Overview of US LAIV Policy · US Recommendations for influenza vaccination have changed over time 0 10 20 30 40 50 60 70 80 90 100 1960 2000 2004 2006 2008 2010 65+ yrs chronic conditions

National Center for Immunization & Respiratory Diseases

Overview of US LAIV Policy

Alicia Fry, MD MPH

Chief , Epidemiology and Prevention Branch

Influenza Division, CDC

Australia Immunisation Coalition Meeting

Feb 3, 2019

US Recommendations for influenza vaccination have changed over time

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1960 2000 2004 2006 2008 2010

65+ yrs chronic conditions pregnant woman 50-64 yrs

children 6-23mo children 24-59 mo children 6-18 years all >6mo

2010-11: Annual vaccination for all persons6 mo and olderA

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Drivers for pediatric vaccination policy

Bhat, et al NEJM 2005

N=94 N=110N=185

N=19

• 50% of deaths have no underlying disease• Rates inversely correlated with age• ~80% unvaccinated• 40% die before admission to the hospital

Finelli, Pediatrics 2008; Blanton, Pediatrics 2012;Wong, Pediatrics 2016, Shang, Pediatrics 2018

Drivers for pediatric vaccination policy

Vaccine coverage

https://www.cdc.gov/flu/fluvaxview/coverage-1718estimates-children.htm

US LAIV Policy timeline

ACIP preferentially recommends LAIV (vs IIV) for healthy 2-8 yrs

for 2014-15

LAIV3 licensed by FDA 5-49 yrs;

ACIP recommends

for use

2003

LAIV4 licensed by FDA;

ACIP recommends for use for 2013-14

2012 Feb 2014

2013-14 Flu seasonH1N1pdm09

LAIV3 licensed for

2-49 yrs;ACIP

recommends

2007

Evidence Profile—LAIV vs. IIV—2-8-year-oldsLab-confirmed Influenza—Randomized Studies

Studies(n)

Risk ofBias

Inconsistency Indirectness Imprecision

Effect

QualityRR[95% CI]

Risk Differencewith LAIV [95% CI]

2Not

seriousNot

SeriousNot

SeriousNot

Serious0.47

[0.38 – 0.58]46 fewer per 1000

[36 – 54 fewer]1

(High)

7

• Data from both studies restricted to children aged ≥24 months (meta-analysis by Ambrose et al, Vaccine 2012)

(24-71M)

(24-59M)

ACIP minutes June 2014



for 2014-15

LAIV3 licensed by FDA 5-49 yrs;

ACIP recommends

for use

2003

LAIV4 licensed by FDA;

ACIP recommends for use for 2013-14

2012 Feb 2014

2013-14 final LAIV and IIV VE

estimates shared with ACIP

Oct 2014


LAIV3 licensed for

2-49 yrs;ACIP

recommends

2007

During 2013-14 LAIV did not provide protection in children; IIV was protective

US Influenza VE Network; Chung et al Pediatrics, 2016 and Gaglani, et al JID 2016

H1N1pdm09 LAIV component did not protect

• For 2013-14, Medimmune US ICICLE study and US DoD VE Network found similar findings ACIP Oct 2014; Chung et al Pediatrics, 2016;Gaglani, et al JID 2016; Caspard Vaccine 2016


ACIP removes preference for 2015-16.

Feb 2014

2013-14 final LAIV and IIV VE

estimates shared with ACIP

October 2014


Feb 2015

2014-15 Flu seasonDrifted H3N2

2015-16 LAIV H1 changed to A/Bolivia/H1N1


for 2014-15

2014-15 Interim (mid season) LAIV and IIV VE

shared with ACIP

Pre 2009 RCT data: LAIV VE against mismatch

Belshe 2007 NEJM

LAIV and IIIV performed equally against the drifted H3N2 3c.2a viruses

Confirmed in two US observational studies: Medimmune ICICLE and DoD

ACIP Feb 2015; Zimmerman CID 2016


ACIP removes preference for 2015-16.

Feb 2015

2014-15 Flu seasonDrifted H3N2

2015-16 LAIV H1 changed to A/Bolivia/H1N1

2014-15 Interim season LAIV and IIV VE shared

with ACIP


June 2016

ACIP does not recommended LAIV for 2016-17

2015-16 final season LAIV and IIV VE shared with

ACIP

2016-17 Flu seasonH3N2

2015-16: LAIV worked less well against H1N1pdm09 than IIV

Other US studies: Medimmune ICICLE and DoD

Other countries with LAIV VE: UK, Finland, Canada, Germany

ACIP June 2015; Jackson NEJM 2017


2015-16 Flu seasonH1N1pdm09 June

2016


2015-16 final season LAIV and IIV VE shared with

ACIP

2016-17 Flu seasonH3N2 June

2017


Revised methodology to select H1 LAIV virus, human cell lines, ferret studies LAIV H1 changed to A/Slovenia

Worked on meta-analysis of global studies and IPD analysis of US studies since 2013-14




