ABSTRACT
Introduction
Despite the introduction of effective pneumococcal conjugate vaccines (PCV), Streptococcus pneumoniae remains a major cause of acute otitis media (AOM) worldwide. New, higher valency vaccines that offer broader serotype coverage have been recently developed and others are in development. However, given the capsular serotypes expressed by pneumococci causing AOM, it is unclear to what extent differing or higher valency PCVs will provide additional protection.
Areas Covered
We conducted a systematic literature search of the MEDLINE database to identify articles published from January 2016 to September 2021 in 4 low and middle income and 10 high-income countries. We searched PubMed with terms: (Streptococcus pneumoniae) OR pneumococcal AND serotype AND (conjugate vaccine). We evaluated serotype distribution and the actual or projected coverage of pneumococcal serotypes by PCV10 (GlaxoSmithKline), PCV13 (Pfizer), PCV10SII (Serum Institute of India) PCV15 (Merck) and PCV20 (Pfizer).
Expert Opinion
Our review highlights the important epidemiological differences in serotype distribution and coverage by existing and higher valency vaccines to protect against AOM in children. These data provide support for further evaluation of serotype-independent vaccines for optimal control of pneumococcal AOM disease worldwide.
1. Introduction
According to the American Academy of Pediatrics, over 5 million acute otitis media (AOM) cases occur in United States children annually, resulting in >10 million antibiotic prescriptions [Citation1]. About 30 million visits to medical care providers occur due to AOM, resulting in direct and indirect health care costs of about $4-6 billion annually (using cost estimates that are more than a decade old) [Citation2–4]. In the US, in studies conducted after widespread utilization of a 13-valent pneumococcal conjugate vaccine (PCV13), Streptococcus pneumoniae (pneumococcus) has been shown to cause about 25% of AOM [Citation5,Citation6]. In countries without a successful national immunization program (NIP) that includes PCVs, pneumococci cause 30–60% of AOM, as was the situation in the USA before PCV introduction [Citation7]. Thus, pneumococcal AOM is a major cause of childhood morbidity, healthcare costs, and is a highly relevant contributor to estimates of PCV cost-effectiveness analyses.
Nasopharyngeal (NP) colonization is a necessary pathogenic step in progression to pneumococcal disease [Citation8]. However, not all strains of pneumococci expressing different capsular serotypes are equally virulent and are likely to cause disease [Citation6,Citation9]. In PCV-vaccinated populations, non-vaccine serotypes (NVTs) that colonize the NP as commensals tend to acquire virulence determinants and antibiotic resistance and emerge as new strains causing pneumococcal disease [Citation9,Citation10]. Vaccine pressure and antibiotic resistance drive PCV serotype replacement with NVTs, reducing the net effectiveness of deployed PCV vaccines [Citation11]. Therefore, knowledge of prevalent NVTs colonizing the NP in a country identifies pneumococcal serotypes most likely to emerge as pathogenic.
A PCV10 produced by the Serum Institute of India (PCV10SII) was licensed in 2021, anticipating deployment in NIPs in low/middle income countries (LMICs) in the coming years, especially in South Asia and Southeast Asia. PCV15 (PCV13 + 22 F and 33 F) manufactured by Merck and PCV20 (PCV15 + 8, 10A, 11A, 12 F, and 15B) manufactured by Pfizer were licensed in Europe and the USA for use in adults in 2021. Licensure for use in children for PCV15 occurred in 2022 and is anticipated for PCV20 in 2023. There is geographic variation in prevalent serotypes of pneumococcal strains that cause disease in adults that differ from those in children. There is divergence of serotypes that cause less common but potentially fatal invasive pneumococcal disease (IPD) -versus more common and costly mucosal infections (non-bacteremic community-acquired pneumonia and AOM). These differences will complicate choices about PCVs for NIPs.
The near-term impact of the new PCVs on AOM might be predicted based on prevalent serotypes causing those specific infections in specific countries. However, there are limited data from middle ear fluid (MEF) cultures to base such analyses. Tympanocentesis is the gold standard for securing MEF for culture but very few publications have such data. As an alternative, some papers report results of drainage following spontaneous perforation of the tympanic membrane (SPTM). Some investigators rely on nasopharyngeal (NP) cultures at time of clinical diagnosis of AOM to define serotypes causing AOM, recognizing that clinical diagnosis may be inaccurate and that there is high discordance between NP and MEF cultures [Citation12].
This review describes the serotype distribution of strains causing AOM and/or colonizing the NP at the time of AOM, and serotypes in the NP at ‘health,’ i.e. at clinical contacts with no suspected AOM. Selected publications from 4 LMICs and 10 high-income countries are included. Differences by region and country in relation to the PCVs introduced in NIPs or available through more limited distribution are described. The potential impact of expansion of included serotypes in PCV15 and PCV20 and introduction of PCV10SII to reduce AOM and NP colonization based on prevalent serotypes – in comparison with the serotypes targeted by the vaccines – are described. Thus, based on prevalent serotypes colonizing the NP in the regions and countries included in this review, serotypes that might be effectively included in near-future PCVs are identified, recognizing that prevalence and invasiveness of strains expressing NVTs has proven challenging to predict into the future.
2. Methods
2.1. Search strategy and data sources
A systematic literature search of MEDLINE database was conducted to identify articles related to AOM and NP colonization published from January 2016 to September 2021 in the following regions and countries: South Asia: India and Bangladesh; Southeast Asia: Indonesia and Thailand; Europe: Belgium, Germany, Finland, France, Switzerland, Italy, Spain, Iceland and Sweden; Israel; and USA. We searched PubMed for articles with the following Title/Abstract terms: (Streptococcus pneumoniae) OR pneumococcal AND serotype AND (conjugate vaccine). All articles were screened in a 2-step process, (1) title/abstract and (2) full-text review. Only articles from the pre-specified countries that included serotype-specific information relating to AOM or NP colonization in children were included. Articles written in non-English languages and related to IPD were excluded. Relevant data were extracted from the included articles: 1. Region/ country; 2. Subject age; 3. Years involved in data collection; 4. Health status (AOM disease or healthy) 5. Type of sample collection (NP or spontaneous perforation of tympanic membrane (SPTM) or tympanocentesis-obtained middle ear fluid); 6. Number of subjects in the study cohort; 7. Number of pneumococcal isolates serotyped; 8. Method of serotyping (Quellung or polymerase-chain reaction); 9. Dominant serotypes; 10. Anticipated coverage of serotyped pneumococcal isolates by PCV10 manufactured by GlaxoSmithKline (PCV10GSK) and PCV13 manufactured by Pfizer and by newer PCVs: PCV10 manufactured by the Serum Institute of India (PCV10SII), PCV15 manufactured by Merck and PVC20 manufactured by Pfizer.
2.2. Data quality
The quality of surveillance data available varied. If data were sufficient to enable analysis for pre-specified regions/countries, age group, and the serotypes causing AOM cases, of NP colonization isolates used as a surrogate for identification of AOM-causing strains when MEF culture results were not available, or NP colonization at times of health, then the report was included.
2.3 National immunization programs
Some PCVs were introduced as part of NIPs, resulting in rapid uptake and widespread use. However, PCVs were introduced in some countries without inclusion in NIPs, resulting in slower and incomplete uptake. Those data are included in this review, and we tabulated the data in a manner to reflect that variable.
3. Results
includes articles reporting AOM pneumococcal etiology and serotypes – including pneumococci collected by NP culture at an AOM clinical diagnosis, spontaneous perforation of the tympanic membrane (SPTM, ear discharge) and culture by tympanocentesis (middle ear fluid, MEF) as specified. Relevant PCV usage for each country is summarized in the table sub-headings. General comments are as follows:
Table 1. AOM – determined by culture of MEF by tympanocentesis or spontaneous ear discharge or nasopharyngeal (NP) culture at the time of diagnosis of AOM.
