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A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older

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Organization:Public Health Agency of Canada

Date published: 2016

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as the Agency) with ongoing and timely medical, scientific, and public health advice relating to immunization. The Agency 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 monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its 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 Agency's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Table of Contents

Executive Summary

Adults 65 years of age and older are at higher risk of becoming seriously ill or dying if they become sick with influenza, and their immune response to influenza vaccines is lower than that of younger people. Several influenza vaccines have been developed in an attempt to induce higher antibody responses that may increase effectiveness in older adults, including Fluad®, which is an adjuvanted vaccine with the same amount of antigen (15μg haemagglutinin [HA] per virus strain) as the standard inactivated influenza vaccine, Intanza®, which is an intradermally administered vaccine (15μg HA/strain), and Fluzone®High Dose vaccine, which has four times the concentration of influenza virus antigen as the standard inactivated influenza vaccine. As noted in the Statement on Seasonal Influenza Vaccine for 2015-2016 (subsequent to the completion of the initial review of the literature), Sanofi Pasteur confirmed that Intanza®is no longer available on the Canadian market, however studies involving Intanza®are still summarized in this review as this announcement was not made until after the preparation of this report. Additionally, Fluzone®High Dose vaccine has since (Autumn 2015) received authorization for use in Canada.

In one large randomized controlled trial, people 65 years and older who received Fluzone®High Dose were 18-24% less likely to have laboratory-confirmed influenza than people who received Fluzone®(standard dose). Fluzone®High Dose vaccine has been shown to have significantly higher rates of antibody production (seroconversion, seroprotection, and post-vaccination geometric mean antibody titres) than Fluzone®(15μg HA/strain) and the intradermal inactivated influenza vaccine, Intanza®(15 μg HA/strain). The high dose vaccine and the intradermal vaccine did induce higher rates of reaction post-injection than the standard dose, but they were short-lived.

In conclusion, in people 65 years of age and older, the inactivated influenza vaccine containing higher doses of antigen (15 μg HA/strain for intradermal vaccine and >15 μg HA/strain for intramuscular vaccine) induced relatively higher serologic responses. Reduced influenza illness compared to the standard dose intramuscular inactivated vaccine was demonstrated in a few studies. A higher rate of post-injection local adverse events was noted with the higher dose product.

Note: An update to the literature review was conducted to find new studies indexed between June 27, 2014 and June 22, 2015. The additional literature included support to the original findings (see Section VII for more details).

I. Introduction

Background

The risk of becoming severely ill or dying when infected with influenza increases as adults age. During the influenza seasons from 2003-04 through 2010-11, excepting the pandemic of 2009, 55-65% of hospital separations in Canada and about 87% of deaths due to influenza occurred in citizens 65 years or older, although this age group only made up about 14% of the population Footnote 1. Although vaccination against influenza is the best strategy to prevent illness Footnote 2, studies show a reduced response to vaccines as people age Footnote 3, with the presence of one or more chronic diseases a marker for reduced response Footnote 4,Footnote 5. Immunosenescence is hypothesized to play a role in older adults' response to vaccines. Goodwin et al. Footnote 3 estimate that, after adjusting for vaccine and host factors, rates of seroconversion and seroprotection in older adults were 50-75% lower than that of younger adults.

In a recent meta-analysis, Beyer et al. Footnote 6 estimate that vaccine effectiveness against laboratory-confirmed influenza was about 49% (CI95% 33, 62) in adults 65 years and older. This is lower than the effectiveness of 59% (CI95% 51, 67) for healthy adults 18-64 years old as estimated by Osterholm et al. Footnote 7 in their meta-analysis of the literature. There is growing pressure to improve influenza vaccine effectiveness, especially in older adults who are at higher risk of complications when they contract influenza.

There are influenza vaccines specifically formulated for older adults. Fluad®, which is available in Canada, is an adjuvanted vaccine that has 15μg haemagglutinin of each strain in the vaccine and is injected intramuscularly; Intanza®, which was previously available in Canada, has 15μg haemagglutinin of each strain and is injected intradermally. The 15μg formulation of Intanza®is considered high-dose compared to the 9μg formulation that was intended for adults aged 18 to 59 years of age. Both the 9μg and 15μg intradermal products are no longer available in Canada. Fluzone®High Dose, which is authorized for use in Canada as of Autumn 2015, contains 60μg of haemagglutinin per strain and is injected intramuscularly. Another vaccine referred to in this review is Flublok®. It is an intramuscular, recombinant influenza vaccine that uses insect cells in the replication process rather than chicken eggs and contains 45μg of haemagglutinin of each strain. It is authorized in the United States of America for adults 18 years of age and older, but is not authorized in Canada.

Purpose and Objectives

The purpose of this report is to review, to assess, and to synthesize the currently available literature to determine whether the burden of influenza-related disease is lower in people 65 years and older (or subgroups thereof) who receive high dose trivalent inactivated influenza vaccine compared with those who receive standard dose inactivated trivalent, adjuvanted inactivated trivalent, or quadrivalent inactivated influenza vaccines.

II. Methods

This project includes information for adults 65 years and older, with no limit on their underlying health conditions. Publications with data from a wider range of age groups are included when subgroup data are available for some or all of the target age group (65 years and older). The review includes all high dose influenza vaccines, whether authorized or not, but with clear explication of whether they are authorized in Canada, experimental, or authorized in other countriesFootnote a. The review excludes the 2009 H1N1pdm vaccine and experimental pandemic vaccines (e.g., H5N1 or H7N9).

The literature search was conducted in three databases: Medline, Embase, and EBM reviews-Cochrane Central Register of Controlled Trials. The search strategy was designed with the keywords and limits intended to capture all the articles in these databases that were relevant to the systematic review's disease, interventions, outcomes, population and time period of interest. The search strategy applied to each of the three databases on June 27, 2014 to capture records published since January 1, 2000 is detailed in Appendix A. Clinical trials registered on clinicaltrials.gov were also downloaded and matched, as possible, with existing publications. Two studies had data available but were not yet published, or published only as abstract. These data were included in the review.

The search yielded 8338 non-duplicate records (Appendix B). Two individuals screened the titles and abstracts for relevance. Records were excluded if it was clear from their title and abstract that their study population did not contain at least some proportion of adults aged 65 years and older, they were not influenza vaccine related, or if it was only about pandemic influenza vaccines and did not investigate seasonal influenza in any analyses. Finally, records were excluded if it was clear that their outcomes did not include any of: efficacy or effectiveness information (laboratory-confirmed influenza, clinic or physician visit, hospitalization, influenza-related mortality), immunological data (seroconversion, seroprotection, or antibody titres), or safety (reactogenicity, local, systemic, or adverse reactions). Upon applying these criteria, 7779 records were excluded. The remaining records were retrieved for full-text review.

Each of the 559 articles retrieved for full-text review were screened again for relevance by two reviewers. Articles were only excluded if they were assessed as ineligible by both reviewers. If the first and second reviewers could not agree on the article's eligibility, the article was assessed by a third reviewer. Articles were designated as ineligible if they had greater than 10% of their study population either outside the age range or did not provide separate analysis for the age group of interest. Articles were also excluded if they did not present some data, whether through sub-group analyses or otherwise, that were about seasonal influenza vaccines, including data about vaccine efficacy or effectiveness, immunogenicity, or safety or reactogenicity. In addition, secondary research articles were excluded, as well as articles that analyzed data that were already included in the review via another article (unless it added information pertinent to the review). Lastly, studies were excluded if they contained insufficient information to assess its eligibility for the review or if it was a foreign language article that could not be reliably translated to and assessed in English. Based on these criteria 531 articles were excluded upon full-text review.

All remaining articles were assessed with regard to the level of evidence (see Appendix C, Table 1) and the quality of the study (see Appendix C, Table 2). Appendix D contains extracted information on efficacy and effectiveness, Appendix E on immunogenicity, and Appendix F on safety.

III. Results

III.1 Epidemiology

Illnesses caused by influenza viruses occur throughout the year with widespread seasonal waves happening almost every year. The annual global attack rate of influenza is estimated at 5-10% in adults and 20-30% in children Footnote 8. Although rates of influenza infection are higher in children, rates of serious morbidity and mortality are highest in children younger than 2 years of age, adults 65 years of age or older, and people with underlying medical conditions Footnote 8,Footnote 9.

Molinari et al. Footnote 12 estimated attack rates of 20% of American children under 5 years of age, 10% in children 5-17 years, 6.6% in adults 18 to 64 years, and 9% in adults 65 years and older. Using the Canadian national surveillance system for monitoring influenza, FluWatch, from the 2011-12 to 2013-14 influenza season, seniors accounted for 21-44% of all influenza detections per season. A larger proportion of seniors tested positive for influenza A(H3) subtype (range: 35-56% per season) compared to influenza A(H1) (8-12%) or influenza B (20-37%) in the past three seasons, however this is also attributed in part to the predominance of A(H3N2) during 2011-12 and 2012-13. The number of laboratory-confirmed outbreaks in long-term care facilities reported to FluWatch ranged from 180 in the predominantly A(H1N1) 2013-2014 season to 676 in the predominantly A(H3N2) 2012-2013 season Footnote 13.

An estimated 175,000 emergency department visits per year are attributable to influenza-related illnesses in Canada Footnote 11,Footnote 14,Footnote 1. Between 1997 and 2004, rates of visits to healthcare practitioners and emergency rooms for pneumonia and influenza-related illnesses were higher for Canadian children younger than 5 years of age (107/1000) and adults 65 years and older (81/1000) than for people 5 to 64 years old (34/1000) Footnote 15.

It is also estimated that an average of 12,200 influenza related hospital admissions occur annually in Canada Footnote 1,Footnote 11,Footnote 14. Rates of hospitalization due to influenza are highest in adults 65 years and older (18/1000), followed by rates of 8/1000 for children younger than 5 years and 1/1000 in people 5 to 64 years old Footnote 15. Data reported to FluWatch from the PHAC/CIHR Influenza Research Network (PCIRN) Serious Outcomes Surveillance (SOS) network indicates that for the 2011-12 through 2013-14 influenza seasons, people 65 years and older accounted for 33-68% of people hospitalized and 34-58% of people admitted to ICU who had laboratory-confirmed influenza. Adults 65 years and older account for approximately 15% of the Canadian populationFootnote 61.

In Canada, as many as 4,000 deaths (range 300 to 6700 annually) may be caused, directly or indirectly, by influenza Footnote 14,Footnote 16. The highest mortality rates are in people 65 years and older (108.8/100,000) followed by people 50-64 years old (4.0/100,000) and people younger than 50 years (0.04/100,000) Footnote 16. Even among older adults, the estimated risk of influenza-attributable death increases with age, from 23/100,000 Canadians 65-69 years old to 831/100,000 in people 90 years and older Footnote 17. The estimated risk of death due to influenza is about 12 times higher in older adults with chronic lung disease than those without chronic lung disease and about 5 times higher for those with heart disease than those without heart disease Footnote 17. Data reported to FluWatch from the SOS network indicates that for the 2011-12 through 2013-14 influenza seasons, of people who had laboratory-confirmed influenza, people 65 years and older accounted for 55-85% of those who died.

The NACI annual statement on seasonal influenza vaccine contains a full background on influenza and a description of vaccines available for use in Canada.

III.2 Efficacy and Effectiveness

Four studies comparing the relative efficacy of high dose vaccines were identified and described below.

The relative efficacy of Fluzone®High Dose (60μg HA/strain) compared with Fluzone®(15μg HA/strain) has been evaluated in two studies to date. The first study of 9158 ambulatory, medically-stable adults 65 years and older was conducted in 2009-2010 during the H1N1 pandemicFootnote 21. The relative efficacy was 12.5% in favour of Fluzone®High Dose against laboratory-confirmed influenza, but with exceedingly wide confidence bounds (CI95% -140, 66); in this study 21 of the 22 symptomatic cases of influenza were caused by the A(H1N1)pdm09 strain, which was not in the seasonal vaccine.

The second study was conducted in 2011-2012 and 2012-2013 Footnote 22. In this study of almost 32,000 older adults, 18-24% fewer illnesses caused by influenza occurred in people who received Fluzone®High Dose compared with those who received Fluzone®(standard dose). The relative efficacy against laboratory-confirmed influenza of the high dose vaccine compared to the standard dose vaccine was 18% (CI95% 5,30) in participants who provided swabs when they had an acute respiratory illness, with 2.0% and 2.4%, respectively, diagnosed with influenza. The relative efficacy against laboratory-confirmed influenza was 24% (CI95% 10,36), with 1.4% and 1.9%, respectively, diagnosed with influenza, in those who provided swabs when they had an influenza-like illness (i.e., acute respiratory illness with systemic symptom(s)).

The relative efficacy of FluBlok®(~45 μg HA/strain), compared with Fluzone®(15μg HA/strain) against culture-confirmed influenza was 25%(CI95% -448, 96) in adults 65 years and older and 50% (CI95% -76, 68) against culture- or serologic-confirmed influenza in this small (N=836) trial conducted in the USA Footnote 23. FluBlok®is not authorized for use in Canada; in the USA, it is only authorized for use in adults 18-49 years of age Footnote 24.

The relative effectiveness of Intanza®(15μg HA/strain) compared with Inflexal®V (15μg HA/strain), a virosome-adjuvanted subunit influenza vaccine, was 33% (CI95% 15, 48) against influenza-related hospitalization, for community-dwelling older adults in Spain Footnote 25. This large (N=164,021) retrospective cohort study limited analysis to hospital admissions with either laboratory-confirmed influenza or a main hospital discharge diagnosis of influenza in 2011-2012. Neither of these vaccines are currently available in Canada.

III.3 Serological criteria for assessment of influenza vaccines

A common measure of immunogenicity is to assess the level of serum antibodies produced in response to antigens included in the vaccine through a laboratory test called a hemagglutination inhibition (HI) assay. Seroconversion is measured as the proportion of participants with a minimum of a four-fold increase from pre- to post-immunization titres (≤1:10 to ≥1:40 or at least 4-fold rise in antibody titres). Seroprotection is a measure of the proportion of participants with a HI titre of ≥1:40 (or ≥1:32 in some studies) post-vaccination Footnote 26 and is generally accepted as being correlated with a 50% reduction in the risk of influenza Footnote 27. The geometric mean titre (GMT) is the geometric mean of the participants' (average of the logarithmic values of the titres) serum antibodies. The geometric mean fold rise (GMFR) is the ratio of the post-vaccination/pre-vaccination serum anti-haemagglutinin antibody titres.

When comparing two vaccines, there are two commonly used assessments: 1) the geometric mean titre ratio (GMTR), which uses the ratio of the post-vaccination GMT of people receiving each vaccine, and 2) the difference in the proportion of people who seroconvert in each group Footnote 27.
Non-inferiority of a new vaccine when comparing it to a licensed vaccine requires that: 1) the ratio of the post-vaccine GMT (GMT1/GMT0) has an upper-bound of 2-sided 95% confidence interval (CI) of <1.5 [or lower bound of >0.67], and 2) the difference in seroconversion rates (seroconversion1 - seroconversion0) has an upper bound of 2-sided 95% CI of <10 percentage points.

Table 1: Criteria for assessment of seasonal influenza vaccines for adults 60 years and older
(not for assessment of live attenuated vaccines)
Committee Seroconversion (or significant increase) Seroprotection (1:40 HA) GMFR Requirement
Committee for Proprietary Medicinal Products (Europe) Footnote 26 >30% of participants >60% of participants >2.0 At least one of three measures
Center for Biologics Evaluation & Research (USA) Footnote 27 Lower bound of 2-sided 95% CI ≥30% Lower bound of 2-sided 95% CI ≥60% NA Meets both

III.4 Immunogenicity

Immunogenicity refers to the ability of a vaccine to induce an immune response and is used to predict vaccine efficacy. As stated in the previous section, there are three common measures of immune response: seroprotection, seroconversion, and level of antibody titres as measured by geometric means.

