- Email: [email protected]
Vaccines for otitis media and other pediatric pneumococcal diseases
Drug Discovery Today: Therapeutic Strategies
Vol. 3, No. 2 2006
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Infectious diseases
Vaccines for otitis media and other pediatric pneumococcal diseases Frank J. Malinoski MedImmune, Inc., One MedImmune Way, Gaithersburg, MD 20878, USA
The study of vaccines to prevent disease caused by Streptococcus pneumoniae is a study of the diversity, adaptability and tenacity of this human pathogen. In parts of the world, an effective protein conjugate vac-
Section Editors: Gary Woodnutt – CovX, San Diego, USA Paul-Henri Lambert – Centre of Vaccinology, University of Geneva, Switzerland
cine is now eliminating pneumococcal meningitis and bacteremia in children and, through herd effects, is reducing the burden of invasive disease in older, unvac-
strategies are needed to effectively induce a sustained reduction of SPn OM.
cinated populations. Use of conjugate vaccines also has impacted otitis media, but this protection is limited and replacement disease has emerged as a concern.
Introduction Streptococcus pneumoniae (SPn; see Glossary) is the leading cause of respiratory tract related death, bacterial meningitis and bacteremia globally among children [1]. SPn is also the leading cause of bacterial otitis media (OM), one of the most common diseases of childhood with enormous direct and indirect annual healthcare costs. The burden of SPn OM is aggravated by the organism’s ability to rapidly acquire antibiotic resistance genes under selective pressure from the community use of antibiotics [2]. The 7-valent pneumococcal protein CONJUGATE VACCINE (see Glossary) Prevenar (PnCV-7, Wyeth) has amassed impressive results against INVASIVE PNEUMOCOCCAL DISEASE (IPD; see Glossary) and pneumonia in children. However, protein conjugate vaccines have had only marginal impact on OM because nonvaccine serotypes and other pathogens replace vaccine serotypes in nasopharyngeal carriage and mucosal disease in both prelicensure and postlicensure experience. New E-mail address: F.J. Malinoski ([email protected]) 1740-6773/$ ß 2006 Published by Elsevier Ltd.
DOI: 10.1016/j.ddstr.2006.06.004
Pneumococcal vaccines and their efficacy against invasive diseases The pneumococcus is, in part, classified and defined by the polysaccharide capsule surrounding the organism. This capsule is a virulence factor and offers protection from opsonophagocytic killing by the human immune system [3]. Based on the dominance of the capsule in immunologic response to infection and the ability of passively administered anticapsular antibody to protect against disease, two types of vaccines have emerged thus far to prevent pneumococcal disease. First, polysaccharide vaccines that contain capsular polysaccharide from the 23 dominant serotypes are licensed for use in adults. Licensure was based primarily on efficacy studies in adult mine workers in South Africa where 6- and 12valent vaccines were up to 92% effective against pneumonia [4]. Because these vaccines rely on primarily T-cell independent antibody responses, their effectiveness over time is limited and they are largely ineffective in children. The second class of vaccines is based on covalently linking the capsular saccharides to proteins to induce a T-cell dependent immune response characterized by immunologic memory; a response necessary to protect infants and children. In controlled clinical trials a 7-valent conjugate vaccine based on diphtheria toxoid carrier protein CRM197 (PnCV-7; containing protein conjugates of serotypes 4, 6B, 9V, 14, 18C, 19F 121
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Vol. 3, No. 2 2006
Glossary Conjugate vaccine: vaccine in which saccharide capsular component of selected serotypes of pneumococcus are covalently linked to a carrier protein. Conjugate vaccines are processed by the immune system to generate both antibody and cellular memory responses that are protective in infants and children. Invasive pneumococcal disease: meningitis, bacteremia, pneumonia with bacteremia, infection of other normally sterile sites (e.g. joint, pericardium). Noninvasive or mucosal pneumococcal disease: otitis media, sinusitis, pneumonia without bacteremia. Streptococcus pneumoniae (SPn): Gram-positive encapsulated bacterium with over 90 distinct capsular types identified by serologic Quelung assay. SPn has evolved various mechanisms of resistance to multiple antibiotics.
immune responses of the populations, or differences in the number of doses or the schedule of those doses administered in these different populations. Strikingly consistent across these studies is an overall significant impact on pneumonia of 20% or greater. When these data were pooled to evaluate recommendations for immunization with conjugate vaccines against IPD in A Cochrane Database Review, the analysis of the available literature related to the 7- and 9-valent CRM197 protein conjugate vaccines confirmed a pooled vaccine efficacy against vaccine serotype IPD of 88%, a pooled efficacy against all SPn IPD of 66% and a pooled efficacy against x-ray confirmed pneumonia of 22% [11].