3.1. Southeast and South Asia
Wahyono et al. [Citation13] used NP samples at the time of diagnosis of AOM to determine the distribution of S. pneumoniae serotypes in school children in Central Java, Indonesia from 2018 to 2019, prior to introduction of PCV. 4.6% of school children were diagnosed with AOM. The carriage rate was 73%, with serotypes 23A (11%) and 6A/B (10%) being the most dominant. Based on the serotypes, 22% would be contained in PCV10GSK, 27% in PCV10SII, 38% in PCV13, 39% in PCV15 and 46% in PCV20.
In the Vellore district of Tamil Nadu of Southern India, NP swabs were obtained from children ≤6 years of age diagnosed with AOM at a Pediatric ENT outpatient hospital [Citation14]. S. pneumoniae was the dominant otopathogen (54%) followed by non-typeable H. influenzae (32%). Although 54% of these children had received a PCV, the vaccination records showed that only 43% received PCV13. The major serotypes were 11A (15%), 19 F (15%), and 15B/C (11%). PCV coverage of the serotypes would be 37% from PCV10GSK, 41% from PCV10SII, 44% from PCV13 and PCV15, and 72% from PCV20.
Naziat et al. [Citation15] conducted a study of pathogens isolated from ear swabs from children <18 years of age with otorrhea, from April 2014 to March 2015 at the Dhaka Shishu Hospital in Bangladesh. PCV10gsk was introduced in Bangladesh in March 2015. Among 891 children, S. pneumoniae was detected in 164 (18%). The dominant serotypes were 19A (16%) and 19 F (14%). Based on the serotypes detected, PCV10GSK coverage would be 46%, for PCV10SII that contains 19A coverage would be 62%, PCV13 would be 73% and PCV20 would be 82%.
3.1.1. Middle East (Israel)
Ben-Shimol et al. [Citation16] performed a surveillance study of NP S. pneumoniae isolates from children <24 months of age in Southern Israel from early PCV10/PCV13 (2009–2011) and late PCV13 (2015–2017) immunization periods. The proportions of PCV13 serotypes among all pneumococcal isolates decreased when comparing the late PCV13 period to the early PCV10/PCV13 period, while non-PCV13 serotypes increased. The authors analyzed the serotype isolates that are unique to PCV20 that are not in PCV13 (VT20-13), and those not in PCV20 (NVT20). In the late PCV13 period, the ratio of prevalence of pneumococcal VT20-13:NVT20 isolates was 0.37 for healthy and 0.60 for AOM cultures. The top four serotyping results were: NT (12%), 15B/C (11%), 16 F (5%) and 23B (5%) in a healthy group, and 15B/C (16%), 16 F (8%), 35B (8%) and 11A (7%) in an AOM group. PCV13 coverage was 10% in the healthy group and 14% in the AOM group.
3.1.2. Europe
3.1.2.1. France
Children 3 months-15 years old with AOM were prospectively enrolled throughout France from October 2015 to January 2018 (5 to 8 years after PCV13 implementation), and MEF was obtained by sampling SPTM [Citation17]. S. pneumoniae was isolated in 61 of 470 samples, of which 56 serotypes were reported. Coverage of serotypes contained in PCVs was or would be 11% in PCV10gsk, 32% in PCV13, 38% in PCV15, and 57% in PCV20. Serotype 3 (contained in PCV13) was the most dominant serotype detected (16%). Non-PCV13 serotypes most frequently isolated were 23B (11%), 11A (9%) and 15B/C (7%).
3.1.2.2. Germany
Imohl et al. [Citation18] analyzed NP swabs and drainage from SPTM occurring in children 2 months to 5 years of age in Germany from 2008 to 2015. After PCV10gsk was introduced in 2009, carriage of pneumococci decreased from 57% in 2009–2010 to 46% in 2013–2014 and then increased to 54% in 2014–2015. The percentage of children with pneumococci in MEF dropped to its lowest in 2010–2011 (6%) and then slightly increased to 7% in the final year of study. Combining the last 2 years of their data (2013–2015), carriage serotype PCV coverage was or would be 4% by PCV10, 25% by PCV13, 30% by PCV15, and 49% by PCV20; while MEF serotype PCV coverage was/would be 7% by PCV10, 50% by PCV13, 53% by PCV15, and 67% by PCV20. Serotype 3 was the most dominant serotype in MEF (43%) and carriage (16%).
3.1.2.3. Belgium
In 2011, Belgium implemented PCV13 into their NIP but then switched to PCV10 in 2016. Ekinci et al. [Citation19] investigated the pneumococcal serotypes carried by children with AOM in Belgium from 2016 to 2018. Pneumococcal carriage was 79% in children with AOM). The PCV13-specific serotype 19A increased after implementation of PCV10GSK. The dominant serotypes were 23B (12%) and 11A (8%), 15B (8%) for AOM children. Non-PCV13 vaccine serotypes accounted for 85% of AOM isolates. Overall, serotype coverage for AOM children was/would be 3% from PCV10gsk, 10% from PCV13, 14% from PCV15, and 37% from PCV20.
3.1.2.4. Italy
Marchisio et al. [Citation20] studied the MEF from children with SPTM in the Milan area of Italy from April 2015 to March 2016. In this study, ≥90% of the children had received PCV13 in their first year of life. S. pneumoniae was identified in the MEF of 27% of the 177 children enrolled [Citation20]. A real-time PCR technique was used for detection in the study that might have detected S. pneumoniae more frequently than traditional culture methods. Of the 52 types determined, PCV13 types accounted for 27% of all serotypes. The major serotypes were 3 and 15A/F (10% each) and 19 F, 24A/B/F, 11A/D (8% each). Approximately 5 years after the introduction of PCV13 in greater Milan, 73% of the SPTM serotypes were not covered in PCV13.
3.1.2.5. Spain
A study of the effect of PCV13 on children diagnosed with AOM with SPTM was conducted in two northern regions of Spain, Gipuzkoa and Barcelona between 2008 and 2016 [Citation21]. A decrease in the rate of S. pneumoniae AOM was observed in both regions from the 2008–2010 (pre-PCV13) compared to 2011–2013 (early PCV13) period, mainly due to fewer infections caused by PCV13 serotypes, and then leveled off between the early PCV13 period and 2014–2016 (late post-PCV13). The serotype data from ear drainage swabs during the late post-PCV13 period, where all of the children have been vaccinated, showed the overall PCV13 coverage was 30%, with 11A as the most dominant serotype (30%).
3.1.2.6. Iceland
Quirk et al. [Citation22] investigated the impact of PCV10gsk on the S. pneumoniae serotypes isolated from carriage of healthy children and the middle ear from children with AOM in Reykjavik, Iceland from 2009 to 2017. NP swabs were taken from children attending day-care centers, and none were <1 year of age. Middle ear samples were taken from 67 children <7 years of age with otitis media that had SPTM. PCV10gsk was introduced in the NIP in 2011, with there not having been any previous PCV included. We took data from the last 2 years of their study (2016–2017), which is 5 years post-PCV10, to report here. Non-PCV10GSK vaccine types increased in middle ear samples from 28% pre-vaccination era (2009–2010) to 97% post-PCV10 era (2016–2017). The major serotypes were 6C (18%), 15B/C (13%), and 23A (10%) in middle ear samples. PCV serotype coverage in the post-vaccination era was/would be 3% from PCV10gsk, 8% from PCV13, 9% from PCV15, and 20% from PCV20 for children with otitis media.
