# Presentation: 272674

## NVAC Workshop9-10 September, 2003

**Pneumococcal Disease Prevention in Adults: **
**Potential Vaccine Strategies**
**Pneumococcal Polysaccharide Vaccine**

**David S. Fedson, M.D.**
**Sergy Haut, France**
**dfedson@wanadoo.fr**

## The Overlap Between Pneumococcal Pneumonia and Invasive Pneumococcal Disease

**    ****Fedson DS. *****Drugs Aging***** 1999;15 Suppl.1:21-30. **

## Invasive Pneumococcal Disease by Age and RaceUnited States, 1998

**Robinson KA, et al. *****JAMA***** 2000; 285: 1729-35.**

## 		                        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

**Country****	****Years(s)****	****                All Ages****	****Elderly Persons****1****	**
**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****	**** 80****2**

**Invasive Pneumococcal Disease Among Elderly People in Western Europe**

**1****3 65 years in age                          ****2****3 60 years in age    **

## Invasive Pneumococcal Disease in Denmark, 1969 - 97

**Konradsen HB. *****Epi-news***** 1998; No.**** ****18: 1. **

## 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.**

## Prospective Clinical Trials of Pneumococcal VaccineWhich Outcomes Are Acceptable?

## Prospective Clinical Trials of Pneumococcal Vaccine 

**in Elderly and High-risk Adults**

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

**.20 to 1.25**

**      ****.50**

**   ****.91 to 1.12**

**1.01**

**All studies*******

**.07 to 1.90**

**      ****.37**

**  ****.91 to 1.48**

**1.16**

**Honkanen**

**  ****.41 to 29.37**

**      ****.21**** **

**  ****.80 to 1.75**

**1.18**

**Örtqvist**

**–**

**   –****    **

**  ****.81 to 1.59**

**1.13**

**Koivula**

**  ****.18 to 22.20**

**     ****2.01**

**  ****.92 to 2.10**

**1.39**

**Simberkoff**

**not calculated**

**.09 to .46**

**  ****.20**

**Gaillat**

**–**

**  –**

** ****.55 to 1.75**

**   ****.98**

**Austrian-2**

**–**

**   –**

**1.13 to 1.48**

**1.30**

**Austrian-1**

**95% CI**

**Unadjusted RR**

**  ****95% CI**

** ****Unadjusted RR**

**Principal Investigator**

**All Pneumonia**

**Pneumococcal Bacteremia**

## Randomized Controlled Trials:

**How Can You Rule Out False-negative Results ?**

## Sample Size and the Meta-analyses of Clinical Trials of Pneumococcal Vaccine: Pneumococcal  Bacteremia

|  |  | Person Years of Observation |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Unadjusted
RR ‡ | Approximate No. During the Trials |  |  Retrospective Sample Size |  |  |  |  |
| Investigator |  |  |  | VE = 50% |  |  | VE = 70% |  |
|  |  |  |  |  |  |  |  |  |
| Fine | 1.23 | 10,650 |  | 170,000 |  |  | 76,600 |  |
| Hutchison | 1.22 | 10,377 |  | 170,000 |  |  | 78,600 |  |
| Moore |   .51 | 2009 |  | 17,200 |  |  | 8200 |  |
| Cornu |   .35 | 11,741 |  | 72,800 |  |  | 32,100 |  |
| Watson |   .46 | 43,697 |  | 176,000 |  |  | 79,400 |  |
|  |  |  |  |  |  |  |  |  |

