Pneumococcal Vaccination for Prevention of Otitis Media
Jan 7 2004, R3 施偉勛
Epidemiology
 24 million cases with AOM each year in children under 2 y/o in USA
 Hearing loss in 20% of AOM
 Pnc disease in meta-analysis: 15% death, 12-28% neurologic sequelae
 Average of 42 days of Abx for otitis by 1 y/o in Pittsburgh (2253)
 nasopharyngeal carriage: 44% in children ≦ 6 y/o
 90 serotypes of pneumoncocci (Pnc), 85% caused by 8 types (4, 6A,
6B, 9V, 14, 18C, 19F, 23F, cross reactivity between 6A and 6B)
Historical Perspective in Pneumococcal vaccines and OM
 1880--pneumococcus isolated by Sternberg in USA, Pasteur in France
 1887--first report of pneumococcus in OM by Zauful and Netter
 1894--Strep pyogens: reflect the significant attack rate of scarlet fever
7118 isolates in 1906-1951: 1st rank with downward trend
 1911--develop vaccine of killed pneumococcus in S Africa by Lister
40 billion killed pneumococci IV in a million humans, effect?
 1927--immunogenicity of the capsular polysaccharide by Schiemann
 1930--sulfonamides develop vaccine abandoned
 1937--lack of responsiveness of polysaccharide in 2-14 mo infants
 World War II--efficacy of pneumococcal polysaccharide vaccine by
US Air Force: 50 ug capsular polysaccharide 4 types  carrier rate
 1950s--withdrawn from the market due to the advent of penicillin
 1977--relicensure of polyvalent vaccine (14-23 serotype) after trial in
12000 African gold miners:  78.5% in pneumococcal pneumonia; 
82.3% bacteremia
 1980--develop pneumococcal polysaccharide conjugate vaccine (PCV),
encourage by HIB vaccine ( invasive infection and carrier rate)
 2000---FDA licensed a 7-valent PCV (Pnc-CRM197)
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Cell Biology of Tubotympanium in Otitis Media
1. mucocillary defense:
 pneumococcus in np : pneumococcus+adenovirus =20% : 80%
 amotile ciliary syndrome (Kartagener’s): 100% have CPS and OM
2. Mucins
 high-molecular weight glycoprotein to trap bacteria and viruses for
mucociliary clearance
 as a receptor for bacterial adherence to epithelial surface and mucous
blanket ex: HI  keep pathogens in the region with antimicrobal agents
 9 human mucin genes (1, 2, 3, 4, 5AC, 5B, 6, 7, and 8): nontypeable HI
induce MUC5AC upregulate
3. Aquaporins
 intergral membrane proteins as water channels
 responsible for maintaining fluid homeostasis
 abnormal changes in membrane potential  fluid accumulation
 7 AQP genes: AQP1 and AQP9 in rat middle ear
4. Lysozyme
 disrupt bacterial walls
 from serous glands of E-tube and middle ear mucosa, PMN
 pre-exposure of bacteria to Lz enhance bactericidal activity of β
defensins against NTHI
5. Lactoferrin
 iron-binding glycoprotein in milk, middle ear mucosa, and PMN
 proteolytic activity to 2 related proteins of NTHI (non-pilus Hap
adehesion and the IgA protease precursor)
 antibacterial lysozyme and lactoferrin in human milk to prevent OM
6. Defensins
 broad-spetrum microbicidal and viricidal agents
 most abundant polypeptides secreted by PMN
 75 different α, β-defensins
7. Collectins and antimicrobial surfactant proteins (SP-A, SP-D)
 lectin domains bind carbohydrate structures of pathogen, and
collagenous regions are ligands to phagocytes
 mediate C1q-independent activation of classical complement pathway
 SP-A, SP-D bind pathogens via carbohydrate groups causing them to
agglutinate promote phagocytosis
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Pathogenesis of Pneumococcal Otitis Media---from commensal
to pathogen
 invade human cells may be more result of changes in the human cell
surface than in the bacteria itself
 activation of np cells by cytokines due to virus infection receptor
presentation  gain access to the middle ear by change in the
presentation of lectins cytokines, IL-6, IL-1, TNF influx of
neutrophil profound inflammation
 PAF receptor in lung cells bind choline in pneumococcal cell wall
 IgA receptor in NP cells bind CbpA (choline binding protein)
 cell wall pieces of coccus activate alternative pathway and  cytokine,
PAF  enhancement of inflammation with bacterial lysis by Abx
injury the hair cell
 Pneumolysin
a. thiol-activated cytotoxin of pneumocci, water soluble monomer
b. bind cholesterol  pore formation in cell membrane
c. into the scala tympani of cochlea damage to organ of Corti
d. in meningitis: bacteria and PMN in CSF along cochlear aqueduct
into inner ear damage from base to apexpermanent bil SNHL
Cost and Benefit
 For OM, $6.28 million in OPD, 1.08 million in hospitalization, 60000
