk after influenza-like illness, consistent with preceding respiratory infection as a possible trigger(119).

During the 2000-2001 influenza season, PHAC received an increased number of reports of vaccine-associated symptoms and signs that were subsequently described as “oculorespiratory syndrome” (ORS) (120). 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.

Approximately 5% to 34% of patients who have previously experienced ORS may have a recurrence attributable to the vaccine, but these episodes are usually milder than the original one, and vaccinees indicate willingness to be immunized in subsequent years(121;122). Persons who have a recurrence of ORS upon revaccination do not necessarily experience further episodes with future vaccinations. Data on clinically significant adverse events do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.

Recently a series of five studies of vaccine-effectiveness done in four Canadian provinces identified an association between prior receipt of seasonal influenza vaccine and medically-attended pH1N1 infection during the spring/summer 2009. If real, these findings suggest that prior 2008-2009 seasonal vaccine recipients in Canada were at 1.5-2.0-fold greater risk of medically-attended, laboratory confirmed pH1N1 illness. This effect was shown prominently among younger people (<50 years of age) in all studies but less consistently in older individuals (possibly due to sample size limitations). Among cases in the Canadian studies no increase in the risk of hospitalization associated with vaccine was found (123;124). While Canadian studies to date have been consistent in their findings, no association between a history of previous receipt of seasonal influenza vaccine has been seen in studies from Australia (125), Mexico (126) the United States, or the UK. NACI has reviewed available evidence from each of these studies. In general the Canadian study, designs place them in category II-2 level of evidence (evidence from cohort or case–control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy) with quality ratings of “good.”

The studies conducted by the US Centers for Disease Control and Prevention investigations in the United States (including a test-negative case-control study, a case-cohort study, and two retrospective cohort studies conducted during outbreak investigations) found no evidence of effect of TIV on disease due to pH1N1 (127). NACI found these studies to be level II-2, and of "good" quality. In particular it is noted that vaccine exposure could be ascertained through the individual's health record in the US case-control study.

A test-negative case control study conducted in Australia between April 27 and July 12 2009 similarly found no evidence of the effect of seasonal influenza vaccine in pH1N1 in any age group (125) (level II-2, quality “fair”). In Mexico, a case-control study investigated the link between the 2008-2009 seasonal influenza vaccine and cases of pH1N1 during the epidemic in Mexico City and found that seasonal TIV offers partial protection against pH1N1 (126), (level II-2, quality “poor”).

Further investigations (including prospective studies) on a possible association suggested by the Canadian studies between risk of pH1N1 infection and prior receipt of seasonal TIV (including exploration of co-factors including individual co-morbidities) are needed. Although a statistical difference in the prevalence of prior TIV was found among persons with pH1N1, the clinical significance of this observation is not clear.

Relative risks and benefits of TIV, including the morbidity and mortality associated with seasonal influenza, should be discussed prior to vaccination. People vaccinated with the seasonal TIV should be encouraged to also receive the pandemic H1N1 influenza vaccine if eligible.

Please refer to the Canadian Immunization Guide(128)for further details about administration of vaccine and management of adverse events.

Contraindications and precautions

Influenza vaccine should not be given to people who have had an anaphylactic reaction to a previous dose. For more information on vaccine safety and anaphylaxis, please see the Canadian Immunization Guide at http://www.phac-aspc.gc.ca/publicat/cig-gci/p02-03-eng.php.

Persons with known IgE-mediated hypersensitivity to eggs (manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension or shock) should not be routinely vaccinated with influenza vaccine. Egg-allergic individuals who are at risk of the complications of influenza 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. The Canadian Immunization Guide's recommendations for those with a known hypersensitivity to eggs can be found at http://www.phac-aspc.gc.ca/publicat/cig-gci/p02-04-eng.php.

Expert review of the risks and benefits of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent allergic reaction to the vaccine, or any other symptoms (e.g. throat constriction, difficulty swallowing) that raise concern regarding the safety of re-immunization. This advice may be obtained from local medical officers of health or other experts in infectious disease, allergy/immunology, and/or public health.

Individuals who have experienced ORS symptoms, including severe ORS consisting of non-lower respiratory symptoms (bilateral red eyes, cough, sore throat, hoarseness, facial swelling), may be safely re-immunized with influenza vaccine. Health care providers who are unsure whether an individual previously experienced ORS versus an IgE-mediated hypersensitivity immune response should seek advice. In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation (which may involve skin testing) from an allergy/immunology expert.

Persons with serious acute febrile illness usually should not be vaccinated 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.

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

Although influenza vaccine 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.

Therapy with beta-blocker medication is not a contraindication to influenza vaccination. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine.