High (>15 μg HA/strain) versus Standard Dose (15 μg HA/strain) Intramuscular Vaccines

60μg HA/strain Inactivated Intramuscular Vaccines

Four studies available at the time of this review compared the rates of seroconversion for study participants receiving vaccine containing 60μg (high dose) versus 15μg (standard dose) haemagglutinin (HA) per influenza strain. Rates of seroconversion were about 19% higher (ranging from 10-28%) for those receiving the higher dose vaccine - across all three strains in the vaccines and in all four studies Footnote 28,Footnote 29,Footnote 30,Footnote 31,Footnote 32. In the two studies that assessed significance, the rates of seroconversion were significantly higher for all three strains in the vaccine Footnote 28,Footnote 29. Similarly, rates of seroconversion were higher for those receiving the high compared to standard dose vaccines for participants 75 years and older and for a cohort of participants with underlying cardiopulmonary disease Footnote 28.

Five studies report higher rates of seroprotection for older adults vaccinated with the 60μg/strain product compared to those vaccinated with 15μg/strain vaccines Footnote 21,Footnote 28,Footnote 29,Footnote 30,Footnote 31,Footnote 32,Footnote 33. Four of the five studies assessed significance in these, seroprotection was significantly higher in the groups receiving the high dose vaccine for all three strains in three of the studies Footnote 28,Footnote 33,Footnote 34, but only against A(H1N1) in the fourth study Footnote 29. The relative lack of difference in response to the high dose vaccine in the fourth study may be attributable to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the study.

Geometric mean titre ratios (GMTR) of participants' responses to the high versus the standard dose influenza vaccines were reported by several authors and were calculated for those that provided group-specific post-vaccination titres for each of the vaccines. Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3-1.7) to the high dose vaccines than the standard dose vaccines. The GMTR of the A strains was about 1.8 times higher for those receiving the high dose vaccines compared to the standard dose vaccines; ranging from 1.6-2.3, depending on the study Footnote 21,Footnote 28,Footnote 29,Footnote 30,Footnote 31,Footnote 32,Footnote 33.

One unpublished study Footnote 35 followed older adults for two years following vaccination with either 15- or 60μg HA/strain. There were no differences between the small (N=50) groups in their geometric mean antibody titres two years after vaccination.

Authors of one study reported that older adults vaccinated with Fluzone®High Dose had higher rates of seroconversion and seroprotection and the ratio of post-vaccination geometric mean titres was significantly higher (1.3-1.4 to 1.0) for all three strains compared with those who received Intanza®(15μg HA per strain) Footnote 32.

30μg HA/strain Inactivated Intramuscular Vaccines

Della Cioppa et al. Footnote 36,Footnote 37 conducted a trial comparing the immune responses of a small number of older adults to a range of levels of H3N2 antigen (6- versus 12- and 15- versus 30μg HA), a range of amounts of adjuvant (0-100% of the amount used in the licensed vaccine, Fluad®), and intradermal compared with intramuscular administration. There were no significant differences in seroresponse between people who received 15μg versus 30μg HA of A(H3N2) antigen intramuscularly or people who received 6μg versus 12μg HA of A(H3N2) antigen intradermally.

A trial comparing nursing home residents who received a double dose (two injections of 15μg HA/strain licensed influenza vaccine in the same arm on the same day) were compared with residents who received the standard single dose Footnote 38. A significantly higher proportion of residents who received a double dose seroconverted and were seroprotected against the A(H3N2) strain 25 days after vaccination, and remained so 84 days afterwards. There were no differences between the groups 106 days after vaccination. Only results for the A(H3N2) strain were reported.

60μg HA/strain Subunit Intramuscular Vaccines

In 1988 Palache et al. Footnote 39 conducted a randomized controlled trial in which older adults living in nursing homes in the Netherlands received 10-, 20-, or 60μg HA/strain trivalent subunit influenza vaccine (Duphar BV). The rates of seroprotection were higher for those who received the 60μg HA/strain vaccine than the vaccines with lower doses. The geometric mean titre ratio did not change by dose for the A(H1N1) antigen. However, for people receiving the 60μg/strain vaccine, the GMTR was 1.6 for A(H3N2) and 2.1 for the B strain compared to those receiving the 10μg/strain vaccine.

Recombinant Haemagglutinin Intramuscular Vaccines

A randomized controlled trial comparing the recombinant influenza vaccine Flublok®, containing ~45μg HA/strain with Fluzone®containing 15μg/strain was conducted with community-dwelling people 65 years and older Footnote 23. The rates of seroconversion were significantly higher for both A strains of influenza for those receiving the higher dose vaccine. On the other hand, the rates of seroprotection were similar for the two vaccines. The B strain could not be compared since the strains were not the same in the two vaccines.

A randomized controlled trial compared the immunogenicity of several antigen levels of a recombinant influenza vaccine with Fluzone®containing 15μg/strain in participants 65 years and older Footnote 40. The rates of seroprotection and seroconversion were higher for those receiving the 45μg and 135μg HA/strain of the recombinant vaccine than those receiving Fluzone®for the A(H3N2) strain but rates were similar for the A(H1N1) and B strains. In comparison, participants receiving the 15μg/strain of recombinant vaccine had similar responses to the A(H3N2) strain and lower responses to both the A(H1N1) and B strains than those receiving Fluzone®.

High (>9μg HA/strain) Intradermal Influenza Vaccines

15μg HA/strain Inactivated Intradermal versus Standard Dose Inactivated Intramuscular Vaccines

Seven randomized controlled trials have been conducted with older adults comparing the immune responses of 15μg HA/strain intradermal influenza vaccines with 15μg HA/strain intramuscular vaccines Footnote 41,Footnote 42,Footnote 43,Footnote 44,Footnote 45,Footnote 46,Footnote 47. The rates of seroconversion, seroprotection, and the GMTR were generally higher for people who received the high dose intradermal vaccine than those receiving standard dose intramuscular vaccines. However, in only two of the studies, both with large sample sizes, were the differences statistically significant Footnote 42,Footnote 46. Arnou et al. Footnote 46 vaccinated older adults with the same vaccine annually for three years. Although rates of seroconversion and seroprotection were higher for those receiving the intradermal vaccine in the first year of the study, the rates were similar between the groups in the next two years when the sample size greatly diminished. Holland et al. Footnote 42 reported superior response to the intradermal vaccine compared with the standard dose intramuscular vaccine based on GMTR and significantly higher rates of serconversion for all three strains. The ratio of post-vaccination geometric mean titres for those vaccinated with the intradermal compared with intramuscular vaccines was about 1.3 times higher (range 1.0 to 1.8) across all studies.

15μg HA/strain Inactivated Intradermal versus 60μg HA/strain Inactivated Intramuscular Vaccine

In the one study that compared seroresponses, a higher percentage of participants receiving the 60μg HA/strain intramuscular vaccine seroconverted and were seroprotected than those receiving the 15μg HA/strain intradermal vaccine Footnote 32. The post-vaccination geometric mean titres for those receiving the 60μg HA/strain intramuscular vaccine were significantly higher than those receiving the 15μg HA/strain intradermal vaccine.

15μg HA/strain Inactivated Intradermal versus Adjuvanted Standard Dose Intramuscular Vaccines

Five randomized trials compared serological responses for older adults vaccinated with 15μg HA/strain intradermal influenza vaccines and 15μg HA/strain adjuvanted intramuscular vaccines Footnote 41,Footnote 45,Footnote 48,Footnote 49,Footnote 50. In one study with 905 participants, the adjuvanted intramuscular vaccine produced significantly higher rates of immunological response than the intradermal vaccine Footnote 41 while the participants in the other four studies had similar rates of seroconversion, seroprotection, and had similar GMFR. The post-vaccination ratio of geometric mean titres for those vaccinated with inactivated intramuscular influenza vaccine with an adjuvant was slightly higher than those vaccinated with an intradermal vaccine - about 1.1-1.2 (range 0.9 to 1.3).

III.5 Safety and adverse events

In adults 60 years and older, common local reactions to influenza vaccines without adjuvant that are injected intramuscularly include redness, swelling, pain, and induration. Local reactions common to vaccines injected intradermally include itchiness, soreness, redness, swelling, pain, and induration. These reactions last 2-3 days and rarely interfere with normal activities. Systemic reactions common to adults 60 years and older who receive influenza vaccines include headache, malaise, myalgia, fatigue, arthralgia, and fever.

High (>15μg HA/strain) versus Standard Dose (15μg HA/strain) Intramuscular Vaccines

60μg HA/strain Inactivated Intramuscular Influenza Vaccines

The 60μg HA/strain vaccines produce a significantly higher rate of systemic reactions than the 15μg HA/strain vaccines to which they were compared. One study reported a higher rate of systemic reaction without specifying the specific reactionFootnote 32. Other studies reported significantly higher rates of malaiseFootnote 28, myalgiaFootnote 28,Footnote 31, and moderate/severe feverFootnote 28.

Rates of systemic reactions in the first 7 days after vaccination include (15μg versus 60μg, respectively): myalgia (15-18% vs. 13-29%), malaise (13-14% vs. 16-18%), headache (14-17% vs. 11-17%), and fever (0.5-2.3% vs. 0.7-4.4%)Footnote 28,Footnote 29,Footnote 31. Rates of local reactions include: (15μg versus 60μg, respectively): pain (14-24% vs. 36-53%), redness (5-28 v 9-29%), and swelling (3-18% v 6-24%)Footnote 28,Footnote 29,Footnote 31.

Serious adverse events were similar in frequency between the 15- and 60-μg HA/strain vaccines. In 25,440 older adults who received the 60μg HA/strain vaccines, 6 (2.36/10,000) vaccine-related serious adverse events were reported including cardiac chest painFootnote 21, oculorespiratory syndromeFootnote 29, cranial nerve VI palsyFootnote 33, hypovolemic shockFootnote 33, acute disseminated encephalomyelitisFootnote 33, and Crohn's disease exacerbationFootnote 28. These events were classified by the study investigators as being vaccine-related.

30μg HA/strain Inactivated Intramuscular Influenza Vaccines

In the two studies there were no reported differences in the rate of local or systemic reactions for people who received the 15- or 30- μg HA/strain vaccines. There were no reported serious adverse events related to the vaccine among the 80 people who received the 30μg HA/strain vaccinesFootnote 30,Footnote 37.

Recombinant Haemagglutinin Vaccines

Recombinant subunit influenza vaccines elicited significantly higher rates of injection site painFootnote 40 and immediate injection site rednessFootnote 23 than standard dose inactivated influenza vaccines. No serious adverse events were reported in the 730 recipients.

High (>9μg HA/strain) Dose Intradermal Vaccines

15μg HA/strain Intradermal

The intradermal administration of influenza vaccines produces significantly higher rates of local reaction including redness, swelling, induration, and pruritus than either of the standard dose inactivated vaccines (i.e. those with and those without adjuvant)Footnote 41,Footnote 42,Footnote 43,Footnote 44,Footnote 45,Footnote 46,Footnote 49,Footnote 50. Rates of systemic and local reactions (non-adjuvanted intramuscular versus intradermal, respectively) include: headache (11-18% vs. 4-17%), myalgia (6-19% vs. 6-23%), malaise (6-13% vs. 5-20%), fever (0-4% vs. 1-3%), and pain (6-21% vs. 4-30%), redness (4-15% vs. 26-76%), swelling (2-13% vs. 19-62%), induration (5-17% vs. 25-64%), and pruritus (2-9% vs. 20-29%)Footnote 41,Footnote 42,Footnote 43,Footnote 46,Footnote 50.

Four severe adverse events that may have been related to receipt of the intradermal vaccine were reported in 4815 older adults (8.31/10,000) including myopericarditisFootnote 46, facial neuralgiaFootnote 46, brachial neuritisFootnote 42, and pneumoniaFootnote 49.

For an overview of contraindications and precautions for influenza vaccines in general, please see the NACI annual statement on seasonal influenza vaccines.

IV. Evidence gaps

IV.1 Older Adults with Risk Factors

The majority of studies reviewed for this report were conducted with ambulatory, community-dwelling older adults without immune suppressing diseases and who were not using immune suppressing medication. Also, the mean age of the participants is in the early 70s, when the immune response is expected to be better than for older adults. Studies need to be completed in older adults with immune suppressing conditions or using immune suppressing medications, people who are institutionalized, and adults who are 75 years of age and older to determine whether these vaccines are as effective in these cohorts as they are in the younger, healthier cohorts of seniors.

IV.2 Types of Vaccines Compared

There are no studies, at present, to compare the efficacy or effectiveness of 60μg HA/strain inactivated intramuscular influenza vaccine to 1) 15μg HA/strain inactivated intramuscular influenza vaccine containing an adjuvant, or 2) 15μg HA/strain inactivated intradermal vaccine. Since these vaccines are manufactured specifically for use in older adults, a head-to-head comparison would be informative for decision-makers. Only one study compared the immune responses of older adults vaccinated with 60μg HA/strain to those vaccinated with 15μg HA/strain intradermal vaccine and none have compared the immunogenicity of the 60μg HA/strain product to 15μg HA/strain intramuscular influenza vaccine containing an adjuvant.

There are also no studies that compare any of these vaccines with the quadrivalent influenza vaccines. Although a previous review found similar immune responses and safety profiles for inactivated quadrivalent compared with inactivated trivalent influenza vaccines in older adults, no studies have assessed the efficacy or effectiveness of the quadrivalent vaccines in seniors.

V. Discussion/Summary

In one large randomized controlled trial, people 65 years and older who received Fluzone®High Dose were 18-24% less likely to have laboratory-confirmed influenza than people who received Fluzone®(standard dose)Footnote 33. The high dose vaccine was shown to have significantly higher rates of seroconversion and seroprotection than its 15μg HA/strain standard dose counterpart. The post-vaccination geometric mean titres of people receiving the high dose vaccine was about 1.5-1.8 times higher than those receiving the standard dose vaccine, indicating higher relative antibody immune response 28 days after vaccination. The high dose vaccine does, however, induce higher rates of reaction post-injection but they were short-lived.

Intanza®(15μg HA/strain), which was produced for adults 60 years and older, was shown in one retrospective cohort study to reduce influenza-related hospitalization by 33% compared to the standard dose virosomal subunit trivalent influenza vaccine in community-dwelling adults 65 years and olderFootnote 25. Compared with standard dose intramuscular influenza vaccines, the rates of seroconversion and seroprotection are slightly higher in those receiving Intanza®. The post-vaccination geometric mean titres of people receiving Intanza®is about 1.3 times higher than those receiving the standard dose intramuscular vaccine. In comparison, people vaccinated with Intanza®(15μg HA/strain) had lower serological responses than those vaccinated with Fluzone®High Dose, but similar to those receiving adjuvanted formulations of influenza vaccines. The intradermal vaccine induced higher rates of reactogenicity than the non-adjuvanted intramuscular influenza vaccines.

VI. Conclusions

Higher dose intramuscular, trivalent inactivated influenza vaccine for older adultsFootnote b should provide superior protection compared with the standard dose intramuscular vaccines, but whether it is superior to the currently-available adjuvanted intramuscular formulations is, as-yet, unknown. The higher dose intradermal influenza vaccine indicated for older adults induces higher serological immune responses than the standard dose intramuscular vaccines to which it has been compared, similar responses as adjuvanted inactivated influenza vaccines, but lower responses than the high dose intramuscular inactivated influenza vaccine. The intradermal product is no longer available in Canada. Fluzone®High Dose and Intanza®(15μg) influenza vaccines induce higher rates of post-injection reactions, but these reactions are short-lived.

VII. Update to the review of the literature

Although anticipated, an intramuscular high dose seasonal influenza vaccine was not available on the market in Canada at the completion of the initial literature review. An update was conducted to ensure recommendations for the use of such a vaccine would be informed by a body of evidence that included the most current literature. The initial search strategy was replicated in Medline and EMBASE for literature indexed between June 27, 2014 and June 22, 2015. With the intradermal vaccine (Intanza®) no longer offered in Canada, studies using intradermal influenza vaccine as the high dose comparator were excluded.

