Pediatric Annals

OTITIS MEDIA 

Vaccines and Otitis Media

Steven Black, MD; Henry Shinefield, MD

Abstract

The microbiologie causes of acute otitis media (AOM) have been documented by numerous studies of middle ear aspirations sent for bactériologie cultures, viral cultures, and, more recently, polymerase chain reaction analysis. In the largest series of bacterial cultures of middle ear fluids in 2,807 children, 38% of positive cultures were due to Streptococcus pneumoniae, 27% to Haemophilus influenzae, 10% to Moraxella, 3% to group A streptococcus, and 2% to Staphylococcus aureus, with the remaining infections due to other bacteria.1 In the same study, 28% of cultures were sterile, suggesting a viral etiology. In children, respiratory syncytial virus was the most common viral isolate, followed by rhinovirus and influenza virus.2

Recently, increasing antibiotic resistance of pneumococci, H. influenzae, and Moraxella has made treatment of otitis media more difficult and failures more common. This increasing difficulty of treatment and the growing recognition of the role of viruses have prompted a renewed effort to prevent rather than treat AOM. Accordingly, vaccines have recently been approved or are in development that promise to make this prevention a reality. This article reviews the rationale for and current status of vaccines directed against the primary pathogens of otitis media in childhood.

PHEUMOCOCCAL VACCINES

As noted above, the pneumococcus is the single most important bacterial pathogen in otitis media. Although once uniformly sensitive to penicillin, its treatment has been problematic as antibiotic resistance has become more prevalent. Increasing resistance to penicillin has also been accompanied by growing resistance to other antibiotics. Although there are more than 90 serotypes of pneumococci, relatively few account for most middle ear and invasive disease. In a survey of 5,469 middle ear isolates, 7 serotypes accounted for more than 75% of all pneumococcal infections.3

Pneumococcal polysaccharide vaccines have been available for decades, but they have not played a role in the prevention of otitis media for several reasons. Foremost is the lack of immunogenicity of polysaccharide vaccines in children younger than 2 years for most serotypes. In addition, the nature of the immune response to polysaccharide vaccine is such that even when used in older children, the vaccine does not prime the immune system and no "booster" response is observed with subsequent doses. Because of these factors, it is not surprising that an evaluation of pneumococcal polysaccharide vaccine in children younger than 2 years found no protective effect for otitis media compared with control subjects.4

Following the success of the H. influenzae type b (Hib) conjugate vaccines in young children, work began to develop conjugate vaccines against the pneumococcus using the same technology. Unlike Hib, where only one serotype was responsible for almost all invasive disease, multiple serotypes of pneumococci produce invasive disease and otitis media in the United States. Accordingly, it was necessary to develop pneumococcal conjugate vaccines with multiple serotypes to provide protection against most disease.

The first such conjugate vaccine has just been licensed in the United States. It contains separate conjugates for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. All are conjugated to CRM197 protein, the same carrier used in the HbOC Hib vaccine. Immunologie studies revealed this to be highly immunogenic when used beginning at 2 months old.5'6 A large-scale evaluation of the safety and efficacy of this vaccine in more than 37,000 children found it to be 97.4% effective in the prevention of invasive disease when given at 2, 4, and 6 months with a booster dose in the second year of life/ Although invasive disease was the primary outcome, the impact against clinical episodes of otitis media was also evaluated. Visits for otitis media were identified from computer-stored diagnostic information routinely obtained from…

The microbiologie causes of acute otitis media (AOM) have been documented by numerous studies of middle ear aspirations sent for bactériologie cultures, viral cultures, and, more recently, polymerase chain reaction analysis. In the largest series of bacterial cultures of middle ear fluids in 2,807 children, 38% of positive cultures were due to Streptococcus pneumoniae, 27% to Haemophilus influenzae, 10% to Moraxella, 3% to group A streptococcus, and 2% to Staphylococcus aureus, with the remaining infections due to other bacteria.1 In the same study, 28% of cultures were sterile, suggesting a viral etiology. In children, respiratory syncytial virus was the most common viral isolate, followed by rhinovirus and influenza virus.2

Recently, increasing antibiotic resistance of pneumococci, H. influenzae, and Moraxella has made treatment of otitis media more difficult and failures more common. This increasing difficulty of treatment and the growing recognition of the role of viruses have prompted a renewed effort to prevent rather than treat AOM. Accordingly, vaccines have recently been approved or are in development that promise to make this prevention a reality. This article reviews the rationale for and current status of vaccines directed against the primary pathogens of otitis media in childhood.

