The New England Journal of Medicine

Review Article
Current Concepts
Volume 345:1177-1183

October 18, 2001

Number 16



The Prevention of Pneumococcal Disease in Children
G. Scott Giebink, M.D.

Otitis media in children leads to more than 20 million visits to physicians
annually in the United States. 1
<http://content.nejm.org/cgi/content/short/345/16/#R1> , 2
<http://content.nejm.org/cgi/content/short/345/16/#R2> , 3
<http://content.nejm.org/cgi/content/short/345/16/#R3>  By three years of
age, 80 percent of all children in the United States have had at least one
episode of otitis media, and 50 percent have had at least three episodes. 2
<http://content.nejm.org/cgi/content/short/345/16/#R2>  Recurrent acute
otitis media has its onset almost exclusively before a child's second
birthday. 2 <http://content.nejm.org/cgi/content/short/345/16/#R2>
Streptococcus pneumoniae (pneumococcus) is the most common cause of acute
otitis media, accounting for approximately 50 percent of all cases. 4
<http://content.nejm.org/cgi/content/short/345/16/#R4> , 5
<http://content.nejm.org/cgi/content/short/345/16/#R5> , 6
<http://content.nejm.org/cgi/content/short/345/16/#R6>
In addition to being a cause of otitis media, S. pneumoniae remains a major
cause of childhood illness and death. At least 1 million children die of
pneumococcal infections (pneumonia, meningitis, and bacteremia) each year,
mostly in developing countries. 7
<http://content.nejm.org/cgi/content/short/345/16/#R7>  A meta-analysis of
the outcomes of bacterial meningitis in developed countries revealed that
pneumococcal disease was associated with higher rates of death (15 percent)
and neurologic sequelae (12 to 28 percent) than either Haemophilus
influenzae or Neisseria meningitidis infection. 8
<http://content.nejm.org/cgi/content/short/345/16/#R8>  Studies in Finland 9
<http://content.nejm.org/cgi/content/short/345/16/#R9>  and France 10
<http://content.nejm.org/cgi/content/short/345/16/#R10>  suggest that 13 to
38 percent of community-acquired pneumonia in children is caused by
pneumococcus, a finding consistent with the results of a controlled efficacy
trial of pneumococcal conjugate vaccine. 11
<http://content.nejm.org/cgi/content/short/345/16/#R11>  Hence, pneumococcal
pneumonia also represents a major disease burden in children.
In February 2000, the Food and Drug Administration (FDA) licensed a 7-valent
pneumococcal conjugate vaccine (pneumococcal–CRM197, Wyeth Lederle Vaccines,
Pearl River, N.Y.), which is recommended for routine use in infants. This
vaccine, together with the identification of risk factors for otitis media
and pneumococcal colonization of the nasopharynx, provides new opportunities
for preventing and managing pneumococcal disease. Given the increasing
prevalence of pneumococci with resistance to multiple antimicrobial drugs,
these new approaches should find immediate use.
Pneumococcal Antibiotic Resistance
The overuse of antibiotics has contributed to the rapidly increasing
prevalence of drug-resistant S. pneumoniae, making it more complicated to
treat pneumococcal disease in young children successfully ( Figure 1
<http://content.nejm.org/cgi/content/short/345/16/#F1> ). Antibiotics are
prescribed empirically to virtually all children in the United States who
have acute otitis media. Yet 70 percent of severe cases and 90 percent of
mild cases of acute otitis media resolve spontaneously with placebo
treatment. 14 <http://content.nejm.org/cgi/content/short/345/16/#R14>
Moreover, 10 to 30 percent of samples of middle-ear fluid from patients with
acute otitis media do not contain viable bacteria. Unfortunately, it is
difficult and time-consuming to sample middle-ear fluid by tympanocentesis
for culture, a practice that would eliminate empiricism from the selection
and use of antibiotics.


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Figure 1. Prevalence of Penicillin-Resistant and Multidrug-Resistant
Streptococcus pneumoniae.