Vaccine effects on nasopharyngeal carriage and 23F) has shown high efficacy against the invasive SPn diseases; bacteremia, meningitis and bacteremic pneumonia [5–7]. Studies have also shown that a 9-valent CRM197 conjugate vaccine (PnCV-7 serotypes plus types 1 and 5) was efficacious against IPD and pneumonia in both HIV negative and HIV positive children in South Africa and had an overall impact on child survival in The Gambia [8–10] (Table 1). The highest efficacy results for PnCV-7 (97% against vaccine serotype IPD and 90% against all SPn IPD) were seen in the US Kaiser study in healthy infants at moderate risk of IPD and given four doses of vaccine (2, 4, 6 month primary series and a fourth dose at12–15 months). In populations at higher risk of IPD (Native American, Gambian and South African (including an HIV infected cohort) children) the efficacy was still dramatic, ranging from 65% in HIV positive children in South Africa to 86% in Native American children. Importantly, in both of the studies in Africa children received only a three dose series according to the current WHO Expanded Program of Immunization (EPI) schedule of 6, 10 and 14 weeks of age. It is quite possible that the variations in the results are either due to differences in the ecology of SPn, differences in the
As an exclusive human pathogen with no known animal reservoir, it is indeed possible to eradicate pneumococcal disease. However, it is important to understand that, unlike many pathogens, invasive disease caused by SPn is a relatively rare event compared to the frequency with which this organism is found asymptomatically residing in (colonizing) the human nasopharynx. Indeed, in one study, 95% of a US cohort of children was colonized at least once through their first 24 months of life. Similarly, the prevalence of nasopharyngeal (NP) carriage has been reported to approach 95% in children during the first 3 years of life in developing countries, with 40% in adults in those countries also colonized, and up to four serotypes isolated over several months time [12]. Thus, vaccines intended to eliminate SPn disease will need to eliminate nasopharyngeal colonization by the organism. Polysaccharide vaccines have failed to impact the nasopharyngeal carriage of SPn. By contrast, protein conjugate vaccines have reproducibly reduced carriage of vaccine serotypes [13]. In addition, there is significant epidemiologic evidence that the reduction in carriage has resulted in clinical benefit. Specifically, the use of the PnCV-7 conjugate vaccine
Table 1. Efficacy of protein conjugate vaccines against IPD Protein conjugate vaccine
Vaccine efficacy in Population
Other IPD Overall
7-valent CRM197 (4-dose)
US healthy N = 37,868 [5,6]
7-valent CRM197 (4 dose)
US healthy N = 8091 [7]
9-valent CRM197 (3-dose, EPIc)
RSA HIV N = 37,259 [8,9]
9-valent CRM197 (3 dose, EPIc)
Serotype
Overall a
Serotype
94
20
90a (bacteremic)
54
86a
n.r.b
n.r.b
42
83a
17a 38 (bacteremic)
a
a
89
a
53
65
15 45 (bacteremic)
59a (bacteremic)
Gambia healthy N = 17,437 [10]
50a
77a
37a
n.r.b
Statistically significant. n.r., not reported. c EPI, Expanded Program of Immunization (6, 10, 14 weeks). b
www.drugdiscoverytoday.com
a
a
67 (bacteremic)
RSA HIV+ N = 2577 [8,9]
a
122
a
Pneumonia
16% efficacy against mortality
Vol. 3, No. 2 2006
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
An 11-valent protein D conjugate vaccine (11pn-PD) from GSK Biologicals is distinct from the two 7-valent vaccines in that it contains four additional SPn serotype conjugates (types 1, 3, 5 and 7F) and uses a highly conserved surface lipoprotein, protein D, as the carrier protein [18]. Protein D is derived from NTHi, another common bacterial pathogen responsible for OM. This vaccine was associated with a significant reduction in pneumococcal vaccine serotype OM (53%) with no significant change in disease caused by SPn nonvaccine serotypes (9% vs. 27 to 33% efficacy for the 7valent vaccines) and had significant activity against NTHi OM (35% vs. 9 to 11% efficacy for the 7-valent vaccines). In addition, the overall impact on any OM was significant at 34% versus the nonsignificant impact of 6 and 1% with the 7-valent vaccines. The FinOM trial that tested the efficacy of the 7-valent formulations was not powered to establish an impact on overall OM disease. However, the Kaiser IPD efficacy trial conducted with PnCV-7 enrolled over 37,000 subjects and therefore had more power to evaluate the impact of PnCV-7 on OM related endpoints [15]. Four major conclusions were possible from that study. First, there was a statistically significant, although small (7%), reduction in overall OM. Second, the vaccine had a greater impact on frequent visits for OM than on first visits and that protection increased with the frequency of OM visits. Although first visits were reduced by 5%, the risk of three or more visits was reduced by 10% and the risk of ten or more visits was reduced by 26%. Third, associated with the reduction in frequent visits was an overall 24% reduction in tympanostomy tube (TT) placement. Lastly, PnCV-7 use was associated with over a 5% reduction in antibiotic prescriptions, beginning as early as dose 1 in the immunization series. Consistent with the reductions in TT
in the US has been associated with significant reductions of vaccine serotype IPD in populations that were not immunized. Within the first 2 years of PnCV-7 use in US children there was over a 30% reduction in vaccine serotype IPD in what can be considered the parent generation (20 to 39 years of age) and an 18% reduction in what could be considered the grandparent generation (those over 65 years of age) of vaccine recipients [14]. These effects were accompanied by a 35% reduction in penicillin-nonsusceptible strains. Because of these and other findings, there are expectations that the use of this and other protein conjugate vaccines will induce a significant and sustained protection from NONINVASIVE (see Glossary), mucosal SPn diseases such as otitis media.
Pneumococcal vaccine efficacy against otitis media Prelicensure evidence
Three different protein conjugate vaccines have been evaluated for their impact on SPn OM in four randomized, controlled trials ([15–18]; Table 2). Although these studies vary significantly in their design and conduct, there are remarkable similarities in the performance of these vaccine candidates. Where measured, all three vaccines significantly reduced SPn OM caused by vaccine serotypes by at least 50% and any SPn OM by 25–50%. Notably, in comparing the performance of the CRM and OMP conjugate vaccines in the FinOM trial where the same control group was used by both vaccines, the degree of replacement disease (noted by negative efficacy) was strikingly similar with both nonvaccine serotypes (33 and 27%) and nontypeable Haemophilus influenzae (NTHi) (11 and 9%). Although not statistically different, the CRM conjugate vaccine had a higher point estimate for reduction in any OM, 6%, versus a 1% point estimate with the OMP vaccine.
Table 2. Randomized controlled trials of pneumococcal vaccine otitis media efficacy Protein conjugate vaccine
Population
Vaccine efficacy (%)a
Other effects
SPn VT
SPn NVT
Any SPn
H.flu (n.t.)
Any OM
7-valent CRM197 (4-dose)
N = 37,868 US [15]
n.r.
n.r.