The search yielded 1,003 non-duplicate records, with 73 articles undergoing full-text review. The review of the search results was conducted by two reviewers. Articles were only excluded if they were assessed as ineligible by both reviewers. If the first and second reviewers could not agree on the article's eligibility, the article was assessed by a third reviewer. Titles and abstracts, and full-text articles were screened for relevance and reasons for exclusion were the same as the initial review by two reviewers (see Methods section). Also excluded were articles that had previously been included in the review.

Two articles were subsequently selected for inclusion and were assessed for level of evidence (Appendix C, Table 1) and the quality of the study (Appendix C, Table 2). Appendix D contains extracted information on efficacy and effectiveness, and Appendix E on immunogenicity.

One study compared the relative efficacy of high dose vaccine and one assessed immunogenicity. Both are described below.

Izurieta et al. (2015) evaluated the relative efficacy of a high dose influenza vaccine [Fluzone®High Dose (60μg HA/strain)] and any standard dose influenza vaccine (15μg HA/strain) administered during the 2012-13 influenza season against probable influenza-related illness (community medical encounter with a rapid influenza diagnostic test and dispensing of oseltamivir), and hospital-in patient admission or emergency department visit with an influenza diagnosisFootnote 62. The study participants included 2,545,275 community-based adults 65 years and older who were enrolled in Medicare in the United States. Fewer events were observed in recipients of the high dose vaccine for both outcomes and the relative efficacy was 22% in favour of the high dose vaccine for both outcomes (95% CI: 15, 29 for probable influenza-related illness, and 95% CI:16, 27 for hospitalization or emergency department visit). Relative efficacy for probable influenza-related illness increased to 36% (95% CI: 13, 54) in those 85 years and older.

Measures of immunogenicity were assessed in a study by Nace et al. (2015) comparing high dose influenza vaccine [Fluzone®High Dose (60μg HA/strain)] and a standard dose influenza vaccine (15μg HA/strain) in 187 frail adults 65 years and older residing in long-term care facilities over two influenza seasons (2011-12, 2012-13)Footnote 63. While comparable at baseline, at Day 30, GMTs were significantly higher in recipients of the high dose vaccine during both seasons, except for H1N1 in 2012-13 and seroprotection was significantly higher for H3N2 and B during both seasons. At Day 180, GMTs were only significantly higher for H3N2 and seroprotection was only higher for H1N1 and H3N2, during the 2011-12 season in high dose vaccine recipients.

These two studies further support the conclusion of the original review that higher dose intramuscular, trivalent inactivated influenza vaccine for older adults should provide superior protection compared with the standard dose intramuscular vaccine. Izurieta et al (2015) demonstrates that this superior relative protection in older adults is enhanced in those 85 years and older. Nace et al. (2015) was also the first study to look at the use of high dose intramuscular influenza vaccine in a population of frail older adults, and begins to address an identified evidence gap. However, there continues to be a need for studies of high dose intramuscular trivalent inactivated influenza vaccine in high risk patients of all ages and for head-to-head trials of high dose intramuscular influenza vaccine, adjuvanted influenza vaccine, and the quadrivalent influenza vaccine.

VIII. List of abbreviations

Abbreviation Term
AE Adverse event
ADV Adjuvanted vaccine
ARI Acute respiratory illness
GMFR Geometric mean fold rise (post-vaccine GMT/pre-vaccine GMT)
GMT Geometric mean titre
GMTR Geometric mean titre ratio (post-vaccine GMT1/post-vaccineGMT0)
HI Haemagglutination inhibition
ID Intradermally-administered vaccine
ILI Influenza-like illness
IM Intramuscularly-administered vaccine
LAIV Live attenuated influenza vaccine
SAE Serious adverse event
v Versus

IX. References

Appendix A: Search strategy and results

Set History Results Comments
MEDLINE
1 ([influenza* or flu or "caiv-t" or laiv or grippe or "h1n1" or "h3n2"] adj5 [vaccin* or inocul* or inject*]).mp. 23003 Influenza vaccine textword Terms
2 (admune or afluria or agrippal or agriflu or alorbat or adiugrip or berigripina or biaflu-zonale or celvapan or chiromas or evagrip or flu-imune or fluogen or fluvaccin or gripavac or grippe-impfstoff or grippeimpfstoff or imovax or inflexal or influenzainum or influmix or influpozzi or influsplit or influvac or influvirus or isiflu or miniflu or nasalflu or niligrip or prodigrip or sandovac or anflu or batrevac or begrivac or "flu immune" or "flu imune" or "flu-vac" or flulaval or fluvirin or fluzone or fluarix or alluria or fluad or fluarix or fluax or "adju-fluax" or flublok or flucelvax or fluenz or flumist or fluinsure or "intranasal TIV" or flulaval or fluogen or flushield or fluvax or fluviral or fluvirin* or fluzone or gammaflu or grippovac or idflu or intanza or inflexal or influject or influpozzi or influsplit or influvac or intanza or invivac or mastaflu or "mfv ject" or munevan or mutagrip or niligrip or optaflu or preflucel or previgrip or trivalent or vacciflu or vaxigrip or "x-flu").mp. 5006 Specific vaccine textword Terms
3 (fluvax or Imuvac or Viroflu or Fluval or virosome or virosomal or Enzira or fluvirix or AS03 or MF59 or AS04 or virsomes).mp. 946 Specific vaccine textword Terms
4 Influenza Vaccines/ 16309 Influenza Vaccines MeSH terms
5 orthomyxoviridae infections/ or influenza, human/ 41942 Influenza Virus MeSH terms
6 influenzavirus a/ or influenza a virus/ or influenza a virus, h1n1 subtype/ or influenza a virus, h3n2 subtype/ or influenzavirus b/ or influenza b virus/ 28418 Influenza Virus MeSH terms
7 or/1-6 64873 MEDLINE influenza vaccine or virus terms*
8 limit 7 to ("all aged [65 and over]" or "aged [80 and over]") 7844 Age group limit
9 nursing homes/ or Homes for the Aged/ or (aged or senior* or "older adult*" or geriatric or retired or retiree* or elder* or pensioner*).ti,ab. 561491 Aged MeSH or textword terms
10 8 or (7 and 9) 10017 Geriatric age group results - Base Clinical Set
11 (clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or meta analysis or multicenter study or randomized controlled trial or pragmatic clinical trial).pt. or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/ or controlled clinical trials as topic/ or randomized controlled trials as topic/ or pragmatic clinical trials as topic/ or multicenter studies as topic/ or observational study as topic/ or meta-analysis as topic/ or double-blind method/ or single-blind method/ or (rct or rcts or random* or multicent* or placebo* or metaanalysis* or "meta-analysis" or sham or effectiveness or efficacy or compare*).mp. or (meta adj5 analysis).mp. or ([singl: or doubl: or tripl: or trebl:) adj5 (mask: or blind:]) mp. 3492788 Clinical Trial MeSH and Textword Terms
12 10 and 11 3982 Unique Clinical trial results
13 case-control studies/ or cohort studies/ or follow-up studies/ or longitudinal studies/ or prospective studies/ or retrospective studies/ or ([observational or evaluation or comparative] adj3 [study or studies or studied]).mp. 3167204 Cohort/Observational Study MeSH and textword terms
14 10 and 13 2732 Cohort study results
15 14 not 12 1154 Unique cohort results
EMBASE
1 ([influenza* or flu or "caiv-t" or laiv or grippe or "h1n1" or "h3n2") adj5 (vaccin* or inocul* or inject*]).mp. 45225 Influenza vaccine textword Terms
2 (admune or afluria or agrippal or agriflu or alorbat or adiugrip or berigripina or biaflu-zonale or celvapan or chiromas or evagrip or flu-imune or fluogen or fluvaccin or gripavac or grippe-impfstoff or grippeimpfstoff or imovax or inflexal or influenzainum or influmix or influpozzi or influsplit or influvac or influvirus or isiflu or miniflu or nasalflu or niligrip or prodigrip or sandovac or anflu or batrevac or begrivac or "flu immune" or "flu imune" or "flu-vac" or flulaval or fluvirin or fluzone or fluarix or alluria or fluad or fluarix or fluax or "adju-fluax" or flublok or flucelvax or fluenz or flumist or fluinsure or "intranasal TIV" or flulaval or fluogen or flushield or fluvax or fluviral or fluvirin* or fluzone or gammaflu or grippovac or idflu or intanza or inflexal or influject or influpozzi or influsplit or influvac or intanza or invivac or mastaflu or "mfv ject" or munevan or mutagrip or niligrip or optaflu or preflucel or previgrip or trivalent or vacciflu or vaxigrip or "x-flu").mp. 9190 Specific vaccine textword Terms
3 (fluvax or Imuvac or Viroflu or Fluval or virosome or virosomal or Enzira or fluvirix or AS03 or MF59 or AS04 or virsomes).mp. 1478 Specific vaccine textword Terms
4 influenza vaccination/ or influenza vaccine/ 30200 Influenza Vaccines EMBASE terms
5 influenza/ or orthomyxovirus infection/ or seasonal influenza/ 56842 Influenza Virus EMBASE terms
6 influenza virus/ or influenza a/ or 1977 russian influenza/ or 2009 h1n1 influenza/ or asian influenza/ or hong kong influenza/ or "influenza a (h1n1)"/ or "influenza a (h2n2)"/ or "influenza a (h3n2)"/ or influenza virus a h1n2/ or influenza virus a h2n2/ or influenza virus a h3n2/ or influenza virus a h3n8/ or influenza virus b/ or influenza b/ or "influenza b virus (b/jing fang/76/98)"/ 34222 Influenza Virus EMBASE terms
7 or/1-6 103871 EMBASE influenza vaccine or virus terms*
8 limit 7 to aged <65+ years> 8936 Age group limit
9 nursing home/ or nursing home patient/ or elderly care/ or exp geriatric care/ or home for the aged/ or (aged or senior* or "older adult*" or geriatric or retired or retiree* or elder* or pensioner*).ti,ab. 840992 Aged EMBASE or textword terms
10 8 or (7 and 9) 13301 Geriatric age group results - Base Clinical Set
11 limit 10 to (clinical trial or randomized controlled trial or controlled clinical trial or multicenter study or phase 3 clinical trial or phase 4 clinical trial) 2223 Clinical Trial EMBASE limit
12 limit 10 to (meta analysis or "systematic review") 165 Meta-analysis EMBASE limit
13 clinical trial/ or controlled clinical trial/ or randomized controlled trial/ or multicenter study/ or phase 3 clinical trial/ or phase 4 clinical trial/ or meta analysis/ or "clinical trial (topic)"/ or "controlled clinical trial (topic)"/ or "randomized controlled trial (topic)"/ or "multicenter study (topic)"/ or "phase 3 clinical trial (topic)"/ or "phase 4 clinical trial (topic)"/ or "meta analysis (topic)"/ or control group/ or crossover procedure/ or double blind procedure/ or single blind procedure/ or triple blind procedure/ or (rct or rcts or random* or multicent* or placebo* or metaanalysis* or "meta-analysis" or sham or effectiveness or efficacy or compare*).mp. or (meta adj5 analysis).mp. or ([singl: or doubl: or tripl: or trebl:] adj5 [mask: or blind:]).mp. 5442758 Clinical Trial EMBASE and textword terms
14 11 or 12 or (10 and 13) 6349 Unique Clinical trial results
15 cohort analysis/ or observational study/ or comparative study/ or comparative effectiveness/ or case control study/ or hospital based case control study/ or population based case control study/ or longitudinal study/ or postmarketing surveillance/ or drug surveillance program/ or ([observational or evaluation or comparative] adj3 [study or studies or studied]).mp. 1151928 Cohort/Observational Study EMBASE and textword terms
16 10 and 15 1522 Cohort study results
17 16 not 14 534 Unique cohort results
EBM reviews - Cochrane Central Register of Controlled Trials
1 ([influenza* or flu or "caiv-t" or laiv or grippe or "h1n1" or "h3n2"] adj5 [vaccin* or inocul* or inject*]).mp. 2187 Influenza vaccine textword Terms
2 (admune or afluria or agrippal or agriflu or alorbat or adiugrip or berigripina or biaflu-zonale or celvapan or chiromas or evagrip or flu-imune or fluogen or fluvaccin or gripavac or grippe-impfstoff or grippeimpfstoff or imovax or inflexal or influenzainum or influmix or influpozzi or influsplit or influvac or influvirus or isiflu or miniflu or nasalflu or niligrip or prodigrip or sandovac or anflu or batrevac or begrivac or "flu immune" or "flu imune" or "flu-vac" or flulaval or fluvirin or fluzone or fluarix or alluria or fluad or fluarix or fluax or "adju-fluax" or flublok or flucelvax or fluenz or flumist or fluinsure or "intranasal TIV" or flulaval or fluogen or flushield or fluvax or fluviral or fluvirin* or fluzone or gammaflu or grippovac or idflu or intanza or inflexal or influject or influpozzi or influsplit or influvac or intanza or invivac or mastaflu or "mfv ject" or munevan or mutagrip or niligrip or optaflu or preflucel or previgrip or trivalent or vacciflu or vaxigrip or "x-flu").mp. 537 Specific vaccine textword Terms
3 (fluvax or Imuvac or Viroflu or Fluval or virosome or virosomal or Enzira or fluvirix or AS03 or MF59 or AS04 or virsomes).mp. 277 Specific vaccine textword Terms
4 Influenza Vaccines/ or influenza vaccination/ or influenza vaccine/ 1071 Influenza Vaccines MEDLINE and EMBASE terms
5 orthomyxoviridae infections/ or influenza, human/ or influenza/ or orthomyxovirus infection/ or seasonal influenza/ 1049 Influenza Virus MEDLINE and EMBASE terms
6 influenzavirus a/ or influenza a virus/ or influenza a virus, h1n1 subtype/ or influenza a virus, h3n2 subtype/ or influenzavirus b/ or influenza b virus/ or influenza virus/ or influenza a/ or 1977 russian influenza/ or 2009 h1n1 influenza/ or asian influenza/ or hong kong influenza/ or "influenza a (h1n1)"/ or "influenza a (h2n2)"/ or "influenza a (h3n2)"/ or influenza virus a h1n2/ or influenza virus a h2n2/ or influenza virus a h3n2/ or influenza virus a h3n8/ or influenza virus b/ or influenza b/ or "influenza b virus (b/jing fang/76/98)"/ 708 Influenza Virus EMBASE terms
7 0r/1-6 2724 MEDLINE, EMBASE and textword influenza vaccine or virus terms*
8 nursing homes/ or Homes for the Aged/ or nursing home/ or nursing home patient/ or elderly care/ or exp geriatric care/ or home for the aged/ or (aged or senior* or "older adult*" or geriatric or retired or retiree* or elder* or pensioner*).ti,ab. 46889 Age group terms
9 7 and 8 707 FINAL Results

Appendix B: Flow diagram

A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older

Appendix B: Flow diagram
Text Equivalent - Figure 1

The attrition flow diagram describes the process by which articles were selected for the literature review.  The process is broken down into four stages: Identification, Screening, Eligibility and Included. 

Stage 1: Identification

  • 15,292 records were identified through database searching and 28 were discovered through clinical trials dot gov.
  • 8338 records remained after the duplicates were removed from these 15,320 records.

Stage 2: Screening

  • 8338 records were screened.
  • Of these 8338 records, 7779 records were excluded.  The exclusion breakdown is as follows: 4818 non-influenza vaccine records, 443 pandemic or non seasonal influenza vaccine records, 990 age records, 561 no intervention of interest records, 884 no outcome of interest records, and 83 not human subjects records.