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. Different administration sets (needle and syringe) must be used.

The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Health care providers should take the opportunity to vaccinate eligible persons against pneumococcal disease when influenza vaccine is given, according to the Canadian Immunization Guide (128).

Simultaneous administration of seasonal TIV and pH1N1 vaccine

It is a generally acceptable principle that the vaccines can be given at the same visit, using a different needle, syringe and injection site. If not given together, there are no timing restrictions on when additional inactivated vaccines can be administered. It should be noted that the seasonal influenza vaccine given each year results in the co-administration of three different influenza strains.

Preliminary data from a trial conducted by the National Institute of Allergy and Infectious Diseases (part of the US National Institutes of Health) reveal that co-administration of seasonal TIV and the 2009 H1N1 influenza unadjuvanted vaccine in healthy adults in the United States does not impair the immune response to either vaccine, and that both vaccines are well-tolerated. Early data from blood samples of twenty-five volunteers aged 18-64 years and twenty-five volunteers aged 65 years or older who received both vaccines at the same time have been analyzed. Seventy-six percent of those 18-64 years of age and 80% of those aged 65 years of age or older developed robust immune responses to the 2009 H1N1 influenza vaccine, and 80% of those aged 65 years of age or older developed an immune response (129). These results support the public health recommendations of the Centres for Disease Control and Prevention that simultaneous administration of injectable TIV and unadjuvanted pH1N1 vaccines is permissible if different anatomic sites are used (21). Based on these data, and the known safety and immunogenicity of concurrent administration of multiple vaccines in other settings, it is NACI's expert opinion that the adjuvanted pandemic H1N1 influenza vaccine is not expected to alter the effectiveness or safety of another inactivated influenza vaccine co-administered at a separate body site.

NACI recommends that seasonal TIV and unadjuvanted or adjuvanted pH1N1 vaccines may be administered concurrently in opposite limbs. If not administered together, there are no timing restrictions on the administration of the subsequent vaccine.

Storage

Influenza vaccine should be stored at +2°C to +8°C and should not be frozen.

Strategies for reducing the impact of influenza

Vaccination is recognized as the cornerstone for preventing or attenuating influenza for those at high risk of serious illness or death from influenza infection and related complications. Despite this, influenza immunization rates among recommended recipients are suboptimal. The 2005 Canadian Community Health Survey reports coverage rates of influenza vaccination in the previous year of only 30.3% (95% CI 29.7 to 30.9, n = 22,693) for adults aged 18 to 64 years with a chronic medical condition (130). Results from the 2006 Adult National Immunization Coverage Survey on coverage for adults 18 to 64 years of age with a chronic medical condition are similarly low, at 38.2% (95% CI 33.3 to 43.1, n = 395). Results from the latter survey show that non-institutionalized seniors (≥65 years) have higher coverage, with 69.9% (95% CI 64.1 to 75.7, n = 287) receiving influenza vaccine in the previous year. The results for this group have not changed since 2001(69.1%). Kwong et al. compared influenza vaccine rates in Ontario with those in other provinces in relation to introduction of the Universal Influenza Immunization Program (UIIP) in Ontario in 2000(131). Vaccination rate data were obtained from the 1996-1997 cycle of the National Population Health Survey (NPHS) and the 2000-2001, 2003, and 2005 cycles of the Canadian Community Health Survey (CCHS). Between the pre-UIIP 1996-1997 estimate to the mean post-UIIP vaccination rate, influenza vaccination rates for the household population aged ≥12 years increased 20 percentage points (18%-38%) for Ontario, compared with 11 percentage points (13%-24%) for other provinces (p = 0.001). For those <65 years of age, the vaccination rate increases were greater in Ontario than in other provinces, while for those ≥75 years of age, the increase was smaller in Ontario. Evaluation of the impact of universal immunization is to be assessed through systematic review of all relevant and available evidence by NACI prior to making related recommendations.

Coverage rates for residents of LTCFs range from 70% to 91% (132-134). Studies of HCWs in hospitals and LTCFs reveal influenza vaccination coverage rates of 26% to 61%. Coverage rates are higher among those in close contact with patients (69.7%, 95% CI 66.8 to 72.6, n = 727) (unpublished results from the 2006 Adult National Immunization Coverage Survey, Immunization and Respiratory Infections Division (IRID), PHAC).

Low rates of utilization may be due to failure of the health care system to offer the vaccine and refusal by persons who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary. HCWs and their employers have a duty to actively promote, implement, and comply with influenza immunization recommendations in order to decrease the risk of infection and complications among the vulnerable populations for which they care. Educational efforts aimed at HCWs and the public should address common doubts about disease risk for HCWs, their families and patients, vaccine effectiveness, and adverse reactions.