**‡ ****None of the relative risks was statiscally significant.**

## 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****.**

## Prevention of Invasive Pneumococcal Disease:Observational Studies in Older Adults*

| 

Type of Infection | 

Location | 
Number of  Cases/Controls	 |  |  |        Vaccination 
      Effectiveness |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  |  |  |  | % | 95% C.I. |
| Vaccine type ± 
VT-related | Denver |  | 89 / 89   |  | -21 | -221 to 55 |
|  | Connecticut |  | 983 / 983 |  | 56 | 42 to 67 |
|  | CDC |  |  – §  |  | 57 | 45 to 66 |
| All serotypes | Oxford |  | 247 / 247 |  | 32 | -26 to 63 |
|  | Seattle |  |  – † |  | 44 | 7 to 67 |
|  | Connecticut |  | 1054 / 1054 |  |       47 | 30 to 59 |
|  | Toronto |  |  – ‡ |  | 63 | 13 to 85 |
|  | New Haven |  | 90 / 90 |  |  67 | 13 to 87 |
|  | Philadelphia |  | 122 / 244 |  | 70 | 37 to 86 |
|  | Charlottesville |  |  85 / 152 |  | 81 | 34 to 94 |
| Non VT  VT-related | Connecticut |  | 170 / 170 |  | - 73 | -263 to 18 |

***  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.**

## 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.**

**Effectiveness of Influenza and Pneumococcal Vaccination in Reducing Hospital Admissions for Pneumonia**

## 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.

**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.**

**Pneumococcal Vaccine: Vaccine Efficacy,****Vaccination Effectiveness and Epistemological**** ****Confusion**

## Mammogram, 50-65 years, q 3 years	    $		2,700
Papanicolaou test,  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  60 years, diet only		    12,000
Estrogen-progestin,  50 years, symptomatic		    15,000
Home dialysis for end-stage renal disease	

**Papanicolaou test, ******** 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 ******** 60 years, diet only****	****	****    12,000**
**Estrogen-progestin, ******** 50 years, symptomatic****	****	****    15,000**
**Home dialysis for end-stage renal disease****	**

**Cost-effectiveness of Influenza and Pneumococcal Vaccination Compared With Other Interventions Used Among Older People**

**Influenza vaccination, ******** 65 years****	****Cost Saving**
**Pneumococcal vaccination, ******** 65 years ****	****Cost Saving**

**Intervention                                                                   Cost per Life-Year Gained**

**Tengs TO, et al. Five-hundred life-saving interventions and their cost-effectiveness. **
***Risk Analysis***** 1995;15:369-90. All costs are expressed in 1993 dollars.**

**20-46,000**

## Pneumococcal Vaccination in the United States, Western Europe and Canada, Australia and New Zealand, 1978-2000

**Doses distributed / 10, 000  population**

**Western Europe**

**Fedson DS. *****Drugs Aging *****1999; 15 Suppl. 1: 21-30.**

**United States**

**Canada, Australia, New Zealand**

## Pneumococcal Vaccination 

**in 22 Developed Countries, 1991-****2000**

** ****DS Fedson, unpublished observations and OECD, 199****8**

**Cumulative doses distributed per 10,000 persons**

**US dollars at PPP**

**Health Care Spending per Capita, 1998**

**1991-1995**

**1996-2000**

## Pneumococcal Vaccination in the United States, the Netherlands, Spain and Mexico, 1997-2001

**Doses / 1000 pPopulation**

**United States**

**Netherlands**

**Mexico**

**50**

**100**

**200**

**150**

**250**

**300**

**0**

**97   98  99   00  01**

**97   98  99   00  01**

**97   98  99   00  01**

**97   98  99   00  01**

**Spain**

## Influenza Vaccination in the United States, the Netherlands, Spain and Mexico, 1997-2001

**Doses / 10,000  population**

**United States**

**Netherlands**

**Mexico**

**50**

**100**

**200**

**150**

**250**

**300**

**0**

**97   98  99   00  01**

**97   98  99   00  01**

**97   98  99   00  01**

**97   98  99   00  01**

**Spain**

## Treatment vs Prevention in Older Patients 

**Diuretic                                  **
**ACE inhibitor**
**Digitalis                                              **
**Nitrates**
**Spironolactone**

**Influenza vaccine**
**Pneumococcal****vaccine**

**Congestive Heart **
**Failure**

**Respiratory Infection**

## 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 **