3.1.2.7. Switzerland
Allemann et al. [Citation23] investigated the changes in pneumococcal carriage and distribution of serotypes in subjects with AOM before and after PCV in Switzerland. Nasopharyngeal and middle ear samples from SPTM were collected mostly from children ≤15 years of age from 2004 to 2015. PCV7 was introduced in 2007 and PCV13 in 2011. Pneumococcal carriage in AOM subjects decreased from 49% during the PCV7 era (2007–2010) to 36% in the PCV13 era (2011–2015). Likewise, pneumococcal isolates from the MEF decreased from 32% during the PCV7 era to 17% in the PCV13 era. Non-PCV13 vaccine types in carriage increased from 36% in the PCV7 era to 58% in the PCV13 era. Non-PCV13 vaccine types in middle ear samples also showed a slight increase from 21% in the PCV7 era to 26% in the PCV13 era. The dominant carriage serotypes were 3 (16%), 19A (12%), 23 (10%), 11A (10%), and 15 (8%). From MEF samples, the most dominant types were 3 > serogroups 15B/C > 11 and 23. During the PCV13 era, the serotypes contained in the PCV13 vaccine would cover 42% of carriage samples and 74% of MEF samples.
3.1.2.8. USA
In a prospective, longitudinal study in northeastern USA (Rochester, NY), 209 NP and 98 MEF samples were collected by tympanocentesis from children with AOM, ≤3 years of age, from 2015 to 2019 [Citation6]. Pneumococcal carriage was 53.2% in children with AOM. In the MEF, nontypeable H. influenzae was the most dominant isolate (33.5%), followed by S. pneumoniae (23.8%). The three most prevalent serotypes, which accounted for approximately 50% of all the serotypes, were 35B, 15B/C, and 23B. Non-PCV13 serotypes accounted for 93% of total S. pneumoniae in the NP at AOM, and 91% in AOM by MEF culture. PCV20 would increase serotype coverage by 27% based on NP-determined AOM, and 32% based on MEF-determined AOM. Unfortunately, among the top seven serotypes that account for 75% of the serotypes found in the MEF, only type 15B would be covered by PCV20.
summarizes the actual or potential serotype coverage as determined from MEF cultures by various PCVs in USA, Europe, or Asia. summarizes the actual or potential coverage as inferred from NP cultures during AOM.
Figure 1. Pneumococcal AOM serotype projected ‘coverage’ by PCV13 or newer PCVs in USA, Europe, or Asia. The bar graphs show the percentage of serotypes isolated from the middle ear that are contained within the various PCVs.
Figure 2. Actual or projected serotype ‘coverage’ by PCV13 or newer PCVs in USA, Europe, Middle East, or Asia. The bar graphs show the percentage of isolated pneumococcal serotypes within the various PCVs. Panel A: from NP isolates during otitis media. Panel B: from NP isolates from healthy children.
3.2. Nasopharyngeal colonization in healthy subjects
Asymptomatic pneumococcal NP colonization data are shown in from selected countries. This Table includes data from healthy control groups included in the AOM reports of .
Table 2. Healthy Subjects: Pneumococci serotype distribution of nasopharyngeal (NP) cultures.
3.2.1. Southeast and South Asia
3.2.1.1. Indonesia
Salsabila et al. [Citation24] investigated the nasopharyngeal carriage and serotype distribution of S. pneumoniae in non-PCV vaccinated healthy children, <5 years of age, in Kotabaru, South Kalimantan, Indonesia. The overall carriage rate was 45% and varied among ethnic groups and children exposed to cigarette smoke. The most commonly identified serotypes were 6A/B (18%), 15B/C (17%), and 19 F (16%). The PCV10GSK and PCV13 serotype coverage would be 35% and 47%, respectively.
To study the impact of the PCV13 immunization program that began in Indonesia in October 2017, Prayitno et al. [Citation25] examined the changes in nasopharyngeal carriage serotypes among vaccinated and unvaccinated healthy children in Lombok, Indonesia from 2018 to 2019. At 6 months after the booster dose in the vaccinated cohort, there was a marked reduction in vaccine serotypes colonizing the nose. In addition, there was a dramatic change in serotype distribution, with the predominant serotypes in the unvaccinated cohort being 6A/B (35%), 23 F (10%) 14 (7%), 19 F (5%), and 15B/C (5%) compared to the vaccinated group being 34 (14%), 15B/C (11%), 6A/B (7%), and 19 F (6%).
3.2.1.2. Thailand
PCV10GSK and PCV13 were approved for private use in 2014 in Thailand but there was low uptake. In 2012–2014, the most prevalent serotype colonizing the nasopharynx of 375 children in Thailand as reported by Gamil et al. was serotype 19 F [Citation26] Approximately 40% of the healthy children had a respiratory infection but not pneumonia when samples were taken. Other common serotypes were 6B, 23 F, 14, 18C and 3. Based on healthy colonization data from Thai children, vaccine coverage could be 47% for PCV10GSK, 60% for PCV10SII, 62% for PCV13, 63% for PCV15 and 71% for PCV20.
3.2.1.3. India
Pneumococcal carriage rate was estimated in this cohort study among 1020 asymptomatic children in a rural community of northern India between August 2012 and August 2014 [Citation27]. Overall pneumococcal carriage was 5.1%, the highest carriage rate among children < 1 year old. Among 220 pneumococcal isolates, 42 serotypes were identified, with 6B/C (8.6%), 19A (7.2%), 19 F (6.8%), 23 F (6.4%), 35A/B/C (6.4%), 15B (5%), 14 (4.5%) and 11A/C/D (3.2%) accounting for 50%.
Samson et al. [Citation28] studied the prevalence of otitis media and NP carriage among 107 children from birth to 8 years of age in the K.V. Kuppam rural development area of Tamil Nadu of Southern India from 2009 to 2017. Diagnosis of otitis media was performed by an ENT. Of the 107 children, 23.4% experienced at least one episode of AOM in infancy. At the 8-year follow-up 14.0% (15/107) were diagnosed with otitis media. Based on NP swabs at AOM diagnosis, among the 15 with AOM, 4 were positive for S. pneumoniae (none were vaccinated) and 3 of them had PCV13 serotypes (4, 6A and 18C). 48.6% of the nasal swabs collected at the 8-year follow-up were positive for S. pneumoniae, demonstrating a high prevalence of carriage at 8 years of age. The main serotypes were NT (10.7%), 6A (8.9%), and 4 (7.1%). PCV coverage of the serotypes would have been 23% by PCV10GSK, 23% by PCV10SII, and 36% by PCV13 and PCV15, and 46% by PCV20.
3.2.1.4. India and Bangladesh
In a study from 2017 to 2019, a total of 450 and 459 infants were recruited from India and Bangladesh respectively within 7 days after birth in this study [Citation29] Only one Indian child received all three primary doses of PCV10GSK whereas 93% of the Bangladeshi children had received all three primary doses. Almost a 50% reduction of PCV10GSK serotypes in the highly vaccinated PCV10GSK Bangladeshi cohort was observed compared to the ‘unvaccinated’ Indian cohort. Prevalence of pneumococci was 48% in the Indian and 55% in the Bangladeshi cohort at 18 weeks. It increased to 53% and 64.8% respectively at 36 weeks. Results in are from NP swabs at 36 weeks after birth. The average prevalence of vaccine serotypes was higher in the Indian cohort (18% vs 10% for PCV10GSK and 26% vs 18% for PCV-13) with 6A, 6B, 19 F, 23 F, and 19A as the common serotypes. The prevalence of non-vaccine serotypes was higher (44% vs 27% for non-PCV13) in the Bangladeshi cohort with 34, 15B, 17 F, and 35B as the common serotypes. Overcrowding was associated with increased risk of pneumococcal carriage. From these data, an estimate of vaccine coverage for India and Bangladeshi infants would be 24% for PCV10GSK, 34% for PCV10SII, 38% for PCV13, 40% for PCV15 and 52% for PCV20.
3.2.3. Middle East
3.2.3.1. Israel
In this study from southern Israel described above and in , data from 1076 NP cultures were obtained from children during 2015–2017 [Citation16]. Although the most common serotypes in healthy children were similar to the NP samples taken at time of AOM (), more serotypes were identified. Accordingly, potential coverage of colonization isolates from healthy children decreased from 23% to 14% for PCV15 and from 40% to 29% for PCV20.