62b,c
n.r.d
7
24%b # placement tympanostomy tube (TT) 5% # antibiotic prescriptions
7-valent CRM197 (4-dose)
N = 1662 Finland [16,19]
57b
33
34b
11
6
4% # placement TT (2–24 month-old) 39% b # placement TT (after 24-month-old)
7-valent OMP (4-dose or 3-dose plus PS boost)
N = 1666 Finland [17]
56b
27
25b
9
1
11-valent NTHi Protein D (4-dose)
N = 4968 Czech Republic [18]
53b
9
52b
35b
34b
a
VT, vaccine serotypes; NVT, nonvaccine serotypes, H.flu (n.t.), nontypeable Haemophilus influenzae. Statistically significant. c Based on isolates from spontaneous ruptured eardrums; PS: 23-valent polysaccharide vaccine. d n.r., not reported. b
www.drugdiscoverytoday.com
123
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Vol. 3, No. 2 2006
Table 3. Changes in OM ecology after introduction of PnCV-7 vaccine Study site
Rochester [21]
Rural Kentucky [22]
Multicenter hospitals [23]
Population: source of isolates tested
Children with persistent acute OM followed from 1995 to 2003
Sample of patients (7 to 24-month-old) with acute OM culture (94% vaccine coverage in post period)
Sample of five hospital isolates from acute OM from 1999 to 2002
Percent of isolates
Percent of isolates
Percent of isolatesa
No vaccine
3–4 doses
Pre
Post
1dose
2–4 doses
N
204
152
336
83
435
63
Time periods
’98–00
’00–03
’92–99
’00–03
’99–02
’99–02
VT + VRTb
n.r.c
n.r.
n.r.
78
68
#10%d
70
41
#29%d
NVTb
n.r.
n.r.
n.r.
22
32
"10%
Change
Change
Change
SPn
All
44 b
NTHi
b
M. cat
31
d
#13%
d
48
31
18
35
"17%d
d
n.r.
n.r.
n.r.
d
#17%
43
57
"14%
41
56
"15%
n.r.
n.r.
n.r.
5
1
" 4%
9
11
"2%
n.r.
n.r.
n.r.
a
Defined by direct history of vaccination with PnCV-7 as noted. b VT, vaccine serotypes; NVT, nonvaccine serotypes; NTHi, nontypeable Haemophilus influenzae; M. cat, Moraxella catarrhalis. c n.r., not reported. d Statistically significant.
placement seen in the Kaiser study, an open-label follow-up study of the FinOM recipients of the PnCV-7 vaccine showed that although TT placements were not reduced during the blinded study (between 2 and 24 months of age), TT placement after the study (i.e. after subjects were 24-months-old) was reduced 39% in the vaccine group compared to controls [19]. Taken together, these results suggest that protein conjugate vaccines might have a significant and measurable impact on SPn OM. Given the high prevalence and significant cost burden of OM there are significant benefits to be gained. However, expectations need to be managed because the only product to reach licensure, PnCV-7, has shown only a 6% reduction in overall OM and the best prelicensure candidate might only reduce the burden of OM by one-third. This caution is underscored by the fact that a recent Cochrane review concludes that the pooled results of four protein conjugate vaccine trials showed a significant but only a small effect on prevention of acute OM with a rate ratio of 0.921 and, therefore, that conjugate vaccines cannot yet be recommended specifically for prevention of acute or recurrent OM in children [20]. Postlicensure experience with PnCV-7 vaccine
Widespread use of PnCV-7 vaccine in the US began in 2000 after licensure. Measuring the impact of the vaccine postlicensure is challenging because of the need to compare data on changes in OM disease patterns to historic controls rather than prospectively with matched cohorts trials and the fact that historic data are not necessarily robust. Nevertheless, three published trials provide important information regarding changes in the microbiology of acute OM following introduction of the PnCV-7 vaccine ([21–23]; Table 3). In 124
www.drugdiscoverytoday.com
spite of the variety of methods and sources in these studies, the consistent observation was an overall reduction in the frequency of OM isolates caused by any SPn of 13–17% following the introduction of PnCV-7 vaccine. As expected, there were significant reductions in vaccine and vaccine related serotypes isolated from children with or without recurrent OM; ranging from 10 to 29%. Counterbalancing this was an increase in nonvaccine serotypes (10–17%) and other pathogens, notably significant increases in the isolation of NTHi (approximately 15%). In the multicenter study where serotyping was conducted, it is interesting to note that the prominent nonvaccine serotype was type 3 whereas the prominent vaccine and vaccine related serotypes isolated (i.e. breakthrough cases) belonged to serogroup 19. By contrast, the nonvaccine serotypes isolated in the rural Kentucky study were 1, 11A, 15A, 29 and 33F. It is not clear how these trends will play out. When the data from McEllistrem is reviewed by year there appears to be a flattening of the increase in the percentage of nonvaccine SPn at the end of their study (Fig. 1). Whether this trend will continue remains to be seen. Also unclear is whether initial reductions in the total burden of penicillin-nonsusceptible isolates will remain low, stable or increase. Lastly, as vaccine developers consider increasing the numbers of serotypes covered in future protein conjugate vaccines to address these emerging nonvaccine serotypes, there is no clear indication at this time which serotypes ought to be included. Future alternative vaccine strategies
A broad range of SPn vaccine candidates are being considered as next generation products for the prevention of SPn IPD and
Vol. 3, No. 2 2006
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Figure 1. Change in SPn serotype distribution in OM Isolates associated with the introduction of PnCV-7 vaccine (adapted from 23). Reduction in the proportion of vaccine serotypes (VT) and vaccine related serotypes (VRT) compared to the increase in nonvaccine serotypes (NVT) following the introduction of PnCV-7 vaccine.
otitis media. These targets include both intracellular and surface SPn proteins. Candidates currently in animal model testing include cell wall components such as lipoteichoic acid, surface binding proteins such as PspA and PsaA, choline binding proteins, hyaluronidase, neuraminidase and IgA1protease. One conserved surface protein, BVH [24], has been developed as a chimeric molecule called BGCvax, has completed Phase I clinical testing, and is now undergoing additional clinical evaluations that are likely to include the vaccine’s impact on colonization and otitis media.
