Correspondence
A Pneumococcal Conjugate Vaccine and Acute Otitis Media
N Engl J Med 2001; 344:1719-1720May 31, 2001
- Article
To the Editor:
In the report by Eskola et al. (Feb. 8 issue)1 of the efficacy of a pneumococcal conjugate vaccine against otitis media, the data argue strongly against their conclusion that “the effect of the pneumococcal conjugate vaccine can be substantial.” In the case of 94 percent of those immunized with the pneumococcal conjugate vaccine, otitis media would not have been prevented. The study also substantiates one of the greatest feared limits of the heptavalent pneumococcal conjugate vaccine — that the frequency of disease would remain the same as a result of increases in the rates of infection with all the pneumococcal serotypes that were not included in the vaccine (a phenomenon sometimes referred to as serotype replacement). The data of Eskola et al. demonstrate a 33 percent increase in the incidence of otitis media from pneumococcal serotypes that were not included in the vaccine.
1 ReferencesArthur Lavin, M.D.
Pediatric Partners of Cleveland, Beachwood, OH 44122-54161
Eskola J ,Kilpi T ,Palmu A , et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403-409
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To the Editor:
Eskola et al. state that “up to 1.2 million of the 20 million yearly episodes of acute otitis media in the United States could theoretically be prevented if the [pneumococcal conjugate] vaccine were widely used.” This theoretical benefit must not be used as an official justification for vaccination.
The vaccine was officially recommended for use in all children on the basis of its efficacy against invasive diseases.1 The reported relative reduction in the risk of episodes of 6 percent achieved by vaccination still leaves the total risk high enough for many immunized children to have acute otitis media. This factor could lessen the credibility of the recommendation for vaccination.
A more powerful trial2 reported a reduction in acute otitis media of up to 22.8 percent in one subgroup of children with frequent episodes. Since 14 percent of children account for approximately 50 percent of the episodes of acute otitis media, the number of episodes could be significantly reduced by the selection of appropriate candidates for immunization. In countries that will not adopt the U.S. recommendation, selective vaccination of high-risk subgroups is a better way to keep the public trust.
2 ReferencesYishay Ofran, M.D.
Hebrew University, Jerusalem 91240, IsraelAriella Ofran, M.D.
Maccabi Healthcare Services, Tel Aviv 68125, Israel1
Committee on Infectious Diseases
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Black S ,Shinefield H ,Fireman B , et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195
CrossRef | Web of Science | Medline
To the Editor:
Given the poor overall efficacy of the pneumococcal conjugate vaccine in the study by Eskola et al., the authors' conclusions are a bit too optimistic. According to the protocol, all infants received four vaccinations, which were certainly not painless and which led to the prevention of only 6 percent of all cases of acute otitis media.
For the moment, more could be gained by changing our attitude toward acute otitis media. In the Netherlands, acute otitis media is seen as a self-limiting disease. Often, parents do not take their children to the doctor for this common childhood disease. The efficacy of antibiotics for this disease is moderate,1 even in the youngest children.2 Educating doctors and parents about acute otitis media will lead to a decrease in antibiotic prescriptions for this illness, as has been shown in a recent trial.3
3 ReferencesRoger A.M.J. Damoiseaux, M.D., Ph.D.
Flessenbergerweg 5, 8191 LH Wapenveld, the Netherlands1
Del Mar C ,Glasziou P ,Hayem M . Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-1529
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Damoiseaux RAMJ ,van Balen FAM ,Hoes AW ,Verheij TJ ,de Melker RA . Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ 2000;320:350-354
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Little P ,Gould C ,Williamson I ,Moore M ,Warner G ,Dunleavy J . Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;322:336-342
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To the Editor:
The vaccine manufacturer's vice president and contractors conclude that the new pneumococcal vaccine is “efficacious in the prevention of acute otitis media.” Given the 95 percent confidence interval of –4 to 16 percent, the data presented by Eskola et al. do not support this conclusion. As the authors admit, “the negative number indicates” that the treated group could have had more episodes than the controls. These same data — 1251 episodes in the vaccine group as compared with 1345 episodes in the control group, a clinically and statistically insignificant difference in the rate of 3.6 percent (absolute benefit) — were presented to an advisory committee of the Food and Drug Administration (FDA) in November 1999. Therefore, the FDA rejected the use of this vaccine for otitis media. Moreover, the authors' use of the number of episodes instead of the number of patients as the experimental unit is incorrect because it inflates the outcome.
The most interesting results concern the pneumococcal ecology. In a short time span, the predicted serotype replacement1 (also observed with other bacterial vaccines2-4) was realized. Eskola et al. report that the “number of episodes due to all other [pneumococcal] serotypes increased by 33 percent.” With this clear warning sign, it is a perilous experiment in microbial ecology to push the use of the heptavalent pneumococcal vaccine.