The data shown on the left are from a 1997 nationwide surveillance study of
pneumococci in which 113 isolates were obtained from blood (60 percent from
children 2 years of age or younger), 415 isolates from the nasopharynx (76
percent from children 10 years of age or younger), and 440 isolates from the
middle ear (66 percent from children 2 years of age or younger). 12
<http://content.nejm.org/cgi/content/short/345/16/#R12>  The data shown on
the right, illustrating the percentage of pneumococcal isolates that were
resistant to more than two classes of antibiotics, were obtained in 1998
from eight U.S. metropolitan regions or states with a total population of
16.5 million under surveillance. 13
<http://content.nejm.org/cgi/content/short/345/16/#R13>  Of the 3474
isolates obtained in the 1998 series, 26 percent were from children younger
than five years of age.

Among invasive isolates of pneumococcus collected from patients of all ages
in sentinel hospitals throughout the United States during 1991 and 1992, 6.6
percent were resistant to penicillin and 5.9 percent had multidrug
resistance. 15 <http://content.nejm.org/cgi/content/short/345/16/#R15>  By
1993 to 1994, 18.4 percent of the isolates collected from children younger
than six years old nationwide were resistant to penicillin, and 13.1 percent
were resistant to multiple antibiotics. 16
<http://content.nejm.org/cgi/content/short/345/16/#R16>  In a 1997 study of
290 isolates collected from the middle ear of children two years old or
younger with acute otitis media throughout the United States, the prevalence
of strains that were highly resistant to penicillin (49.7 percent) was
higher than that of strains with an intermediate level of resistance to
penicillin (19.5 percent). 12
<http://content.nejm.org/cgi/content/short/345/16/#R12>  The emergence of
cross-resistance among antibiotics extends to trimethoprim–sulfamethoxazole,
macrolides, cephalosporins, and clindamycin, and the prevalence of multidrug
resistance continues to increase. 13
<http://content.nejm.org/cgi/content/short/345/16/#R13>
Risk Factors for Otitis Media and Nasopharyngeal Carriage
Risk factors have been identified that predispose children to otitis media
and drug-resistant S. pneumoniae disease. Male sex, attendance at a
child-care center outside the home, the absence of breast-feeding, passive
exposure to tobacco smoke, and having a sibling with a history of recurrent
otitis media all correlate with an increased risk of otitis media in young
children. 2 <http://content.nejm.org/cgi/content/short/345/16/#R2> , 17
<http://content.nejm.org/cgi/content/short/345/16/#R17>  As with many
childhood infectious diseases, attendance at a child-care center outside the
home greatly increases the risk of otitis media, any pneumococcal infection,
and infection with drug-resistant S. pneumoniae. 18
<http://content.nejm.org/cgi/content/short/345/16/#R18> , 19
<http://content.nejm.org/cgi/content/short/345/16/#R19>  Previous antibiotic
treatment and an age of less than two years are additional risk factors for
otitis media caused by drug-resistant S. pneumoniae. 20
<http://content.nejm.org/cgi/content/short/345/16/#R20> , 21
<http://content.nejm.org/cgi/content/short/345/16/#R21>
The nasopharyngeal carriage of pneumococcus is highly prevalent among young
children and predisposes the carrier, his or her siblings, and others in
close contact with the carrier to pneumococcal infection. The rates of
nasopharyngeal carriage are 44 percent among all children six years old or
younger, 22 <http://content.nejm.org/cgi/content/short/345/16/#R22>  60 to
80 percent among children attending child-care centers outside the home, 23
<http://content.nejm.org/cgi/content/short/345/16/#R23> , 24
<http://content.nejm.org/cgi/content/short/345/16/#R24> , 25
<http://content.nejm.org/cgi/content/short/345/16/#R25>  and more than 70
percent among children younger than three years of age who have acute otitis
 media. 26 <http://content.nejm.org/cgi/content/short/345/16/#R26>
Drug-resistant strains of S. pneumoniae are highly prevalent among children
colonized with pneumococcus. In several studies, drug-resistant S.