Conclusions The role of pneumococcus in human disease, including otitis media, is not new [25]. The problem came to center stage, however, with the rapid and widespread emergence of antibiotic resistance in pneumococcal isolates at the end of the past century [26]. The introduction of the 7-valent pneumococcal conjugate vaccine Prevenar is a significant advance. However, it is clear that this vaccine is not the vaccine that will eliminate pneumococcal disease. Significant challenges with the PnCV-7 vaccine exist not only in vaccine accessibility and affordability, but also in vaccine serotype coverage
which is inadequate for many parts of the world. An additional gap lies in the limited impact of PnCV-7 against OM and the accumulating data that nonvaccine serotypes and other pathogens are replacing the vaccine types as ‘reemerging’ and ‘emerging’ causes of OM. Although pathogens like NTHi and Moraxella are already common OM pathogens, there is also a report of increased colonization with Staphylococcus aureus in healthy children following the use of PnCV7 vaccine that raises concerns that this pathogen, already noted for its ability to acquire substantial resistance to antibiotics, will emerge as a greater clinical threat [27]. Clearly, the elimination of pneumococcal disease has to consider the complex role of colonization, aerosol spread and local and systemic invasion mechanisms used by this organism in causing a broad spectrum of disease (Fig. 2). Several strategies are possible to improve on the current PnCV-7 vaccine. Such approaches include expanding the number of serotypes included in future protein conjugate vaccine formulations, adapting a way to rotate different vaccine serotype formulations in use (e.g. use the current 7-valent formulation for ‘x’ years and then switch to a new 7-valent formulation for another set number of year), using www.drugdiscoverytoday.com
125
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Vol. 3, No. 2 2006
Figure 2. Role of NP carriage in SPn IPD and potential impact of protein conjugate vaccines (adapted from 12). Exposure to SPn in the environment through airborne droplets results in multiple potential outcomes (solid lines) which can be influenced by adequate immune responses to PnCV-7 vaccine (dotted lines).
carrier proteins, such as protein D, that offer broader protection against SPn or other pathogens, or using universal and ubiquitous proteins that will induce protective immunity either as stand alone vaccine components used in addition to or in place of protein conjugate vaccines. Although we await the promise of these new vaccine candidates, we will need to continue and expand our diligence in monitoring the pathogens and their antibiotic resistance characteristics that persist and/or emerge in this era of expanding use of protein conjugate vaccines to prevent pneumococcal disease.
Outstanding issues Will the SPn serotypes emerging as prominent OM pathogens in the PnCV-7 vaccine era acquire antibiotic resistance? Will those emerging serotypes cause significant increases in IPD? Will the next generation protein conjugate vaccine using NTHi carrier protein prove to have a sustained impact on OM caused by both SPn and NTHi? What is the optimal vaccine formulation to induce sustained prevention of SPn OM?
References 1 WHO position paper (2003) Wkly. Epidemiol. Rec. 78, 97–120. 2 Barkai, G. et al. (2005) Community prescribing and resistant Streptococcus pneumoniae. Emerg. Infect. Dis. 11, 829–837 3 Hava, D.L. et al. (2003) From nose to lung: the regulation behind Streptococcus pneumoniae virulence factors. Mol. Microbiol. 50, 1103–1110 4 Smit, P. et al. (1977) Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 238, 2613–2616
126
www.drugdiscoverytoday.com
5 Black, S. et al. (2000) Efficacy, safety and immunogenicity of an elevenvalent pneumococcal conjugate vaccine in children. Pediatr. Infect. Dis. J. 19, 187–195 6 Black, S.B. et al. (2002) Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr. Infect. Dis. J. 21, 810–815 7 O’Brien, K.L. et al. (2003) A group-randomized efficacy and safety trial of a seven valent conjugate pneumococcal vaccine against invasive pneumococcal disease among high risk American Indian children. Lancet 362, 355–361 8 Klugman, K.P. et al. (2003) A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N. Engl. J. Med. 349, 1341–1348 9 Madhi, S.A. et al. (2005) The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and uninfected children. Clin. Infect. Dis. 40, 1511–1518 10 Cutts, F.T. et al. (2005) Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomized, double-blind, placebo-controlled trial. Lancet 365, 1113–1114 11 Lucero, M.G. et al. (2004) Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and pneumonia with consolidation on x-ray in children under two years of age. Cochrane Database Syst. Rev. 4, CD004977 12 Obaro, S. and Adegbola, R. (2002) The pneumococcus: carriage, disease and conjugate vaccines. J. Med. Microbiol. 51, 98–104 13 O’Brien, K.L. and Santosham, M. (2004) Potential impact of conjugate pneumococcal vaccines on pediatric pneumococcal diseases. Am. J. Epidemiol. 159, 634–644 14 Whitney, C.G. et al. (2003) Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N. Engl. J. Med. 348, 1737–1746 15 Fireman, B. et al. (2003) Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr. Infect. Dis. J. 22, 10–16 16 Eskola, J. et al. (2001) Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N. Engl. J. Med. 344, 403–409 17 Kilpi, T. et al. (2003) Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal
Vol. 3, No. 2 2006
18
19
20 21
polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin. Infect. Dis. 37, 1155–1164 Prymula, R. et al. (2006) Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomized double-blind efficacy study. Lancet 367, 740–748 Palmu, A.A. et al. (2004) The seven-valent pneumococcal conjugate vaccine reduces typanostomy tube placement in children. Pediatr. Infect. Dis. J. 23, 732–738 Straetemans M et al. (2004) Pneumococcal vaccines for preventing otitis media (Review). Cochrane Database of Syst. Rev. 1, CD001480.pub2 Casey, J.R. and Pichichero, M.E. (1995-2003) Changes in frequency and pathogens causing acute otitis media in. Pediatr. Infect. Dis. J. 23, 824–828
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
22
23
24
25 26
27
Block, S.L. et al. (2004) Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr. Infect. Dis. J. 23, 829–833 McEllistrem, M.C. et al. (2005) Acute otitis media due to penicillinnonsusceptible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine. Clin. Infect. Dis. 40, 1738–1744 Hamel, J. et al. (2004) Prevention of pneumococcal disease in mice immunized with conserved surface-accessible proteins. Infect. Immun. 72, 2659–2670 Austrian R, (2001) Pneumococcal otitis media and pneumococcal vaccines, a historical perspective. Vaccine 19, S71–S77 Whitney, C.G. et al. (2000) Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N. Engl. J. Med. 343, 1917– 1924 Bogaert, D. et al. (2004) Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. The Lancet 363, 1871–1872
www.drugdiscoverytoday.com
127
Vol. 3, No. 2 2006
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Infectious diseases
Vaccines for otitis media and other pediatric pneumococcal diseases Frank J. Malinoski MedImmune, Inc., One MedImmune Way, Gaithersburg, MD 20878, USA
The study of vaccines to prevent disease caused by Streptococcus pneumoniae is a study of the diversity, adaptability and tenacity of this human pathogen. In parts of the world, an effective protein conjugate vac-
Section Editors: Gary Woodnutt – CovX, San Diego, USA Paul-Henri Lambert – Centre of Vaccinology, University of Geneva, Switzerland
cine is now eliminating pneumococcal meningitis and bacteremia in children and, through herd effects, is reducing the burden of invasive disease in older, unvac-
strategies are needed to effectively induce a sustained reduction of SPn OM.