in Abx, missed work 5.9 hr costing $120 in one adult
 vaccination program wound reduce $342 million in medical and $415
million in work-loss and other cost in each year
 From societal perspective, net savings if vaccine cost ≦ $46
 From the health care payer perspective, net savings if vaccine ≦ $18
 current price per dose: $58, still relatively cost-effective than others
Effect
1. Trial in Israel
 PCV in 12-18 mo toddlers
 4% were carriers one year after vaccination; 14% in control group
2. Trial in Northern California (Table )
 heptavalent PCV (18927) vs meningococcal conjugate vaccine (18941)
 vaccinate in 2,4,6 and 12-15 months of age
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 efficacy against pneumonia, otitis episodes, frequent otitis, and tube
replacement were 11%, 7%, 22.8%, and 20%
 no evidence of an increase of disease due to non-vaccine serotypes
3. Trial in Finnish
 HBV vaccine as control group, 2596 episodes of AOM
 reduction in 57% against culture-confirmed, serotype-specific AOM
34% against culture-confirmed pneumococcal AOM
6% against AOM irrespective of the etiology
100% against invasive infection by serotype-specific Pnc
4. 500 isolates from OME
 67%, 67% and 77% of isolates were covered by 7-, 9-, 11-valent PCV
 97% of antibiotic-resistant strains were covered by each PCV
5. Metaanalysis in 2003
 prevent 8% of AOM episodes in infants and toddlers
 prevent 17% of AOM episodes in children attending day care
 prevent 19% of AOM episodes in children with previous AOM
 cannot recommend large scale PCV, suggest only in high risk group
Will New Pathogens Emerge when facing Selective pressure
 Microbiology of OM in children with amoxicillin prophylaxis(Table )
 increase in β-lactamase(+) HI or M catarrhalis
 with bacterial polysaccharide immune globulin (BPIG)
 increase in NTHI, M catarrhalis, No unusual pathogens (Table )
 with 9-valent PCV---evaluate in NP carriage (Table )
 carriage of vaccine serotypes decrease from 36% to 18%
 carriage of non-vaccine serotypes increase from 24% to 36%
 inhibitory effect of the resident of Pnc
 Drug-resistent pathogens (snowball effect) (Fig )
a. 70% severe and 90% mild AOM resolve spontaneously
b. 6.6% resist to penicillin, 5.9% multidrugs resistance in 1991
c. 18.4% resist to PCN, 13.1% multidrugs resistance in 1994
d. 49.7% resist to PCN, 19.5% multidrugs resistance in 1997
Future in the vaccine
 improve the immunogenicity of polysaccharide: with IL-2, CD40 Ab
 using pneumococcal protein as carrier or pure protein vaccine (Table )
a. less immunologic conflict with other vaccines
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b. target more than one mechanism for broader protection
c. improve anamnestic responses to any subsequent Pnc infection
d. against invasive infection: PspA+pneumolysin
e. against carriage or otitis media: PsaA+PspA (and/or PspC)
 intranasal immunization against mucosal infections
a. antigens+nontoxic B unit of cholera toxin
b. pneumococcal surface protein A (PspA) or 6B
polysaccharide-tetanus toxoid conjugate into mice can induce
mucosal and systemic antibody response against Pnc
Other Prevention Methods
1. Xylitol in Preventing AOM
 polyol sugar alcohol, produced from birch, in plums, strawberries etc
 inhibit the growth of Pnc by fructose phosphotransferase system (Fig )
 inhibit attachment of Pnc to NP cells in 5% xylitol (Fig )
 2 pieces chewing gums 5 times per day with total 8.4 g xylitol
5 ml 5 times per day with total 10 g xylitol daily
 the number of children with AOM  42%, Abx usage  36%
 In a high-risk children with tympanostomy tube insertion
 xylitol was ineffective in preventing otitis
 Side effects: loose stool due to slowly absorption (up to 45g)
5% children did not take xylitol due to abdominal discomfort
2. Antibiotics prophylaxis
 amoxicillin can decrease AOM attack rate, however,
follow-up 1 year later, attack rates similar in others
3. Tympanostomy tubes:
 not as beneficial in recurrent AOM, but good for MEE
4. Adenoidectomy
 reduce MEE prevalence during 1st and 2nd follow-up years
 reduce overall MEE prevalence only for children with prior tubes
 does prevent the need for tympanostomy tube reinsertion
6. Risk factor modification
 age, sex, race, genetic predisposition, early onset of OM
 alter host defenses and underlying disease, allergy, air pollution
 exposure to tobacco smoke, not breast fed, season, poverty
 sleeping position, use of a pacifier
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