pneumoniae accounted for 37 to 53 percent of these pneumococci, and the
frequency of resistant strains was highest in children younger than two
years of age. 22 <http://content.nejm.org/cgi/content/short/345/16/#R22> ,
23 <http://content.nejm.org/cgi/content/short/345/16/#R23> , 24
<http://content.nejm.org/cgi/content/short/345/16/#R24>  Nasopharyngeal
carriage of pneumococci is significantly associated with the development of
acute otitis media, and children colonized with resistant strains are more
likely than others to have unresolved acute otitis media. 22
<http://content.nejm.org/cgi/content/short/345/16/#R22>
Treatment of Acute Otitis Media
The widespread prescription of broad-spectrum antibiotics for acute otitis
media regardless of the pathogens involved contributes substantially to the
current trend toward increasing resistance to antimicrobial drugs, as does
the frequent use of antibiotics for nonbacterial pharyngitis and bronchitis.
Clinicians should educate parents regarding the appropriate use of
antibiotics and strategies to reduce the likelihood of acute otitis media,
including breast-feeding for at least three months and eliminating
children's exposure to tobacco smoke. The judicious use of antibiotics
requires an approach of watchful waiting in cases in which the child is
asymptomatic or has red tympanic membrane but no middle-ear effusion. 27
<http://content.nejm.org/cgi/content/short/345/16/#R27>  The use of
tympanocentesis for the culture of middle-ear fluid in patients with acute
otitis media that is unresponsive to antibiotic treatment would go far
toward the more accurate determination of the appropriate choice of
antibiotic therapy. 28
<http://content.nejm.org/cgi/content/short/345/16/#R28>
The antimicrobial drugs selected for children in whom first-line treatment
of acute otitis media with amoxicillin has failed must meet two criteria —
effectiveness against beta-lactamase–producing H. influenzae and Moraxella
catarrhalis and effectiveness against drug-resistant S. pneumoniae. 5
<http://content.nejm.org/cgi/content/short/345/16/#R5>  The latter
requirement is the more restrictive, since recent data on the eradication of
drug-resistant S. pneumoniae from the middle ear are lacking for most
antibiotics. High-dose amoxicillin (80 to 90 mg per kilogram of body weight
per day) plus clavulanate, cefuroxime axetil, and intramuscular ceftriaxone
meet these requirements in most cases, and clindamycin is often effective
when drug-resistant S. pneumoniae has been proved by tympanocentesis to be
the infecting organism. 5
<http://content.nejm.org/cgi/content/short/345/16/#R5>
Vaccination to Prevent Pneumococcal Acute Otitis Media
Clinicians have fewer treatment options today for pneumococcal acute otitis
media, given the increasing resistance to antibiotics, the widespread
nasopharyngeal carriage among young children, and the associated risk of
chronic otitis media. Age, family history, and sex are not modifiable risk
factors, and attendance at a child-care center outside the home is a
necessity for many families. However, more can be done to prevent otitis
media.
Pneumococcal capsular polysaccharide is the principal virulence factor
protecting pneumococci against the defense mechanisms of the host. Capsular
polysaccharide is a T-cell–independent antigen and, consequently, does not
elicit antibody responses in young infants, who lack the mature B
lymphocytes necessary for T-cell–independent antibody-mediated immunity. For
a vaccine to be effective in infants, it must stimulate a T-cell–dependent
antibody response, which is present soon after birth. The 23-valent
pneumococcal polysaccharide vaccines that have been available since 1977
elicit a T-cell–independent response and thus do not protect young children,
nor do they reduce the nasopharyngeal carriage of pneumococcus.