The advice of a health care provider is a very important factor affecting whether a person accepts immunization. Most people at high risk are already under medical care and should be vaccinated during regular fall visits. Strategies to improve coverage include, but are not limited to, the following:

  • Standing-order policies in institutions allowing nurses to administer vaccine and simultaneous immunization of staff and patients in nursing homes and chronic care facilities. In these settings, increased vaccination rates are associated with
    • a single, non-physician staff person organizing the program,
    • having program aspects covered by written policies, and
    • instituting a policy of obtaining consent on admission that is durable for future years.
  • Vaccinating people at high risk who are being discharged from hospital or visiting the emergency department.
  • Promoting influenza vaccination in clinics in which high-risk groups are seen (e.g. cancer clinics, cardiac clinics, pulmonary clinics, obstetrics clinics).
  • Using community newspapers, radio, television, other media, and influenza information lines, and collaborating with pharmacists and specialist physicians to distribute information about the benefits and risks of influenza immunization.
  • Issuing computer-generated reminders to HCWs, mailing reminder letters to patients, or using other recall methods to identify outpatients at high risk.
  • Issuing patient-carried reminder cards.
  • Increasing the accessibility of immunization clinics for staff in institutions and for community-based elderly (e.g. mobile programs).
  • Organizing activities such as vaccination fairs and competitions between institutions.
  • Working with multicultural groups to plan and implement effective programs.
  • Incorporating influenza vaccination within the provision of home health care.

Much of the research which has been proposed or is underway aims to deliver data on the effectiveness and safety of the influenza vaccination program, and has been necessitated by the lack of existing systems. This underscores the medium and long term need to establish in Canada population-based public health systems to evaluate influenza vaccine program effectiveness and safety through detailed integrated surveillance of vaccination coverage, disease and adverse events ("phase IV surveillance").

Immunization of HCWs

Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality. Studies have demonstrated that HCWs who are ill with influenza frequently continue to work, thereby potentially transmitting the virus to both patients and co-workers. In one study, 59% of HCWs with serologic evidence of recent influenza infection could not recall having influenza, suggesting that many HCWs experience subclinical infection (135). These individuals continued to work, potentially transmitting infection to their patients. In two other studies, HCWs reported four to ten times as many days of respiratory illness as days absent from work due to respiratory illness, suggesting that many HCWs worked while they were ill and were potentially able to transmit infection (64;136). In addition, absenteeism of HCWs who are sick with influenza results in excess economic costs and, in some cases, potential endangerment of health care delivery because of the scarcity of replacement workers.

For the purposes of this document, we define a HCW as a person who provides direct patient care, as well as one who provides health services in an indirect fashion, such as through administrative activities in a setting where patient care is conducted. The latter group may come into close contact with patients through the sharing of common areas within facilities, such as cafeterias and waiting areas. The term “direct patient contact” is defined as activities that allow opportunities for influenza transmission between HCWs and a patient.

NACI considers the provision of influenza vaccination for HCWs who have direct patient contact to be an essential component of the standard of care 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 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.

In order to protect vulnerable patients during an outbreak, it is reasonable to exclude from direct patient contact HCWs with confirmed or presumed influenza and unvaccinated HCWs who are not receiving antiviral prophylaxis. Health care organizations should have policies in place to deal with this issue.

Members: Dr. J. Langley (Chairperson), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Dr. N. Crowcroft , Ms. A. Hanrahan, Dr. B. Henry, Dr. D Kumar, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. B. Seifert, Dr. C. Quach-Thanh, Dr. D. Skowronski, Dr. B. Tan

Liaison Representatives: Dr. B. Bell (Center for Disease Control and Prevention), Dr. P. Orr (Association of Medical Microbiology and Infectious Disease Canada), Ms. K. Pielak (Canadian Nursing Coalition for Immunization), Dr. S. Rechner (College of Family Physicians of Canada), Dr. M. Salvadori (Canadian Paediatric Society), Dr. C. Cooper (Canadian Association for Immunization Research and Evaluation), Dr. S. Pelletier (Community Hospital Infection Control Association), Dr. N. Sicard (Canadian Public Health Association), Dr. V. Senikas (Society of Obstetricians and Gynaecologists of Canada), Dr. P. Plourde (Committee to Advise on Tropical Medicine and Travel)

Ex-Officio Representatives: Ms. M. FarhangMehr, Dr. S. Desai, Dr. B. Law (Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada), LCol (Dr.) James Anderson (Department of National Defence), Dr. Ezzat Farzad (First Nations and Inuit Health Branch – Office of Community Medicine, Health Canada), Dr. F. Hindieh (Biologics and Genetic Therapies Directorate, Health Canada)

†This statement was prepared and approved by NACI.

