NVAC Workshop 910 September, 2003

1
NVAC Workshop9-10 September, 2003

• Pneumococcal Disease Prevention in Adults
• Potential Vaccine Strategies
• Pneumococcal Polysaccharide Vaccine

David S. Fedson, M.D. Sergy Haut,
France dfedson_at_wanadoo.fr
2
The Overlap Between Pneumococcal Pneumonia and
Invasive Pneumococcal Disease
Fedson DS. Drugs Aging 199915 Suppl.121-30.
3
Invasive Pneumococcal Disease by Age and
RaceUnited States, 1998
Robinson KA, et al. JAMA 2000 285 1729-35.
4
Invasive Pneumococcal Disease Among Elderly
People in Western Europe

• Number of Cases Annual
  Incidence/100,000
• Country Years(s) All Ages Elderly
  Persons1
• Finland 1983-92 1045 27
• England Wales 1996 4802 31
• France 1996 4991 31
• Scotland 1997 529 34
• Belgium - Brabant 1995-97 398 36
• Sweden 1996 1336 47
• Norway 1997 817 55
• Spain - Valencia 1995 274 57
• The Netherlands 1996 - 57
• Iceland 1996 41 64
• Denmark 1996 1417 802

1³ 65 years in age 2³ 60
years in age
5
Invasive Pneumococcal Disease in Denmark, 1969 -
97
Konradsen HB. Epi-news 1998 No. 18 1.
6
Pneumococcal Vaccination The Views of
Hirschmann and Lipsky

• Pneumococcal bacteremia is "very uncommon, 50
  per 100,000 for those over 65 years of age."
• "Conjecture, case-control studies, complicated
  statistical analysis, and edicts from prestigious
  organizations cannot resolve this unsettled
  issue only a large, prospective randomized trial
  could."
• " even if vaccine efficacy derived from
  case-control studies is correct, the unimpressive
  reduction in pneumococcal disease makes the
  recommendations of immunizing all people 65 years
  of age or older a dubious public health policy."
• "We believe the evidence justifies not
  vaccinating immunocompromised or elderly
  populations."

Hirschmann JV, Lipsky BA. Arch Intern Med 1994
154 373-377.
7
Prospective Clinical Trials of Pneumococcal
VaccineWhich Outcomes Are Acceptable?
8
Prospective Clinical Trials of Pneumococcal
Vaccine in Elderly and High-risk Adults
All Pneumonia
Pneumococcal Bacteremia
Principal Investigator
95 CI
95 CI
Unadjusted RR
Unadjusted RR


1.13 to 1.48
1.30
Austrian-1


.55 to 1.75
.98
Austrian-2
not calculated
.09 to .46
.20
Gaillat
.18 to 22.20
2.01
.92 to 2.10
1.39
Simberkoff


.81 to 1.59
1.13
Koivula
.41 to 29.37
.21
.80 to 1.75
1.18
Örtqvist
.07 to 1.90
.37
.91 to 1.48
1.16
Honkanen
.20 to 1.25
.50
.91 to 1.12
1.01
All studies

• Includes three small clinical trials by
  Klatersky, Davis and Leech

9
Randomized Controlled Trials How Can You Rule
Out False-negative Results ?
10
Sample Size and the Meta-analyses of Clinical
Trials of Pneumococcal Vaccine Pneumococcal
Bacteremia
None of the relative risks was statiscally
significant.
11
Randomized Controlled Trials Are They the Only
Way to Get at the Truth ?
" there is neither a theoretical nor an
empirical justification for a general negative
attitude or even a rejection of nonrandomized
studies as necessity fallacious."
Abel U, Koch A.The role of randomization in
clinical studies Myths and Beliefs. J Clin
Epidemiol 1999 52 487-97.
12
Prevention of Invasive Pneumococcal
DiseaseObservational Studies in Older Adults
Case-control studies unless otherwise
indicated Retrospective cohort study of
47,365 subjects ? 65 years in age. Indirect
cohort study in a population of 3.1 million
persons. Indirect cohort study that evaluated
515 vaccinated and 2322 unvaccinated subjects.
13
Effectiveness of Influenza and Pneumococcal
Vaccination in Reducing Hospital Admissions for
Pneumonia
Vaccination Effectiveness ()
Retrospective cohort study of 1892 patients with
COPD 95 C.I. of the odds ratio excludes 1.0.
95 C.I. of the odds ratio is 0.37 to 1.02.
Nichol KL, et al. Arch Intern Med 2000 160 1699.
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Pneumococcal Vaccine Vaccine Efficacy,Vaccinatio
n Effectiveness and Epistemological Confusion