3.2.4. Europe
3.2.4.1. Belgium
In this study described above and in , the pneumococcal serotypes carried by 1956 healthy children attending day-care centers was described [Citation19]. Pneumococcal carriage was 78% in the healthy children. The PCV13-specific serotype 19A increased after implementation of PCV10GSK. The dominant serotypes were 23B (18%), 23A (8.0%), 11A (8%) and 15B (7%). Non-PCV13 vaccine serotypes accounted for 92% of healthy isolates. Overall, serotype coverage for healthy children was/would be 3% from PCV10gsk, 8% from PCV13, 11% from PCV15, and 32% from PCV20.
3.2.4.2. Spain
In a multi-center study conducted in Murcia, Spain, Miguélez et al. [Citation30] investigated the pneumococcal serotype carriage in healthy children at 1 and at 4 years of age, five years after PCV13 was put into the NIP. Nasopharyngeal colonization was similar in both age groups (18.6 and 20.7%, respectively). The dominant serotypes detected were 23B (13%), 11A (8%), 10A (7%), 35 F (6%), and 23A (5%) – which are all non-PCV13 vaccine serotypes. Overall, PCV13 coverage was 14%, and would have been 8% by PCV10GSK, 17% by PCV15, and 35% by PCV20.
3.2.4.3. Iceland
In this study described above and in , data from 626 NP cultures from healthy children attending day care centers during 2016–2017, 5 years post-PCV10GSK introduction were obtained [Citation22]. Pneumococcal carriage rates were 67% in the pre-PCV10GSK vaccination time frame (2009–2010) and 62% post-PCV10GSK. Non-PCV10GSK vaccine types in carriage increased from 50% pre-vaccination era to 98% post-PCV10GSK era (2016–2017). The major serotypes were 6C (16%), 23B (10%), and 19A (9%). PCV serotype coverage in the post-vaccination era was/would be 2% from PCV10gsk, 22% from PCV13, 26% from PCV15, and 34% from PCV20 for healthy children,
3.2.4.4. USA
In this prospective, longitudinal study from Rochester NY described above and in , pneumococcal carriage was 32.2% in healthy children [Citation6]. Non-PCV13 serotypes accounted for 93% of total S. pneumoniae in the NP in the children. PCV20 would only increase serotype coverage in the NP to 20% at health,
3.3. Potential effectiveness of PCVs in prevention of AOM and NP colonization
In this review, we selected countries in South and Southeast Asia as examples of LMICs that will likely adopt PCV10SII into their NIP. Prevalent serotypes in South Asia and Southeast Asia countries largely resemble what was the case in high-income countries before PCV7 was introduced. In South and Southeast Asia, if effectiveness of the included serotypes were to be 100% (not likely as discussed later) and high vaccination uptake was achieved (a challenging prospect), then an imprecise estimate would be that 49% of AOM in children might be prevented in the first years after introduction.
Merck (PCV15) and Pfizer (PCV20) vaccines were licensed in Europe and USA in 2021 for adult use. Licensure of PCV15 for children occurred in 2022 and is anticipated in 2023 for PCV20. Prevalent serotypes in Belgium, Germany, France, Italy, Spain, Sweden and USA are largely similar but differences are also apparent. In Europe, if effectiveness of the included serotypes was to be 100% for both PCV15 and PCV20 (unlikely), and if cross coverage of serotype 15C by vaccination with serotype 15B is 100% (unknown)–then an imprecise estimate woud be that a total of 28% of AOM in vaccinated children might be prevented in the first years after introduction of PCV15, and 48% of AOM in vaccinated children might be prevented in the first years after introduction of PCV20. In USA, the corresponding numbers would be 17% and 32%, based on MEF cultures () and 13% and 27% based on NP cultures taken at the onset of AOM ().
summarizes the actual or potential serotype coverages by various PCVs as determined from cultures from healthy children.
As data from the tables show, the vaccine type efficacy of PCV13 against MEF-positive AOM has not been perfect, particularly for serotypes 3, 19A, and 19 F. Failures have been more frequent in Europe (nearly 30%) than USA (nearly 10%), as summarized in . It is unclear what the VT efficacy in the newer PCVs will prove to be. For simplicity in our projections based upon serotype isolations, however, we have assumed complete efficacy.
Figure 3. Percentages of PCV13 vaccine type failures as determined from middle ear culture or NP cultures during AOM or in healthy children – in Europe or USA. The major vaccine type isolates observed were 3, 19A, and 19 F.
The projected impact due to the additional serotypes in PCV15 and PCV20 in AOM and healthy children in Europe and USA are shown in (assuming 100% VT efficacy).
Figure 4. Projected additional coverage beyond PCV13 by the additional serotypes in PCV15 and PCV20, as determined from middle ear culture or from NP culture during AOM or in healthy children – in Europe or USA. The added serotypes in PCV15 are 22 F and 33 F, and in PCV20 are 8, 10, 11A, 12 F, 15B, 22 F and 33 F. The projections assume the added types will be 100% effective.
4. Discussion
Prevention of pneumococcal AOM in children by adding PCVs to NIPs in LMICs and increased coverage of additional serotypes with higher valency PCVs in high-income countries would improve child health. Our review suggests that pneumococcal serotypes among predominant strains causing AOM in South Asia and Southeast Asia, representing LMICs without widespread use of PCVs, resemble those observed in high-income countries before PCV introduction. Pneumococcal serotypes among predominant strains causing AOM in European countries, Israel and USA, representing high-income countries with high vaccine uptake rates, are predominantly caused by NVTs not included in higher valency PCVs. Serotype diversity in LMICs and serotype replacement in high-income countries represent a major challenge to serotype-dependent pneumococcal conjugate vaccine development for prevention of AOM.
Pneumococci are major pathogens causing AOM [Citation5,Citation7,Citation31]. AOM is a far more common pneumococcal infection than IPD. AOM is a pneumococcal infection that causes some mortality (mainly in LMICs) and much morbidity worldwide. AOM contributes significantly in cost-effectiveness analyses of PCVs. In a systematic review of published reports of the microbiology of AOM from 1970 − 2014, using PubMed databases, Ngo et al. [Citation32] found S. pneumoniae was the predominant bacterium in the majority of reports.
In LMICs the availability of any PCV will likely produce a reduction in pneumococcal AOM among vaccinated children. Using the 2005 Global Burden of Diseases, Injuries, and Risk Factors Study data from 21 WHO regional areas, Monasta et al. [Citation33] estimated AOM incidence to be 10.85%, i.e. 709 million cases/year, with 51% of these cases occurring in children under 5 years old and the chronic suppurative OM incidence rate to be 4.76%, i.e. 31 million cases, with 22.6% of cases occurring annually in children <5 years old. Otitis media (OM)-related hearing impairment is a major morbidity of OM, with an estimated incidence of 30.8/ten-thousand. WHO has noted that children living in LMICs have a high prevalence of severe OM with recurrent perforation of the tympanic membrane leading to chronic suppurative OM [Citation34]. Hearing impairment because of chronic suppurative OM is a major form of disability in LMICs [Citation35–43]. The prevalence of chronic suppurative OM has been estimated to be 15/1000 school children in India [Citation39] and 5.3/1000 in Malaysia [Citation35]. OM causes 21 thousand deaths/year [Citation33,Citation34].