References

Reference List

  • (1) Shaw MW, Xu X, Li Y, Normand S, Ueki RT, Kunimoto GY, et al. Reappearance and global spread of variants of influenza B/Victoria/2/87 lineage viruses in the 2000-2001 and 2001-2002 seasons. Virology 2002 Nov 10;303(1):1-8.
  • (2) Levandowski RA, Gross PA, Weksler M, Staton E, Williams MS, Bonelli J. Cross-reactive antibodies induced by a monovalent influenza B virus vaccine. J Clin Microbiol 1991;29(7):1530-2.
  • (3) Heckler R, Baillot A, Engelman H, Neumeier E, Windorfer A. Cross-protection against homologous drift variants of influenza A and B after vaccination with split vaccine. Intervirology 2007;50(1):58-62.
  • (4) World Health Organization. Recommended composition of influenza virus vaccines for use in the 2008-2009 influenza season. Weekly Epidemiological Record 2008;83(9):81-7.
  • (5) World Health Organization. Recommended composition of influenza virus vaccines for use in the 2009-2010 influenza season. Weekly Epidemiological Record 2009 200984(9):65-76. Available from: URL: http://www.who.int/csr/disease/influenza/200902_recommendation.pdf
  • (6) Walter EB, Neuzil KM, Zhu Y, et al. Influenza vaccine immunogenicity in 6 to 23-month-old children: are identical antigens necessary for priming? Pediatrics 2006;118:e570-e578.
  • (7) Englund JA, Walter EB, Gbadebo A, et al. Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics 2006;118(3):e579-e585.
  • (8) Levandowski RA, Regnery HL, Staton E, Burgess BG, Williams MS, Groothuis JR. Antibody responses to influenza B viruses in immunologically unprimed children. Pediatrics 1991;88(5):1031-6.
  • (9) Reyes F, Macey JF, Aziz S, Li Y, Watkins K, Winchester B, et al. Influenza in Canada: 2005-2006 season. Can Commun Dis Rep 2007 Feb 1;33(3):21-41.
  • (10) FluWatch. August 23, 2009 - August 29, 2009 (Week 34). Public Health Agency of Canada 2009 [cited 2009 Oct 14]; Available from: URL: http://www.phac-aspc.gc.ca/fluwatch/08-09/w34_09/index-eng.php
  • (11) Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J, et al. Critically Ill Patients With 2009 Influenza A (H1N1) Infection in Canada. JAMA 2009 Oct 12.
  • (12) Hospitalized patients with novel influenza A (H1N1) virus infection - California, April-May, 2009. MMWR Morb Mortal Wkly Rep 2009 May 22;58(19):536-41.
  • (13) Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep 2009 Jul 17;58(27):749-52.
  • (14) Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep 2009 May 22;58(19):521-4.
  • (15) National Advisory Committee on Immunization (NACI). Advisory Committee Statement (ACS): Statement on Influenza Vaccination for the 2009-2010 Season. Can Commun Dis Rep. In press 2009.
  • (16) WHO / Europe Influenza Surveillance (EuroFlu). World Health Organization 2009 Available from: URL: http://www.euroflu.org/cgi-files/bulletin_v2.cgi
  • (17) Centers for Disease Control and Prevention. FluView: A weekly influenza surveillance report prepared by the Influenza Division. 2008-09 influenza season week 15 ending April 18, 2009. Centers for Disease Control and Prevention 2009 Available from: URL: http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/weekly15.htm
  • (18) Update: influenza activity--United States, April-August 2009. MMWR Morb Mortal Wkly Rep 2009 Sep 18;58(36):1009-12.
  • (19) Cumulative number of confirmed human cases of avian influenza A / (H5N1) reported to WHO. World Health Organization 2009 August 31 [cited 2009 Oct 14]; Available from: URL: http://www.who.int/csr/disease/avian_influenza/country/ cases_table_2009_08_31/en/index.html
  • (20) Current WHO phase of pandemic alert. World Health Organization 2009 [cited 2009 Oct 14]; Available from: URL: http://www.who.int/csr/disease/avian_influenza/phase/en/index.html
  • (21) Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009 Aug 28;58(RR-10):1-8.
  • (22) Law, B. and Van Buynder, P. 2009-10 seasonal influenza vaccination program in Sweden. 10-14-2009. Personal Communication
  • (23) Public Health Agency of Canada. Final Report of Outcomes from the National Consensus Conference for Vaccine-Preventable Diseases in Canada. Public Health Agency of Canada 2008 March 2008(34S2):28-32. Available from: URL: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/08vol34/34s2/index-eng.php
  • (24) Skowronski DM, Tweed SA, De Serres G. Rapid decline of influenza vaccine-induced antibody in the elderly: is it real, or is it relevant? J Infect Dis 2008;197:490-502.