June 2017

Feb 2018

Meta-analysis of global estimates; IPD of US data

ACIP recommends LAIV for 2018-19

RCT comparing shedding and Abs for LAIV with A/Bolivia and A/Slovenia


Review of LAIV Effectiveness data, 2010-11 through 2016-17

Combined individual patient-level analysis of U.S. studies• 5 studies and three seasons with LAIV4 (2013-14 through 2015-16)

• Greater power for age group analyses

• More precise estimates through pooling of data across multiple studies

• Evaluation of effect of prior vaccination

Systematic review and meta-analysis• Global studies from 2010-11 season forward

• Evaluation of quality of individual studies (risk of bias; problems related to small sample size); for observational studies: ROBINS-I and sparse data bias

• Summary VE results and exploration of heterogeneity

ACIP Feb 2018; Chung et al., Pediatrics 2019

Adjusted VE of LAIV by influenza (sub)type and age group—Combined US-

IPD analysis

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2834

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36

712

83

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66 66

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-20

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2–17 2–4 5–8 9–17 2–17 2–4 5–8 9–17 2–17 2–4 5–8 9–17 2–17 2–4 5–8 9–17

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(%

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Age group (years)

Any influenza(all 3 seasons)

A/H1N1pdm09(2013–14, 2015–16)

A/H3N2(2014–15)

Influenza B(all 3 seasons)

Adjusted VE of IIV by influenza (sub)type and age group—Combined US-

IPD analysis

51

58

47 45

67 68 66 68

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55

25

9

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4346

58

-40

-20

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2–17 2–4 5–8 9–17 2–17 2–4 5–8 9–17 2–17 2–4 5–8 9–17 2–17 2–4 5–8 9–17

Ad

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cin

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Age group (years)

Any influenza(all 3 seasons)

A/H1N1pdm09(2013–14, 2015–16)

A/H3N2(2014–15)

Influenza B(all 3 seasons)

Effect on prior vaccination on VE against A/H1N1pdm09, 2013–14 and 2015–16 seasons—Combined US-IPD analysis

Total 567 213 3311 1412 220 859 217 329 292

Flu+ (%) 28 (5) 32 (15) 542 (16) 98 (7) 29 (13) 97 (11) 16 (7) 57 (17) 58 (20)

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IIV LAIV Unvaccinated IIV LAIV Unvaccinated IIV LAIV Unvaccinated

Ad

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Prior Season Unvaccinated Prior Season IIV Prior Season LAIV

REF REF REF

Systematic Review and Meta-analysis of Global studies: Odds of influenza A(H1N1)pdm09 virus infection among children receiving LAIV compared to unvaccinated children, age 2-17 yr, by precision (n=10)

Less precise

More precise

Pooled VELAIV vs. unvaccinated25% (6 to 40)

ACIP Feb 2018

Without Nohynek 2016 With Nohynek 2016

Sensitivity Analysis: Inclusion of Nohynek 2016 influenza A estimate†Odds of influenza A(H1N1)pdm09 virus infection among children receiving

LAIV compared to unvaccinated children, age 2-17 yr

Pooled VE excluding Nohynek et alLAIV vs. unvaccinated:25% (6 to 40)

Pooled VE including Nohynek et alLAIV vs. unvaccinated:31% (13 to 46)

†Estimate for Influenza A, presumed predominantly H1N1pdm09; study population includes only 2-year-olds

Odds of influenza A(H1N1)pdm09 virus infection among children receiving LAIV compared to children receiving IIV (relative effectiveness), age 2-17 yr (n=4)

Favors LAIV Favors IIV

ACIP Feb 2018

Odds of influenza B virus infection among children receiving LAIV compared to children receiving IIV (relative effectiveness), age 2-17 yr (n=5)


ACIP Feb 2018

Odds of influenza A(H3N2) virus infection among children receiving LAIV compared to children receiving IIV (relative effectiveness), age 2-17 yr (n=4)


ACIP Feb 2018

Medimmune presentations at ACIP: • A/Slovenia/H1N1pdm-like virus performed better in human cell lines and

ferret studies that A/CA or A/Bolivia

• Better immunogenicity and shedding of A/Slovenia/H1N1pdm-like virus compared to A/Bolivia in RCT in young children

ACIP, Feb 2017 Conclusions:• Since 2013-14, a plausible root cause of poor effectiveness of LAIV4 against

H1N1pdm09 identified

• New LAIV vaccine virus selection processes to be applied going forward

• Encouraging shedding and immunogenicity evidence that problem may be addressed with new H1N1pdm09 virus

• Caveat: whether this problem is solved will not be known until there is an effectiveness estimate against H1N1pdm09

UK 2017-18

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/726342/Influenza_vaccine_effectiveness_in_primary_care_2017_2018.pdf

*Sample sizes not reported

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/726342/Influenza_vaccine_effectiveness_in_primary_care_2017_2018.pdf

Thanks

Acknowledgements:

• Lisa Grohskopf

• Jessie Chung

• Brendan Flannery

• Jill Ferdinands

Documents

Overview of US LAIV Policy · US Recommendations for influenza vaccination have changed over time 0 10 20 30 40 50 60 70 80 90 100 1960 2000 2004 2006 2008 2010 65+ yrs chronic conditions