In high-income countries, the diagnosis of AOM typically leads to prescription of antibiotics, contributing to the increasing problem of bacterial resistance. The estimated direct and indirect annual costs associated with pneumococcal AOM make prevention by effective vaccines an important goal in high-income countries with PCVs in their NIPs. In 2008, Zhou et al. [Citation4] from the US Centers for Disease Control and Prevention reported pre-PCV7 (1997–1999) to post PCV7 (2004) rates of ambulatory visits and antibiotic prescriptions attributable to AOM fell 42.7% and 41.9%, respectively. Total, estimated, national direct medical expenditures for AOM-related ambulatory visits and antibiotic prescriptions for children <2 years of age decreased 32.3%. This provided a conclusion that AOM-related health care utilization and associated antibiotic prescriptions for privately insured young children in the USA decreased more than expected (on the basis of efficacy estimates in pre-licensure clinical trials) after the introduction of routine PCV7 immunization. In 2016, Dagan et al. [Citation44] hypothesized that widespread use of PCVs led to reductions in early life AOM episodes caused by vaccine-type S pneumoniae, which in turn abrogated the subsequent pathogenic process that leads to complex otitis media, reducing the disease burden beyond that directly caused by vaccine-type serotypes. In 2018, Tong et al. [Citation45] reported that the overall annual rate of AOM-related healthcare utilization was 60.5 per 1000 person-years, and the rate changed little from 2008 to 2014 after introduction of PCV13 in USA. Most of healthcare utilization was due to office/outpatient visits (55.7/per 1000 person-years) and emergency department/urgent care visits (4.7/1000 person-years). The mean cost per AOM episode in 2013–2014 was $199 for office or outpatient visits, $330 for emergency department/urgent care visits, and $1593 for hospitalization. The investigators concluded that in the USA, AOM-associated healthcare utilization and costs remained substantial following the introduction of PCV13, and more effective preventive measures such as new vaccines were needed to reduce the burden of AOM.
In 2014, a Cochrane review by Fortanier et al. [Citation46] assessed the effect of PCVs in preventing AOM in children up to 12 years of age. PCV7, administered during early infancy, was associated with a relative risk reduction of all-cause AOM of 7% (95% confidence interval = 4% to 9%). Administering PCV7 in high-risk infants after early infancy, and in older children with a history of AOM, appeared to have no benefit in preventing further episodes. Lau et al. [Citation47] conducted an observational cohort study to investigate the trends in OM incidence and associated antibiotic prescriptions in UK children <10 years old. During high uptake of PCV7 in the NIP, overall annual OM incidence declined by 51.3%; and antibiotic prescription rates for OM declined by 72.9%. In Sweden, for the years 2005–2014 in areas of the country using PCV10 and/or PCV13, AOM incidence decreased in outpatients (39%) and ventilation tube insertions decreased by 18% [Citation48]. In 2018, Kawai et al. [Citation49] examined the long-term trend of OM-associated ambulatory visits from 1997 to 2014 to evaluate the impact of PCV7 and PCV13 in the USA. Compared with the pre-PCV7 period, office visit rates for OM declined by 51% among children younger than 2 years of age and by 37% among children 2–4 years of age during the post-PCV13 period. An effectiveness study of PCV13 in USA reported by Pichichero et al. [Citation50], where tympanocentesis provided pneumococcal serotype-specific etiology, a relative reduction of 86% in AOM caused by strains expressing PCV13 serotypes was observed. The greatest reduction in middle ear fluid samples was in serotype 19A, with relative reduction 91%. In a systematic literature review, Izurieta et al. [Citation51] found reductions in all-cause and complicated OM, tympanostomy tube placement; and OM-related hospitalizations were consistently observed after the introduction of PCV10 and PCV13. Impact studies with data in children <2 years old, when PCV13 was in widespread use, reported 47–51% and 34–43% reduction of all-cause OM (primary care, outpatient, ambulatory, emergency department visits) compared to periods before PCV introduction.
Licensure of Serum Institute of India PCV10SII, Merck (PCV15) and Pfizer (PCV20) for an IPD indication was based on serologic equivalency to exceed a pre-identified threshold adopted by World Health Organization, European Medicines Agency, and US Food and Drug Administration of 0.35 micrograms/mL serotype-specific anti-capsular antibody in blood measured by quantitative assay. PCV10GSK and PCV13 were licensed on this same basis. While a reasonable and practical rationale was used by the recommending and regulatory agencies to use a single concentration of antibody as minimally protective for the IPD indication, the correlation of protection likely varies widely according to pneumococcal serotype [Citation52]. Secondly, antibody levels necessary to achieve effectiveness in the field setting may vary by density of NP colonization of pneumococci, known to occur at a younger age and in higher density in LMICs [Citation53–56], and likely will vary if the host/environment differs, e.g. in nutrition status, from that of high-income countries where the 0.35 microgram/mL threshold was established. Thirdly, as discussed below, the antibody level correlation of protection against mucosal infections (non-bacteremic pneumonia, otitis media and sinusitis) is almost certainly several fold higher than the antibody level correlate of protection against IPD [Citation57].
In LMICs, there is a greater diversity of serotypes causing AOM beyond what was the situation in high-income countries when PCV7 was introduced, and the data suggest wide country-to-country variation as well–so that the potential impact of introduction of various PCVs varies widely. In Europe and USA, as mentioned above, a significant percentage of AOM is caused by strains expressing serotypes that are included in the PCVs in their NIPs, consistent with less effectiveness against these noninvasive mucosal infections confined to a closed space in the middle ear compared to effectiveness against IPD. Presumably the circulating IgG antibody must first exude onto mucosa to be effective. Serotypes 3, 19 F and 19A are notable among VT vaccine failures (). Predominant serotypes causing AOM in Europe have diverged from those causing AOM in the Middle East; and USA has yet a different serotype composition, particularly the emergence of serotype 35B in USA [Citation58–60] – which is not an included serotype in any of the PCVs included in this review.
S. pneumoniae asymptomatically colonize the nasopharynx (NP) as the initial step in pathogenesis. NP carriage is also the major reservoir of S. pneumoniae and the source of horizontal spread of this pathogen. Colonization is usually cleared 4–8 weeks after a new strain is acquired. However, particularly during respiratory virus infections, S. pneumoniae may invade locally to cause AOM or other local mucosal infections or invade systemically to cause IPD [Citation61,Citation62]. Determining serotypes that asymptomatically colonize children during health is a means to anticipate likely NVTs that will emerge in the future. However, this prediction must be viewed cautiously because not all NVT strains will transition from commensal to pathogen and prior work has clearly shown that detection of pneumococci in the nasopharynx at onset of AOM and during health poorly correlates with pathogens detected in middle ear fluid as determined by tympanocentesis [Citation12] Nevertheless, from among the asymptomatic colonizing strains will be the next generation of disease-causing strains. We found that the predominant serotypes varied among LMICs and among high-income countries. These data bring more challenges for developing serotype-specific PCVs that would have a similar global effectiveness when of a single composition.
Limitations. Our review has limitations. Most importantly, the subject has many publications from many countries and we were selective in which papers to include in this review and that may have introduced bias. We did not make a formal assessment of quality of the papers included. The study designs, populations, methods of detecting and serotyping pneumococci and time frame of collecting samples varied. Quellung reaction was used to define serotypes in most studies whereas PCR or a combination of Quellung and PCR was used in others. Both methods are thought to provide reliable results; therefore we did not make distinctions in tabulations.
5. Conclusion
After two decades of use, the serotype-effectiveness and safety of PCVs has been established. In LMICs where PCVs have not been widely available, largely due to their high cost to purchase, AOM rates and their costs to healthcare and society remain high. Pneumococcal serotypes among predominant strains in LMICs resemble those observed in high-income countries before PCV introduction. In Europe and USA, which have included PCVs in their NIPs for 2 decades, a reduction in pneumococcal AOM has occurred due to effectiveness against strains expressing serotypes in the PCVs deployed. However, replacement pneumococcal serotypes now predominate in these high-income countries with high vaccine uptake rates. Tracking asymptomatic colonizing strains collected during times of health identifies the likely next generation of disease-causing strains.
6. Expert opinion
The pneumococcal AOM disease burden in LMICs is high [Citation63]. The mortality, morbidity and costs in healthcare and to society of AOM have been grossly underestimated compared to IPD. The data in this review may prove useful for LMICs to adjust their cost-effectiveness estimates to include AOM prevention along with prevention of IPD.
The US Centers for Disease Control and Prevention estimated that, in 2004, pneumococcal disease in the US caused 4.0 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5.0 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled $3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. AOM and sinusitis (1.5 million cases each) comprised 75% of cases and 16% of direct medical costs [Citation64]. However, if indirect costs are taken into account, such as work loss by parents of young children, the cost of pneumococcal disease caused by AOM alone may exceed $6 billion annually [Citation2], and become dominant in cost-effectiveness analysis in high-income countries.