  • (25) Simonsen L, Fukuda K, Schonberger LB, et al. The impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831-7.
  • (26) Schanzer DL, Tam TW, Langley JM, Winchester BT, et al. Influenza-attributable deaths, Canada 1990-1999. Epidemiol Infect 2007;1-8.
  • (27) Schanzer DL, Langley JM, Tam TW. Hospitalization attributable to influenza and other viral respiratory illnesses in Canadian children. Pediatr Infect Dis J 2006;25(9):795-800.
  • (28) Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342(4):232-9.
  • (29) Smith S, Demicheli V, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2006;2006(1):CD004879.
  • (30) Negri E, Colombo C, Giordano L, et al. Influenza vaccine in healthy children: a meta-analysis. Vaccine 2005;23(22):2851-61.
  • (31) Manzoli L, Schioppa F, Boccia A, et al. The efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential sources of variation in efficacy estimates including study quality. Pediatr Infect Dis J 2007;26(2):97-106.
  • (32) Skowronski DM, Woolcott JC, Tweed SA, et al. Potential cost-effectiveness of annual influenza immunization for infants and toddlers: experience from Canada. Vaccine 2006;24(19):4222-32.
  • (33) Esposito S, Marchisio P, Bosis S, et al. Clinical and economic impact of influenza vaccination on healthy children aged 2-5 years. Vaccine 2006;24(5):629-35.
  • (34) NACI. Statement on Influenza Vaccination for the 2007-2008 Season. Can Commun Dis Rep 2007 Jul 1;33.
  • (35) Black SB, Shinefield HR, France EK, et al. Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants. Amer J Perinatology 2004;6:333-9.
  • (36) Schanzer DL, Langley JM, Tam TW. Influenza-attributed hospitalization rates among pregnant women in Canada 1994-2000. JOGC 2007;29:622-9.
  • (37) Tuyishime JD, De Wals P, Moutquin JM, et al. Influenza-like illness during pregnancy:results from a study in the eastern townships, province of Quebec. JOGC 2003;25:1020-5.
  • (38) MacDonald NE, Riley LE, Steinhoff MC. Influenza immunization in pregnancy. Obstetrics and Gynecology. In press 2009.
  • (39) Skowronski DM, De Serres G. Is routine influenza immunization warranted in early pregnancy. Vaccine. In press 2009.
  • (40) McNeil SA, Halperin B, MacDonald NE. Influenza in pregnancy: the case for prevention. Adv Exp Med Biol 2009;2009(634):161-83.
  • (41) Mak TK MPLJWJPD. Influenza vaccination in pregnancy: current evidence and selected national policies. Lancet Infectious Diseases 2008;8:42-52.
  • (42) Neuzil KM, Reed GW, Mitchel EF, et al. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. AJE 1997;148:1094-8.
  • (43) Dodds L, McNeil SA, Fell SB, et al. Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ 2007;176:463-8.
  • (44) Hartert TV, Neuzil KM, Shintani AK, et al. Maternal morbidity and perinatal outcomes among pregnant women with respiratory hospitalizations during influenza season. Am J Obstet Gynecol 2003;189:1705-12.
  • (45) Ashley J, Smith T, Dunell K. Deaths in Great Britain associated with the influenza epidemic of 1989/90. Pop Trends 1991;65:16-20.
  • (46) Mulloolly JP, Barker WH, Nolan TF. Risk of acute respiratory disease among pregnant women during influenza A epidemics. Public Health Rep 1986;101:205-10.
  • (47) Schoenbaum SC, Weinstein L. Respiratory infection in pregnancy. Clin Obstet Gynecol 1979;22:293-300.
  • (48) Widelock D, Csizmas L, Klein S. Influenza, pregnancy, and fetal outcome. Public Health Reports 1963;78:1-11.
  • (49) Houseworth J, Langmuir AD. Excess mortality from epidemic influenza, 1957-1966. Amer J Epidemiol 1974;100:40-8.
  • (50) Hulka JF. Effectiveness of polyvalent influenza vaccine in pregnancy:report of a controlled study during an outbreak of Asian influenza. Obstetrics and Gynecology 1964;23:830-7.
  • (51) Munoz FM, Greisinger AJ, Wehmanen OA, et al. Safety of influenza vaccination during pregnancy. Am J Obset Gynecol 2005;192:1098-106.
  • (52) France EK, Smith-Ray R, McClure D, et al. Impact of maternal influenza vaccination during pregnancy on the incidence of acute respiratory illness visits among infants. Arch Pedatr Adolesc Med 2006;160:1277-83.
  • (53) Zaman K, Roy E, Arifeen SE, Rahman M, Raquib R, Wilson E, et al. Effectiveness of maternal influenza immunization in mothers and infants. NEJM 2008;359:1-10.