The conjugation of capsular polysaccharides to proteins alters the
properties of the antigen complex and converts the antibody response from
T-cell–independent to T-cell–dependent. The experience with H. influenzae
type b conjugate vaccines shows how effective this type of vaccine can be in
young children. Several pneumococcal conjugate vaccines are in development,
and they vary with respect to the serotypes they contain, the carrier
proteins they use, and their conjugation chemistry. 29
<http://content.nejm.org/cgi/content/short/345/16/#R29>  One such conjugate
vaccine, the pneumococcal–CRM197 conjugate vaccine, has been approved by the
FDA for routine use in infants and toddlers to prevent invasive pneumococcal
disease. This conjugate vaccine is a mixture of six purified pneumococcal
capsular polysaccharides and one capsular oligosaccharide, each coupled to a
nontoxic variant of diphtheria toxin (CRM197). Although no vaccine has been
developed to cover all 90 known pneumococcal serotypes, the 7 serotypes
included in this vaccine — 4, 6B, 9V, 14, 18C, 19F, and 23F — are those that
cause 80 percent of invasive pneumococcal disease in children and
approximately 60 percent of pneumococcal acute otitis media. 30
<http://content.nejm.org/cgi/content/short/345/16/#R30> , 31
<http://content.nejm.org/cgi/content/short/345/16/#R31>  These serotypes are
also the most resistant to antibiotic therapy, 30
<http://content.nejm.org/cgi/content/short/345/16/#R30> , 31
<http://content.nejm.org/cgi/content/short/345/16/#R31> , 32
<http://content.nejm.org/cgi/content/short/345/16/#R32>  although resistance
is emerging among serotypes not covered by the vaccine. 13
<http://content.nejm.org/cgi/content/short/345/16/#R13>  Other pneumococcal
conjugate vaccines that are in development include more serotypes and use
different carrier proteins for conjugation and different conjugation
chemistry. For example, a 9-valent pneumococcal conjugate vaccine currently
under study in Israel and Gambia contains serotypes 1 and 5 in addition to
those contained in the pneumococcal–CRM197 conjugate vaccine.
When it is given according to a four-dose schedule of administration at 2,
4, 6, and 12 to 15 months of age, the pneumococcal–CRM197 conjugate vaccine
is more than 97 percent effective in preventing invasive pneumococcal
disease in healthy infants who have received some or all of these doses of
vaccine. 11 <http://content.nejm.org/cgi/content/short/345/16/#R11>  Unlike
the 23-valent pneumococcal polysaccharide vaccines, the pneumococcal–CRM197
conjugate vaccine can induce immunity in the population that is at highest
risk for disease. Recently, the Advisory Committee on Immunization Practices
and the American Academy of Pediatrics issued recommendations advocating the
routine administration of this vaccine to all children 23 months of age or
younger and to children between 24 and 59 months of age who are at high risk
for pneumococcal infection (i.e., those with conditions causing
immunocompromise and certain underlying medical conditions). 33
<http://content.nejm.org/cgi/content/short/345/16/#R33> , 34
<http://content.nejm.org/cgi/content/short/345/16/#R34>  The recommendations
also indicate that, when possible, clinicians should consider vaccinating
all other children 24 to 59 months of age, with priority given to those who
are at moderate risk for pneumococcal infection, including Alaskan Native
and American Indian children, those of African-American descent, and
children attending child-care centers outside the home. 33
<http://content.nejm.org/cgi/content/short/345/16/#R33>
In addition to their immunogenicity and efficacy in preventing invasive
disease, pneumococcal conjugate vaccines have been shown to reduce
nasopharyngeal carriage of pneumococci 35
<http://content.nejm.org/cgi/content/short/345/16/#R35> , 36
<http://content.nejm.org/cgi/content/short/345/16/#R36> , 37
<http://content.nejm.org/cgi/content/short/345/16/#R37>  and to reduce the
frequency of acute otitis media. 11
<http://content.nejm.org/cgi/content/short/345/16/#R11> , 38