Despite the inclusion of PCVs in NIPs in high-income countries, pneumococcus has shown its resilience under vaccine pressure such that the organism remains a very common AOM pathogen. All-cause AOM has declined modestly and pneumococcal AOM caused by the specific serotypes in PCVs has declined dramatically since the introduction of PCVs [Citation65–69]. However, the burden of pneumococcal AOM disease is still considerable in the current vaccine era [Citation70]. The data in this review may prove useful for high-income countries in their cost-effectiveness estimates when considering AOM prevention along with prevention of IPD and other pneumococcal infections.
PCVs elicit highly effective protective serotype-specific antibodies to the capsular polysaccharides of included types; however, 100 serotypes are known. Limitations of PCVs are increasingly apparent. They are costly to purchase and consume a large portion of NIP budgets in high-income countries. Children in the developing world remain largely unvaccinated due to high cost of purchase. NVTs have emerged to cause disease, vary by country, vary by adult vs. pediatric populations, and are dynamically changing year to year [Citation71,Citation72]. Forthcoming PCVs of 15 and 20 serotypes will be even more costly than PCV13, will not include many newly emerged serotypes, and will probably likewise encounter ‘serotype replacement’ due to high immune evasion by pneumococci.
Limitations of PCVs led to searches for protective ‘common’ antigens: surface-expressed even in capsulated pneumococci. Toxins such as autolysin and pneumolysin, cell wall polysaccharides (C, F antigens), and proteins such as PspA were considered [Citation73]. However, as purified antigens, tested singly or mixtures of a few, none has reached approval for human use. Possibly, exposure of one or a few common antigens in capsulated pneumococci is insufficient to permit docking of sufficient antibody for protection.
Alternatively, a pneumococcal vaccine consisting simply of killed non-capsulated whole cells (WCV) has advanced to phase II clinical trials in children. The development of WCV was based on the premise that many cell wall antigens would be presented in the same configuration as expressed at the bacterial surface, that the absence of the [immunodominant and shielding] capsule would improve presentation of the cell wall antigens, that presentation as a particle rather than as soluble antigens would improve immunogenicity, and that the mixture of antibodies induced (both known and not known) would suffice for protection [Citation74–79].
Five-Year View: The notion that strains expressing serotypes that were not included in PCV7 were less virulent was proven wrong within a few years after introduction of PCV7 in high-income countries, e.g. with the emergence of strains expressing serotype 19A, and others. The same cycle occurred after the introduction of PCV13. It appears to take about 4 years after the introduction of a PCV before peak effectiveness is achieved–which then begins to erode with the emergence of NVTs. First, the NVTs are observed to colonize the NP as commensals and then from among those strains new disease-causing strains emerge.
The pneumococcus has more than 100 capsular types currently identified, and the incidence of strains expressing that diversity of serotypes grows year by year. When PCV manufacturers made their decisions on serotype composition, it was based on available data at the time regarding predominant serotypes causing IPD in countries that had the best data and would be the market for their products. However, from the time of the decision to licensure of vaccine takes many years, and during that time the pneumococcal serotypes may change; this review confirms that change has occurred and predicts more change will occur in the future.
Defining PCV compositions for a world market is a complex goal, as the serotype diversity widens in comparisons among high-income countries and comparisons to LMICs (and the many countries that comprise the latter designation, most of which have no data to know the predominant serotypes). This makes decisions by NIPs more complicated than in the past, and that level of complexity is likely to increase in the coming years.
It might be contemplated that PCVs with even higher valency could be produced, albeit at a likely higher cost [Citation80]. However, with the development of PCV10 and PCV13 after the introduction of PCV7, a reduction in levels of induced antibodies for some of the serotypes in the vaccine compositions was observed [Citation81–83]. Although not considered clinically significant for IPD, the lowered antibody generating effects may be a cause of lower effectiveness in prevention of AOM and NP colonization. Thus, higher valency compositions of PCV, e.g. PCV15 and PCV20, and future compositions with even higher valency may result in a reduction in levels of induced antibodies for some of the serotypes in the vaccine compositions.
PCVs have produced an impact in reducing pneumococcal AOM and asymptomatic NP colonization, thereby providing a herd immunity effect. However, in the longer term view an alternative to serotype-specific pneumococcal vaccines will likely be needed to effectively reduce infections and colonization by pneumococci. Prior efforts to introduce multi-component protein vaccines by GlaxoSmithKline [Citation84,Citation85] and Sanofi [Citation85,Citation86] were abandoned; so new formulations will be needed to restart that serotype-independent strategy. Whole-cell pneumococcal vaccines are another serotype-independent strategy that has been pursued [Citation61,Citation87,Citation88] and early phase human trials have occurred [Citation88]. Those vaccines could be produced at low cost and widely deployed if they prove effective in preventing IPD, mucosal infections like AOM, and prevent or reduce NP colonization density to below a transmission/pathogenic threshold.
Article highlights
Pneumococcal serotypes among predominant strains causing AOM in South Asia and Southeast Asia, representing LMICs without widespread use of PCVs, resemble those observed in high-income countries before PCV introduction.
Pneumococcal serotypes among predominant strains causing AOM in European countries, Israel and USA, representing high-income countries with high vaccine uptake rates, are predominantly caused by NVTs not included in higher valency PCVs.
Serotype diversity in LMICs and serotype replacement in high-income countries represent a major challenge to serotype-dependent pneumococcal conjugate vaccine development for prevention of AOM.
Declaration of interest
R Malley and P Anderson are co-inventors of a whole-cell pneumococcal vaccine in clinical development. R Malley owns stock in Affinvax, Inc. that has a pneumococcal vaccine in clinical development. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
M Pichichero substantially contributed to the conception and design of the review article and interpreting the relevant literature and was involved in all phases of writing. R Malley substantially contributed to revising the article for intellectual content. R Kaur substantially contributed to the writing and prepared the figures. R Zagursky performed the literature search, prepared the tables and contributed in the writing. P Anderson substantially contributed to the design and revising the article for intellectual content.
Acknowledgments
Would like to thank the following people for supplying additional data: Drs. Esra Ekinci, Laura Willen and Prof. Heidi Theeten for the Belgium data, Drs. Ron Dagan and Bart Adrian Van Der Beek for the Israeli data, Ashish Bavdekar for the Indonesia and Bangladesh data and Dr Henry Baggett for the Thai data.
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References
- Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131(3):e964–999.
- Casey JR, Pichichero ME. Payment analysis of two diagnosis and management approaches of acute otitis media. Clin Pediatr (Phila). 2014;53(9):865–873.
- O’Brien MA, Prosser LA, Paradise JL, et al. New vaccines against otitis media: projected benefits and cost-effectiveness. Pediatrics. 2009;123(6):1452–1463.
- Zhou F, Shefer A, Kong Y, et al. Trends in acute otitis media-related health care utilization by privately insured young children in the United States, 1997-2004. Pediatrics. 2008;121(2):253–260.
- Kaur R, Morris M, Pichichero ME. Epidemiology of acute otitis media in the postpneumococcal conjugate vaccine era. Pediatrics. 2017;140(3). DOI:10.1542/peds.2017-0181
- Kaur R, Fuji N, Pichichero ME. Dynamic changes in otopathogens colonizing the nasopharynx and causing acute otitis media in children after 13-valent (PCV13) pneumococcal conjugate vaccination during 2015-2019. Eur J Clin Microbiol Infect Dis. 2021;41(1):37–44 •• The only report on AOM using tympanocentesis. Unique data from USA.
- Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995-2003. Pediatr Infect Dis J. 2004;23(9):824–828.
- Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004;4(3):144–154.
- Lo SW, Gladstone RA, van Tonder AJ, et al. Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study. Lancet Infect Dis. 2019;19(7):759–769.