cinated populations. Use of conjugate vaccines also has impacted otitis media, but this protection is limited and replacement disease has emerged as a concern.
Introduction Streptococcus pneumoniae (SPn; see Glossary) is the leading cause of respiratory tract related death, bacterial meningitis and bacteremia globally among children [1]. SPn is also the leading cause of bacterial otitis media (OM), one of the most common diseases of childhood with enormous direct and indirect annual healthcare costs. The burden of SPn OM is aggravated by the organism’s ability to rapidly acquire antibiotic resistance genes under selective pressure from the community use of antibiotics [2]. The 7-valent pneumococcal protein CONJUGATE VACCINE (see Glossary) Prevenar (PnCV-7, Wyeth) has amassed impressive results against INVASIVE PNEUMOCOCCAL DISEASE (IPD; see Glossary) and pneumonia in children. However, protein conjugate vaccines have had only marginal impact on OM because nonvaccine serotypes and other pathogens replace vaccine serotypes in nasopharyngeal carriage and mucosal disease in both prelicensure and postlicensure experience. New E-mail address: F.J. Malinoski ([email protected]) 1740-6773/$ ß 2006 Published by Elsevier Ltd.
DOI: 10.1016/j.ddstr.2006.06.004
Pneumococcal vaccines and their efficacy against invasive diseases The pneumococcus is, in part, classified and defined by the polysaccharide capsule surrounding the organism. This capsule is a virulence factor and offers protection from opsonophagocytic killing by the human immune system [3]. Based on the dominance of the capsule in immunologic response to infection and the ability of passively administered anticapsular antibody to protect against disease, two types of vaccines have emerged thus far to prevent pneumococcal disease. First, polysaccharide vaccines that contain capsular polysaccharide from the 23 dominant serotypes are licensed for use in adults. Licensure was based primarily on efficacy studies in adult mine workers in South Africa where 6- and 12valent vaccines were up to 92% effective against pneumonia [4]. Because these vaccines rely on primarily T-cell independent antibody responses, their effectiveness over time is limited and they are largely ineffective in children. The second class of vaccines is based on covalently linking the capsular saccharides to proteins to induce a T-cell dependent immune response characterized by immunologic memory; a response necessary to protect infants and children. In controlled clinical trials a 7-valent conjugate vaccine based on diphtheria toxoid carrier protein CRM197 (PnCV-7; containing protein conjugates of serotypes 4, 6B, 9V, 14, 18C, 19F 121
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Vol. 3, No. 2 2006
Glossary Conjugate vaccine: vaccine in which saccharide capsular component of selected serotypes of pneumococcus are covalently linked to a carrier protein. Conjugate vaccines are processed by the immune system to generate both antibody and cellular memory responses that are protective in infants and children. Invasive pneumococcal disease: meningitis, bacteremia, pneumonia with bacteremia, infection of other normally sterile sites (e.g. joint, pericardium). Noninvasive or mucosal pneumococcal disease: otitis media, sinusitis, pneumonia without bacteremia. Streptococcus pneumoniae (SPn): Gram-positive encapsulated bacterium with over 90 distinct capsular types identified by serologic Quelung assay. SPn has evolved various mechanisms of resistance to multiple antibiotics.
immune responses of the populations, or differences in the number of doses or the schedule of those doses administered in these different populations. Strikingly consistent across these studies is an overall significant impact on pneumonia of 20% or greater. When these data were pooled to evaluate recommendations for immunization with conjugate vaccines against IPD in A Cochrane Database Review, the analysis of the available literature related to the 7- and 9-valent CRM197 protein conjugate vaccines confirmed a pooled vaccine efficacy against vaccine serotype IPD of 88%, a pooled efficacy against all SPn IPD of 66% and a pooled efficacy against x-ray confirmed pneumonia of 22% [11].
