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Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine PowerPoint PPT Presentation

Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine Carolyn B. Bridges, MD National immunization Program, CDC for NVAC/ACIP Influenza Vaccine Working Group April 20, 2005 Influenza Vaccine Effectiveness (VE)

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Influenza vaccine effectiveness considerations for prioritization of pandemic influenza vaccine l.jpg

Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine

Carolyn B. Bridges, MD

National immunization Program, CDC

for

NVAC/ACIP Influenza Vaccine Working Group

April 20, 2005


Influenza vaccine effectiveness ve l.jpg

Influenza Vaccine Effectiveness (VE)

  • Reviewed by ACIP Influenza Working Group January 2005 meeting on inter-pandemic prioritization

    • Kristin Nichol

    • John Treanor

    • Wendy Keitel

    • Lone Simonsen

    • Litjen Tan

    • Niranjan Bhat

    • Guillermo Herrera

    • Raymond Strikas


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Outline

  • VE TIV during inter-pandemic years

    • By age group and chronic condition

  • VE LAIV

  • 1 versus 2 doses in immunologically naïve populations

    • TIV in children

    • LAIV in children

    • Swine flu and “Russian flu” H1N1 vaccines

  • Studies of H5 vaccines


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Vaccine Effectiveness

  • Varies by age group, risk group, and antigenic match

  • Variety of outcomes/methods in literature

    • Influenza-like illness

    • Laboratory-confirmed influenza

    • Influenza-related hospitalization and death largely based on modeling

  • Herd immunity effects may also be considered


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Healthy Adults < 65 Yrs

  • Key literature reviewed

    • US military trials

    • Cochrane review (updated 2004)

    • 8 clinical trial papers published since 1988


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Efficacy of Influenza Vaccine in Healthy Young Adults

US Army Field Trials* US Air Force Field Trials+

* Adapted from Davenport, Med J Aust 1973 (suppl): 33-8.

+ Adapted from Meiklejohn. J Infect Dis 1983; 148: 775-84.


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VE Healthy Adults

  • VE estimates (Cochrane review for IV)

    • Lab-C illness70% (56% - 80%)

    • Clinical ILI25% (13% - 35%)

    • Work loss reduction:

      • 0.16 days per person vaccinated (0.04 – 0.29)

  • Other studies generally similar

    • Vaccination also associated with reductions in health care provider visits & antibiotic use due to URI / ILI

  • Insufficient data on serious complications


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VE During Pregnancy (1 cohort study)

  • Black SB, Am J Perinatology 2004

  • Subjects: 49,585 women with live births Nov thru Feb 97-98 thru 00-01 (KPNC)

  • Results

    • Hospitalizations: very rare

    • Outpt visits for resp illness: HR 1.15 (p = .09)

  • Note: vaccination rates low (4.7% - 11.9%)


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Community Dwelling Elderly

  • 4 clinical trials published from 1994 on

  • Numerous observational studies

  • 1 meta analysis


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VE in Community Dwelling Elderly Persons (meta analysis)

Vu T, et al. Vaccine 2002; 20: 1831.


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VE by Risk Status


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VE: Elderly in Nursing Homes

  • 1 meta analysis

  • Several observational studies


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VE Nursing Home Residents


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VE: Poor Match Yrs


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Summary of VE in Adults

  • Healthy adults

    • Vaccination reduces illness / work loss

  • Elderly

    • Vaccination reduces illness & serious complications of influenza

      • Vaccination provides benefits for healthy & high risk elderly & for community dwelling & NH residents

  • VE with mismatch is variably reduced

  • Even with lower VE, NNT must be considered


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Influenza VE Studies in Children

  • Data more limited compared with adults

  • Hoberman, et al JAMA 2003

    • 2 dose TIV vs placebo among children 6-24 months

    • 66% VE in year 1 and 0% in year 2 with low incidence influenza

    • No VE versus otitis media

    • Good immune responses to vaccine


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Pediatric VE Summary TIV

  • Influenza vaccine is efficacious in children

    • 21-76% for ILI

    • 30-95% for lab-confirmed influenza

    • 32-36% for otitis media

  • Generally similar results for healthy and high risk


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Pediatric VE Summary, cont

  • Vaccine efficacy in children increases with age

  • Limited data in children aged 6-23 months


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LAIV vs. TIV


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Live and inactivated vaccines

  • Theoretical considerations

    • Live vaccines must replicate

      • Level of replication depends on the host

        • Children > adults > elderly

    • Live vaccine stimulate mucosal immunity

      • May be more effective at limiting shedding

      • No well standardized immune correlates


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Live and inactivated vaccines

  • Theoretical considerations

    • Inactivated vaccines do not replicate

      • Level of immunity depends on host priming

        • Adults > children > elderly

    • Inactivated vaccines stimulate serum antibody

      • Well standardized immune correlate


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Live and inactivated vaccines

  • There are few direct comparisons

    • Indirect comparisons can be difficult to interpret

    • Randomized direct comparisons

      • Pediatric

      • Adult

      • Elderly

  • More definitive comparisons in adult and pediatric populations are underway


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Pooled results of experimental infection studies in adults Vaccine 18:899 (2000)