Stage 3: Eligibility

  • 559 full text articles were assessed for eligibility
  • Of these 559 full text articles, 532 full text articles were excluded.  The exclusion breakdown is as follows: 5 pandemic or non seasonal vaccine, 154 age, 306 no intervention of interest, 4 no outcome of interest, 50 secondary research and 13 other.

Stage 4: Included

  • Of the 559 full text articles assessed for eligibility, 27 studies were included in the synthesis.   There were 26 randomized control trials and 1 cohort study.

Appendix C: Level of evidence based on research design and quality (internal validity) rating of evidence

Table 1: Levels of Evidence Based on Research Design
I Evidence from randomized controlled trial(s).
II-1 Evidence from controlled trial(s) without randomization.
II-2 Evidence from cohort or case–control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.

Table 2: Definition of overall study quality
Good A study (including meta-analyses or systematic reviews) that meets all design- specific criteria* well.
Fair A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion but has no known "fatal flaw".
Poor A study (including meta-analyses or systematic reviews) that has at least one design-specific "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
*General design specific criteria are outlined in Harris et al., 20011.

Appendix D: Summary of evidence related to efficacy/effectiveness of high dose influenza vaccines in adults 65 years and older

STUDY DETAILS SUMMARY
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality

Diaz Granados (2013)Footnote 21

NCT00976027

60μg: Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

15μg: Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/Brisbane/59/07 (H1N1)
A/Uruguay/716/2007 (H3N2)
B/Brisbane/60/2008

RCT
Double-blind
Multi-centre
Phase 3b

Country
USA
99 centres

Year 2009-10

Age ≥65 yrs
Mean 72.8 yrs
(64-99 yrs)
Male 46.3%

N=9158
60μg=6107
15μg=3051

85% Caucasian
89% vaccinated last season

Ambulatory, medically stable

Excluded
Bed-ridden, Immune suppressing disease

Follow up: 7 months, during 2009pdm
Outcome: ILI with lab-confirmed NP swab

PCR-confirmed influenza (any subtype)
Attack rates (per protocol)
15 μg 60 μg
2.66/1000 2.33/1000

Relative vaccine efficacy
ILI 12.5% (-140.9,65.7)

Notes:
21/22 cases were A/California/7/2009-like

24% of 60μg and 15μg participants received the H1N1 2009pdm vaccine respectively

ILI defined as: ≥ 1 of temperature >37.2oC, feverishness, chills, tiredness, headaches or myalgia; and ≥ 1 of nasal congestion, rhinorrhoea, sore throat, cough, sputum production, wheezing, chest tightness, shortness of breath, or chest pain with breathing

Level 1

Good

Diaz Granados
(2014)Footnote 33

NCT01427309

60μg: Fluzone®High Dose
60μg HA/strain
0.5mL/dose

15μg: Fluzone® 
15μg HA/strain
0.5mL/dose

2011-12 strains
A/California/
7/2009 (H1N1) A/Victoria/210/2009 (H3N2)
B/Brisbane/60/2008

2012-13 strains
A/California/7/2009 (H1N1) A/Victoria/361/
2011 (H3N2)
B/Texas/6/2011

RCT
Double-blind
Multicenter Phase 3b-4

Country
USA, Canada
126 centres

Year 2011-12
& 2012-13

Age ≥65 yrs Mean: 73.3 yrs
Male 43.4%

N=31,983
60μg=15,990
15μg=15,993

95% Caucasian
74% previous vaccination
67% ≥ 1 chronic condition

Follow-up: active weekly January-April 30

Outcome: ILI with lab-confirmed NP swab

Lab-confirmed influenza 
Attack rates: (any subtype)
  15 μg 60 μg
ILI 1.9 1.4%
ARI 2.4 2.0%

Relative efficacy
  60μg:15μg
ILI 24.2% (9.7,36.5)S
ARI 18.3% (5.0,29.8)

Notes:
ILI: ≥1 of sore throat, cough, sputum production, wheezing, or difficulty breathing and ≥1 of temperature >37.2oC, chills, tiredness, headaches, or myalgia
ARI: sneezing, nasal congestion, rhinorrhoea, sore throat, cough, sputum production, wheezing, or difficulty breathing

Level 1

Good

Izurieta (2015)62

IM: Fluzone High-Dose (Sanofi Pasteur) (60µg HA/strain)

IM: Standard-dose vaccine (15 µg HA/strain)

Retrospective cohort

Country USA

Year: 2012-2013

Community based adults, ≥65 years of age

N=2,545,275
60µg=929,730
15µg=1,615,545

Participants had to meet Medicare enrollment, duration and survival criteria, and have received vaccine from a community pharmacy that vaccinated at least one other beneficiary with the alternative vaccine within two weeks of index vaccination

Primary outcome: Probable episode of influenza-related illness defined as a community medical encounter with provision of a rapid influenza diagnostic test, followed by therapeutic dispensing of oseltamivir within a 2-day period)

Secondary outcome: Hospital in-patient admission or emergency department visit diagnosis of influenza

Outcomes per 10,000 person-weeks
  60µg 15 µg Risk Difference
Primary 1.01 1.30 0.29 (0.19, 0.38)
Secondary 0.86 1.10 0.24 (0.17, 0.30)

Relative vaccine effectiveness (60 µg v. 15 µg):
Primary: 22% (15, 29)
Secondary: 22% (16, 27)

Notes:

  • Groups well balanced, with only substantial differences being noted in geographic region
  • Effect estimates consistent whether from univariate or multivariate Poisson regression
  • Relative VE for primary outcome increased to 36% (13, 54) for those aged ≥85yrs

II-2

Good

Keitel (2009)Footnote 23

NCT00395174

45μg: FluBlok®(Protein
Sciences Corp)
~45μg rHA/strain
0.5mL/dose

Strains
A/Wisconsin (H3N2)
A/New Caledonia (H1N1)
B/Ohio

15μg: Fluzone®(Sanofi Pasteur).
15μg HA/strain
0.5mL/dose

Strains
A/Wisconsin (H3N2)
A/New Caledonia (H1N1)
B/Malaysia

RCT
Double-blind
Multi-centre Phase 3

Country
USA
7 centres

Year 2006-07

Age ≥65 yrs
Mean:
45μg 72.9 yrs
15μg 73.9 yrs
Male 47%

N=869
45μg N=436
15μg N=433

98% Caucasian
83% vaccinated last season

Ambulatory, medically-stable,
community
dwelling

Follow-up 2006-2007 season

Outcome: ILI with culture-confirmed nasal and throat swabs

Lab-confirmed influenza attack rates
(any subtype)
  15 μg 45μg
Culture 0.5% 0.2%
Serological 2.8% 2.1%

Relative VE (computed)
Culture 0.50 (0.01,9.56)
Serological 0.79 (0.27,2.25)
Either 0.74 (0.27,1.94)

Notes:
ILI: fever with cough and/or sore throat

Level 1

Good

Puig-Barberà (2014)Footnote 25

ID: Intanza®(Sanofi Pasteur)
15µg HA/strain
0.1mL/dose

IM: Inflexal-V®(Crucell) virosomal, subunit
15µg HA/strain 0.5mL/dose

Strains
A/California/7/2009 (H1N1)
A/Perth/16/2009 (H3N2)
B/Brisbane/60/2008

Retrospective cohort

Country
Spain
9 hospital service areas

Year 2011-12

Age ≥65 yrs
Mean: 76.7 yrs
Male: 44.7%

N=164,021
ID=101,963
IM= 62,058

87% vaccinated last season

Excluded readmissions within 30 days, institutionalized, receipt of other
influenza vaccines

Follow up Dec 2011-Mar 2012

Influenza-related hospitalization: Rate/100,000 person-week
  ID IM RR(CI95%)
All ages 8.8 13.9 0.64 (0.50,0.81)
65-69 yrs 1.9 6.0 0.31 (0.12,0.83)
70-74 yrs 5.9 8.8 0.67 (0.36,1.27)
75-79 yrs 10.4 15.5 0.67 (0.42,1.07)
80-84 yrs 12.9 20.1 0.64 (0.40,1.02)
≥85 yrs 16.0 23.4 0.68 (0.42,1.14)

Relative effectiveness
  ID:IM
Crude 36% (19:50)
Adjusted 33% (15:48)

Notes:
Influenza-related admission:
Vaccine ≥15 days before hospitalization & one of:

  • main discharge diagnosis of influenza
  • admission with PCR-confirmed influenza

Level II-2

Good

Appendix E: Summary of evidence related to immunogenicity of high dose seasonal influenza vaccines in adults 65 years and older

STUDY DETAILS
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality

Couch (2007)Footnote 29

NCT00115531 NCT00170508
NCT00170482

60μg: Experimental
60µg HA/strain
0.5mL/dose IM

15μg: Fluzone®(Sanofi Pasteur)
15µg HA/strain
0.5mL/dose IM

Strains
A/New Caledonia/20/99 (H1N1), A/Wyoming/03/2003 (H3N2) B/Jiangsu/10/2003

RCT
Double blind
Multi-site
Phase II

Country USA

Year 2004-05

Stratified by receipt of influenza vaccine in same season

Age ≥65
Mean: 73-74 yrs
Male 51%

N=414
60μg=206
15μg=208

78% vaccinated in fall of 2004 (same season)

96% Caucasian

Follow-up 28 days

Seroconversion
  15 μg 60 μg
A(H1N1) 23.6 51.5%*
A(H3N2) 24.5 41.3*
B 16.8 35.0*

Seroprotection ≥1:32
  15 μg 60μg
A(H1N1) 48.1 62.2%*
A(H3N2) 91.8 94.7
B 57.2 62.1

GMTR
Significantly higher for 60μg, all strains*

Notes:
Same participants included in Chen et al. 2011

Level I

Good

DiazGranados (2013)Footnote 21

NCT00976027

60μg: Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

15μg: Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/Brisbane/59/07 (H1N1)
A/Uruguay/716/2007 (H3N2)
B/Brisbane/60/2008

RCT
Double-blind
Multi-centre
Phase 3b

Country
USA
99 centres

Year 2009-10

Age ≥65 yrs
Mean 72.8 yrs
(64-99 yrs)
Male 46.3 %

N=9158
60μg=6107
15μg=3051

85% Caucasian
89% vaccinated last season
Ambulatory, medically stable

Excluded
Bed-ridden, Immune suppressing disease

Follow up 28 days

Seroprotection
  15 μg 60 μg
A(H1N1) 87.4 (85.2,89.4) 94.9 (93.9,95.9)*
A(H3N2) 94.8 (93.2,96.1) 97.3 (96.5,98.0)*
B 84.5 (82.1,86.7) 93.4 (92.2,94.4)*

GMFR
  60/15μg
A(H1N1) 1.57 (1.44; 1.71)*
A(H3N2) 1.74 (1.57; 1.94)*
B 1.61 (1.48; 1.75)*

Level 1

Good

DiazGranados,
(2014)Footnote 33

NCT01427309

60μg: Fluzone®high dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

15μg: Fluzone® 
15μg HA/strain
0.5mL/dose

2011-12 strains
A/California/
7/2009 (H1N1) A/Victoria/210/2009 (H3N2)
B/Brisbane/60/2008

2012-13 strains
A/California/7/2009 (H1N1) A/Victoria/361/
2011 (H3N2)
B/Texas/6/2011

RCT
Double-blind
Multicenter Phase IIIb-IV

Country
USA, Canada
126 centres

Yr 1 2011-12

Yr 2 2012-13

Age ≥65 yrs Mean 73.3 yrs
Male 43.4%

Immuno-genicity subset

Year 1
60μg=2375
15μg=2382

Year 2
60μg=2879
15μg=2872

95% Caucasian
74% previously vaccinated
67% ≥ 1 chronic condition

Follow-Up: 28 days

Seroprotection

Year 1
  15 μg 60 μg
A(H1N1) 94.2 (93.2,95.1) 98.1 (97.5,98.6)*
A(H3N2) 96.5 (95.6,97.2) 99.2 (98.7,99.5)*
B 83.9 (82.3,85.3) 91.6 (90.4,92.7)*

Year 2
  15 μg 60 μg
A(H1N1) 93.3 (92.3,94.2) 98.8 (98.3, 99.2)*
A(H3N2) 95.0 (94.2,95.8) 98.6 (98.2, 99.0)*
B 72.8 (71.1,74.4) 86.2 (84.9,87.4)

GMFR

Year 1
  60:15 μg
A(H1N1) 1.8 (1.6,1.9)*
A(H3N2) 2.0 (1.8, 2.1)*
B 1.4 (1.3,1.5)*

Year 2
  60:15 μg
A(H1N1) 1.8 (1.7,1.9)*
A(H3N2) 1.8 (1.7,1.9)*
B 1.6 (1.5,1.7)*

Level 1

Good

Falsey (2009)Footnote 28

NCT0091053

60μg: Experimental TIV split-virus
60μg/strain
0.5mL/dose

15μg: Fluzone®(Sanofi Pasteur)
15μg HA/strain 0.5mL /dose

Strains
A/New Caledonia/20/99 (H1N1)
A/Wisconsin/67/2005 (H3N2)
B/Malaysia/2506/04

RCT
Double-blind
Multi-centre Phase III

Country USA
30 centres

Year 2006-07

Age ≥65 years
(65-97)
Mean 73 yrs
Male 52%

N=3876
60μg=2576
15μg=1275

82% vaccinated last season
79% underlying condition

Medically stable, community dwelling

Follow-up 28 days

Seroconversion % (CI95%)
  15 μg 60 μg
A(H1N1) 23.1 (20.2,25.6) 48.6 (46.6,50.5)S
A(H3N2) 50.7 (47.9,53.5) 69.1 (67.3,70.9)S
B 29.9 (27.4.32.6) 41.8 (39.8,43.7)N

Seroprotection
  15 μg 60 μg
A(H1N1) 76.8 (74.3,79.1) 89.9 (88.7,91.0)*
A(H3N2) 96.5 (95.3,97.4) 99.3 (98.9,99.6)*
B 67.6 (64.9,70.2 79.3 (77.6,80.3)*

GMFR
  60/15 μg
A(H1N1) 1.7 (1.6,1.8)S
A(H3N2) 1.8 (1.7,2.0)S
B 1.3 (1.2,1.4)N

Cohort of ≥75 years of age

Seroconversion 15 v 60μg
  15 μg 60 μg
A(H1N1) 20.7 (17.1,24.8) 46.8 (43.5,50.2)
A(H3N2) 15.2 (9.6,20.7) 52.5 (47.7,57.2)
B 10.1 (5.0,15.2) 25.4 (21.4,29.7)

GMT Ratio ≥75
  60:15 μg
A(H1N1) 1.8 (1.7,2.0)S
A(H3N2) 1.8 (1.6,2.0)S
B 1.3 (1.2,1.4)N

Cohort with cardiopulmonary disease

Seroconversion
  15 μg 60 μg
A(H1N1) 22.0 (19.3,24.8) 48.4 (46.0,50.7)*
A(H3N2) 48.5 (45.5,52.2) 68.5 (66.3,70.6)*
B 13.1 (9.4,16.8) 28.4 (25.5,31.4)*

GMT ratio
  60:15 μg
A(H1N1) 1.8 (1.6,1.9)S
A(H3N2) 1.8 (1.7,2.0)S
B 1.3 (1.2,1.4)N

Level I

Good

Nace (2015)Footnote 63

NCT01654224

IM: Fluzone High-Dose (Sanofi Pasteur) (60µg HA/strain)

IM: Standard-dose vaccine (15 µg HA/strain)

RCT
Single blind
15 community-based LTCFs

Country USA

Years: 2011-2012 & 2012-13

Age: ≥65 years
Mean: 86.7 (71% ≥85 yrs)
Male: 32%

N at 30 days =187
60µg = 89
15µg =98

Frail and residing in LTCFs

Follow up: 30 and 180 (±14) days from baseline

GMT 60µg v. 15µg

Year 1 - Day 0
  60 μg 15 μg
A(H1N1) 17.1 (11.3, 25.9 16.6 (10.3, 26.7)
A(H3N2) 8.9 (6.5, 12.3) 7.3 (5.3, 10.0)
B 15.3 (10.3, 22.6) 11.6 (8.6, 15.5)