  • (54) Heinonen OP, Shapiro S, Monson RR, et al. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Intern J Epidemiol 1973;2:229-35.
  • (55) Heinonen OP, Slone D, Shapiro S. Immunizing agents. In: Kaufman DW, editor. Birth defects and drugs in pregnancy. Boston, MA: Littleton Publishing Sciences Group; 1977. p. 314-21.
  • (56) Sumaya CV, Gibbs RS. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine:reactogenicity and immunogenicity in mother and infant. J Infect Dis 1979;140:141-6.
  • (57) Englund JA, Mbawuike IN, Hammill H, et al. Maternal immunization with influenza or tetanus toxoid vaccine for passive antibody protection in young infants. J Infect Dis 1993;68:647-56.
  • (58) Deinard AS, Ogburn Jr P. A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome. Am J Obstet Gynecol 1981;140:240-5.
  • (59) Hayward AC, Harling R, Wetten S, et al. Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial. BMJ 2006;333(7581):1241.
  • (60) Potter J, Stott DJ, Roberts MA, et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. J Infect Dis 1997;175(1):1-6.
  • (61) Pearson ML, Bridges CB, Harper SA. Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-2):1-16.
  • (62) Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000;355(9198):93-7.
  • (63) Wilde JA, McMillan JA, Serwint J, et al. Effectiveness of influenza vaccine in health care professionals:a randomized trial. JAMA 1999;281(10):908-13.
  • (64) Saxen H, Virtanen M. Randomized, placebo-controlled double blind study on the efficacy of influenza immunization on absenteeism of health care workers. Pediatr Infect Dis J 1999;18(9):779-83.
  • (65) Shugarman LR, Hales C, Setodji CM, et al. The influence of staff and resident immunization rates on influenza-like illness outbreaks in nursing homes. J Am Med Dir Assoc 2006;7(9):562-7.
  • (66) Bridges CB, Lim W, Hu-Primmer J, et al. Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997-1998. J Infect Dis 2002;185(8):1005-10.
  • (67) Puzelli S, Di Trani L, Fabiani C, et al. Serological analysis of serum samples from humans exposed to avian H7 influenza viruses in Italy between 1999 and 2003. J Infect Dis 2005;192(8):1318-22.
  • (68) Tweed SA, Skowronski DM, David ST, et al. Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis 2004;10(12):2196-9.
  • (69) Skowronski DM, Li Y, Tweed SA, et al. Protective measures and human antibody response during an avian influenza H7N3 outbreak in poultry in British Columbia, Canada. CMAJ 2006;176(1):47-53.
  • (70) Department of Health UK. Flu vaccination for poultry workers. Department of Health UK 2007 [cited 2007 Jul 3]; Available from: URL: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAnd- Guidance/DH_063041
  • (71) Gray GC, Trampel DW, Roth JA. Pandemic influenza planning: Shouldn't swine and poultry workers be included? Vaccine 200725(22):4376-4381.
  • (72) Demicheli V, Rivelli D, Deeks JJ, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2004;2004(3):CD001269.
  • (73) Jefferson TO, Rivetti D, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews 2007;2007(2):CD001269.
  • (74) Turner DA, Wailoo AJ, Cooper NJ, et al. The cost-effectiveness of influenza vaccination of healthy adults 50-64 years of age. Vaccine 2006;24(7):1035-43.
  • (75) Poehling KA, Edwards KM, Weinberg GA, t al. The underrecognized burden of influenza in young children. N Engl J Med 2006;355(1):31-40.
  • (76) Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA, et al. Prevention and Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006 Jul 28;55 (RR-10):1-42.
  • (77) Advisory Committee on Immunization Practices. ACIP Recommendations for the Prevention and Control of Influenza. MMWR Recomm Rep. In press 2008.
  • (78) CATMAT. Statement on travel, influenza, and prevention. CCDR 2005;31(ACS-2):1-8.
  • (79) GlaxoSmithKline. Additional information on the immunogenicity of the 2009-10 TIV (FluViral®) influenza strains. 2009. Personal Communication
  • (80) sanofi pasteur. Clinical Study GRT86 (data on file). 10-2-2009. Personal Communication
  • (81) Langley JM, Faughnan ME. Prevention of influenza in the general population. Can Med Assoc J 2004;171(10):1213-22.
  • (82) Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 2006;355(24):2513-22.
  • (83) Herrera GA, Iwane MK, Cortese M, et al. Influenza vaccine effectiveness among 50-64-year-old persons during a season of poor antigenic match between vaccine and circulating influenza virus strains: Colorado, United States, 2003-2004. Vaccine 2007;25(1):154-60.