<http://content.nejm.org/cgi/content/short/345/16/#R38> , 39
<http://content.nejm.org/cgi/content/short/345/16/#R39>  In a randomized,
double-blind clinical trial conducted at 23 Northern California Kaiser
Permanente medical centers enrolling more than 37,000 children, 11
<http://content.nejm.org/cgi/content/short/345/16/#R11>  the efficacy of the
pneumococcal–CRM197 conjugate vaccine in preventing otitis media was
assessed as a secondary outcome. Vaccination reduced the number of episodes
of acute otitis media by 7.0 percent and the number of visits to physicians'
offices for otitis media by 8.9 percent. The efficacy rate was higher — 22.8
percent — when it was measured in terms of the prevention of frequent otitis
media, defined as the occurrence of five episodes of acute otitis media
during a six-month period or six episodes during the course of one year
 Table 1 <http://content.nejm.org/cgi/content/short/345/16/#T1> ). Children
who received the vaccine were 20.1 percent less likely than controls to
require tympanostomy tubes for recurrent acute otitis media or chronic
otitis media with effusion. These results are consistent with a study that
demonstrated significantly higher concentrations of anticapsular antibody in
otitis-prone children after the administration of the pneumococcal–CRM197
conjugate vaccine than after the administration of a 23-valent pneumococcal
polysaccharide vaccine. 40
<http://content.nejm.org/cgi/content/short/345/16/#R40>


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Table 1. Summary Results from Three Randomized Clinical Trials Comparing the
Efficacy of Two Pneumococcal Polysaccharide–Protein Conjugate Vaccines
(Pneumococcal–CRM197 and Pneumococcal–OMPC) in Preventing Otitis Media,
Pneumococcal Otitis Media, and Vaccine-Serotype–Specific Pneumococcal Otitis
Media.

The ability of pneumococcal conjugate vaccines to protect children against
acute otitis media was more thoroughly evaluated in the Finnish Otitis Media
Study. 38 <http://content.nejm.org/cgi/content/short/345/16/#R38> , 39
<http://content.nejm.org/cgi/content/short/345/16/#R39>  A total of 2497
children were randomly assigned to receive either the pneumococcal–CRM197
conjugate vaccine, another 7-valent pneumococcal conjugate vaccine
(pneumococcal polysaccharides conjugated to meningococcal outer membrane
protein complex [OMPC]), or a control (hepatitis B) vaccine at 2, 4, 6, and
12 months of age. Children were followed to 24 months of age. In the
comparison between the pneumococcal–CRM197 group and the control group, 2596
episodes of acute otitis media were diagnosed. The overall incidence of
acute otitis media was 1.16 episodes per person-year in the
pneumococcal–CRM197 vaccine group and 1.24 episodes per person-year in the
control group. Samples of middle-ear fluid were obtained for culture from
children during 93 percent of all episodes of acute otitis media; 271
episodes of culture-confirmed pneumococcal acute otitis media occurred in
the pneumococcal-vaccine group, and 414 episodes occurred in the control
group — a 34 percent reduction in the incidence of pneumococcal acute otitis
media as a result of vaccination. The efficacy rates were 57 percent against
episodes due to the serotypes contained in the vaccine and 51 percent
against cross-reactive serotypes (6A, 9N, 18B, 19A, and 23A).
In the comparison between the pneumococcal–OMPC vaccine group and the
control group in the Finnish Otitis Media Study, there were 110 episodes of
acute otitis media attributed to the serotypes contained in the vaccine in
the pneumococcal–OMPC vaccine group and 250 such episodes in the control
group — a reduction of 56 percent (95 percent confidence interval, 44 to 66
percent) with vaccination. 39
<http://content.nejm.org/cgi/content/short/345/16/#R39>  The overall
incidence of acute otitis media did not differ between the groups. For the
booster dose at 12 months, the last 187 children in the pneumococcal–OMPC
conjugate-vaccine group received the 23-valent pneumococcal polysaccharide
vaccine, and the others in that group received pneumococcal–OMPC vaccine.