4 ReferencesErdem I. Cantekin, Ph.D.
University of Pittsburgh School of Medicine, Pittsburgh, PA 152131
Spratt BG ,Greenwood BM . Prevention of pneumococcal disease by vaccination: does serotype replacement matter? Lancet 2000;356:1210-1211
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Perdue DG ,Bulkow LR ,Gellin BG , et al. Invasive Haemophilus influenzae disease in Alaskan residents aged 10 years and older before and after infant vaccination programs. JAMA 2000;283:3089-3094
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Ramsay ME ,Andrews N ,Kaczmarski EB ,Miller E . Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England. Lancet 2001;357:195-196
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Lipsitch M . Bacterial vaccines and serotype replacement: lessons from Haemophilus influenzae and prospects for Streptococcus pneumoniae. Emerg Infect Dis 1999;5:336-345
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To the Editor:
As a general pediatrician, I think we must proceed with caution when relaying the data of Eskola et al. to our patients' parents. Although the vaccine reduced the incidence of acute otitis media caused by pneumococcus, especially by the strains included in the vaccine, the overall reduction in cases of acute otitis media was only 6 percent. The clinical significance of this finding is questionable.
I have already had several parents ask me why their child had an ear infection after having received the “ear-infection vaccine.” At a time when many parents are already suspicious of the reported safety and efficacy of vaccines, unrealistic expectations may hinder the use of this vaccine and therefore limit the documented protection it affords against invasive pneumococcal disease.1
1 ReferencesKurtis L. Sauder, M.D.
Blue Ridge Pediatrics, Staunton, VA 24402-26651
Black S ,Shinefield H ,Fireman B , et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: It is important to make a distinction between the effect of the pneumococcal conjugate vaccine on a larger population and the expected benefits in an individual child. Even though the proportion of vaccine-preventable episodes of otitis media is small, the absolute number of potentially preventable attacks at the population level is considerable, because otitis media is such a common disease. The impact on otitis media has been estimated to account for 60 percent of the cost savings expected from the prevention of pneumococcal disease through a vaccination program.1 Thus, our conclusion that the effect of the pneumococcal conjugate vaccine on otitis media could be substantial is correct and is an important message to policymakers who are deciding whether the vaccine should be included in national immunization programs. However, we fully agree that the information given to parents should focus on protection provided by the vaccine against invasive pneumococcal disease. Furthermore, the suggestion of targeting the vaccine to selected otitis-prone groups would be difficult to implement and would obscure the primary objective of preventing invasive disease.
We cannot agree with Dr. Cantekin that using the number of episodes instead of the number of children as experimental units is incorrect. The tendency to recurrence is characteristic of acute otitis media. A vaccine that does not afford protection against recurrent attacks would be of little value. We therefore purposely calculated the efficacy of the vaccine against all episodes of otitis media, not just the first ones (i.e., counting only one episode per child). This approach did not inflate the outcome, as shown by the efficacy rates against first as compared with all episodes of otitis media (52 percent vs. 57 percent for infections caused by serotypes included in the vaccine and 12 percent vs. 6 percent for episodes from any cause). The reduction of 12 percent is statistically significant (95 percent confidence interval, 1 to 22 percent).
We share the concern about the increase in otitis media caused by the serotypes that were not included in the vaccine among those who received the conjugate vaccine. However, we find it reassuring that after several years of follow-up, no indication of serotype replacement has been observed in invasive disease among the participants of the California trial.2,3 The long-term effects of serotype replacement remain unknown. This warrants careful serotype-specific surveillance of the effect of vaccination on both pneumococcal carriage and invasive disease, rather than the discontinuation of vaccination. Fortunately, data on the effect of broad-scale vaccination on the pneumococcal serotypes causing invasive disease are rapidly accumulating in the United States, where the pneumococcal conjugate vaccine is now in wide use.
3 ReferencesTerhi Kilpi, M.D.
Juhani Eskola, M.D.
P. Helena Mäkelä, M.D.
National Public Health Institute, FIN-00300 Helsinki, Finlandfor the Finnish Otitis Media Study Group
1
Lieu TA ,Ray GT ,Black SB , et al. Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA 2000;283:1460-1468
CrossRef | Web of Science | Medline2
Black S ,Shinefield H ,Fireman B , et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195
CrossRef | Web of Science | Medline3
Shinefield HR, Black S. The efficacy and safety of heptavalent pneumococcal conjugate vaccine in children. Presented at the Millennium Second World Congress on Vaccines and Immunization, Liège, Belgium, August 29–September 3, 2000. abstract.
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