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Influenza Vaccine Effectiveness: Morbidity and Mortality
2019 Infection Prevention and Control
Southwestern Ontario IPAC Chapter, London, September 27, 2019
Bryna Warshawsky, Public Health Physician, Public Health Ontario
PublicHealthOntario.ca
Outline
2
• Quick overview of influenza basics
• 2018-19 influenza season and 2019 influenza season in Australia
• How we measure how well the influenza vaccine works
• Influenza vaccine effectiveness from the surveillance networks
• Meta-analyses of influenza vaccine effectiveness
• Factors that impact influenza vaccine effectiveness
• Vaccine choices for 2019-20, focusing on adults 65 years of age and over
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Overview of Influenza
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Symptoms of Influenza
4
• Every year between November and April
• Affects about 5% of the population
• Sudden onset of:
• Fever
• Cough
• Runny nose
• Muscle aches
• Fatigue
• Sore throat
• Gastro-intestinal symptoms not classic
• Lasts 2 - 7 days
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Complications
5
Primary viral or secondary bacterial pneumonia
Worsening of chronic lung disease or other underlying
medical conditions
Miscellaneous complications
In Canada, an approximate annual average of
• 12,200 hospitalizations
• 3,500 deaths1
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Most at Risk for Complications
6
People with chronic underlying medical conditions
• Heart disease
• Lung disease (asthma)
• Diabetes
• Cancer
• Immunosuppressive conditions
Elderly
Infants and young children
Pregnant women
Indigenous populations
Obesity
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Influenza Virus Nomenclature
7
Influenza
Influenza A Influenza B
Influenza AH1N1
Influenza AH3N2
Influenza BYamagata
Influenza BVictoria
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2018-19 Influenza Season Summary
2019 Influenza Season on Australia
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0
2000
4000
6000
8000
10000
12000
14000
Influenza A Influenza B
Ontario, 2003-04 to 2018-19 - Total influenza A and B cases
Public Health Ontario: 2012-13, 2013-14, 2014-15 , 2015-16, 2016-17, 2017-18 Respiratory Pathogen Seasonal Summaries, 2018-19 Week 27 Ontario Respiratory Pathogen Bulletin.
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Comparison to Previous Seasons
10
Ontario Respiratory Pathogen Bulletin: https://www.publichealthontario.ca/-/media/documents/surveillance-reports/orpb/orpb-wk18-2018-19.pdf?la=en
2018-19
H1N1 firstH3N2 laterAlmost no B
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Canada – Circulating Virus Characterization
11
• H1N1
• 97% antigenically similar to 2018-19 vaccine strain
• H3N2
• 61% belong to 3C.2a1 (clade of 2018-19 vaccine strain)
• 33% belong to 3C.3a (clade of 2019-20 vaccine strain)
• 6% belong to 3C.2a
• From Sentinel Practitioner Surveillance Network • 58% belong to 3C.2a1b
• 35% belong to 3C.3a
Public Health Agency of Canada: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/fluwatch/2018-2019/week26-29-june-23-july-20-2019.html#a6a
Sabaiduc S et al. Genotypic and antigenic characterization of influenza A(H1N1)pdm09 and A(H3N2) viruses circulating during the 2018-19 epidemic season in Canada. Poster Presentation. OptionsX Conference September 2019
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United States, 2018-19 (as of August 17, 2019)
12
Centers for Disease Control and Prevention: https://www.cdc.gov/flu/weekly/index.htm
H1N1 followed by H3N2
H3N2 3C.3a (73%)3C.2a1 (20%)3C.2a (7%)
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Australia 2019 (data to August 25, 2019)
13
Australian Government, Department of Health: https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm/$File/flu-09-2019.pdf
2018
2019
2018
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More and early cases, but similar severity indicators
14
Australian Government, Department of Health: https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm/$File/flu-09-2019.pdf
20192019
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Australia 2019 – Percent positivity by type/subtype
15
Australian Government, Department of Health: https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm/$File/flu-09-2019.pdf
H1N1 unsubtyped
H3N2
B
H1N1 Unsubtyped A
H3N2
B
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How We Measure How Well the Influenza Vaccine Works
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Terms
17
• Immunogenicity • Immune response to the vaccine
• Genetic relatedness • Compares circulating and vaccine strains based on
sequencing of genes
• Efficacy• How well the vaccine works in a clinical trial
• Effectiveness• How well the vaccine works in real life
• Determined each year using the test negative design
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Antigenic Characterization of Influenza Viruses
18
• Hemagglutination inhibition (HI) assay
• How well do antibodies bind to (and thus inactivate) influenza viruses?