PHEUMOCOCCAL VACCINES

As noted above, the pneumococcus is the single most important bacterial pathogen in otitis media. Although once uniformly sensitive to penicillin, its treatment has been problematic as antibiotic resistance has become more prevalent. Increasing resistance to penicillin has also been accompanied by growing resistance to other antibiotics. Although there are more than 90 serotypes of pneumococci, relatively few account for most middle ear and invasive disease. In a survey of 5,469 middle ear isolates, 7 serotypes accounted for more than 75% of all pneumococcal infections.3

Pneumococcal polysaccharide vaccines have been available for decades, but they have not played a role in the prevention of otitis media for several reasons. Foremost is the lack of immunogenicity of polysaccharide vaccines in children younger than 2 years for most serotypes. In addition, the nature of the immune response to polysaccharide vaccine is such that even when used in older children, the vaccine does not prime the immune system and no "booster" response is observed with subsequent doses. Because of these factors, it is not surprising that an evaluation of pneumococcal polysaccharide vaccine in children younger than 2 years found no protective effect for otitis media compared with control subjects.4

Following the success of the H. influenzae type b (Hib) conjugate vaccines in young children, work began to develop conjugate vaccines against the pneumococcus using the same technology. Unlike Hib, where only one serotype was responsible for almost all invasive disease, multiple serotypes of pneumococci produce invasive disease and otitis media in the United States. Accordingly, it was necessary to develop pneumococcal conjugate vaccines with multiple serotypes to provide protection against most disease.

The first such conjugate vaccine has just been licensed in the United States. It contains separate conjugates for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. All are conjugated to CRM197 protein, the same carrier used in the HbOC Hib vaccine. Immunologie studies revealed this to be highly immunogenic when used beginning at 2 months old.5'6 A large-scale evaluation of the safety and efficacy of this vaccine in more than 37,000 children found it to be 97.4% effective in the prevention of invasive disease when given at 2, 4, and 6 months with a booster dose in the second year of life/ Although invasive disease was the primary outcome, the impact against clinical episodes of otitis media was also evaluated. Visits for otitis media were identified from computer-stored diagnostic information routinely obtained from all clinic and emergency visits within the Northern California Kaiser Permanente program. With the use of the automated data, a new episode of otitis media was defined as occurring when a visit for otitis media happened more than 21 days following a previous visit. The impact of vaccination on frequent otitis media and ventilatory tube placement was also evaluated7 and the results are summarized in Table 1.

Twenty-three of the children in the study population had pneumococci of vaccine serotype cultured from spontaneously ruptured tympanic membranes (TMs). In the intent-to-treat analysis, there were 17 cases in control subjects and 6 cases in the pneumococcal vaccine group, for a point estimate of efficacy of 64.7% (P = .035). In the analysis of fully vaccinated children, there were 12 cases in control subjects and 4 in the pneumococcal group, for a point estimate of efficacy of 66.7% (P = .077). All of the vaccine failures in both analyses were serotype 19F.

Table

TABLE 1Efficacy of Vaccination of Infants With Heptavalent Pneumococcal Conjugate Vaccine Against Otitis Media and Otitis Media-Related Outcomes Based on the Kaiser Permanente Efficacy Trial

TABLE 1

Efficacy of Vaccination of Infants With Heptavalent Pneumococcal Conjugate Vaccine Against Otitis Media and Otitis Media-Related Outcomes Based on the Kaiser Permanente Efficacy Trial

The impact of vaccination on severity of otitis media was also evaluated by comparing the number of children with a given number of medical visits for 1 episode in the vaccine and control groups. For children 6 to 12 months old, the reduction in the number experiencing 1, 2, 3, or 5 or more visits was 2%, 6%, 15%, and 18%, respectively. Similarly, for children older than 12 months, the reductions for the same numbers of visits were 7%, 8%, 15%, and 43%, respectively.