  • (84) Rivetti D, Jefferson T, Thomas R, et al. Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2006;2006(3):CD004876.
  • (85) Nichol KL, Nordin JD, Nelson DB, et al. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med 2007;357:1373-81.
  • (86) Poole PJ, Chacko E, Wood-Baker RW, et al. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;2006(1):CD002733.
  • (87) Hak E, Buskens E, van Essen GA, et al. Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: the PRISMA study. Arch Intern Med 2005;165(3):274-80.
  • (88) Nichol KL, Nordin J, Mullooly J, et al. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 2003;348(14):1322-32.
  • (89) Looijmans-Van den Akker I, Verheij TS, Buskens E, et al. Clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients. Diabetes care 2006;29(8):1771-6.
  • (90) Orenstein EW, De Serres G, Haber MJ, et al. Methodologic issues regarding the use of three observational study designs to assess influenza vaccine effectiveness. International J of Epidemiology 2007;36:623-31.
  • (91) Simonsen L. Commentary: Observational studies and the art of accurately measuring influenza vaccine benefits. International J of Epidemiology 2007;36:631-2.
  • (92) Jackson LA, Jackson ML, Nelson JC, et al. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J of Epidemiology 2006;35:337-44.
  • (93) Jackson LA, Nelson JC, Berson P, et al. Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors. Int J of Epidemiology 2006;35:345-52.
  • (94) Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis 2007;7:658-66.
  • (95) Simonsen L, Viboud C, Taylor RJ. Effectiveness of influenza vaccination [letter]. N Engl J Med 2007;357:2729-30.
  • (96) Ritzwoller DP, Bridges CB, Shetterley S, et al. Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8 years of age, with 1 vs 2 doses. Pediatrics 2005;116(1):153-9.
  • (97) Neuzil KM, Jackson LA, Nelson J, et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5-8-year-old children. J Infect Dis 2006;194:1032-9.
  • (98) Shuler CM, Iwamoto M, Bridges CB. Vaccine effectiveness against medically-attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003-2004. Pediatrics 2007;119:587-95.
  • (99) Allison MA, Daley MF, Crane LA, et al. Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003-2004 season. J Pediatr 2006;149(6):755-62.
  • (100) Englund JA, Walter EB, Fairchok MP, et al. A comparison of 2 influenza vaccine schedules in 6- to 23-month-old children. Pediatrics 2005;115(4):1039-47.
  • (101) Anema A. Efficacity of influenza vaccination among HIV+ patients: a systematic review and meta-analysis. 2008.
  • (102) Cooper CL. A review of influenza vaccine immunogenicity and efficacity in HIV-infected adults. 2008.
  • (103) Scharpe J, Evenepoel P, Maes B, Bammens B, Claes K, Osterhaus AD, et al. Influenza vaccination is efficacious and safe in renal transplant recipients. Am J Transplant 2008 Feb;8(2):332-7.
  • (104) Manuel O, Humar A, Chen MH, Chernenko S, Singer LG, Cobos I, et al. Immunogenicity and safety of an intradermal boosting strategy for vaccination against influenza in lung transplant recipients. Am J Transplant 2007 Nov;7(11):2567-72.
  • (105) Buxton JA. Influenza revaccination of elderly travelers: antibody response to single influenza vaccination and revaccination at 12 weeks. 2001 Jul 15.
  • (106) Ljungman P. Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine: a randomised case study. 2005.
  • (107) Lo W. Antibody response to a two-dose influenza vaccine regimen in adult lymphoma patients on chemotherapy. 1993.
  • (108) McElhaney JE. Comparison of single versus booster dose of influenza vaccination on humoral and cellular immune responses in older adults. 2005 May 9.
  • (109) Gross PA. Immunization of elderly people with two doses of influenza vaccine. 1987 Sep.
  • (110) Gemmill I. National Advisory Committee on Immunization (NACI) Statement on thimerosal. Can Commun Dis Rep 2003;29:1-10.
  • (111) NACI. Thimerosal: updated statement. Can Commun Dis Rep 2007;33(ACS-6):1-13.
  • (112) Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. Clin Infect Dis 2009;48:456-61.
  • (113) Langmuir AD, Bregman DJ, Kurland LT, et al. An epidemiologic and clinical evaluation of Guillain-Barre syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol 1984;119(6):841-79.