• Large-scale prospective efficacy trials have not
  been undertaken in older persons, and the results
  of smaller trials and their meta-analyses have
  been inconclusive.
• Population-based observational studies
  (case-control, indirect cohort and retrospective
  cohort) convincingly show that pneumococcal
  vaccination is effective in preventing
  hospitalization for invasive disease and
  pneumonia and in preventing death.
• Unwillingness to accept the results of
  observational studies reflects scientific bias,
  not problems intrinsic to the studies themselves.

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Cost-effectiveness of Influenza and Pneumococcal
Vaccination Compared With Other Interventions
Used Among Older People
Intervention
Cost per Life-Year
Gained
Influenza vaccination, ³ 65 years Cost
Saving Pneumococcal vaccination, ³ 65 years Cost
Saving

• Mammogram, 50-65 years, q 3 years 2,700
• Papanicolaou test, ³ 65 years, q 3 years 2,800
• Coronary angioplasty, men 55 years, severe
  angina 5,300
• Coronary bypass surgery, men 55 years, left main
  disease 5,600
• Hypertension screening, 60 years, asymptomatic
  11,000
• Cholesterol 180 mg/dL, men ³ 60 years, diet
  only 12,000
• Estrogen-progestin, ³ 50 years, symptomatic
  15,000
• Home dialysis for end-stage renal disease

20-46,000
Tengs TO, et al. Five-hundred life-saving
interventions and their cost-effectiveness. Risk
Analysis 199515369-90. All costs are expressed
in 1993 dollars.
16
Pneumococcal Vaccination in the United States,
Western Europe and Canada, Australia and New
Zealand, 1978-2000
Doses distributed / 10, 000 population
Western Europe
Canada, Australia, New Zealand
United States
Fedson DS. Drugs Aging 1999 15 Suppl. 1 21-30.
17
Pneumococcal Vaccination in 22 Developed
Countries, 1991-2000
Health Care Spending per Capita, 1998
1991-1995
1996-2000
Cumulative doses distributed per 10,000 persons
US dollars at PPP
DS Fedson, unpublished observations and OECD,
1998
18
Pneumococcal Vaccination in the United States,
the Netherlands, Spain and Mexico, 1997-2001
300
250
200
150

• Doses / 1000 pPopulation

100
50
0
97 98 99 00 01
97 98 99 00 01
97 98 99 00 01
97 98 99 00 01
United States
Netherlands
Mexico
Spain
19
Influenza Vaccination in the United States, the
Netherlands, Spain and Mexico, 1997-2001
300
250
200
150

• Doses / 10,000 population

100
50
0
97 98 99 00 01
97 98 99 00 01
97 98 99 00 01
97 98 99 00 01
United States
Netherlands
Mexico
Spain
20
Treatment vs Prevention in Older Patients
Respiratory Infection
Congestive Heart Failure
Influenza vaccine Pneumococcalvaccine
Diuretic ACE
inhibitor Digitalis
Nitrates Spironolactone
21
Pneumococcal Polysaccharide Vaccination for Older
Adults

• the burden of invasive pneumococcal disease among
  older adults is substantial (50 cases/100,000)
• the clinical effectiveness and cost-effectiveness
  of pneumococcal vaccination to prevent invasive
  disease in older adults are firmly established
• pneumococcal vaccination has been introduced
  recently in many countries
• persistent doubts about the effectiveness of
  pneumococcal vaccination are responsible for the
  lack of vaccine use in some countries