Correspondence

The Conjugate Vaccine and Invasive Pneumococcal Disease

N Engl J Med 2003; 349:714-716August 14, 2003

Article

To the Editor:

Whitney and colleagues (May 1 issue)1 observed, among adults, a decline in the rates of invasive pneumococcal disease caused by 7-valent conjugate serotypes but not by nonconjugate vaccine serotypes. They cautiously suggest that vaccination of children may be exerting a population effect. Adults in households with young children have high rates of nasopharyngeal carriage of Streptococcus pneumoniae, 2 and Whitney et al. found a strong correlation between the magnitude of the decline in the incidence of disease among children less than 2 years of age and that among adults 20 to 39 years of age. However, adults 65 years of age or older have much lower carriage rates,2 and no such correlation was seen. In addition, no change in the incidence of disease was seen among persons infected with the human immunodeficiency virus.

Although the percent changes in the incidence of pneumococcal meningitis and other pneumococcal syndromes in children were similar, changes in blood-culturing practices might have accounted for the decline in the incidence of invasive disease in older adults. Finally, the 15 percent increase in the use of the polysaccharide vaccine in older adults during the period from 1997 to 2001 could have accounted for at least 25 percent of the decline in the incidence of invasive disease.3,4 Nonetheless, the central observation made by Whitney and colleagues is striking, and if confirmed, its implications for international public health could be immense.

David S. Fedson, M.D.
57 Chemin du Lavoir, 01630 Sergy Haut, France
dfedson@wanadoo.fr

4 References

1. 1

   Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737-1746
   Full Text | Web of Science | Medline

2. 2

   Hendley JO, Sande MA, Stewart PM, Gwaltney JM Jr. Spread of Streptococcus pneumoniae in families. I. Carriage rates and distribution of types. J Infect Dis 1975;132:55-61
   CrossRef | Web of Science | Medline

3. 3

   Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993;270:1826-1831
   CrossRef | Web of Science | Medline

4. 4

   Influenza and pneumococcal vaccination levels among persons aged > or = 65 years -- United States, 2001. MMWR Morb Mortal Wkly Rep 2002;51:1019-1024
   Medline

To the Editor:

Whitney and colleagues report a decline in the incidence of invasive pneumococcal disease in adults in the United States from 1998 and 1999 to 2001, after a conjugate vaccine against pneumococcal disease was introduced for use in children. In Denmark and Norway, where the conjugate vaccine is not used and where use of the polysaccharide vaccine is not widespread,1 no such change was observed (as shown by the data for all serotypes in Table 1Table 1Changes in the Incidence of Invasive Pneumococcal Disease in the United States, Denmark, and Norway.). However, from 1996 to 1999, a different pattern was seen2 (and unpublished observations). Among adults in Denmark during this period, the percentage decline in the incidence of invasive disease caused by all serotypes was greater than that subsequently seen in the United States. In Norway, the change was much less.

During the period from 1998 to 2001 in the United States, the decline in the incidence of invasive disease was seen primarily among cases of disease caused by the seven serotypes included in the conjugate vaccine. This pattern was not as striking among bacteremic isolates in Denmark during the same period, but during the earlier period (from 1996 to 1999), substantial declines were seen in the incidence of disease due to conjugate serotypes (among persons >65 years of age) and nonconjugate serotypes (among persons 20 to 39 years of age and those older than 65). The epidemiology of invasive pneumococcal disease in different age groups varies considerably over time.2,3 Investigators need to be cautious in interpreting short-term changes.