Year 1 - Day 30
  60 μg 15 μg
A(H1N1) 78.2 (45.1, 135.7) 27.4 (17,44.3)*
A(H3N2) 26.2 (17.1, 40.0 10.2 (7.0, 14.8)*
B 25.6 (18.7, 34.9) 14.3 (11.1, 18.4)*

Year 1 - Day 180
  60 μg 15 μg
A(H1N1) 59.7 (33.5, 106.3) 28.3 (15.3, 52.4)
A(H3N2) 22.3 (14.5, 34.3) 9.4 (6, 14.8)*
B 22.9 (16.3, 32) 15.4 (11.8, 20.2)

Year 2 - Day 0
  60 μg 15 μg
A(H1N1) 23.6 (16.7, 33.4) 32.3 (23.8, 43.9)
A(H3N2) 7.2 (6.1, 8.3) 6.2 (5.4, 7.1)
B 7.9 (6.5, 9.5) 9.1 (7.5, 11)

Year 2 - Day 30
  60 μg 15 μg
A(H1N1) 45.6 (32.9, 63.2) 50.0 (37.4, 67)
A(H3N2) 23.4 (17.6, 31) 14.2 (11.0, 18.4)*
B 26.0 (21.2, 31.9) 17.4 (13.9, 21.9)*

Year 2 - Day 180
  60 μg 15 μg
A(H1N1) 46.8 (33.2, 65.9) 51.8 (37.8, 71.1)
A(H3N2) 24.7 (18.3, 33.2) 13.4 (10.3, 17.5)*
B 25.3 (20.8, 30.9) 18.9 (14.9, 23.9)

Seroprotection ( %) 60µg v. 15µg

Year 1 - Day 0
  60 μg (n=31) 15 μg (n=33)
A(H1N1) 32.3 36.4
A(H3N2) 6.5 6.1
B 25.8 15.2

Year 1 - Day 30
  60 μg (n=31) 15 μg (n=33)
A(H1N1) 71.0 51.5
A(H3N2) 45.2 18.2*
B 45.2 21.2*

Year 1 - Day 180
  60 μg (n=26) 15 μg (n=24)
A(H1N1) 76.9 45.8*
A(H3N2) 42.3 12.5*
B 23.1 4.2

Year 2 - Day 0
  60 μg (n=58) 15 μg (n=65)
A(H1N1) 44.8 53.8
A(H3N2) 3.4 4.6
B 8.6 6.2

Year 2 - Day 30
  60 μg (n=58) 15 μg (n=65)
A(H1N1) 58.6 72.3
A(H3N2) 51.7 24.6*
B 48.3 29.2*

Year 2 - Day 180
  60 μg (n=53) 15 μg (n=59)
A(H1N1) 47.2 52.5
A(H3N2) 52.8 39.0
B 32.1 33.9

I

Fair

Sanofi Pasteur (2013)Footnote 57
Robertson (2012)Footnote 58

NCT01430819

60μg: Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

15μg:Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/California/07/2009 (H1N1)
A/Victoria/210/2009 (H3N2)
B/Brisbane/60/2008

RCT
Double-blind
Multi-centre
Phase IV

Country
USA
6 centres

Year 2011-12

Age ≥ 65 yrs
Mean 72.1 yrs
Male: 39%

N=300
60μg=145
15μg=147

96% Caucasian

96.3
96.3

Follow up 21 days

Seroconversion
  15 μg 60 μg
A(H1N1) 36 (28,44) 61 (53,69)
A(H3N2) 41 (33,49) 69 (61,76)
B 22 (15,29) 41 (33,50)

Seroprotection

(≥1 :40)
  15 μg 60 μg
A(H1N1) 94 97
A(H3N2) 99 100
B 80 88

≥1 :160
  15 μg 60 μg
A(H1N1) 71 86
A(H3N2) 82 95
B 28 39

GMTR
  15 μg 60 μg
A(H1N1) 3.3 (2.7,4.0) 7.1 (5.6,9.1)
A(H3N2) 3.5 (2.9,4.2) 8.2 (6.4,10.5)
B 2.1 (1.9,2.4) 3.1 (2.7,3.7)

Level 1

Good

Talbot (2014)Footnote 59

NCT01189123

60μg: Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

15μg: Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains not stated

RCT
Double-blind
Single centre

Country
USA

Years: not stated

Age 67-79 yrs
Mean 73 yrs
Male 51.4%

N=105
60μg=47
15μg=50

Follow-up 2 years

GMT
  15 μg 60 μg
A(H1N1) 40 (10,80) 80 (40,140)
A(H3N2) 20 (20,40) 80 (10,160)
B 40 (20,80) 40 (40,80)

Notes:
CD4+ and CD8+ data not abstracted

Level 1

Good

Small sample size

Tsang (2014)Footnote 32

NCT00551031

60IM: High Dose IM15 (Sanofi Pasteur)
60μg/strain
0.5mL IM

ID15: (Sanofi Pasteur)
15μg/strain 
0.1 mL/dose ID
21ID: (Sanofi Pasteur) 21μg/strain 
0.1 mL/dose ID

15IM: FluZone®(Sanofi Pasteur)
15μg/strain
0.5mL/dose IM

Strains
A/Solomon Islands/3/2006 (H1N1)
A/Wisconsin/67/2005 (H3N2)
B/Malaysia/2506/2004

RCT
Open label for route
Double-blind for dose
Multi-centre Phase II

Country USA
31 centres

Year 2007-08

Age 47-99 yrs
Mean 73 yrs
Male 44%

N=1912
60μg IM=319
15μg IM=320
15μg ID=635
21μg ID=635

87% previously vaccinated
94% Caucasian

Medically stable
Ambulatory

Follow-up 28 days

60 vs 15μg IM

Seroconversion Difference in rates (60-15μg)
  (60-15μg)
A(H1N1) 19.7 (12.8,26.6)
A(H3N2) 16.8 (9.2,24.5)
B 16.4 (10.7,22.1)

Seroprotection Difference in rates (60-15μg)
  (60-15μg)
A(H1N1) 13.6 (8.4,18.8)
A(H3N2) 1.9 (-0.2,4.0)
B 15.6 (8.5,22.7)

GMTR ratios
  (60/15IM)
A(H1N1) 2.1 (1.7,2.6)*
A(H3N2) 1.8 (1.5,2.1)*
B 1.4 (1.2,1.6)*

60IM vs 15ID

Seroconversion Difference in rates (60IM-15ID)
  (60/15IM)
A(H1N1) 9.2 (3.6,14.7)
A(H3N2) 13.7 (7.0,20.4)
B 10.5 (5.0,16.1)

Seroprotection Difference in rates
  (60/15IM)
A(H1N1) 5.7 (2.0,9.5)
A(H3N2) 1.0 (-0.6,2.5)
B 12.4 (6.4,18.3)

GMTR (60IM/15ID)
  (60IM/15ID)
A(H1N1) 1.4 (1.2,1.6)*
A(H3N2) 1.4 (1.2,1.6)*
B 1.3 (1.2,1.5)*

60IM vs 21ID

Seroconversion Difference in rates (60IM-21ID)
  (60IM-21ID)
A(H1N1) 6.3 (0.8,11.8)
A(H3N2) 13.1 (6.4,19.8)
B 10.2 (4.6,15.7)

Seroprotection Difference in rates
  (60IM-21ID)
A(H1N1) 3.7 (0,7.3)
A(H3N2) 1.6 (0,3.3)
B 10.6 (4.7,16.6)

GMTR
  (60IM/21ID)
A(H1N1) 1.3 (1.1,1.5)*
A(H3N2) 1.3 (1.1,1.5)*
B 1.2 (1.1,1.4)*

15ID vs 15IM

Seroconversion Difference in rates (ID-IM)
  (ID-IM)
A(H1N1) 10.5 (4.1,16.9)
A(H3N2) 3.5 (-3.0,10.1)
B 5.8 (1.7,10.0)

GMTR (15ID/15IM)
  (15ID/15IM)
A(H1N1) 1.50 (1.3,1.8)S
A(H3N2) 1.23 (1.1,1.4)S
B 1.04 (0.9,1.2)N

21ID vs 15IM

Seroconversion Difference in rates (ID-IM)
  (ID-IM)
A(H1N1) 13.4 (7.0,19.8)
A(H3N2) 4.2 (-2.4,10.8)
B 6.2 (2.0,10.4)

GMTR (21ID/15IM)
  (21ID/15IM)
A(H1N1) 1.6 (1.4,1.9)S
A(H3N2) 1.3 (1.2,1.5)S
B 1.1 (1.0,1.2)N

Level 1

Good
Intramuscular, Other

Della Cioppa (2012)
Della Cioppa (2014)Footnote 37

NCT00848848

IM15: 15μg HA/strain
0.5mL/dose
no adjuvant

IM30: 30μg H3N2 & 15μg each of H1N1 & B; 0.5mL/dose no adjuvant

ADV15: Fluad®(Novartis)
15μg/strain
0.5mL/dose
100% of MF59

ADV30: 30μg H3N2 & 15μg each of H1N1 & B
0.5mL/dose
100% of MF59

ID6: 6μg HA/strain
0.2mL/dose

ID12: 12μg H3N2 & 6μg each of H1N1 & B; 0.2mL/dose

Strains
A/Brisbane/59/2007 (H1N1) A/Uruguay/716/2007 (H3N2) B/Florida/4/2006

RCT
Observer-blind
Multicenter

Countries
Poland
Belgium
Germany

Year 2008-09

Age ≥65 yrs
Mean 69 yrs
Male 40-68%

N=450
IM15=43
IM30=43
ADV15=46
ADV30=42
ID6=43
ID12=46

(other groups excluded)

73-81% previously vaccinated

Healthy volunteers

Excluded impaired immune system

Follow-up 22 days

Seroconversion A(H3N2) only
IM15 IM30
70 63

ADV15 ADV30
87 95

ID6 ID12
77 71

Seroprotection
IM15 IM30
93 80

ADV15 ADV30
96 100

ID6 ID12
88 90

GMFR
IM15 IM30
9.0 7.3

ADV15 ADV30
15.0 19.0

ID6 ID12
16.0 13.0

Seroconversion
  IM ADV ID
A(H1N1) 30 62 44
B 30 49 36

Seroprotection
  IM ADV ID
A(H1N1) 77 95 84
B 49 66 61

GMTR
  IM ADV ID
A(H1N1) 2.8 7.1 5.1 (ID>IM*)
B 2.5 4.1 3.0

  ADV:ID IM:ID
A(H1N1) 1.6 (1.1,2.3)* 0.7 (0.5,1.0)*
B 1.4 (1.0,1.8)*  

Notes:

  • Increase in H3N2 antigen dose did not affect the antibody response to H1N1 and B strains
  • Increase in H3N2 antigen level did not increase responses
  • Inclusion of adjuvant improved serological response

Level 1

Good

Small sample size

Keitel (2006)Footnote 30

60μg: subvirion TIV
(Aventis Pasteur)
60μg HA/strain
0.5mL/dose
30μg: subvirion TIV (Aventis Pasteur)
30μg HA/strain
0.5mL/dose

15μg: subvirion TIV
(Aventis Pasteur)
15μg HA/strain
0.5mL/dose

Placebo: saline

Strains
A/NewCaledonia/20/99 (H1N1) A/Panama/2007/99 (H3N2)
B/Victoria/504/2000

RCT
Single-center

Country
USA

Year 2001-02

Age ≥65 years
Mean 72.4 yrs
(65-88 yrs)
Male 59 %

N=202
60μg=50
30μg=51
15μg=51
Saline=50

97% Caucasian
82% vaccinated last season

Ambulatory, medically stable
.

Follow up 28 days

Seroconversion
  15 μg 30 μg 60 μg
A(H1N1) 17.6 31.4 38.0
A(H3N2) 21.6 27.5 32.0
B 23.5 21.6 42.0

Seroprotection ≥1:32
Dose-related increases for all subtypes

GMFR
Significant differences for all subtypes (p<0.01)
Dose-related increases for all subtypes

Level 1

Good

Small sample size

Same
antigens as previous season
60µg "experimental" Sub unit Intramuscular

Palache (1993)Footnote 39

60μg : Experimental trivalent subunit (Duphar BV)
60μg HA/strain 0.5mL/dose

10μg: 10μg HA/strain
20μg: 20μg HA/strain
Experimental trivalent subunit
Saline/placebo
0.5mL/dose

Strains A/Taiwan/2/86 (H1N1)
A/Sichuan/2/87 (H3N2)
B/Beijing/1/87

RCT
Double-blind
Multi-centre
Placebo-controlled

Country Netherlands
Israel

Year 1988

See Remarque (1993) for same participants - for IgG, IgA, IgM responses to H3N2 strain

Data for 65+ yrs
Age 68-99 yrs
Mean 80 yrs

N=262
60μg=66
10μg=67
20μg=64
Saline=65

22% previously vaccinated

Nursing home residents

Excluded
Immune suppressing drug treatment

Follow-up 21 days

Seroconversion
N/A

Seroprotection (≥1:100 for A; ≥1:200 for B)
  10 μg 20 μg 60 μg
A(H1N1) 33 33 42
A(H3N2) 72 75 80
B 23.52 67 77

GMFR
  20/10μg 60/10μg
A(H1N1) No dose response effect
A(H3N2) 1.3 1.6
B 1.4 2.1

Level 1

Good

Small sample size
Recombinant Vaccines

Keitel (2009)Footnote 23

NCT00395174

FluBlok®(Protein
Sciences Corp.)
~45μg rHA/strain
0.5mL/dose
(Total: 131μg)

Strains
A/Wisconsin (H3N2)
A/New Caledonia (H1N1)
B/Ohio

15μg: Fluzone®(Sanofi Pasteur).
15μg HA/strain
0.5mL/dose

Strains
A/Wisconsin (H3N2)
A/New Caledonia (H1N1)
B/Malaysia

RCT
Double-blind
Multi-centre Phase 3

Country
USA
7 centres

Year 2006-07

Age ≥65 yrs
Mean
45μg 72.9 yrs
15μg 73.9 yrs
Male 47%

N=869 (all)
45μg=431
15μg=430

≥75 years
45μg=163
15μg=159

98% Caucasian
83% vaccinated last season

Ambulatory, medically-stable,
community
dwelling

Follow-up: 28 days

Seroconversion 
  15 μg 45 μg
A(H1N1) 33(28,37) 43(39,48)N
A(H3N2) 58(53,62) 78(74,82)N
B/Ohio 39(34,44) 29(25,34)
B/Malaysia 10(7,12.8) 20(16,23.5)

Seroprotection
  15 μg 45 μg
A(H1N1) 95(92,97) 95(92,97)
A(H3N2) 93(90,95) 97(94,98)
B/Ohio 97(95,99) 92(89,94)
B/Malaysia 30(26,34) 40(35,45)

GMFR (CI95) 15:45μg
  15:45μg
A(H1N1) 0.84 (0.81, 0.86)N
A(H3N2) 0.59 (0.57, 0.60)N
B/Ohio 1.30 (1.26, 1.34)N
B/Malaysia 1.37 (1.0, 1.7)

Seroconversion 
  45 μg 15 μg
A(H1N1) 43(39,48) 33(28,37)*N
A(H3N2) 78(74,82) 58(53,62)*N
B/Ohio 29(25,34) 39(34,44)
B/Malaysia 10(7,13) 20(16,23)

Cohort of ≥75 years

Seroprotection
  15 μg 45 μg
A(H1N1) 94(91,98) 91(87,96)
A(H3N2) 93(89,97) 96(93,99)
B/Ohio 99(98,100) 96(93,99)
B/Malaysia 31(24,38) 47(39,54)