Centers for Disease Control and Prevention: https://www.cdc.gov/flu/about/professionals/antigenic.htm#hi-test
Antibodies against vaccine-strain virus
Isolates of currently circulating virus strains
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Genetic characterization of influenza viruses
19
• Nextstrain - Sequencing the genes of influenza viruses
Nextstrain: https://nextstrain.org/flu/seasonal/h3n2/ha/3y
3C.3a
3C.2a1b
Vaccine 2019-20
Vaccine 2018-19
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Vaccine Effectiveness in Ambulatory Patients
20
• Determined using sentinel networks of health care providers
• Canada – Sentinel Practitioner Surveillance Network (SPSN)
• Ontario, Quebec, Alberta and British Columbia
• US Flu Vaccine Effectiveness (VE) Network
• Five sites in the US
• Use test negative design
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Test negative design
21
InfluenzaPositive
InfluenzaNegative
% vaccinated
% vaccinated
• Compare vaccination rates in those who are influenza positive and negative
• Vaccine effectiveness = (1-odd ratio) X 100
Person with respiratory illness
Naso-pharyngeal swab
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Serious Outcome Surveillance (SOS) Network for Hospitalized Patients
22
• 15 hospitals in five provinces
• Ontario, Quebec, British Columbia, New Brunswick, Nova Scotia (lead)
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United States Vaccine Effectiveness Networks
Centers for Disease Control and Prevention, June 2019 Advisory Committee on Immunization Practices https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/flu-3-flannery-508.pdf
US Flu VE HAIVEN NVSN
Setting Ambulatory Hospitalized Hospitalized
Ages 6 months and older
18 years and older
6 months to 17 years
Symptom duration
7 days or less
10 days or less
10 days or less
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Influenza Vaccine Effectiveness from the Surveillance Networks
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SPSN Vaccine Effectiveness 2012-13 to 2018-19Season Any
FluA A/H1N1 A/H3N2 B Dom A
(ON)Circulating/TIV B (ON)
2012/13 50(33,63)
45(24,60)
59(16,80)
41(17,59)
68(44,82)
H3N2 Yamagata/Yamagata
2013/14 68(58,76)
66(52,76)
71(58,80)
NA 72(55,82)
H1N1 Yamagata/Yamagata
2014/15 9(-14,27)
-13(-45,12)
NA -17(-50,9)
45(18,64)
H3N2 Yamagata /Yamagata
2015/16 46(32,57)
44(27,57)
43(25,57)
NA 50(31,63)
H1N1 Victoria (66%)/Yamagata
2016/17 45(31,56)
37(20,51)
NA 37(20,51)
73(52,84)
H3N2 Yamagata/Victoria
2017/18 38(27,47)
24(7,38)
58(30,75)
15(-6,32)
46 (34,56)
H3N2 Yamagata/Victoria
2018/19 61(53,69)
61(52,68)
69(60,76)
23(-9,46)
- H1N1/H3N2
Victoria/Victoria
SPSN: http://www.bccdc.ca/resource-gallery/Documents/Statistics%20and%20Research/Publications/Epid/Influenza%20and%20Respiratory/SPSN_VE_By_Year_Table.pdf
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United States Flu VE Network, 2018-19
26
Centers for Disease Control and Prevention, June 2019 Advisory Committee on Immunization Practices https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/flu-3-flannery-508.pdf
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Hospitalized Adult (HAIVEN) Vaccine Effectiveness Results, 2018-19
Centers for Disease Control and Prevention, June 2019 Advisory Committee on Immunization Practices https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/flu-3-flannery-508.pdf
FLU VE
29%
9%44%
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New Vaccine Surveillance Network (NVSN) Vaccine Effectiveness Results, 2018-19
Centers for Disease Control and Prevention, June 2019 Advisory Committee on Immunization Practices https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/flu-3-flannery-508.pdf
FLU VE
29%
9%44%
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Meta-analyses of Influenza Vaccine Effectiveness
Meta-analysis of Influenza Vaccine Effectiveness on Ambulatory Patients
• 56 articles
• 99 estimates: 34 A(H3N2), 36 B, 29 A(H1N1)pdm09
• January 1, 2004 to March 31, 2015
• Pediatric and adult
30Belongia EA et al. Lancet Infect Dis;2016:16(8):942-951 http://dx.doi.org/10.1016/S1473-3099(16)00129-8
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Ambulatory Meta-Analysis by Age and Strain
Belongia EA et al. Lancet Infect Dis;2016:16(8):942-951 http://dx.doi.org/10.1016/S1473-3099(16)00129-8
A(H3N2) A(H1N1)pdm09
B
All agesPediatric and adult
33%(26 to 39)
61%(57 to 65)
54%(46 to 61)
Working age adult 20-64
35%(14 to 51)
73%(52 to 84)
54%(16 to 75)
Seniors>60
24%(-6 to 45)
62%(36 to 78)
63%(33 to 79)
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Meta-Analysis of Influenza Vaccine Effectiveness on Hospitalization
32
• 30 studies
• 59 estimates: 28 A(H3N2), 11 B, 18 A(H1N1)pdm09
• January 2009 to November 2016
• Adult only
• By age and by strain
• A(H3N2) by match
Rondy M et al. Journal of Infection; 2017:75:381-394 https://doi.org/10.1016/j.jinf.2017.09.010
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Hospitalization Meta-Analysis by Age and Strain
Rondy M et al. Journal of Infection; 2017:75:381-394 https://doi.org/10.1016/j.jinf.2017.09.010
A(H3N2) A(H1N1)pdm09
B
All adults 37%(24 to 50)
48%(37 to 59)
38%(23 to 53)
Adultsunder 65
50%(38 to 62)
55%(34 to 76)
45%(8 to 81)
65+ 33%(21 to 45)
54%(26 to 82)
31%(11 to 51)
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Hospitalization Meta-Analysis by Match for A(H3N2)
Rondy M et al. Journal of Infection; 2017:75:381-394 https://doi.org/10.1016/j.jinf.2017.09.010
Similar A(H3N2)
VariantA(H3N2)
All adults 52%(39 to 66)
29%(13 to 44)
Adults under 65 59%(38 to 80)
46%(30 to 61)
65+ 43%(33 to 53)
14%(-3 to 30)
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Comparison of Hospitalized and Ambulatory Meta-Analyses in Older Adults
2 Belongia EA et al. Lancet Infect Dis;2016:16(8):942-951 http://dx.doi.org/10.1016/S1473-3099(16)00129-8
A(H3N2) A(H1N1)pdm09
B
Hospitalized1
65+33%
(21 to 45)
54%(26 to 82)
31%(11 to 51)
Ambulatory2
60+24%
(-6 to 45)
62%(36 to 78)
63%(33 to 79)
1 Rondy M et al. Journal of Infection; 2017:75:381-394 https://doi.org/10.1016/j.jinf.2017.09.010
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Factors that Impact Influenza Vaccine Effectiveness
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Factors that Determine Vaccine Effectiveness
37
• Human factors• Age / Immune status
• Underlying susceptibility / immunity
• Vaccine factors• Type of vaccine
• Manufacturing process of the vaccine
• Timing in the season / Duration of protection
• Repeated vaccination
• Virus factors• Match between vaccine and circulating strains
• Type /subtype of influenza
Typ
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Factors that Determine Vaccine Effectiveness
38
• Human factors• Age / Immune status
• Underlying susceptibility / immunity
• Vaccine factors• Type of vaccine
• Manufacturing process of the vaccine
• Timing in the season / Duration of protection
• Repeated vaccination
• Virus factors• Match between vaccine and circulating strains
• Type /subtype of influenza
Typ
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Age
39
• Older adults undergo immunosenescence
• Changes in immune function that contribute to the increased susceptibility to disease in older adults and decreased response to vaccines
• National Advisory Committee on Immunization
• In older adults, vaccine effectiveness of the trivalent vaccine is about half of that in healthy adults and varies depending on the outcome measures and the study population
National Advisory Committee on Immunization (NACI), : https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2019-2020.html
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Immune Status
40
• Immunocompromised individuals more at risk for complications of influenza
• Immune response to vaccine may be impaired, but effectiveness still demonstrated
Zbinden D. et al. Immunotherapy. 2014;6(2) http://dx.doi.org.proxy1.lib.uwo.ca/10.2217/imt.13.171
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Underlying Susceptibility / Immunity
41
Nachbagauer R et al. Clinical Microbiology and Infection. 2017;23(4):222-228 https://www.sciencedirect.com/science/article/pii/S1198743X17300976?via%3Dihub
See Figure 1a of Nachbagauer R et al. for influenza A subtypes that have circulated over time.
Initial exposure to influenza may influence later immune response to vaccines and infection.
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Factors that Determine Vaccine Effectiveness
42
• Human factors• Age / Immune status
• Underlying susceptibility / immunity
• Vaccine factors• Type of vaccine
• Manufacturing process of the vaccine
• Timing in the season / Duration of protection
• Repeated vaccination
• Virus factors• Match between vaccine and circulating strains
• Type /subtype of influenza
Typ
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Type of Vaccine
43
• Trivalent vs. quadrivalent
• Standard-dose vs. high-dose
• Adjuvanted
• Live attenuated
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Manufacturing Process of Vaccine
44
• Egg-based
• When vaccine strain grows in eggs, can pick up mutations that make it different from the circulating strain – “egg-adapted mutations”
• Mammalian cell-based
• Recombinant made in insect cells
• Virus-like particles made in tobacco plants
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Timing of Vaccination
45
• Vaccine effectiveness may decline over time
• Meta-analysis based on 14 studies
• Compared vaccine effectiveness 15-90 days after vaccination to 91-180 days after
• A(H3) - 33% (95% CI: -57 to -12)
• A(H1) -8% (95% CI: -27 to 21)
• B -19% (95% CI: -33 to -6)
Young B et al. The Journal of Infectious Disease. 2018; 217(5) 731-41
https://academic.oup.com/jid/article/217/5/731/4694421
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Repeated Vaccination
46
Ramsay LC, et al. BMC Medicine. 2019;17(9) https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-018-1239-8
Vaccine Effectiveness
ComparisonH1N1 H3N2 B
Both Seasons vs.
Prior Season Only
25% (14 to 35)
7%(–7 to 21)
18% (3 to 33)
Current Season vs.
Neither Season
62%(51 to 70)
45% (35 to 53)
64%(57 to 71)
Both Seasons vs.
Current Season Only
3% (–8 to 13)
–20%
(–36 to –4)
–11%
(–20 to –2)
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Repeated Vaccination
47
Vaccine Effectiveness
Comparison
Both Seasons vs.
Prior Season Only
• For A(H1N1) and B better to be vaccinated
in both seasons than relying on prior season
• No difference for A(H3N2)
Current Season vs.
Neither Season
• Better to be vaccinated in current season
than not in either season
Both Seasons vs.
Current Season Only
• For A(H3N2) and B, lower vaccine
effectiveness if vaccinated in both season
compared to current season only
• No difference for A(H1N1)
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Factors that Determine Vaccine Effectiveness
48
• Human factors• Age / Immune status
• Underlying susceptibility / immunity
• Vaccine factors• Type of vaccine
• Manufacturing process of the vaccine
• Timing in the season / Duration of protection
• Repeated vaccination
• Virus factors• Match between vaccine and circulating strains
• Type /subtype of influenza
Typ
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Match Between Vaccine and Circulating Strain
49
• Mismatch for A(H3N2) in 2014-15
• Very low vaccine effectiveness -17% (95% CI: -50 to 9)
• Potential for issues in 2019-20 if A(H3N2) circulates and it is not 3C.3a
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Type / Subtype of Influenza
A(H3N2) A(H1N1)pdm09
B
All ages 33%(26 to 39)
61%(57 to 65)
54%(46 to 61)
A(H3N2) A(H1N1)pdm09
B
All adults 37%(24 to 50)
48%(37 to 59)
38%(23 to 53)
Ambulatory, Belongia et al
Inpatient, Rondy et al
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Influenza Vaccines for 2019-20
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Influenza Vaccine Composition
52
2018-19Northern Hemisphere
2019Southern Hemisphere
2019-20Northern Hemisphere
A/Michigan/45/2015 (H1N1)pdm09
A/Michigan/45/2015 (H1N1)pdm09
A/Brisbane/02/2018 (H1N1)pdm09-like virus
A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
3C.2a1
A/Switzerland/8060/2017 (H3N2)-like virus3C.2a2
A/Kansas/14/2017 (H3N2)-like virus 3C.3a
B/Colorado/06/2017-like virus (Victoria lineage)
B/Colorado/06/2017-like virus (Victoria lineage)
B/Colorado/06/2017-like virus (Victoria lineage)
Quadrivalent
B/Phuket/3073/2013–like virus (Yamagata lineage)
Quadrivalent
B/Phuket/3073/2013–like virus (Yamagata lineage)
Quadrivalent
B/Phuket/3073/2013-like virus (Yamagata lineage)
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Recommended UIIP Vaccines for 2019-20
Age Type of product Product name
6 months up to and including 4 years
Standard-dosequadrivalent
FluLaval® Tetra Fluzone® Quadrivalent
5 years up to and including 64 years
Standard-dosequadrivalent
FluLaval® Tetra Fluzone® Quadrivalent Afluria® Tetra
65 year and older High-dose trivalent
Standard-dosequadrivalent
Fluzone® high-dose
FluLaval® Tetra Fluzone® Quadrivalent Afluria® Tetra
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Vaccines for Adults 65 Years of Age and Older
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Vaccine for Adults 65 Years of Age and Older
55
• Standard-dose quadrivalent (QIV) influenza vaccine
• High-dose trivalent (TIV) inactivated influenza vaccine
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Vaccine for Adults 65 Years of Age and Older
56
• Standard-dose quadrivalent influenza vaccines
• 2 A (H3N2 and H1N1) and 2 B strains (Victoria and Yamagata lineage)
• 15 micrograms of hemagglutinin per strain
• High-dose trivalent influenza vaccine
• 2 A (H3N2 and H1N1) and only B (Victoria lineage)
• 60 micrograms of hemagglutinin per strain
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High-Dose Influenza Vaccine
57
• Compared to standard-dose trivalent vaccine, the high-dose influenza vaccine has been shown to have better:
• Immunogenicity
• Effectiveness
• Efficacy
• High-dose vaccine has higher rates of local and systemic reactions than standard-dose
• generally mild and transient
Canadian Immunization Guide chapter on influenza and statement on seasonal influenza vaccine for 2019-2020 https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2019-2020.html
.
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National Advisory Committee on Immunization (NACI) 2019-20 Recommendations
58
Recommendation for individual-level decision making for adults 65 years of age and older
• High-dose TIV should be used over standard-dose TIV, given the burden of disease associated with influenza A(H3N2) and the good evidence of better efficacy compared to standard-dose TIV in this age group.
• There is insufficient evidence to make comparative recommendations….among high-dose TIV and standard-dose QIV.
National Advisory Committee on Immunization (NACI), : https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2019-2020.html
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Considerations Regarding A(H3N2)
59
• High-dose trivalent influenza vaccine works better against A(H3N2) than standard-dose trivalent vaccine
• Same A(H3N2) benefit expected against standard-dose quadrivalent vaccine
• A(H3N2) very important in adults 65 years of age and over with regard to burden of illness leading to hospitalizations and deaths
• Influenza B less important in that age group
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Contribution of Type/Subtype Varies by Age
Ontario, 2010-11 to 2017-18 influenza seasons
60
Data were obtained from the Ministry of Health and Long-Term Care (MOHLTC) integrated Public Health Information System (iPHIS) database, extracted by Public Health Ontario on September 10, 2018
61.5% A(H3N2)
B
A
BB
BB
A92.4% A(H3N2)
65+ years
A ABB
B
A
B
20-64years
Influenza A 75.8%
Influenza A 71.6%
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Cross Protection Between B Lineages
61
• Vaccine against one B lineage protects against the other
• B/Yamagata in vaccine protects against circulating B/Victoria
• B/Victoria in vaccine protects against circulating B/Yamagata
• A number of studies (although not all) demonstrate cross protection
• May vary by season, age and/or past vaccination history
• So trivalent vaccine may protect against the B lineage not in the vaccine
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Acknowledgements
62
• Dr. Michelle Murti
• Karin Hohenadel
• Erik Kristjanson
• Sandya Menon
• Romy Olsha
• Adriana Peci
• Christina Renda
• Ministry of Health
• Public health units
• Pubic Health Ontario
• Knowledge Services
• Communications
• Library
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Questions ??
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