A randomized, double-blinded study using the same CRM197 conjugate pneumococcal vaccine was completed in Finland8 consisted of 1,662 infants enrolled at 2 months old. The immunization schedule was similar to that used by Northern California Kaiser Permanente. The clinical diagnosis of AOM was based on predefined pneumo-otoscopic criteria, whereas the bactériologie diagnosis was based on middle ear fluid cultured by myringotomy. The overall efficacy was 6% for AOM. Culture-confirmed pneumococcal cases, any serotype, were reduced by 34%, and culture-confirmed, serotype-specific AOM was reduced by 57% (Table 2). The similarity in the results of the two trials is striking despite differences in diagnostic techniques and ethnicity.

Table

TABLE 2Efficacy of Vaccination of Infants With Heptavalent Pneumococcal Conjugate Vaccine Against Acute Otitis Media (AOM) Based on the Finnish Efficacy Trial of 1,662 Infants

TABLE 2

Efficacy of Vaccination of Infants With Heptavalent Pneumococcal Conjugate Vaccine Against Acute Otitis Media (AOM) Based on the Finnish Efficacy Trial of 1,662 Infants

With routine use of this heptavalent conjugate vaccine in the United States, it is anticipated that there will be 1,00O7OOO fewer visits for otitis media each year and that up to 500,000 fewer children will undergo ventilatory tube placement each year.9 However, the impact on the average child's otitis media experience will be relatively modest.

Other pneumococcal conjugate vaccines are in development that employ different protein carriers and target more serotypes. These, however, are several years from licensure. In addition, vaccines using outer membrane proteins of the pneumococcus that offer the potential of using a single antigen to provide protection against all serotypes are in early clinical testing.

OTHER BACTERIAL VACCINES

Vaccines against the other bacterial pathogens that cause otitis media, including non-typeable H. influenzile and Moraxella, are in much earlier stages of development. Almost all invasive disease due to H. influenzae is due to serotype b. On the other hand, otitis media due to H. influenzae is almost always caused by non-typeable strains. These account for 20% to 30% of cases of otitis media and more than 40% that result in chronic effusions.9 Nasopharyngeal colonization with non-typeable H. influenzae is common, with rates of 20% reported by the age of 1 year and rates greater than 50% in school-age children.9 Vaccine development has been hampered by the high anrigenic variability of surface proteins and the lack of complete data about antibody correlates of protection. To date, evaluation of potential vaccine candidates has focused on high molecular weight proteins, including P5 and an adhesion factor designated as Hia. Currently, a pneumococcal conjugate vaccine using the non-typeable H. influenzae P5, protein as a carrier has been developed and is in clinical testing.10 It is not known whether antibody to the carrier of this pneumococcal conjugate might also provide protection against non-typeable H. influenzae.

Before 1983, Moraxella catarrhalis was infrequently isolated from middle ear isolates. More recent studies in the United States estimate that this organism accounts for 10% to 12% of all cases of otitis media, and higher percentages have been reported from other countries.11 Most of these now produce penicillinase. Vaccine development for M. catarrhalis is in the antigen-identification stage. M. catarrhalis does not appear to synthesize antigens such as exotoxins, nor does it possess a carbohydrate capsule. Thus far, the search for potential vaccine antigens has focused on purified outer surface proteins. With the use of animal models, several vaccine candidates have been identified.

VIRAL VACCINES

Efforts to develop viral vaccines that could have a significant impact on otitis media have focused on influenza and respiratory syncytial virus. Influenza has been associated with otitis media in 28% of infected children.9 In addition, up to 80% of such infected children have demonstrable eustachian tube dysfunction.9 Licensed vaccines for influenza are currently available for children. However, as-yet unlicensed live attenuated nasal influenza vaccines offer the potential for both demonstrated efficacy against otitis media and ease of administration. Relatively recent randomized clinical trials of this vaccine in children have shown an 83% reduction in cases of AOM identified by positive results on influenza virus culture and an overall 36% reduction in the number of all otitis media cases during the influenza season.12