GMFR 15:45μg
  15:45μg
A(H1N1) 0.82 (0.79, 0.85)N
A(H3N2) 0.59 (0.58, 0.61)N
B/Ohio 1.21 (1.18, 1.24)N
B/Malaysia 1.40 (1.1, 1.7)

Level 1

Good

Different
B strains in vaccines

Treanor (2006)Footnote 40

Baculovirus-expressed (rHA)
135μg rHA/strain
45μg rHA/strain
15μg rHA/strain
0.5mL/dose

IM15: Fluzone®(Sanofi Pasteur).
15μg HA/strain
0.5mL/dose

Strains
A/Panama/2007/99 (H3N2)
A/NewCaledonia/20/99 (H1N1)
B/HongKong/330/2001

RCT
Double-blind

Country
USA

Year not stated (2002-03 or 2003-04)

Age 65-90 yrs 
Mean: 72 yrs
49% male

N=399
135rHA=101
45rHA= 99
15rHA=98
IM15=98

96% Caucasian

Community-dwelling, medically stable

Follow-up 28 days

Seroconversion
  IM15 15rHA 45rHA 135rHA
A(H1N1) 37 16 32 37
A(H3N2) 33 38 55 88*
B 63 51 65 66

Seroprotection ≥1 :128
  IM15 15rHA 45rHA 135rHA
A(H1N1) 21 12 26 20
A(H3N2) 49 95 76 88*
B 63 51 65 66

*Significantly higher (p ≤0.01) compared to IM15

Level 1

Good
Double dose; TIV 15μg/strain

Cools (2009)Footnote 38
Roos-van Eijndhoven (2001)Footnote 60

30μg : 15μg HA/strain
0.5mL/dose x 2 doses (same arm) Split virion (Pasteur Mérieux)

15μg : 15μg HA/strain 0.5mL/dose Split virion (Pasteur Mérieux)

Strains:
A/Nanchang/933/95 (H3N2),
A/Johannes-
burg/82/96 (H1N1), and B/Harbin/7/94

RCT
Multi-centre

Country: Netherlands
14 nursing homes

Year 1997-98

Age 96% were ≥65 years
Median 83-84
Male 25%

N=815
30μg (15*2)
Day 25=360
Day 84=340
Day106=155

15μg
Day 25=347
Day 84=325
Day106=158

39% previously vaccinated

Long-term care residents

Follow-up: 25, 84, 109 days
DATA for A(H3N2) strain only

Seroconversion
  15 μg 30 μg
Day 25 33.3 45.3*
Day 84 28.6 37.1*
Day106 27.1 35.4

Seroprotection
  15 μg 30 μg
Day 25 66.3 73.3*
Day 84 61.2 67.6
Day106 63.9 64.6

GMT
  15 μg 30 μg
Day 25 57.8 (49.2,68.2) 70.6 (61.1,81.7)
Day 84 48.6 (41.1,56.9) 53.5 (45.9,61.9)
Day106 49.3 (39.5,61.9) 46.9 (37.6,58.8)

Notes:
Significantly greater rates of seroprotection and seroconversion at Day 25 & 84 for participants with pre-vaccination titres of <1:40 (only at Day 25 for ≥1:40)
Data regarding 'booster' doses not abstracted

Level 1

Good
15µg Intradermal

Arnou (2009)Footnote 46

NCT00383526

ID:(Sanofi Pasteur; experimental) 15ug HA/strain 0.1mL/dose

15IM: Vaxigrip®(Sanofi Pasteur)
15ug HA/strain 0.5mL/dose

Strains as recommended for
2006-2007
2007-2008
2008-2009

*Analysis includes only participants vaccinated with the same vaccine sequentially

RCT
Open-label
Multi-centre

Country:
France, Belgium, Lithuania, Italy

Years
2006-2009

Age 60-95 years
Mean 71 years
Male 20%

N=3707

Year 1
ID=2604
IM=1081

Year 2
ID→ID =133
IM→IM =143

Year 3
ID→ID→ID=121
IM→IM→IM=67

65% chronic condition

Excluded congenital or acquired immuno-deficiency

IDàID signifies ID injection in first year followed by ID in second year

Follow-up: 21 days post vaccination

First vaccination 2006
GMT non-inferior for all 3 strains (ID vs IM)
Seroprotection superior for all 3 strains (ID vs IM)
GMTR All 3 strains ID significantly higher (p<0.0001) than IM
Seroconversion ID significantly higher (p<0.001) than IM

Second Vaccination 2007

Seroconversion
  ID→ID IM→IM
A(H1N1) 74.2 (65.9,81.5) 63.6 (55.2,71.5)
A(H3N2) 36.6 (28.4,45.5) 40.1 (32.0,48.7)
B 14.3 (8.8,21.4) 9.8 (5.5,15.9)

Seroprotection
  ID→ID IM→IM
A(H1N1) 95.5 (90.4,98.3) 81.8 (74.5,87.8)
A(H3N2) 98.5 (94.6,99.8 95.8 (91.0,98.4)
B 55.6 (46.8,64.2) 53.1 (44.6,61.5)

GMFR
  ID→ID IM→IM
A(H1N1) 9.64 (7.70,12.1) 7.24 (5.82,9.02)
A(H3N2) 2.92 (2.43,3.51) 2.88 (2.43,3.41)
B 1.77 (1.57,2.00) 1.67 (1.50,1.86)

Third Vaccination 2008

Seroconversion
  ID→ID→ID IM→IM→IM
A(H1N1) 37.2 (28.6,46.4) 31.8 (20.9,44.4)
A(H3N2) 73.6 (64.8,81.2) 60.6 (47.8,72.4)
B 47.1 (38.0,56.4) 26.9 (16.8,39.1)

Seroprotection
  ID→ID→ID IM→IM→IM
A(H1N1) 81.8 (73.8,88.2) 74.2 (62.0,84.2)
A(H3N2) 92.6 (86.3,96.5) 77.3 (65.3,86.7)
B 70.2 (61.3,78.2) 55.2 (42.6,67.4)

GMFR
  ID→ID→ID IM→IM→IM
A(H1N1) 2.88 (2.43,3.41) 2.86 (2.31,3.54)
A(H3N2) 8.45 (6.79,10.5) 6.94 (5.15,9.36)
B 3.76 (3.16,4.46) 2.40 (1.93,2.98)

Level I

Good

Chan (2014)Footnote 44

NCT01967368

ID: Intanza®(Sanofi Pasteur)
15μg HA/strain
0.1mL/dose

IM: Vaxigrip®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2) B/Massachus-etts/2/2012

RCT
Open-label
Single center

Country:
China (Hong Kong)

Year 2013-14

Age: ≥65 years
Mean 83 years
Male 36%

Total: n=100
ID=50
IM=50

Nursing home residents

Follow-up: 21 days

Day 21

Seroconversion
  ID IM
A(H1N1) 60 36*
A(H3N2) 30 16
B 20 22

Seroprotection
  ID IM
A(H1N1) 96 90
A(H3N2) 96 98
B 98 94

GMT
  ID IM
A(H1N1) 8.6 (5.1,12.1) 5.2 (2.4,7.9)
A(H3N2) 2.7 (1.9,3.5) 2.3 (1.0,3.5)
B 4.9 (1.4,8.4) 2.0 (1.6,2.4)

GMTR
  IM/ID
A(H1N1) 0.85 (0.55,1.01)
A(H3N2) 0.60 (0.47,0.65)
B 0.28 (0.40,1.13)

Day 180

Seroconversion
  ID IM
A(H1N1) 38 22
A(H3N2) 16 2*
B 20 6

Seroprotection
  ID IM
A(H1N1) 82 78
A(H3N2) 96 98
B 90 86

GMT
  ID IM
A(H1N1) 3.8 (2.3,5.3) 2.6 (1.8,3.3)
A(H3N2) 2.0 (1.4,2.7) 1.2 (0.9,1.5)*
B 2.4 (1.6,3.2) 1.4 (0.0,1.8)*

Level I

Good

Hoon Han (2013)Footnote 43

NCT01215669

ID: Intanza®(IDflu)
15μg HA/strain 0.1mL/dose

IM: Vaxigrip®(Sanofi Pasteur) 
15μg HA/strain
0.5 mL/dose

Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2)
B/Brisbane/60/2008

RCT
Open-label Multicentre Phase IV

Country South Korea
6 sites

Year 2010-11

Age: 18+ years
Data for ≥60 years
Mean 64.5-64.9 yrs
Male 38%

N: 120
ID=60
IM= 60

38% vaccinated past year

Follow up: 21 days

Data in figures only

  • CHMP criteria for all three strains met for ID and IM vaccines
  • No statistically significant differences in rates of seroprotection, seroconversion, or for GMTR for ID and IM vaccines

Level I

Fair-Good

(limited data could be abstracted)

Holland (2008)Footnote 42

NCT00296829

15ID: 15µg HA/strain
21ID: 21µg HA/ strain
Intradermal split-virion (Sanofi Pasteur)
0.1mL/dose

15IM: 15µg HA/strain
VaxiGrip®(Sanofi Pasteur)
0.5mL/dose

Strains
A/New Caledonia/20/99 (H1N1)
A/Wellington/1/2004 (H3N2)
B/Jiangsu/10/2003

RCT
Open label for route
Double blind for dose
Multicenter
Phase II

Country
New Zealand
Australia

Year 2006

Age 65-85 yrs
Males 47%

Total n=1101
15ID=366
21ID=369
15IM=366

~85% vaccinated previous season

Medically stable

Follow-up 21 days

Seroconversion
Significantly higher (p<0.05) in the ID than in the IM, for all strains and both strengths

Seroprotection
A(H1N1) no difference
A(H3N2) significantly higher for ID vs IM
B significantly higher for ID vs IM

GMTR
  15ID/15IM 21ID/15IM
A(H1N1) 1.52 (1.28,1.78)S 1.59 (1.36,1.84)S
A(H3N2) 1.70 (1.41,2.04)S 1.70 (1.42,2.03)S
B 1.49 (1.27,1.74)S 1.40 (1.20,1.64)S

Notes:
The 21µg ID vaccine did not induce a statistically significant difference in responses compared with the 15µg ID vaccine

Level I

Good

Seo (2014)Footnote 45

ID : (Sanofi Pasteur)
15μg HA/strain
0.1mL/dose

Comparator
IM15: Aggripal S1®(Novartis)
15μg HA/strain
0.1mL/dose

ADV: Fluad®(Novartis)
15μg HA/strain
0.1mL/dose
adjuvant

Year 2011-12
Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008

RCT
Multicenter

Country
South Korea

Age ≥65 years
Median 71-73 years
Male 32-39%

N=335
IM15 =113
ADV=111
ID =111

Community-dwelling
Good health

28 day follow-up

Seroconversion
  ID IM15 ADV
A(H1N1) 42.5 (34, 52) 38.7 (30,49) 54.1 (45,63)
A(H3N2) 43.2 (34.2,54.3) 26.5 (18.6,34.5) 45.0 (36.0,54.1)
B 7.2 (2.7,12.6 1.8 (0,4.4) 7.2 (2.7,11.7)

Seroprotection
  ID IM15 ADV
A(H1N1) 78.8 (71.7,86.7) 72.1 (63.1,80.2) 84.7 (78.4,91.0)
A(H3N2) 83.8 (75.7,91.0) 71.7 (63.7,79.6) 89.2 (82.9,94.6)
B 18.6 (12.4,25.7) 18.0 (10.8,25.2) 24.3 (17.1,33.3)

GMTR
  ID IM15 ADV
A(H1N1) 3.6 (2.3,5.6) 3.5 (2.2,5.7) 4.4 (2.7,6.3)
A(H3N2) 3.5 (2.4,5.2) 1.9 (1.3,2.8) 3.4 (2.2,5.2),
B 1.4 (1.0,1.9) 1.2 (0.8,1.6) 1.6 (1.1,2.4)

180 day follow-up

Seroconversion
  ID IM15 ADV
A(H1N1) 8.8 (3.5,15.0) 10.8 (5.4,17.1) 5.4 (1.8,9.9)
A(H3N2) 34.2 (25.2,43.2) 37.8 (27.9,47.7) 28.3 (20.4,37.2)
B 1.8 (0,4.5) 1.8 (0,4.5) 2.7 (0,5.3)

Seroprotection
  ID IM15 ADV
A(H1N1) 53.1 (44.2,61.9) 51.4 (42.3,61.3) 37.8 (28.8,46.8)
A(H3N2) 74.8 (66.7,82.9) 77.5 (70.3,84.7) 64.6 (56.6,73.5)
B 18.6 (12.4,25.7) 16.2 (9.9,24.3) 9.9 (4.5,16.2)

GMFR
  ID IM15 ADV
A(H1N1) 1.4 (0.9,2.2) 1.6 (1.0,2.6) 1.3 (0.8,2.1)
A(H3N2) 2.5 (1.7,3.7) 2.1 (1.4,3.2) 1.3 (0.6,1.7)
B 1.0 (0.8,1.4) 1.2 (0.8,1.7) 1.0 (0.7,1.4)

Level I

Good

Scheifele (2013)Footnote 41

NCT01368796

ID: Intanza®
15μg HA/strain
0.1mL/dose

Comparators:
ADV Fluad®(Novartis)
15μg HA/strain
MF59 adjuvant
0.5mL/dose

IM:15 Agriflu®
(Novartis)
15μg HA/strain
0.5mL/dose

Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008

RCT
Evaluator-blind
Multicenter

Country: Canada
8 centres)

Year 2011-12

Age ≥65 years
Mean 74 years
41% male

ID=301
ADV=299
IM15=305

95% Caucasian

100% vaccinated in 1 or 2 of previous two seasons

Community-dwelling or at facilities with minimal assistance

21 day follow-up

Seroconversion
  ID ADV IM15
A(H1N1) 39.0 49.5 36.3
A(H3N2) 35.3 44.7 24.7
B 15.8 16.6 10.9

Seroprotection
  ID ADV IM15
A(H1N1) 81.0 91.2 78.7
A(H3N2) 76.1 87.9 76.5
B 98.3 98.6 98.7

GMFR
  ID ADV IM15
A(H1N1) 3.1 (2.9,3.5) 4.2 (3.7,4.8)* 2.7 (2.5,3.0)
A(H3N2) 2.7 (2.5,3.1) 3.4 (3.1,3.8)* 2.3 (2.1,2.5)
B 1.6 (1.5,1.8) 1.6 (1.5,1.7) 1.4 (1.3,1.5)*

180 day follow-up
Seroprotection rates declined by 21.3-25.6% for A(H1N1), 17.4-26.7% for H3N2 and <3% for B strains.