Vaccine effects on nasopharyngeal carriage and 23F) has shown high efficacy against the invasive SPn diseases; bacteremia, meningitis and bacteremic pneumonia [5–7]. Studies have also shown that a 9-valent CRM197 conjugate vaccine (PnCV-7 serotypes plus types 1 and 5) was efficacious against IPD and pneumonia in both HIV negative and HIV positive children in South Africa and had an overall impact on child survival in The Gambia [8–10] (Table 1). The highest efficacy results for PnCV-7 (97% against vaccine serotype IPD and 90% against all SPn IPD) were seen in the US Kaiser study in healthy infants at moderate risk of IPD and given four doses of vaccine (2, 4, 6 month primary series and a fourth dose at12–15 months). In populations at higher risk of IPD (Native American, Gambian and South African (including an HIV infected cohort) children) the efficacy was still dramatic, ranging from 65% in HIV positive children in South Africa to 86% in Native American children. Importantly, in both of the studies in Africa children received only a three dose series according to the current WHO Expanded Program of Immunization (EPI) schedule of 6, 10 and 14 weeks of age. It is quite possible that the variations in the results are either due to differences in the ecology of SPn, differences in the
As an exclusive human pathogen with no known animal reservoir, it is indeed possible to eradicate pneumococcal disease. However, it is important to understand that, unlike many pathogens, invasive disease caused by SPn is a relatively rare event compared to the frequency with which this organism is found asymptomatically residing in (colonizing) the human nasopharynx. Indeed, in one study, 95% of a US cohort of children was colonized at least once through their first 24 months of life. Similarly, the prevalence of nasopharyngeal (NP) carriage has been reported to approach 95% in children during the first 3 years of life in developing countries, with 40% in adults in those countries also colonized, and up to four serotypes isolated over several months time [12]. Thus, vaccines intended to eliminate SPn disease will need to eliminate nasopharyngeal colonization by the organism. Polysaccharide vaccines have failed to impact the nasopharyngeal carriage of SPn. By contrast, protein conjugate vaccines have reproducibly reduced carriage of vaccine serotypes [13]. In addition, there is significant epidemiologic evidence that the reduction in carriage has resulted in clinical benefit. Specifically, the use of the PnCV-7 conjugate vaccine
Table 1. Efficacy of protein conjugate vaccines against IPD Protein conjugate vaccine
Vaccine efficacy in Population
Other IPD Overall
7-valent CRM197 (4-dose)
US healthy N = 37,868 [5,6]
7-valent CRM197 (4 dose)
US healthy N = 8091 [7]
9-valent CRM197 (3-dose, EPIc)
RSA HIV N = 37,259 [8,9]
9-valent CRM197 (3 dose, EPIc)
Serotype
Overall a
Serotype
94
20
90a (bacteremic)
54
86a
n.r.b
n.r.b
42
83a
17a 38 (bacteremic)
a
a
89
a
53
65
15 45 (bacteremic)
59a (bacteremic)
Gambia healthy N = 17,437 [10]
50a
77a
37a
n.r.b
Statistically significant. n.r., not reported. c EPI, Expanded Program of Immunization (6, 10, 14 weeks). b
www.drugdiscoverytoday.com
a
a
67 (bacteremic)
RSA HIV+ N = 2577 [8,9]
a
122
a
Pneumonia
16% efficacy against mortality
Vol. 3, No. 2 2006
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
An 11-valent protein D conjugate vaccine (11pn-PD) from GSK Biologicals is distinct from the two 7-valent vaccines in that it contains four additional SPn serotype conjugates (types 1, 3, 5 and 7F) and uses a highly conserved surface lipoprotein, protein D, as the carrier protein [18]. Protein D is derived from NTHi, another common bacterial pathogen responsible for OM. This vaccine was associated with a significant reduction in pneumococcal vaccine serotype OM (53%) with no significant change in disease caused by SPn nonvaccine serotypes (9% vs. 27 to 33% efficacy for the 7valent vaccines) and had significant activity against NTHi OM (35% vs. 9 to 11% efficacy for the 7-valent vaccines). In addition, the overall impact on any OM was significant at 34% versus the nonsignificant impact of 6 and 1% with the 7-valent vaccines. The FinOM trial that tested the efficacy of the 7-valent formulations was not powered to establish an impact on overall OM disease. However, the Kaiser IPD efficacy trial conducted with PnCV-7 enrolled over 37,000 subjects and therefore had more power to evaluate the impact of PnCV-7 on OM related endpoints [15]. Four major conclusions were possible from that study. First, there was a statistically significant, although small (7%), reduction in overall OM. Second, the vaccine had a greater impact on frequent visits for OM than on first visits and that protection increased with the frequency of OM visits. Although first visits were reduced by 5%, the risk of three or more visits was reduced by 10% and the risk of ten or more visits was reduced by 26%. Third, associated with the reduction in frequent visits was an overall 24% reduction in tympanostomy tube (TT) placement. Lastly, PnCV-7 use was associated with over a 5% reduction in antibiotic prescriptions, beginning as early as dose 1 in the immunization series. Consistent with the reductions in TT
in the US has been associated with significant reductions of vaccine serotype IPD in populations that were not immunized. Within the first 2 years of PnCV-7 use in US children there was over a 30% reduction in vaccine serotype IPD in what can be considered the parent generation (20 to 39 years of age) and an 18% reduction in what could be considered the grandparent generation (those over 65 years of age) of vaccine recipients [14]. These effects were accompanied by a 35% reduction in penicillin-nonsusceptible strains. Because of these and other findings, there are expectations that the use of this and other protein conjugate vaccines will induce a significant and sustained protection from NONINVASIVE (see Glossary), mucosal SPn diseases such as otitis media.
Pneumococcal vaccine efficacy against otitis media Prelicensure evidence
Three different protein conjugate vaccines have been evaluated for their impact on SPn OM in four randomized, controlled trials ([15–18]; Table 2). Although these studies vary significantly in their design and conduct, there are remarkable similarities in the performance of these vaccine candidates. Where measured, all three vaccines significantly reduced SPn OM caused by vaccine serotypes by at least 50% and any SPn OM by 25–50%. Notably, in comparing the performance of the CRM and OMP conjugate vaccines in the FinOM trial where the same control group was used by both vaccines, the degree of replacement disease (noted by negative efficacy) was strikingly similar with both nonvaccine serotypes (33 and 27%) and nontypeable Haemophilus influenzae (NTHi) (11 and 9%). Although not statistically different, the CRM conjugate vaccine had a higher point estimate for reduction in any OM, 6%, versus a 1% point estimate with the OMP vaccine.
Table 2. Randomized controlled trials of pneumococcal vaccine otitis media efficacy Protein conjugate vaccine
Population
Vaccine efficacy (%)a
Other effects
SPn VT
SPn NVT
Any SPn
H.flu (n.t.)
Any OM
7-valent CRM197 (4-dose)
N = 37,868 US [15]
n.r.
n.r.