Vaccine efficacy after the booster dose was nearly identical in these two
subgroups (62 percent and 61 percent, respectively), suggesting that the
pneumococcal–OMPC conjugate vaccine effectively primes the child's system
for a booster dose of either conjugate or polysaccharide. These results are
interesting in the light of the fact that, when given to infants at 2, 4, 6,
and 15 months of age, the pneumococcal–OMPC vaccine apparently has lower
immunogenicity 41 <http://content.nejm.org/cgi/content/short/345/16/#R41>
than the pneumococcal–CRM197 conjugate vaccine. 42
<http://content.nejm.org/cgi/content/short/345/16/#R42>
A recent analysis of 500 isolates obtained from the middle-ear fluid of
patients with pneumococcal acute otitis media (90 percent of whom were
children) found that 67 percent of all isolates were covered by the 7-valent
pneumococcal conjugate vaccines, and 67 percent and 77 percent,
respectively, would be covered by 9-valent and 11-valent pneumococcal
conjugate vaccines that are now in development. 43
<http://content.nejm.org/cgi/content/short/345/16/#R43>  Moreover, 97
percent of antibiotic-resistant strains were covered by each of the vaccine
formulations, with no significant differences among the three vaccines. The
fact that there was a reduction in pneumococcal carriage and in the
prevalence of drug-resistant S. pneumoniae involving the serotypes contained
in the vaccine suggests that there is potential for herd immunity, in which
the spread of the serotypes that are most commonly associated with disease
and antibiotic resistance would be reduced. 36
<http://content.nejm.org/cgi/content/short/345/16/#R36>
Expectations of Vaccines and Future Vaccine Strategies
Although the pneumococcal–CRM197 conjugate vaccine has a small effect on
individual children, it is likely to have a large effect on the prevalence
of pneumococcal disease at the population level; it is also likely to cause
a considerable reduction in the absolute number of episodes of otitis media,
since otitis media is such a common disease. 44
<http://content.nejm.org/cgi/content/short/345/16/#R44>  It has been
projected that vaccination with pneumococcal–CRM197 conjugate could prevent
more than 12,000 cases of meningitis and bacteremia, 53,000 cases of
pneumonia, 116 pneumococcal-related deaths, and 1 million episodes of otitis
media per vaccinated birth cohort in the United States. 32
<http://content.nejm.org/cgi/content/short/345/16/#R32>  It has also been
estimated that the effect on otitis media would account for 60 percent of
the cost savings expected from the prevention of pneumococcal disease
through a vaccination program. 32
<http://content.nejm.org/cgi/content/short/345/16/#R32>
One problem is that pediatricians and parents expect that universally
administered vaccines will virtually eradicate the disease they target.
Clearly, the pneumococcal–CRM197 conjugate vaccine is highly effective in
reducing the prevalence of invasive pneumococcal disease. However, its rates
of efficacy against acute otitis media are substantially lower than the
efficacy rates of vaccines for other vaccine-preventable diseases. Thus, the
expectations of physicians and parents regarding the vaccine are not likely
to be met solely on the basis of the prevention of otitis media.
The current strategy for the use of the pneumococcal–CRM197 conjugate
vaccine relies on vaccination to eliminate most disease-causing pneumococci,
including those that are most resistant to antibiotic therapy. Two possible
future scenarios could delay progress. The serotypes contained in the
vaccine are capable of capsular transformation into other serotypes that can
cause disease. Serotype 14 variants of the Spanish clone of serotype 9V and
serotype 19F variants of the multidrug-resistant Spanish clone of serotype
23F have arisen through large recombinational replacements of the genetic
locus responsible for biosynthesis of the capsule. 45
<http://content.nejm.org/cgi/content/short/345/16/#R45> , 46
<http://content.nejm.org/cgi/content/short/345/16/#R46>  The
pneumococcal–CRM197 conjugate vaccine is recommended for routine use in
infants and toddlers — persons in whom pneumococcal carriage is
significantly more common than it is in adults, which might increase the
likelihood of capsular transformation.