Notes: Data for single radial hemolysis and microneutralization assays not abstracted but were generally similar to HAI testing ID & IM15 alike re: SP;

Level I

Good

Sibunruang
(2011)Footnote 47

ID12:
12μg/strain
(6μg/strain /site x 2 sites)

ID6: 6μg HA/strain (3μg/strain/site x 2 sites)

IM: (Sanofi Pasteur)
15 μg HA/strain
0.5mL/dose

Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008

RCT
Open-label

Country: Thailand

Year: 2010

Age 60-90 years
Mean 67 years
Male 20%

N=180
12ID=60
6ID=60
IM=60

Healthy, community dwelling

28 day follow-up

Seroconversion
  12ID 6AD IM
A(H1N1) 45.0 33.3 43.3
A(H3N2) 25.0 28.3 35.0
B 71.7 75.0 86.7

Seroprotection
  12ID 6AD IM
A(H1N1) 23.3 25.0 36.0
A(H3N2) 26.7 23.3 38.3
B 76.7 73.3 76.7

GMFR
  12ID 6AD IM
A(H1N1) 2.4 2.3 2.7
A(H3N2) 2.0 2.2 2.4
B 5.2 5.4 7.3

Level 1

Fair-Good

Small sample size

Abstract (Limited data avail-able)

Camilloni (2014)Footnote 48

ID: Intanza®(Sanofi Pasteur)
15μg HA/strain
0.1mL/dose

Comparator:
ADV Fluad®(Novartis) 15μg/strain
0.5mL dose
MF59

Randomized Blinding not stated

Country Italy
Nursing homes

Season 2011,2012

Age ≥65 years
Mean 85 years
Male 15%

N=80
ID=40
ADV=40

100% previously vaccinated
100% chronic underlying disease
Live in nursing home

Follow-up 1 & 6 months
One month

Seroprotection
  ID ADV
A(H1N1) 70.0 (57.1,80.3) 72.5 (59.7,82.4)
A(H3N2) 92.5 (82.6,97.0) 87.5 (76.4,93.8)
B 75.0 (62.4,84.4) 75.0 (62.4,84.4)

Seroconversion
  ID ADV
A(H1N1) 42.5 (30.5,55.5) 50.0 (37.3,62.6)
A(H3N2) 60.0 (47.0,71.7) 47.5 (35.1,60.2)
B 40.0 (28.3,53.0) 10.0 (4.6,20.5)*

GMFR
  ID ADV
H1N1 3.8 (2.2,6.8) 3.7 (2.4,5.6)
H3N2 4.6 (2.8,7.8) 3.3 (1.9,5.7)
B 3.2 (1.7,6.0) 1.6 (1.3,2.0)

6 month follow-up

Seroprotection
  ID ADV
H1N1 50.0 (37.3,62.6) 40.0 (28.3,53.0)
H3N2 67.5 (54.5,78.2) 66.5 (52.0,76.1)
B 60.0 (47.0,71.7) 57.5 (44.5,69.5)

Seroconversion
  ID ADV
H1N1 7.5 (3.0,17.4) 17.5 (9.8,29.4)
H3N2 17.5 (9.8,29.4) 30.0 (19.6,42.9)
B 0.0 (0,6.3) 17.5 (9.8,29.4)*

GMFR
  ID ADV
H1N1 1.9 (1.2,2.8) v 1.5 (1.1,2.0)
H3N2 2.4 (1.3,4.4) 2.1 (1.1,4.1)
B 1.8 (1.0,3.1) 1.0 (0.9,1.1)

Level II

Good

Small sample size

Ansaldi (2013)Footnote 50

EUDRACT: 2009-014637-24

ID: Intanza®(Sanofi Pasteur)
15µg HA/strain
0.1ml dose

Comparator:
ADV Inflexal®V (Crucell)
15µg HA/strain 0.5mL/dose
Adjuvant: virosome

Strains A/California/7/2009(H1N1)
A/Perth/16/2009 (H3N2)
B/Brisbane/60/2008

RCT
Open-label
Multicenter
Phase IV

Country: Italy

Year 2010

Age: ≥60
Mean 75-77 years

Total: N=50 for serology
ID=24
ADV=23

Excluded: alcoholic, unstable chronic illness

Follow-up: 28 days

Seroconversion
  ID ADV
A(H1N1) 50 (31,69) 43 (26,43)
A(H3N2) 50 (31,69) 35 (19,55)
B 46 (28,65) 0 (0,14)

Seroprotection
  ID ADV
A(H1N1) 63 (43,79) 57 (37,74)
A(H3N2) 71 (51,85) 48 (29,67)
B 100 (86,100) 100 (86,100)

GMFR (CI95%)
  ID ADV
A(H1N1) 3.4 (1.9,5.9) 2.3 (1.3,3.8)
A(H3N2) 2.9 (1.8,4.8) 2.1 (1.4,3.1)
B 2.7 (1.5,4.9) 1.5 (1.0,2.3)

3 month follow-up

Seroprotection
  ID IM
A(H1N1) 45 (26,66) 47 (27,68)
A(H3N2) 60 (39,78) 32 (15,54)
B 95 (76,99) 100 (83,100)

Level I

Fair-Good

Small number for serology

Van Damme
(2010)Footnote 49

NCT00554333

ID: Intanza®(Sanofi Pasteur)
15μg HA/strain
0.1 mL/dose

ADV: Fluad®(Novartis)
15μg HA/strain
MF59 adjuvant 0.5mL/dose

Strains
A/Solomon Islands/3/2006 (H1N1)
A/Wisconsin/67/2005 (H3N2)
B/Malaysia/2506/2004

RCT
Open-label
Parallel-group
Multi-centre Phase II

Country Belgium, France
10 centres

Year 2007-08

Age ≥65 yrs
Mean 74.3 yrs
Male 46.5%

N 795
ID=390
ADV=385

72% vaccinated last year
53% underlying disease

Follow-up: 21 days

Seroprotection
  ID ADV
A(H1N1) 81.3 87.1

GMFR (CI95%)
  ADV/ID
A(H1N1) 1.13 (0.95,1.34)N
A(H3N2) 1.31 (1.13,1.53)
B 1.08 (0.95,1.23)N

GMTR
  ADV/ID
A(H1N1) 1.12
A(H3N2) 1.31
B 1.07

Level 1

Good

Appendix F: Summary of evidence related to safety of high dose seasonal influenza vaccines in adults 65 years and older

STUDY DETAILS
Study Vaccine Study Design Participants Summary of Key Findings Level of Evidence Quality
60µg HA/strain inactivated intramuscular

Couch (2007)Footnote 29

NCT00115531
NCT00170508

Experimental IM:
60µg HA/strain
0.5mL/dose

Comparator:
Fluzone®(Sanofi Pasteur)
15µg HA/strain
0.5mL/dose

Strains
A/New Caledonia/20/99 (H1N1), A/Wyoming/03/2003 (H3N2) B/Jiangsu/10/2003

RCT
Double blind
Multi-site
Phase II

Country USA

Year 2004-05

Stratified by receipt of influenza vaccine in same season

Age ≥65
Mean: 73-74 yrs
Male 51%

N=414
60μg=206
15μg=208

78% vaccinated in fall of 2004 (same season)

96% Caucasian

Follow up: 7 days active; 210 days passive

Reactogenicity
  15μg 60μg
Systemic
Fever (≥37.5oC) 0.5 4.4
Myalgia 15.4 12.6
Headache 17.3 11.1
Malaise 13.0 16.5
Local
Pain 19.7 40.3
Redness 27.9 29.1
Swelling 18.3 23.8

Vaccine-related SAE
60μg: oculo-respiratory syndrome day of vaccination

Level 1

Good

DiazGranados (2013)Footnote 21

NCT00976027

Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

Comparator:
Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/Brisbane/59/07 (H1N1)
A/Uruguay/716/2007 (H3N2)
B/Brisbane/60/2008

RCT
Double-blind
Multi-centre
Phase 3b

Country
USA
99 centres

Year 2009-10

Age ≥65 yrs
Mean 72.8 yrs
(64-99 yrs)
Male 46.3%

N=9158
60μg N=6107
15μg N=3051

85% Caucasian
89% vaccinated last season

Ambulatory, medically stable

Key Exclusion Criteria:
Bed-ridden, Immune suppressing disease

Follow-up 180 days, weekly calls
Adverse events

60μg

  • 3 cases of Bell's Palsy (116, 126, & 178 days post-vaccination)

15μg

  • 2 cases of Bell's Palsy (34 & 176 days post-vaccination)
Serious adverse events
  15μg 60μg
At least one 197 (6.5%) 408 (6.7%)
Fatal SAE 10 (0.3%) 24 (0.4%)
Vaccine -related 2 1

Vaccine-related SAE
60μg 15μg
cardiac chest pain starting one day after vaccination (recovered in 2 days) Bell's palsy 34 days after injection and unresolved at study completion.
Immune thrombocytopenia 13 days after injection and recovered after 5 days

No reactogenicity data gathered

Level 1

Good

DiazGranados (2014)Footnote 33

NCT01427309

Fluzone®High- Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

Fluzone® 
15μg HA/strain
0.5mL/dose

RCT
Double-blind
Multicenter Phase IIIb-IV

Country
USA, Canada
126 centres

Yr 1 2011-12

Yr 2 2012-13

Age ≥65 yrs Mean: 73.3 yrs
Male 43.4%

N=31,983
60μg=15,990
15μg=15,993

95% Caucasian
74% previous vaccination
67% ≥ 1 chronic condition

Follow-up: ~180 days

Vaccine-related SAE
60μg 15μg
3 0

60μg

  • cranial-nerve VI palsy
    (1 day post-vaccination)
  • hypovolemic shock including diarrhoea
    (1 day post-vaccination)
  • acute disseminated encephalomyelitis
    (117 days post-vaccination)

Level 1

Good

Falsey (2009)Footnote 28

NCT00391053

Experimental TIV split-virus
60μg/strain
0.5mL/dose

Comparator : Fluzone®(Sanofi Pasteur)
15μg HA/strain 0.5mL /dose

Strains
A/New Caledonia/20/99 (H1N1)
A/Wisconsin/67/2005 (H3N2)
B/Malaysia/2506/04

RCT
Double-blind
Multi-centre Phase III

Country USA
30 centres

Year 2006-07

Age 65-97 years
Mean 73 years
Male 52%

N=3876
60μg=2576
15μg=1275

82% vaccinated last season
79% underlying condition

Medically stable, community dwelling

Follow-up 7 days active, 180 days passive

Reactogenicity
  60μg 15μg
Systemic
Fever (≥37.5oC) 3.6 (2.9,4.4)
1.1 (0.8,1.6)		 2.3 (1.5,3.3)
0.3 (0.1,0.8)* mod/severe
Myalgia 21.4 (19.8,23.0)
5.8 (5.0,6.8)		 18.3 (16.2,20.5)
3.4 (2.5,4.6)* mod/severe
Headache 16.8 (16.5,19.5) 14.4 (12.1,16.0)
Malaise 18.0 (16.5,19.5)* 14.0 (12.1,16.0)*
Local
Pain 36 24
Reness 15 11
Swelling 6 4

SAE 
60μg 15μg
6% 7%

Vaccine related SAE
60μg 15μg
Crohn's disease exacerbation requiring hospitalization (2 days post-vaccination) Myasthenia gravis
(~ 1 month post-vaccination)

Level 1

Good.

Sanofi Pasteur (2013)Footnote 57
Robertson (2012)Footnote 58

NCT01430819

Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

Comparator:
Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/California/07/2009 (H1N1)
A/Victoria/210/2009 (H3N2)
B/Brisbane/60/2008

RCT
Double-blind
Multi-centre
Phase IV

Country
USA
6 centres

Year 2011-12

Age ≥ 65 yrs
Mean: 72.1 yrs
Male: 39%

N=300
60μg=145
15μg=147

96% Caucasian

96.3
96.3

Follow-up 7 days active, 21 days passive

Reactogenicity
  60μg 15μg
Systemic
Fever (undefined) 0.7 1.3
Myalgia 29.3 16.7*
Headache 16.7 17.3
Malaise 16.0 14.0
Local
Pain 52.7 24.0*
Erythema 8.7 4.7
Swelling 6.7 2.7

Vaccine-related SAE
None

Level 1

Good

Talbot (2014)Footnote 59

NCT01189123

Fluzone®High-Dose (Sanofi Pasteur)
60μg HA/strain
0.5mL/dose

Comparator:
Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains not stated

RCT
Double-blind
Single centre

Country
USA

Years: not stated (possibly 2010-2012)

Age 67-79 yrs
Mean 73 yrs
Male 51.4%

N=105
60μg=47
15μg=50

Follow-up Not specified

Vaccine-related SAE
No SAE

Level 1

Fair

Small sample size

Tsang (2014)Footnote 32

NCT00551031

60IM: High Dose IM15 (Sanofi Pasteur)
60μg/strain
0.5mL IM

Investigational ID (Sanofi Pasteur)
15ID: 15μg/strain 
0.1 mL/dose ID
21ID: 21μg/strain 
0.1 mL/dose

Comparator:
FluZone®(Sanofi Pasteur)
15IM: 15μg/strain
0.5mL/dose

Strains
A/Solomon Islands/3/2006 (H1N1)
A/Wisconsin/67/2005 (H3N2)
B/Malaysia/2506/2004

RCT
Open label for route
Double-blind for dose Multi-centre Phase II

Country USA
31 centres

Year 2007-08

Age 47-99 years
Mean 73 years
Male 44%

N=1912
60IM=319
15IM=320
15ID=635
21ID=635

87% previously vaccinated
94% Caucasian

Medically stable
Ambulatory

Follow-up 7 days active; 180 days passive

Reactogenicity

Local
15ID 21 ID
76.5 (73.0, 79.8) 77.3 (73.8, 80.5

60IM 15IM
34.5 (29.3, 40.0) 49.5 (43.9, 55.2)*

Systemic
15ID 21 ID
27.2 (23.8, 30.9) 31.1 (27.5, 34.9)

15IM 60IM
25.7 (21.0, 30.9) 36.4 (31.1, 41.9)*

Immediate unsolicited events
15ID: Moderate dizziness lasting one day
15IM: Moderate jaw pain lasting one day

Vaccine-related unsolicited AE
15ID 21 ID
2.7 (1.6, 4.3) 2.4 (1.3, 3.9)

15IM 60IM
1.6 (0.5, 3.6) 1.6 (0.5, 3.6)

Severe vaccine-related non-serious AE 21ID: severe injection-site rash 60IM: Severe vomiting (on vaccination day) 60IM; Severe cough (9 days post-vaccination)

SAE
15ID 21 ID
5.4 (3.7,7.4) 6.0 (4.3,8.1)

15IM 60IM
6.6 (4.1,9.9) 5.0 (2.9,8.0)

Vaccine related SAE
None reported

Level I

Good
30µg inactivated, intramuscular

Keitel (2006)Footnote 30

Subvirion TIV
(Aventis Pasteur)
30μg HA/strain
60μg HA/strain
0.5mL/dose

Comparator:
subvirion TIV
(Aventis Pasteur)
15μg HA/strain
0.5mL/dose
Placebo: saline
Strains
A/NewCaledonia/20/99 (H1N1) A/Panama/2007/99 (H3N2)
B/Victoria/504/2000

RCT
Single-center

Country
USA

Year 2001-02

Age ≥65 years
Mean 72.4 yrs
(65-88 yrs)
Male 59 %

N=202
60μg=50
30μg=51
15μg=51
Saline=50

97% Caucasian
82% vaccinated last season

Ambulatory, medically stable
.