62b,c
n.r.d
7
24%b # placement tympanostomy tube (TT) 5% # antibiotic prescriptions
7-valent CRM197 (4-dose)
N = 1662 Finland [16,19]
57b
33
34b
11
6
4% # placement TT (2–24 month-old) 39% b # placement TT (after 24-month-old)
7-valent OMP (4-dose or 3-dose plus PS boost)
N = 1666 Finland [17]
56b
27
25b
9
1
11-valent NTHi Protein D (4-dose)
N = 4968 Czech Republic [18]
53b
9
52b
35b
34b
a
VT, vaccine serotypes; NVT, nonvaccine serotypes, H.flu (n.t.), nontypeable Haemophilus influenzae. Statistically significant. c Based on isolates from spontaneous ruptured eardrums; PS: 23-valent polysaccharide vaccine. d n.r., not reported. b
www.drugdiscoverytoday.com
123
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Vol. 3, No. 2 2006
Table 3. Changes in OM ecology after introduction of PnCV-7 vaccine Study site
Rochester [21]
Rural Kentucky [22]
Multicenter hospitals [23]
Population: source of isolates tested
Children with persistent acute OM followed from 1995 to 2003
Sample of patients (7 to 24-month-old) with acute OM culture (94% vaccine coverage in post period)
Sample of five hospital isolates from acute OM from 1999 to 2002
Percent of isolates
Percent of isolates
Percent of isolatesa
No vaccine
3–4 doses
Pre
Post
1dose
2–4 doses
N
204
152
336
83
435
63
Time periods
’98–00
’00–03
’92–99
’00–03
’99–02
’99–02
VT + VRTb
n.r.c
n.r.
n.r.
78
68
#10%d
70
41
#29%d
NVTb
n.r.
n.r.
n.r.
22
32
"10%
Change
Change
Change
SPn
All
44 b
NTHi
b
M. cat
31
d
#13%
d
48
31
18
35
"17%d
d
n.r.
n.r.
n.r.
d
#17%
43
57
"14%
41
56
"15%
n.r.
n.r.
n.r.
5
1
" 4%
9
11
"2%
n.r.
n.r.
n.r.
a
Defined by direct history of vaccination with PnCV-7 as noted. b VT, vaccine serotypes; NVT, nonvaccine serotypes; NTHi, nontypeable Haemophilus influenzae; M. cat, Moraxella catarrhalis. c n.r., not reported. d Statistically significant.
placement seen in the Kaiser study, an open-label follow-up study of the FinOM recipients of the PnCV-7 vaccine showed that although TT placements were not reduced during the blinded study (between 2 and 24 months of age), TT placement after the study (i.e. after subjects were 24-months-old) was reduced 39% in the vaccine group compared to controls [19]. Taken together, these results suggest that protein conjugate vaccines might have a significant and measurable impact on SPn OM. Given the high prevalence and significant cost burden of OM there are significant benefits to be gained. However, expectations need to be managed because the only product to reach licensure, PnCV-7, has shown only a 6% reduction in overall OM and the best prelicensure candidate might only reduce the burden of OM by one-third. This caution is underscored by the fact that a recent Cochrane review concludes that the pooled results of four protein conjugate vaccine trials showed a significant but only a small effect on prevention of acute OM with a rate ratio of 0.921 and, therefore, that conjugate vaccines cannot yet be recommended specifically for prevention of acute or recurrent OM in children [20]. Postlicensure experience with PnCV-7 vaccine
Widespread use of PnCV-7 vaccine in the US began in 2000 after licensure. Measuring the impact of the vaccine postlicensure is challenging because of the need to compare data on changes in OM disease patterns to historic controls rather than prospectively with matched cohorts trials and the fact that historic data are not necessarily robust. Nevertheless, three published trials provide important information regarding changes in the microbiology of acute OM following introduction of the PnCV-7 vaccine ([21–23]; Table 3). In 124
www.drugdiscoverytoday.com
spite of the variety of methods and sources in these studies, the consistent observation was an overall reduction in the frequency of OM isolates caused by any SPn of 13–17% following the introduction of PnCV-7 vaccine. As expected, there were significant reductions in vaccine and vaccine related serotypes isolated from children with or without recurrent OM; ranging from 10 to 29%. Counterbalancing this was an increase in nonvaccine serotypes (10–17%) and other pathogens, notably significant increases in the isolation of NTHi (approximately 15%). In the multicenter study where serotyping was conducted, it is interesting to note that the prominent nonvaccine serotype was type 3 whereas the prominent vaccine and vaccine related serotypes isolated (i.e. breakthrough cases) belonged to serogroup 19. By contrast, the nonvaccine serotypes isolated in the rural Kentucky study were 1, 11A, 15A, 29 and 33F. It is not clear how these trends will play out. When the data from McEllistrem is reviewed by year there appears to be a flattening of the increase in the percentage of nonvaccine SPn at the end of their study (Fig. 1). Whether this trend will continue remains to be seen. Also unclear is whether initial reductions in the total burden of penicillin-nonsusceptible isolates will remain low, stable or increase. Lastly, as vaccine developers consider increasing the numbers of serotypes covered in future protein conjugate vaccines to address these emerging nonvaccine serotypes, there is no clear indication at this time which serotypes ought to be included. Future alternative vaccine strategies
A broad range of SPn vaccine candidates are being considered as next generation products for the prevention of SPn IPD and
Vol. 3, No. 2 2006
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Figure 1. Change in SPn serotype distribution in OM Isolates associated with the introduction of PnCV-7 vaccine (adapted from 23). Reduction in the proportion of vaccine serotypes (VT) and vaccine related serotypes (VRT) compared to the increase in nonvaccine serotypes (NVT) following the introduction of PnCV-7 vaccine.
otitis media. These targets include both intracellular and surface SPn proteins. Candidates currently in animal model testing include cell wall components such as lipoteichoic acid, surface binding proteins such as PspA and PsaA, choline binding proteins, hyaluronidase, neuraminidase and IgA1protease. One conserved surface protein, BVH [24], has been developed as a chimeric molecule called BGCvax, has completed Phase I clinical testing, and is now undergoing additional clinical evaluations that are likely to include the vaccine’s impact on colonization and otitis media.
