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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

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
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
outline
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
vaccine effectiveness
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
healthy adults 65 yrs
Healthy Adults < 65 Yrs
  • Key literature reviewed
    • US military trials
    • Cochrane review (updated 2004)
    • 8 clinical trial papers published since 1988
slide6
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.

ve healthy adults
VE Healthy Adults
  • VE estimates (Cochrane review for IV)
    • Lab-C illness 70% (56% - 80%)
    • Clinical ILI 25% (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
ve during pregnancy 1 cohort study
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%)
community dwelling elderly
Community Dwelling Elderly
  • 4 clinical trials published from 1994 on
  • Numerous observational studies
  • 1 meta analysis
ve elderly in nursing homes
VE: Elderly in Nursing Homes
  • 1 meta analysis
  • Several observational studies
summary of ve in adults
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
influenza ve studies in children
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
pediatric ve summary tiv
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
pediatric ve summary cont
Pediatric VE Summary, cont
  • Vaccine efficacy in children increases with age
  • Limited data in children aged 6-23 months
live and inactivated vaccines
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
live and inactivated vaccines21
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
live and inactivated vaccines22
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
pooled results of experimental infection studies in adults vaccine 18 899 2000
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

natural infection in adults
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
pediatric subgroup analysis neuzil 2001 pediatr infect dis j 20 733
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
evaluation of the protective efficacy of laiv in kids
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

elderly
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
1976 swine flu and 1977 russian flu vaccine trials
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
ve of laiv in children 15 71 months belshe rb et al jama 1998 338 1405 12
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
ve of tiv with 1 versus 2 doses ritzwoller dr pediatrics 2005 in press
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
laiv vs inactivated vaccine
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
response to recombinant h5 vaccine treanor jj et al vaccine 2001 19 1732 7
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
slide36
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
overall summary
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