Respiratory syncytial virus infects 50% of children in the first years of life.9 Although respiratory syncytial virus immune globulin has been highly effective in preventing respiratory syncytial virus infections, vaccine development has been delayed because of substantial complications associated with early vaccine candidates.13 A live attenuated cold adapted vaccine has been developed for infants and young children to avoid the toxicity associated with the earlier killed vaccine.14 However, the live attenuated vaccine is not a viable candidate for older children or adults because they are not immunologically naive for respiratory syncytial virus and have antibody. Although this antibody from prior infection is not sufficient to protect against repeat infection due to wild respiratory syncytial virus, it does interfere with the reproduction of the attenuated vaccine strain and thus prevents immunization. Therefore, an F protein subunit killed vaccine has been developed. The killed vaccine has been tested only in adults and in children with preexisting respiratory syncytial virus antibody. There are no data on the efficacy of either vaccine against infection or otitis media.

CONCLUSION

Although the introduction of pneumococcal conjugate vaccine will have a dramatic impact on the total disease burden of otitis media, the impact on each individual child will be small and many parents will not notice the impact. Clearly, although this is an important first step toward a vaccination program to prevent otitis media, a more comprehensive approach awaits the availability of vaccines for respiratory syncytial virus, rhinovirus, influenza, non-typeable H. influenzae, and Moraxella.

Currently, the Advisory Committee on Immunization Practices has recommended routine vaccination with pneumococcal conjugate vaccine for all infants and children younger than 2 years, as well as for high-risk children older than 2 years. We believe that vaccination of children older than 2 years with frequent otitis media should also be considered.

REFERENCES

1. Bluestone CD, Stephenson JS, Martin LM. Ten-year review of otitis media pathogens. Pediatr Infect Dis J. 1992-11 57-511 .

2. Ruuskanen O, Aróla M, Heikkinen T, Zeigler T. Viruses in acute otitis media: increasing evidence for clinical significance. Pediatr Infect Dis ). 1991;10:425-427.

3. Spika JS, Facklam RR, Plikaytis BD, Oxtoby MJ. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987: the Pneumococcal Surveillance Working Group. / Infect Dis. 1991;163: 1273-1278.

4. Makela PH, Leinonen M, Pukander J, Karma P. A study of pneumococcal vaccine in the prevention of clinical acute attacks of recurrent otitis media. Rev Infect Dis. 1981; 3:S124-S132.

5. Shinefield HR, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis ]. 1999; 18:757-763.

6. Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics. 1998;101:604-611.

7. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children: Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis]. 2000;19:1 87-195.

8. Eskola J, Kilpi T. Efficacy of a heptavalent pneumococcal conjugate vaccine (PncCRM) against serotype-spedfic, culture-confirmed pneumococcal acute otitis media in infants and children. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, California. Abstract LB-13.

9. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices. MMWR, 1997;46(RR-08):l-24.

10. Bakaletz LO, Leake ER, Billy JM, Kaumaya PT. Relative immunogenicity and efficacy of two synthetic chimeric peptides of fimbrin as vaccinogene against nasopharyngeal colonization by nontypeable Haemophûus influenzae in the chinchilla. Vaccine. 1997;15:955-961.

11. Bluestone CD, Klein JO. Otitis Media in Infants and Children, 2nd ed. Philadelphia: W. B. Saunders; 1995:56.

12. Heikkinen T, Ruuskanen O, Waris M, et al. Influenza vaccination in the prevention of acute otitis media in children. Am ) Dis Children. 1991;145:445-450.

13. The Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in nigh-risk infants. Pediatrics. 1998;102:531-537.

14. Karron RA, Wright PF, Crowe JE Jr, et al. Evaluation of two live, cold-passaged, temperature-sensitive respiratory syncytial virus vaccines in chimpanzees and in human adults, infants, and children. / Infect Dis. 1997;176:1428-1436.

TABLE 1

Efficacy of Vaccination of Infants With Heptavalent Pneumococcal Conjugate Vaccine Against Otitis Media and Otitis Media-Related Outcomes Based on the Kaiser Permanente Efficacy Trial

TABLE 2

Efficacy of Vaccination of Infants With Heptavalent Pneumococcal Conjugate Vaccine Against Acute Otitis Media (AOM) Based on the Finnish Efficacy Trial of 1,662 Infants

10.3928/0090-4481-20001001-10

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