Conclusions The role of pneumococcus in human disease, including otitis media, is not new [25]. The problem came to center stage, however, with the rapid and widespread emergence of antibiotic resistance in pneumococcal isolates at the end of the past century [26]. The introduction of the 7-valent pneumococcal conjugate vaccine Prevenar is a significant advance. However, it is clear that this vaccine is not the vaccine that will eliminate pneumococcal disease. Significant challenges with the PnCV-7 vaccine exist not only in vaccine accessibility and affordability, but also in vaccine serotype coverage
which is inadequate for many parts of the world. An additional gap lies in the limited impact of PnCV-7 against OM and the accumulating data that nonvaccine serotypes and other pathogens are replacing the vaccine types as ‘reemerging’ and ‘emerging’ causes of OM. Although pathogens like NTHi and Moraxella are already common OM pathogens, there is also a report of increased colonization with Staphylococcus aureus in healthy children following the use of PnCV7 vaccine that raises concerns that this pathogen, already noted for its ability to acquire substantial resistance to antibiotics, will emerge as a greater clinical threat [27]. Clearly, the elimination of pneumococcal disease has to consider the complex role of colonization, aerosol spread and local and systemic invasion mechanisms used by this organism in causing a broad spectrum of disease (Fig. 2). Several strategies are possible to improve on the current PnCV-7 vaccine. Such approaches include expanding the number of serotypes included in future protein conjugate vaccine formulations, adapting a way to rotate different vaccine serotype formulations in use (e.g. use the current 7-valent formulation for ‘x’ years and then switch to a new 7-valent formulation for another set number of year), using www.drugdiscoverytoday.com
125
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
Vol. 3, No. 2 2006
Figure 2. Role of NP carriage in SPn IPD and potential impact of protein conjugate vaccines (adapted from 12). Exposure to SPn in the environment through airborne droplets results in multiple potential outcomes (solid lines) which can be influenced by adequate immune responses to PnCV-7 vaccine (dotted lines).
carrier proteins, such as protein D, that offer broader protection against SPn or other pathogens, or using universal and ubiquitous proteins that will induce protective immunity either as stand alone vaccine components used in addition to or in place of protein conjugate vaccines. Although we await the promise of these new vaccine candidates, we will need to continue and expand our diligence in monitoring the pathogens and their antibiotic resistance characteristics that persist and/or emerge in this era of expanding use of protein conjugate vaccines to prevent pneumococcal disease.
Outstanding issues Will the SPn serotypes emerging as prominent OM pathogens in the PnCV-7 vaccine era acquire antibiotic resistance? Will those emerging serotypes cause significant increases in IPD? Will the next generation protein conjugate vaccine using NTHi carrier protein prove to have a sustained impact on OM caused by both SPn and NTHi? What is the optimal vaccine formulation to induce sustained prevention of SPn OM?
References 1 WHO position paper (2003) Wkly. Epidemiol. Rec. 78, 97–120. 2 Barkai, G. et al. (2005) Community prescribing and resistant Streptococcus pneumoniae. Emerg. Infect. Dis. 11, 829–837 3 Hava, D.L. et al. (2003) From nose to lung: the regulation behind Streptococcus pneumoniae virulence factors. Mol. Microbiol. 50, 1103–1110 4 Smit, P. et al. (1977) Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 238, 2613–2616
126
www.drugdiscoverytoday.com
5 Black, S. et al. (2000) Efficacy, safety and immunogenicity of an elevenvalent pneumococcal conjugate vaccine in children. Pediatr. Infect. Dis. J. 19, 187–195 6 Black, S.B. et al. (2002) Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr. Infect. Dis. J. 21, 810–815 7 O’Brien, K.L. et al. (2003) A group-randomized efficacy and safety trial of a seven valent conjugate pneumococcal vaccine against invasive pneumococcal disease among high risk American Indian children. Lancet 362, 355–361 8 Klugman, K.P. et al. (2003) A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N. Engl. J. Med. 349, 1341–1348 9 Madhi, S.A. et al. (2005) The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and uninfected children. Clin. Infect. Dis. 40, 1511–1518 10 Cutts, F.T. et al. (2005) Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomized, double-blind, placebo-controlled trial. Lancet 365, 1113–1114 11 Lucero, M.G. et al. (2004) Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and pneumonia with consolidation on x-ray in children under two years of age. Cochrane Database Syst. Rev. 4, CD004977 12 Obaro, S. and Adegbola, R. (2002) The pneumococcus: carriage, disease and conjugate vaccines. J. Med. Microbiol. 51, 98–104 13 O’Brien, K.L. and Santosham, M. (2004) Potential impact of conjugate pneumococcal vaccines on pediatric pneumococcal diseases. Am. J. Epidemiol. 159, 634–644 14 Whitney, C.G. et al. (2003) Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N. Engl. J. Med. 348, 1737–1746 15 Fireman, B. et al. (2003) Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr. Infect. Dis. J. 22, 10–16 16 Eskola, J. et al. (2001) Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N. Engl. J. Med. 344, 403–409 17 Kilpi, T. et al. (2003) Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal
Vol. 3, No. 2 2006
18
19
20 21
polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin. Infect. Dis. 37, 1155–1164 Prymula, R. et al. (2006) Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomized double-blind efficacy study. Lancet 367, 740–748 Palmu, A.A. et al. (2004) The seven-valent pneumococcal conjugate vaccine reduces typanostomy tube placement in children. Pediatr. Infect. Dis. J. 23, 732–738 Straetemans M et al. (2004) Pneumococcal vaccines for preventing otitis media (Review). Cochrane Database of Syst. Rev. 1, CD001480.pub2 Casey, J.R. and Pichichero, M.E. (1995-2003) Changes in frequency and pathogens causing acute otitis media in. Pediatr. Infect. Dis. J. 23, 824–828
Drug Discovery Today: Therapeutic Strategies | Infectious diseases
22
23
24
25 26
27
Block, S.L. et al. (2004) Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr. Infect. Dis. J. 23, 829–833 McEllistrem, M.C. et al. (2005) Acute otitis media due to penicillinnonsusceptible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine. Clin. Infect. Dis. 40, 1738–1744 Hamel, J. et al. (2004) Prevention of pneumococcal disease in mice immunized with conserved surface-accessible proteins. Infect. Immun. 72, 2659–2670 Austrian R, (2001) Pneumococcal otitis media and pneumococcal vaccines, a historical perspective. Vaccine 19, S71–S77 Whitney, C.G. et al. (2000) Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N. Engl. J. Med. 343, 1917– 1924 Bogaert, D. et al. (2004) Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. The Lancet 363, 1871–1872
www.drugdiscoverytoday.com
127