Helle B. Konradsen, M.D., D.M.Sc.
Statens Seruminstitut, DK-2300 Copenhagen S, Denmark
hbk@ssi.dk

Hanne Nokleby
National Institute of Public Health, NO-0403 Oslo, Norway

3 References

1. 1

   Fedson DS. Pneumococcal vaccination in the United States and 20 other developed countries, 1981-1996. Clin Infect Dis 1998;26:1117-1123
   CrossRef | Web of Science | Medline

2. 2

   Konradsen HB, Kaltoft MS. Invasive pneumococcal infections in Denmark from 1995-1999: epidemiology, serotypes, and resistance. Clin Diagn Lab Immunol 2002;9:358-365
   Medline

3. 3

   de Neeling AJ, van Pelt W, Hol C, et al. Temporary increase in incidence of invasive infection due to Streptococcus pneumoniae in the Netherlands. Clin Infect Dis 1999;29:1579-1580
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Fedson suggests that a substantial part of the observed reduction in disease rates in older adults have been due to an increase in the use of the 23-valent polysaccharide vaccine. This is unlikely for two reasons. First, we saw a reduction in disease caused by the serotypes included in the conjugate vaccine but no change in disease caused by serotypes included only in the polysaccharide vaccine. Next, using a model based on 1998 Active Bacterial Core Surveillance data and accounting for the effectiveness of the polysaccharide vaccine, the duration of protection, and the serotype coverage, we estimated that use of the polysaccharide vaccine in elderly persons has reduced the rate of invasive disease from approximately 68 cases per 100,000 persons to the observed 60 cases per 100,000 persons — a 12 percent reduction, assuming 50 percent vaccine coverage.1 With an increase in coverage to 60 percent, the rate would drop about 2 percent further. We observed an 18 percent reduction (from 60 to 49 cases per 100,000 persons) after the introduction of the conjugate vaccine, suggesting that reduced transmission of pneumococci from children to adults is a more likely explanation than increased use of the polysaccharide vaccine.

Drs. Konradsen and Nokleby note changes over time in the rates of invasive pneumococcal disease in Denmark and Norway, countries without recent introduction of pneumococcal vaccines. They advocate caution in the interpretation of changes in the rates of pneumococcal disease, since the rates can vary over time for reasons other than the introduction of a vaccine. We agree with this message, especially with regard to changes in smaller populations. Inclusion of the confidence intervals for the changes the correspondents report would facilitate interpretation of whether those changes are, at least from a statistical standpoint, significant. Introduction of a new pneumococcal clone into a community, increasing use of highly active antiretroviral therapy, or variations in annual influenza rates are some of the factors that can affect disease rates. Our reported decreases in disease rates were significant in a large population (16 million persons, as compared with 5.3 million in Denmark and 4.5 million in Norway), were greatest for disease caused by vaccine serotypes, and coincided with the introduction of the vaccine — all findings that suggest that the changes observed in the United States are due to a vaccine effect. Furthermore, these changes were confirmed in a preliminary analysis of data from 2002 (unpublished data).

Cynthia G. Whitney, M.D., M.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 30333
cwhitney@cdc.gov

for the Active Bacterial Core Surveillance Team

1 References

1. 1

   Fry AM, Zell ER, Schuchat A, Butler JC, Whitney CG. Comparing potential benefits of new pneumococcal vaccines with the current polysaccharide vaccine in the elderly. Vaccine 2002;21:303-311
   CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Y. Hansmann, A. Doyle, V. Remy, B. Jaulhac, D. Christmann, O. Lesens, A. Perrocheau. (2006) An Outbreak of Pneumococcal Pneumonia Among Residents of a Retirement Home in France During October 2003 • . Infection Control and Hospital Epidemiology 27:11, 1252-1254
   CrossRef

2. 2

   J. D. Kellner, L. Mandell. (2005) Pneumococcal Serotypes in the Elderly. Clinical Infectious Diseases 41:4, 488-489
   CrossRef

3. 3

   C. L. Byington, M. H. Samore, G. J. Stoddard, S. Barlow, J. Daly, K. Korgenski, S. Firth, D. Glover, J. Jensen, E. O. Mason, C. K. Shutt, A. T. Pavia. (2005) Temporal Trends of Invasive Disease Due to Streptococcus pneumoniae among Children in the Intermountain West: Emergence of Nonvaccine Serogroups. Clinical Infectious Diseases 41:1, 21-29
   CrossRef