Virus shedding

Infection

Influenza illness

0.36

0.14

0.18

TIV

0.64

0.35

0.10

CAIV

0

1

0

1

0

1

Pooled Odds Ratio (95% CI) compared to placebo


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Natural infection in adults

  • Edwards (1994) J Infect Dis 169:68-76

    • Multiple years, subjects remain in group

    • Control vaccines monovalent B/allantoic fluid

    • Children did notreceive 2-dose schedule

    • LAIV given by drops

    • Outcomes included ILI, serologic and culture-confirmed illness


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Evaluation of the protective efficacy of LAIV in adults

Rate per 1,000 subjects

H1N1

H3N2


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Pediatric subgroup analysisNeuzil (2001) Pediatr Infect Dis J 20:733

  • Analysis restricted to children younger than 16 at the time of immunization

    • 474 age 1 to 5

    • 744 age 6 to 10

    • 591 age 11 to 15

  • Two outcomes

    • Culture positive illness

    • Seroconversion


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Evaluation of the protective efficacy of LAIV in kids

Per 1,000

Per 100

Rate per 1,000 or per 100

subjects

Cx positive

Ab positive


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Elderly

  • LAIV is not infectious – less than 10% have detectable shedding by culture

  • Low antibody response rates, even in subjects with low prevaccination antibody

  • Combined vaccine may provide additional protection

    • Nursing home – yes

    • COPD - no


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One Versus 2 Doses In Naïve Populations


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1976 Swine Flu and 1977 “Russian” Flu Vaccine Trials

  • For persons born before H1N1 viruses last circulated (circa 1957)

    • 2 doses needed for best antibody response

    • 7 μg + doses gave comparable responses with 2 doses

    • “Shallow” doses response with 1 dose with >50 μg needed

    • Whole virus vaccine more immunogenic, but more reactogenic at high doses


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VE of LAIV in children 15-71 monthsBelshe RB, et al. JAMA 1998;338:1405-12

  • Trivalent LAIV versus placebo

    • N=532 received placebo

    • N=1070 received 1 or 2 doses

  • VE against culture-confirmed influenza

    • 89% with 1 dose

    • 94% with 2 doses


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VE of TIV with 1 versus 2 dosesRitzwoller DR. Pediatrics 2005 (in press)

  • Retrospective cohort study children 6-23 months enrolled Kaiser Colorado

    • 2003-04 when suboptimal antigenic match

  • >5000 in cohort

  • Controlled for high risk conditions using administrative data

  • No laboratory confirmation

  • VE NS with 1 dose, 25% for ILI and 49% for P&I with 2 doses


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LAIV vs Inactivated Vaccine

  • One dose alone of inactivated vaccine in immunologically naïve persons

    • Less likely to provide protective immune response unless use high doses

    • Not protective in young children

  • 2 doses inactivated vaccine likely to provide ‘protective’ immune response at lower antigenic content

  • LAIV may provide better protection with 1 dose

    • Immune-correlate less well defined, so assessment of probable efficacy based on immune response difficult


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H5 vaccines


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Response to Recombinant H5 VaccineTreanor JJ, et al Vaccine 2001;19:1732-7.

  • Placebo-controlled trial

  • 2 doses at 21, 28 or 42 day intervals

    • 25, 45, or 90μg x 2 doses or 90 then 10μg

  • Serum collected days 0, 14 days after 1st dose, dose 2 day 0, the 1,2,3,4 weeks after dose 2

  • 21%-45% with ELISA immune response

  • 17%-52% with micro-neutralization response

  • Dose-response, highest at 90 μg x 2

  • No significant effect by dosing interval


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Use of adjuvant MF59-H5N3 vaccineStephenson I, et al JID 2005;191:1201-5and Stephenson I, et al Vaccine 2003;21:1687-93

  • Adults 18-45 yrs given 7.5, 15 or 30μg A/duck/Singapore/97 (H5N3)

    • IM injection with and without MF-59

    • 2 doses, 21 days apart

      • 7-14% with MF-59 versus 0-9% without

    • 3rd dose 16 months later to subset

    • Serum tested by micro-neutralization against HPAI H5N1 1997-2004 strains

      • No dose response detected

      • Seroconversion 43%-100% with MF-59 and 0%-27% without

      • No 3rd dose booster effect with non-MF-59

  • Conclusions

    • 3 doses and adjuvant needed to improve response

    • No difference among doses used, but small numbers


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Overall Summary

  • Responses to inter-pandemic influenza vaccines

    • Varies by age and chronic condition

    • Within an age group, generally higher VE against complications than influenza illness

    • LAIV and TIV options for children and adults <65

  • Immunologically naïve persons need 2 doses to reach “protective” immune response for inactivated vaccines

    • May be able to achieve with high single dose

    • May need only 1 dose for live attenuated vaccines?

      • Testing of H5 needed to assess safety and immunogenicity

  • Clinical studies H5 vaccines to date suggest lower immunogenicity without adjuvant

    • Further trials pending


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