- Fuji N, Pichichero M, Ehrlich RL, et al. Transition of serotype 35B pneumococci from commensal to prevalent virulent strain in children. Front Cell Infect Microbiol. 2021;11:744742.
- Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet. 2011;378(9807):1962–1973.
- Kaur R, Czup K, Casey JR, et al. Correlation of nasopharyngeal cultures prior to and at onset of acute otitis media with middle ear fluid cultures. BMC Infect Dis. 2014;14:640 •• The report provides data on mismatch between nasopharyngeal and tympanocentesis culture results at onset of AOM .
- Wahyono DJ, Khoeri MM, Darmawan AB, et al. Nasopharyngeal carriage rates and serotype distribution of Streptococcus pneumoniae among school children with acute otitis media in Central Java, Indonesia. Access Microbiol. 2021;3(7):000249.
- Napolean M, Rosemol V, John M, et al. Nasopharyngeal colonization of otopathogens in South Indian children with acute otitis media - A case control pilot study. J Otol. 2021;16(4):220–224.
- Naziat H, Saha S, Islam M, et al. Epidemiology of otitis media with otorrhea among Bangladeshi children: baseline study for future assessment of pneumococcal conjugate vaccine impact. Pediatr Infect Dis J. 2018;37(7):715–721.
- Ben-Shimol S, Givon-Lavi N, Kotler L, et al. Post-13-Valent pneumococcal conjugate vaccine dynamics in young children of serotypes included in candidate extended-spectrum conjugate vaccines. Emerg Infect Dis. 2021;27(1):150–160.
- Levy C, Varon E, Ouldali N, et al. Bacterial causes of otitis media with spontaneous perforation of the tympanic membrane in the era of 13 valent pneumococcal conjugate vaccine. PLoS One. 2019;14(2):e0211712.
- Imohl M, Perniciaro S, Busse A, et al. Bacterial spectrum of spontaneously ruptured otitis media in a 7-Year, longitudinal, multicenter, epidemiological cross-sectional study in Germany. Front Med (Lausanne). 2021;8:675225.
- Ekinci E, Desmet S, Van Heirstraeten L, et al. Streptococcus pneumoniae serotypes carried by young children and their association with acute otitis media during the period 2016-2019. Front Pediatr. 2021;9:664083.
- Marchisio P, Esposito S, Picca M, et al. Serotypes not Included in 13-Valent pneumococcal vaccine as causes of acute otitis media with spontaneous tympanic membrane perforation in a geographic area with high vaccination coverage. Pediatr Infect Dis J. 2017;36(5):521–523.
- Morales M, Ludwig G, Ercibengoa M, et al. Changes in the serotype distribution of Streptococcus pneumoniae causing otitis media after PCV13 introduction in Spain. PLoS One. 2018;13(12):e0209048.
- Quirk SJ, Haraldsson G, Erlendsdottir H, et al. Effect of vaccination on pneumococci isolated from the nasopharynx of healthy children and the middle ear of children with otitis media in Iceland. J Clin Microbiol. 2018;56(12). DOI:10.1128/JCM.01046-18.
- Allemann A, Frey PM, Brugger SD, et al. Pneumococcal carriage and serotype variation before and after introduction of pneumococcal conjugate vaccines in patients with acute otitis media in Switzerland. Vaccine. 2017;35(15):1946–1953.
- Salsabila K, Paramaiswari WT, Amalia H, et al. Nasopharyngeal carriage rate, serotype distribution, and antimicrobial susceptibility profile of Streptococcus pneumoniae isolated from children under five years old in Kotabaru, South Kalimantan, Indonesia. J Microbiol Immunol Infect. 2021;55(3):482–488.
- Prayitno A, Supriyatno B, Munasir Z, et al. Pneumococcal nasopharyngeal carriage in Indonesia infants and toddlers post-PCV13 vaccination in a 2+1 schedule: a prospective cohort study. PLoS One. 2021;16(1):e0245789.
- Gamil A, Chokephaibulkit K, Phongsamart W, et al. Pneumococcal disease in Thailand. Int J Infect Dis. 2021;102:429–436.
- Kumar S, Purakayastha DR, Kapil A, et al. Carriage rates and antimicrobial sensitivity of pneumococci in the upper respiratory tract of children less than ten years old, in a north Indian rural community. PLoS One. 2021;16(2):e0246522.
- Samson D, Rupa V, Veeraraghavan B, et al. Follow up of a birth cohort to identify prevalence and risk factors for otitis media among Indian children in the eighth year of life. Int J Pediatr Otorhinolaryngol. 2020;137:110201.
- Apte A, Dayma G, Naziat H, et al. Nasopharyngeal pneumococcal carriage in South Asian infants: results of observational cohort studies in vaccinated and unvaccinated populations. J Glob Health. 2021;11:04054.
- Alfayate Miguelez S, Yague Guirao G, Menasalvas Ruiz AI, et al. Impact of pneumococcal vaccination in the nasopharyngeal carriage of streptococcus pneumoniae in healthy children of the Murcia Region in Spain. Vaccines (Basel). 2020;9(1). DOI:10.3390/vaccines9010014.
- Kaur R, Pichichero M, Palmer GH. Lipidation of Haemophilus influenzae antigens P6 and OMP26 improves immunogenicity and protection against nasopharyngeal colonization and ear infection. Infect Immun. 2022;90(5):e0067821.
- Ngo CC, Massa HM, Thornton RB, et al. Predominant bacteria detected from the middle ear fluid of children experiencing otitis media: a systematic review. PLoS One. 2016;11(3):e0150949.
- Monasta L, Ronfani L, Marchetti F, et al. Burden of disease caused by otitis media: systematic review and global estimates. PLoS One. 2012;7(4):e36226.
- WHO. Chronic suppurative otits media-burden of disease and management options. Switzerland. 2004.
- Elango S, Purohit GN, Hashim M, et al. Hearing loss and ear disorders in Malaysian school children. Int J Pediatr Otorhinolaryngol. 1991;22(1):75–80.
- Verma AK, Vohra A, Maitra A, et al. Epidemiology of chronic suppurative otitis media and deafness in a rural area and developing an intervention strategy. Indian J Pediatr. 1995;62(6):725–729.
- Chayarpham S, Stuart J, Chongsuvivatwong V, et al. A study of the prevalence of and risk factors for ear diseases and hearing loss in primary school children in Hat Yai, Thailand. J Med Assoc Thai. 1996;79(7):468–472.
- Jacob A, Rupa V, Job A, et al. Hearing impairment and otitis media in a rural primary school in south India. Int J Pediatr Otorhinolaryngol. 1997;39(2):133–138.
- Rupa V, Jacob A, Joseph A. Chronic suppurative otitis media: prevalence and practices among rural South Indian children. Int J Pediatr Otorhinolaryngol. 1999;48(3):217–221.
- Kamal N, Joarder AH, Chowdhury AA, et al. Prevalence of chronic suppurative otitis media among the children living in two selected slums of Dhaka City. Bangladesh Med Res Counc Bull. 2004;30(3):95–104.
- Chadha SK, Agarwal AK, Gulati A, et al. A comparative evaluation of ear diseases in children of higher versus lower socioeconomic status. J Laryngol Otol. 2006;120(1):16–19.
- Adhikari P. Pattern of ear diseases in rural school children: experiences of free health camps in Nepal. Int J Pediatr Otorhinolaryngol. 2009;73(9):1278–1280.
- Waqar-Uddin HA, Khan A, Ahmad F, et al. Prevalence and comparison of chronic suppurative otitis media in government and private schools. Annals of Pakistan Institute of Medical Sciences. 2009;5(3):141–144.
- Dagan R, Pelton S, Bakaletz L, et al. Prevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease. Lancet Infect Dis. 2016;16(4):480–492.
- Tong S, Amand C, Kieffer A, et al. Trends in healthcare utilization and costs associated with acute otitis media in the United States during 2008-2014. BMC Health Serv Res. 2018;18(1):318.
