Influenza Vaccine Effectiveness: Morbidity and Mortality · •Quick overview of influenza basics •2018-19 influenza season and 2019 influenza season in Australia •How we measure

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

PublicHealthOntario.ca 3

Overview of Influenza


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


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


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


Influenza Virus Nomenclature

7

Influenza

Influenza A Influenza B

Influenza AH1N1

Influenza AH3N2

Influenza BYamagata

Influenza BVictoria


2018-19 Influenza Season Summary

2019 Influenza Season on Australia


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.


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


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

https://www.canada.ca/en/public-health/services/publications/diseases-conditions/fluwatch/2018-2019/week26-29-june-23-july-20-2019.html#a6a


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%)

https://www.cdc.gov/flu/weekly/index.htm


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

https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm/$File/flu-09-2019.pdf


More and early cases, but similar severity indicators

14


20192019



Australia 2019 – Percent positivity by type/subtype

15


H1N1 unsubtyped

H3N2

B

H1N1 Unsubtyped A

H3N2

B



How We Measure How Well the Influenza Vaccine Works


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


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


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


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


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


Serious Outcome Surveillance (SOS) Network for Hospitalized Patients

22

• 15 hospitals in five provinces

• Ontario, Quebec, British Columbia, New Brunswick, Nova Scotia (lead)


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

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/flu-3-flannery-508.pdf


Influenza Vaccine Effectiveness from the Surveillance Networks


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


United States Flu VE Network, 2018-19

26




Hospitalized Adult (HAIVEN) Vaccine Effectiveness Results, 2018-19


FLU VE

29%

9%44%



New Vaccine Surveillance Network (NVSN) Vaccine Effectiveness Results, 2018-19


FLU VE

29%

9%44%



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


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)


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

https://doi.org/10.1016/j.jinf.2017.09.010


Hospitalization Meta-Analysis by Age and Strain



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)



Hospitalization Meta-Analysis by Match for A(H3N2)


Similar A(H3N2)

VariantA(H3N2)


29%(13 to 44)

Adults under 65 59%(38 to 80)

46%(30 to 61)

65+ 43%(33 to 53)

14%(-3 to 30)



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


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



Factors that Impact Influenza Vaccine Effectiveness


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



38









Typ


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

https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2019-2020.html


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

http://dx.doi.org.proxy1.lib.uwo.ca/10.2217/imt.13.171


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.



42









Typ


Type of Vaccine

43

• Trivalent vs. quadrivalent

• Standard-dose vs. high-dose

• Adjuvanted

• Live attenuated


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


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

https://academic.oup.com/jid/article/217/5/731/4694421


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)

https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-018-1239-8


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)



48









Typ


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


Type / Subtype of Influenza


B

All ages 33%(26 to 39)

61%(57 to 65)

54%(46 to 61)


B


48%(37 to 59)

38%(23 to 53)

Ambulatory, Belongia et al

Inpatient, Rondy et al


Influenza Vaccines for 2019-20


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)



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)


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


FluLaval® Tetra Fluzone® Quadrivalent Afluria® Tetra

65 year and older High-dose trivalent


Fluzone® high-dose

FluLaval® Tetra Fluzone® Quadrivalent Afluria® Tetra


Vaccines for Adults 65 Years of Age and Older


Vaccine for Adults 65 Years of Age and Older

55

• Standard-dose quadrivalent (QIV) influenza vaccine

• High-dose trivalent (TIV) inactivated influenza vaccine


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


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

.



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



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


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%


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


Acknowledgements

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• 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


Questions ??

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