Follow-up 7 days; 180 passive

Local Reaction
  60 μg 30 μg 15 μg saline
Any 12 24 20 22(non significant)
Redness/Swelling 6% of high dose

Significant dose-related increases in discomfort and redness/swelling (p<0.005)

Systemic Reaction (%)
No significant differences among groups

SAE
3 in each of the vaccine groups

Vaccine-related SAE
None

Level 1

Good
60µg Intramuscular - subunit

Palache (1993)Footnote 39

Experimental trivalent subunit (Duphar BV)
60 μg HA/strain 0.5mL/dose

Comparator(s)
10μg HA/strain
20μg HA/strain
Saline (placebo)
0.5mL/dose

Strains A/Taiwan/2/86 (H1N1)
A/Sichuan/2/87 (H3N2)
B/Beijing/1/87

RCT
Double-blind
Multi-centre
Placebo-controlled

Country Netherlands
Israel

Year 1988

See Remarque (1993) for same participants - for IgG, IgA, IgM responses to H3N2 strain

Data for 65+ yrs
Age 68-99 yrs
Mean 80 yrs

N=262
60μg=66
10μg=67
20μg=64
Saline=65

22% previously vaccinated

Nursing home residents

Excluded
Immune suppressing drug treatment

Follow-up 2 days of active

Reactogenicity
  Placebo 10 μg 20 μg 60 μg
Systemic
Any		 1 0 2 0
Local
Any		 3 1 5 6

SAE
none reported

Level I

Good
Recombinant vaccines

Keitel (2009)Footnote 23

NCT00395174

FluBlok®(Protein
Sciences Corp.)
~45μg rHA/strain
0.5mL/dose
(Total: 131μg)

Strains
A/Wisconsin (H3N2)
A/New Caledonia (H1N1)
B/Ohio

IM15: Fluzone®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

RCT
Double-blind
Multi-centre Phase 3

Country
USA
7 centres

Year 2006-07

Age ≥65 yrs
Mean:
45μg 72.9 yrs
15μg 73.9 yrs
Male 47%

N=869
rHA45=431
IM15=430

98% Caucasian
83% vaccinated last season

Ambulatory, medically-stable,
community
dwelling

Follow-up: 7 days active, 180 days passive

Reactogenicity
  rHA45 IM15
Any 47 50%
Systemic
Fever (≥37.6oC) 2.5 2.1
Headache 11 10
Tiredness 14 15
Fatigue 9 10
Local
Discomfort 22 23
Erythema 10 12
Swelling 7 10

Erythema immediately after injection 6.1 v 0.6*

Unsolicited AE
rHA45 IM15
21% 20%

Vaccine-related SAE
None

Level 1

Good

Treanor (2006)Footnote 40

Baculovirus-expressed (rHA)
135μg rHA/strain
45μg rHA/strain
15μg rHA/strain
0.5mL/dose

Comparator
IM15: Fluzone®(Sanofi Pasteur).
15μg HA/strain
0.5mL/dose

Strains
A/Panama/2007/99 (H3N2)
A/NewCaledonia/20/99 (H1N1)
B/HongKong/330/2001

RCT
Double-blind

Country
USA

Year not stated (2002-03 or 2003-04)

Age 65-90 yrs 
Mean: 72 yrs
49% male

N=399
135rHA=101
45rHA= 99
15rHA=98
IM=98

96% Caucasian

Community-dwelling, medically stable

Follow-up 7 days active, 28 days passive

Reactogenicity
  135 rHA 45 rHA 15rHA IM
Systemic
Fever (≥37.5oC) 4.0 4.0 3.0 2.0
Myalgia 15.0 8.0 11.1 8.1
Headache 15.0 14.0 15.2 10.1
Malaise 15.0 14.0 13.1 7.1
Local
Pain 19.0 15.0 11.1 6.1*
Swelling 11.0 0 1.0 3.0
Tenderness 29.0 20.0 14.1 29.3

Vaccine-related SAE
None

Level 1

Good
15µg inactivated intradermal

Ansaldi (2013)Footnote 50

EUDRACT: 2009-014637-24

ID: Intanza®(Sanofi Pasteur)
15µg HA/strain
0.1ml dose

Comparator:
Inflexal®V (Crucell)
15µg HA/strain 0.5mL/dose

Strains A/California/7/2009(H1N1)
A/Perth/16/2009 (H3N2)
B/Brisbane/60/2008

RCT
Open-label
Multicenter
Phase IV

Country: Italy

Year 2010

Age: ≥60
Mean 75-77 years

Total: N=500
ID: n=250
IM: n=250

Excluded: alcoholic, unstable chronic illness

Follow-up 21 days active; 180 days passive

Reactogenicity
  IM ID
Systemic
Any 10 (7,15) 11 (7,15)
Fever (≥38oC) 2 (1,14) 2 (1,14)
Chills/shivering 5 (3,9) 3 (2,6)
Myalgia 7 (4,11) 6 (4,10)
Headache 6 (3,10) 4 (2,8)
Malaise 6 (3,10) 5 (3,9)
Local
Any 20 (15,26) 43 (36,49)
Pain 12 (8,17) 13 (9,18)
Redness 7 (4,11)* 33 (27,39)
Swelling 5 (2, 8)* 19 (14,24)
Lump 7 (4,11)* 25 (20,31)
Pruritus 5 (3,9)* 20 (16,26)

Unsolicited Events, days 0-21
IM ID
2.0 (0.8,5.3) 0.9% (0.2,3.1)

Serious adverse events
None reported

Level I

Good

Arnou (2009)Footnote 46

NCT00383526

Experimental ID: (Sanofi Pasteur)
15ug HA/strain 0.1mL/dose

Comparator:
Vaxigrip®(Sanofi Pasteur)
15ug HA/strain 0.5mL/dose

Strains as recommended for
2006-2007
2007-2008
2008-2009

*Analysis includes only participants vaccinated with the same vaccine sequentially

RCT
Open-label
Multi-centre

Country:
France, Belgium, Lithuania, Italy

Years
2006-2009

Age 60-95 years
Mean 71 years
Male 20%

N=3707

Year 1
ID =2604
IM =1081

Year 2
ID→ID =133
IM→IM =143

Year 3
ID→ID→ID=121
IM→IM→IM=67

65% chronic condition

Excluded congenital or acquired immuno-deficiency

Follow up 7 days active; 21 days passive

Reactogenicity
  IM ID
Systemic
Fever (>37.5oC & ≥24 hr) 3.4 (2.4,4.7) 2.5 (1.9,3.1)
Chills 6.1 (4.7,7.7) 4.6 (3.8,5.5)
Myalgia 10.9 (9.1,12.9) 10.6 (9.5,11.9)
Headache 12.7 (10.8,14.9) 13.0 (11.8,14.4)
Malaise 7.8 (6.3,9.6) 8.5 (7.4,9.6)
Local
Pain 17.2 (15.0,19.6) 22.7 (21.1,24.4)
Redness 15.1 (13.0,17.3 70.9 (69.1,72.7)
Swelling 8.4 (6.8,10.2)* 35.8 (33.9,37.7)
Lump 11.3 (9.5,13.3)* 37.6 (35.8,39.5)
Pruritus 6.1 (4.7,7.7)* 29.5 (27.7,31.2)
Bruise 3.7 (2.7, 5.0) 3.4 (2.7, 4.2)

Unsolicited reactions (Day 0-21)
IM ID
1.8 (1.1,2.8) 1.6 (1.2,2.2)

SAE
IM ID
0.6 (0.2,1.2) 0.5 (0.3,0.9)

SAE possibly vaccine-related
IM=0 v ID=2

  • myopericarditis 4 months post-vaccination in a person with history of MI
  • facial neuralgia 8 weeks post-vaccination

Level 1

Good

Chan (2014)Footnote 44

NCT01967368

Intanza®(Sanofi Pasteur)
15μg HA/strain
0.1mL/dose

Comparator:
Vaxigrip®(Sanofi Pasteur)
15μg HA/strain
0.5mL/dose

Strains
A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2) B/Massachus-etts/2/2012

RCT
Open-label
Single center

Country:
China (Hong Kong)

Year 2013-14

Age ≥65 years
Mean 83 years
Male 36%

Total: n=100
ID=50
IM=50

Nursing home residents

Follow-up: 7 days active; 180 days passive

Reactogenicity
  IM ID
Systemic
Fever (≥37.5oC) 4 2
Myalgia 6 10
Arthralgia 4 8
Headache 6 6
Malaise 8 12
Local
Pain 6 4
Redness 4 26*
Swelling 2 20*
Lump 0 0

Serious adverse events:
No vaccine-related SAE

Level I

Good

Hoon Han (2013)Footnote 43

NCT01215669

Intanza®(IDflu)
15μg HA/strain 0.1mL/dose

Comparator:
Vaxigrip®(Sanofi Pasteur) 
15μg HA/strain
0.5 mL/dose

Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2)
B/Brisbane/60/2008

RCT
Open-label Multicentre Phase IV

Country South Korea
6 sites

Year 2010-11

Age: 18+ years
Data for ≥60 years
Mean 64.5-64.9 yrs
Male 38%

N: 120
ID: n= 60
IM: n= 60

38% vaccinated past year

Follow-up: 7 days active, 21 days passive

Reactogenicity 
  IM ID
Systemic
Fever (>38.0oC & ≥1 day) 0 0
Shivering 13.3 18.3
Malaise 13.3 20.0
Local
Induration (≥50mm & ≥3 days) 0 0
Pain, erythema, swelling, induration, and pruritus were higher in ID than IM recipients

Unsolicited AE
  IM ID
Any 25 23.3
Vaccine-related 3.3 3.3

SAE
None

Level I

Good

Holland (2008)Footnote 42

NCT00296829

Intradermal split-virion (Sanofi Pasteur)
15µg HA/strain
21µg HA/ strain 0.1mL/dose

Comparator: VaxiGrip®(Sanofi Pasteur)
15µg HA/strain 0.5mL/dose

Strains
A/New Caledonia/20/99 (H1N1)
A/Wellington/1/2004 (H3N2)
B/Jiangsu/10/2003

RCT
Open label for route
Double blind for dose
Multicenter
Phase II

Country
New Zealand
Australia

Year 2006

Age 65-85 yrs
Males 47%

Total n=1101
15ID=366
21ID=369
15IM=366

~85% vaccinated previous season

Medically stable

Follow-up 7 days reactogenicity; 180 days SAE

Reactogenicity
  15IM 15ID 21ID
Systemic
Any 27.4 30.2 29.1
Fever (>37.5oC & >24hr) 4.1 3.9 4.1
Chills 0.8 0.5 2.2
Myalgia 12.2 12.4 12.2
Headache 17.4 18.1 16.0
Malaise 10.1 13.2 10.0
Local
Any 39.7* 89.6 88.0
Pain 16.8 18.4 16.3
Erythema 19.1* 78.8 77.7
Swelling 13.4* 62.3 58.2
Pruritus 8.7* 27.2 32.1
Induration 16.7* 64.6 65.2

Vaccine-related SAE (180 days)
15ID - 1 vaccine-related, brachial neuritis

Level 1

Good

Seo (2014)Footnote 45

ID: (Sanofi Pasteur)
15μg HA/strain
0.1mL/dose

IM15: Aggripal S1®(Novartis)
15μg HA/strain
0.1mL/dose

ADV: Fluad®(Novartis)
15μg HA/strain
0.1mL/dose
adjuvant

Year 2011-12
Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008

RCT
Multicenter

Country
South Korea

Age ≥65 years
Median 71-73 years
Male 32-39%

N=335
IM =113
ADV=111
ID =111

Community-dwelling
Good health

Follow-up: 7 day active

Reactogenicity
  IM ID ADV
Systemic
Fever (≥38oC) 0 0.9 0
Chills/shivering 1.2 0 2.7
Myalgia 0.9 5.4 8.1
Arthralgia 0.9 2.7 5.4
Headache 0.9 4.5 2.7
Fatigue 0.9 5.4 5.4
Malaise 0 4.5 5.4
Local
Pain 7.1 6.3 10.8
Redness 3.5 9.9 5.4
Swelling 3.5 6.3 2.7

SAE
None reported

Level I

Fair

Short follow-up of SAE

Scheifele (2013)Footnote 41

NCT01368796

ID: Intanza®(Sanofi Pasteur)
15μg HA/strain
0.1mL/dose

Comparators
ADV: Fluad®(Novartis)
15μg HA/strain
MF59 adjuvant
0.5mL/dose

IM15: Agriflu®
(Novartis)
15μg HA/strain
0.5mL/dose

Strains
A/California/7/2009 (H1N1) A/Perth/16/2009 (H3N2) B/Brisbane/60/2008

RCT
Evaluator-blind
Multicenter

Country: Canada
8 centres)

Year 2011-12

Age ≥65 years
Mean 74 years
41% male

ID=301
ADV=299
IM=305

95% Caucasian

100% vaccinated in 1 or 2 of previous two seasons

Community-dwelling or at facilities with minimal assistance

Follow-up Active 7 days; passive 180 days

Reactogenicity
  IM ID ADV
Systemic
Any 39.4 (34.1,45.0) 43.6 (38.1,49.2)* 39.9 (34.5,45.5)
Fever 0.7-1.7% across groups
Myalgia 18.9 (14.9,23.6) 22.8 (18.4,27.8)* 25.9 (21.3,31.1)*
Headache 11.4 ( 8.3,15.4) 14.5 (11.0,18.9) 9.6 (6.8,13.5)
Malaise 11.4 (8.3,15.4)* 16.2 (12.5,20.7)* 11.0 ( 7.9,15.0)*
Tiredness 21.2 (17.0, 26.1)* 23.8(19.3,28.9)* 18.6 (14.6,23.4)*
Arthralgia 11.1 ( 8.0, 15.1) 14.2 (10.7,18.6) 12.6 (9.3,16.9)
Sleep Disturbances 7.2 (4.8,10.6) 7.9 (5.4,11.5) 8.3 (5.7,12.0)
Local
Pain 20.8 29.7 37.9
Redness 12.7 76.2* 13.0
Swelling 6.2 49.2* 12.0
Lump 4.6 46.5* 8.0
Itchiness 1.6 20.8* 3.0

SAE
Day 0-20 8
Day 21-180 37

Vaccine-related SAE
None

Level 1

Good

Van Damme (2010)Footnote 49

NCT00554333

ID: Intanza®(Sanofi Pasteur)
15μg HA/strain
0.1 mL/dose

Comparator
ADV: Fluad®(Novartis)
15μg HA/strain
MF59 adjuvant 0.5mL/dose

Strains
A/Solomon Islands/3/2006 (H1N1)
A/Wisconsin/67/2005 (H3N2)
B/Malaysia/2506/2004

RCT
Open-label
Parallel-group
Multi-centre Phase II

Country Belgium, France
10 centres

Year 2007-08

Age ≥65 yrs
Mean 74.3 yrs
Male 46.5%

N 795
ID=390
ADV=385

72% vaccinated last year
53% underlying disease

Follow up 7 days active, 21 days passive

Reactogenicity
  ID ADV
Systemic
Fever (≥38oC) 4.0 5.8
Chills/shivering* 6.0 (3.9, 8.8) 5.8 (3.7, 8.6)
Malaise 4.8 (2.9, 7.4) 5.0 (3.1 v 7.7)
Local
Pain 19.8 20.9
Redness 63.1 13.4*
Swelling 34.2 8.6*
Lump (induration) 32.9 10.6*
Pruritis 28.1 6.5*
At least one 70.1 33.8

No immediate AE

Unsolicited AE
  ID ADV
Total 26.4 25.9
Severe 2.0 1.8

Vaccine-related SAE
ID: Pneumonia (one day post vaccination)
ADV: Facial herpes zoster (three days post vaccination)

Level I

Good

Della Cioppa (2012)Footnote 36
Della Cioppa (2014)Footnote 37

NCT00848848

IM30: 30μg H3N2 with 15μg each of H1N1 & B strains
(no adjuvant) 0.5mL/dose

ADV30: 30μg H3N2 with 15μg each of H1N1 & B strains & MF59 (100%)
0.5mL/dose
IM15: 15μg /strain (no adjuvant) 0.5mL/dose

ADV15:15μg /strain & MF59 (100%)
Fluad®(Novartis)
0.5mL/dose

Strains
A/Brisbane/59/2007 (H1N1) A/Uruguay/716/2007 (H3N2) B/Florida/4/2006

RCT
Observer-blind
Multicenter

Countries
Poland
Belgium
Germany

Year 2008-09

Age ≥65 yrs
Mean 69 yrs
Male 40-68%

N=450
IM30=43
ADV30=42
IM15=43
ADV15=46
ID12=46

(other groups excluded)

73-81% previously vaccinated

Healthy volunteers
Follow-up 7 days active, 21 days passive
  IM30 ADV30 IM15 ADV15 ID12
Systemic
Fever (≥38.0oC) 0 0 0 0 NR
Chills 0 2 0 2 NR
Myalgia 2 2 0 2 6
Headache 2 0 0 0 NR
Malaise 0 2 0 0 NR
Arthralgia 0 2 0 2 NR
Local
Pain ADV significantly higher than IM or ID
Erythema 0 2 0 0 47-52
Swelling ID significantly higher
Induration ID significantly higher
Pruritus Not stated for IM; ID12-2-6%

Vaccine-related SAE
None

NR: not reported

Level 1

Good
ADV
adjuvant;
ID
intradermal;
IM
intramuscular;
AE
adverse event;
SAE
serious adverse event

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