An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)
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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.
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.
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.
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 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:
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.
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).
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).
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).
Current information (as of October 14, 2009) on the planned seasonal influenza immunization programs for 2009-2010 in the Northern Hemisphere is as follows:
(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.)
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.
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
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 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:
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:
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.
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:
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.
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)
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.
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.
|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*|
|≥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.
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
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
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.
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.
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).
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.
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen.
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:
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").
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.