- Fortanier AC, Venekamp RP, Boonacker CW, et al. Pneumococcal conjugate vaccines for preventing otitis media. Cochrane Database Syst Rev. 2014;4:CD001480.
- Lau WC, Murray M, El-Turki A, et al. Impact of pneumococcal conjugate vaccines on childhood otitis media in the United Kingdom. Vaccine. 2015;33(39):5072–5079.
- Gisselsson-Solen M. Trends in Otitis Media Incidence After Conjugate Pneumococcal Vaccination: a National Observational Study. Pediatr Infect Dis J. 2017;36(11):1027–1031.
- Kawai K, Adil EA, Barrett D, et al. Ambulatory visits for otitis media before and after the introduction of pneumococcal conjugate vaccination. J Pediatr. 2018;201:122–127 e121.
- Pichichero M, Kaur R, Scott DA, et al. Effectiveness of 13-valent pneumococcal conjugate vaccination for protection against acute otitis media caused by Streptococcus pneumoniae in healthy young children: a prospective observational study. Lancet Child Adolesc Health. 2018;2(8):561–568.
- Izurieta P, Nieto Guevara J. Exploring the evidence behind the comparable impact of the pneumococcal conjugate vaccines PHiD-CV and PCV13 on overall pneumococcal disease. Hum Vaccin Immunother. 2022;18(1):1872341.
- Andrews NJ, Waight PA, Burbidge P, et al. Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study. Lancet Infect Dis. 2014;14(9):839–846
- Abdullahi O, Karani A, Tigoi CC, et al. The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya. PLoS One. 2012;7(2):e30787.
- Abdullah MR, Gutierrez-Fernandez J, Pribyl T, et al. Structure of the pneumococcal l,d-carboxypeptidase DacB and pathophysiological effects of disabled cell wall hydrolases DacA and DacB. Mol Microbiol. 2014;93(6):1183–1206.
- Tigoi CC, Gatakaa H, Karani A, et al. Rates of acquisition of pneumococcal colonization and transmission probabilities, by serotype, among newborn infants in Kilifi District, Kenya. Clin Infect Dis. 2012;55(2):180–188.
- Turner P, Turner C, Jankhot A, et al. A longitudinal study of Streptococcus pneumoniae carriage in a cohort of infants and their mothers on the Thailand-Myanmar border. PLoS One. 2012;7(5):e38271.
- Kaur R, Pham M, Pichichero M. Serum antibody levels to pneumococcal polysaccharides 22F, 33F, 19A and 6A that correlate with protection from colonization and acute otitis media in children. Vaccine. 2021;39(29):3900–3906.
- Kaur R, Casey JR, Pichichero ME. Emerging Streptococcus pneumoniae strains colonizing the nasopharynx in children after 13-valent pneumococcal conjugate vaccination in comparison to the 7-valent Era, 2006-2015. Pediatr Infect Dis J. 2016;35(8):901–906.
- Kaur R, Pham M, Yu KOA, et al. Rising pneumococcal antibiotic resistance in the post-13-valent pneumococcal conjugate vaccine era in pediatric isolates from a primary care setting. Clin Infect Dis. 2021;72(5):797–805.
- Kaur R, Schulz S, Fuji N, et al. COVID-19 pandemic impact on respiratory infectious diseases in primary care practice in children. Front Pediatr. 2021;9:722483.
- Jwa MY, Jeong S, Ko EB, et al. Gamma-irradiation of streptococcus pneumoniae for the use as an immunogenic whole cell vaccine. J Microbiol. 2018;56(8):579–585.
- Davis B. Dulbecco R, Eisen HN,et al. Microbiology. Lippincott Williams & Wilkins, Philidelphia PA, USA; 1990.
- O’Brien KL, Wolfson LJ, Watt JP, et al. Burden of disease caused by streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374(9693):893–902.
- Huang SS, Johnson KM, Ray GT, et al. Healthcare utilization and cost of pneumococcal disease in the United States. Vaccine. 2011;29(18):3398–3412.
- Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. Jama. 2007;298(15):1772–1778.
- Casey JR, Adlowitz DG, Pichichero ME. New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2010;29(4):304–309.
- Casey JR, Kaur R, Friedel VC, et al. Acute otitis media otopathogens during 2008 to 2010 in Rochester, New York. Pediatr Infect Dis J. 2013;32(8):805–809.
- Grijalva CG, Poehling KA, Nuorti JP, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics. 2006;118(3):865–873.
- Grijalva CG, Nuorti JP, Arbogast PG, et al. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. 2007;369(9568):1179–1186.
- Huang SS, Hinrichsen VL, Stevenson AE, et al. Continued impact of pneumococcal conjugate vaccine on carriage in young children. Pediatrics. 2009;124(1):e1–11.
- Ladhani SN, Collins S, Djennad A, et al. Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study. Lancet Infect Dis. 2018;18(4):441–451.
- Ouldali N, Levy C, Varon E, et al. Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey. Lancet Infect Dis. 2018;18(9):983–991.
- Briles DE, Tart RC, Swiatlo E, et al. Pneumococcal diversity: considerations for new vaccine strategies with emphasis on pneumococcal surface protein A (PspA). Clin Microbiol Rev. 1998;11(4):645–657.
- Malley R, Lipsitch M, Stack A, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect Immun. 2001;69(8):4870–4873.
- Lu YJ, Leite L, Goncalves VM, et al. GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. Vaccine. 2010;28(47):7468–7475.
- Moffitt KL, Yadav P, Weinberger DM, et al. Broad antibody and T cell reactivity induced by a pneumococcal whole-cell vaccine. Vaccine. 2012;30(29):4316–4322.
- Malley R, Henneke P, Morse SC, et al. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci U S A. 2003;100(4):1966–1971.
- Malley R, Morse SC, Leite LC, et al. Multiserotype protection of mice against pneumococcal colonization of the nasopharynx and middle ear by killed nonencapsulated cells given intranasally with a nontoxic adjuvant. Infect Immun. 2004;72(7):4290–4292
- Goncalves VM, Dias WO, Campos IB, et al. Development of a whole cell pneumococcal vaccine: BPL inactivation, cGMP production, and stability. Vaccine. 2014;32(9):1113–1120.
- Chichili GR, Smulders R, Santos V, et al. Phase 1/2 study of a novel 24-valent pneumococcal vaccine in healthy adults aged 18 to 64 years and in older adults aged 65 to 85 years. Vaccine. 2022;40(31):4190–4198.
- Vesikari T, Wysocki J, Chevallier B, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine. Pediatr Infect Dis J. 2009;28(4 Suppl):S66–76.
- Bryant KA, Block SL, Baker SA, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine. Pediatrics. 2010;125(5):866–875.
- Yeh SH, Gurtman A, Hurley DC, et al. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126(3):e493–505.
- Odutola A, Ota MOC, Antonio M, et al. Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: a phase 2, randomized, controlled, observer-blind study. Vaccine. 2017;35(19):2531–2542.
- Alderson MR, Murphy T, Pelton SI, et al. Panel 8: vaccines and immunology. Int J Pediatr Otorhinolaryngol. 2020;130 Suppl 1:109839.
- Hammitt LL, Campbell JC, Borys D, et al. Efficacy, safety and immunogenicity of a pneumococcal protein-based vaccine co-administered with 13-valent pneumococcal conjugate vaccine against acute otitis media in young children: a phase IIb randomized study. Vaccine. 2019;37(51):7482–7492.
- Rosenfeld RM, Tunkel DE, Schwartz SR, et al. Clinical Practice Guideline: tympanostomy Tubes in Children (Update). Otolaryngol Head Neck Surg. 2022;166(1_suppl):S1–S55.
- Keech CA, Morrison R, Anderson P, et al. A phase 1 randomized, placebo-controlled, observer-blinded trial to evaluate the safety and immunogenicity of inactivated streptococcus pneumoniae whole-cell vaccine in adults. Pediatr Infect Dis J. 2020;39(4):345–351.