The vaccine covers only 7 of the 90 known disease-causing serotypes of
pneumococcus, and its widespread use might therefore allow some of the 83
other serotypes to become predominant pathogens. In the Finnish Otitis Media
Study, there was a 33 percent increase among the children vaccinated with
the pneumococcal–CRM197 conjugate in the incidence of pneumococcal otitis
media caused by serotypes not included in the vaccine. 38
<http://content.nejm.org/cgi/content/short/345/16/#R38>  Although the use of
the 23-valent vaccine has not been associated with an apparent increase in
disease caused by serotypes not included in that vaccine, it has been used
primarily in adults, who have substantially lower rates of pneumococcal
carriage.
In the future, pneumococcal-protein vaccines should offer an alternative
approach to the prevention of pneumococcal disease and the reduction of
carriage. Several proteins that are virulence factors in pneumococcus have
been identified. One, pneumococcal surface protein A (PspA), is effective
against otitis media in rats, and a mixture of two proteins (PspA and
pneumococcal surface adhesion A protein [PsaA]) protects against nasal
carriage of pneumococci in mice. 47
<http://content.nejm.org/cgi/content/short/345/16/#R47>  A third protein,
pneumolysin, together with PspA, elicits protection against invasive
disease. Including these proteins in polysaccharide–protein conjugate
vaccines might enhance the vaccines' efficacy against otitis media while
providing coverage against serotypes not included in the vaccines.
Viral vaccines provide another approach to the prevention of otitis media,
since respiratory virus infection contributes importantly to the
pathogenesis of acute otitis media. 48
<http://content.nejm.org/cgi/content/short/345/16/#R48>  At present,
influenzavirus vaccine is the only commercially available vaccine for the
control of respiratory virus infections. Results of three randomized trials
of influenzavirus vaccine indicate that the prevention of viral infection,
which usually precedes acute otitis media, is an effective way to prevent
the development of acute otitis media. In a Finnish study, the
administration of inactivated influenzavirus vaccine led to an incidence of
acute otitis media associated with influenza A that was 83 percent lower
than that among controls and an overall incidence of acute otitis media that
was 36 percent lower than that among controls. 49
<http://content.nejm.org/cgi/content/short/345/16/#R49>  Similar results
were found in a study in the United States, in which there were 32 percent
fewer episodes of acute otitis media in vaccinated children during the
influenza season studied than in controls. 50
<http://content.nejm.org/cgi/content/short/345/16/#R50>  A live attenuated
intranasal influenzavirus vaccine was 93 percent effective against
culture-confirmed influenza, and vaccinated children had 30 percent fewer
episodes of febrile acute otitis media. 51
<http://content.nejm.org/cgi/content/short/345/16/#R51>
Respiratory syncytial virus vaccines that are currently being developed do
not seem to induce protection against lower-airway disease in young infants
and children, and they have not been evaluated in terms of protection
against otitis media. However, passively administered antibody against this
virus was effective against both respiratory syncytial virus lower-airway
disease 52 <http://content.nejm.org/cgi/content/short/345/16/#R52>  and
otitis media in a multicenter trial. 53
<http://content.nejm.org/cgi/content/short/345/16/#R53>  Two attenuated
parainfluenza virus vaccines have been found to be safe and immunogenic in
infants, but there are insufficient data on their ability to protect against
respiratory disease. 54
<http://content.nejm.org/cgi/content/short/345/16/#R54> , 55
<http://content.nejm.org/cgi/content/short/345/16/#R55>
Currently, routine vaccination of all children with the pneumococcal–CRM197
conjugate vaccine is our best strategy for reducing the burden of
early-childhood pneumococcal diseases, including otitis media. Continued
surveillance of the distribution of pneumococcal serotypes and patterns of
drug resistance is necessary and will dictate the development of future
vaccine approaches.

Source Information
From the Department of Pediatrics, University of Minnesota School of
Medicine, Minneapolis.
Address reprint requests to Dr. Giebink at the Department of Pediatrics,
University of Minnesota School of Medicine, MMC-296, 420 Delaware St. S.E.,
Minneapolis, MN 55455, or at [log in to unmask] <mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.