  • (114) Institute of Medicine. Immunization Safety Review: Influenza Vaccines and Neurological Complications. Washington, DC: Institute of Medicine of the National Academies; 2008.
  • (115) McLean M, Duclos P, Jacob P, et al. Incidence of Guillain-Barre syndrome in Ontario and Quebec, 1983-1989, using hospital service databases. Epidemiology 1994;5(4):443-8.
  • (116) Hughes RA, Cornblath DR. Guillain-Barre syndrome. Lancet 2005;366(9497):1653-66.
  • (117) Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998;339(25):1797-802.
  • (118) Juurlink DN, Stukel TA, Kwong J, et al. Guillain-Barre syndrome after influenza vaccination in adults: a population-based study. Arch Intern Med 2006;166(20):2217-21.
  • (119) Stowe J, Andrew N, Wise L, Miller E. Investigation of temporal association of Guillain-Barré Syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Research database. AJE 2009;169:382-8.
  • (120) NACI. Supplementary Statement for the 2002-2003 influenza season: Update on oculo-respiratory syndrome in association with influenza vaccination. 2002.
  • (121) Skowronski DM, Strauss B, Kendall P, et al. Low risk of recurrence of oculorespiratory syndrome following influenza revaccination. CMAJ 2002;167(853):858.
  • (122) De Serres G, Skowronski DM, Guay M, et al. Recurrence risk of oculorespiratory syndrome after influenza vaccination: randomized controlled trial of previously affected persons. Arch Intern Med 2004;164(20):2266-72.
  • (123) Beaudoin, C. Assessing the impact of seasonal influenza vaccination on pandemic H1N1 infection and disease severity risk at a population level in Manitoba. 10-14-2009. Personal Communication
  • (124) Skowronski DM. Findings from Canada: Seasonal influenza vaccine associated with increases risk of illness due to the 2009 pandemic A/H1N1 virus. 10-14-2009. Personal Communication
  • (125) Kelly H, Grant K. Interim analysis of pandemic influenza (H1N1) 2009 in Australia: surveillance trends, age of infection and effectiveness of seasonal vaccination. Euro Surveill 2009;14(31).
  • (126) Garcia-Garcia L, Valdespino-Gomez JL, Lazcano-Ponce E, Jimenez-Corona A, Higuera-Iglesias A, Cruz-Hervert P, et al. Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case-control study in Mexico City. BMJ 2009;339:b3928.
  • (127) Shay DK. Effect of 2008-09 seasonal influenza vaccination on the risk of infection with 2009 pandemic influenza A (H1N1). 10-7-2009. Personal Communication
  • (128) NACI. Canadian Immunization Guide. 7 ed. Public Works and Government Services Canada; 2006.
  • (129) Bulletin: Early Results: NAID Trial Supports Co-Administration of 2009 H1N1 Influenza Vaccine and Seasonal Influenza Vaccine. National Institute of Allergy and Infectious Diseases 2009 October 9 [cited 2009 Oct 14]; Available from: URL: http://www3.niaid.nih.gov/news/newsreleases/2009/H1N1plusSeasonalVax.htm
  • (130) Statistics Canada. Canadian Community Health Survey - Cycle 3.1 (this data release covers all data collected from January to December 2005). Statistics Canada 2007 [cited 2007 Jul 3]; Available from: URL: http://www. statcan.ca/cgi-bin/imdb/p2SV.pl?Function=getSurvey&S DDS=3226&lang=en&db=IMDB&dbg=f&adm=8&dis= 2
  • (131) Kwong JC, Stukel TA, Lim W, McGeer AJ, Upshur REG, et al. The effect of universal influenza immunization on mortality and health care use. PLoS Med 20085(10) Available from: URL: http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050211
  • (132) Stevenson CG, McArthur MA, Naus M, et al. Prevention of influenza and pneumococcal pneumonia in Canadian long-term care facilities: how are we doing? CMAJ 2001;164(10):1413-9.
  • (133) McArthur MA, Simor AE, Campbell B, et al. Influenza and pneumococcal vaccination and tuberculin skin testing programs in long-term care facilities: where do we stand? Infect Control Hosp Epidemiol 1995;16(1):18-24.
  • (134) Russell ML. Influenza vaccination in long-term care facilities. CMAJ 2001;165(10):1299.
  • (135) Elder A, O'Donnell B, McCruden E, Symington I, Carman W, et al. Incidence and recall of influenza in a cohort of Glasgow healthcare workers during the 1993-4 epidemic: results of serum testing and questionnaire. BMJ 1996;313:1241-2.
  • (136) Lester RT, McGeer A, Tomlinson G, et al. Use of, effectiveness of and attitudes regarding influenza vaccine among housestaff. Infect Control Hosp Epidemiol 2003;24:839-44.

Page details

Date modified: