Heather L Sings

Streptococcus pneumoniae serotype 19A: Worldwide epidemiology.

ABSTRACT Introduction: Streptococcus pneumoniae causes mucosal and invasive diseases with high morbidity and mortality. Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs worldwide resulted in serotype 19A becoming a leading cause of the remaining pneumococcal disease burden in vaccinated and nonvaccinated individuals. This article reviews the impact of the latest generation PCVs (10-valent PCV, PCV10, and 13-valent PCV, PCV13) on serotype 19A. Areas covered: This article covers immune responses elicited by PCV7, PCV10 and PCV13 against serotype 19A and their impact on nasopharyngeal (NP) carriage and disease in vaccinated and unvaccinated populations using data from surveillance systems, randomized controlled trials, and observational studies. Expert commentary: As expected from a PCV containing serotype 19A, PCV13 elicits significantly higher functional immune responses against serotype 19A than PCV7 and PCV10. Higher responses are likely to be linked to both direct impact in vaccinated populations and reductions in 19A NP carriage in children, thus inducing herd protection and reducing 19A invasive pneumococcal disease (IPD) in nonvaccinated children and adults. In contrast, PCV7 and PCV10 have shown mixed evidence of direct short-lived cross-protection and little to no impact on 19A carriage, resulting in continued transmission and disease.

Pneumococcal conjugate vaccine use in adults

ABSTRACT Streptococcus pneumoniae is a leading cause of illness and death in adults. A polysaccharide vaccine has been available for over 30 years, but despite significant use, the public health impact of this vaccine has been limited. The 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed by the US Food and Drug Administration and other international regulatory authorities with the assumption that induction of a T cell–dependent immune response and noninferior immunogenicity to vaccine antigens when compared with the polysaccharide vaccine would be important to satisfy a significant unmet medical need. PCV13 efficacy against vaccine-type pneumococcal community-acquired pneumonia was confirmed in a large randomized controlled trial in older adults and its use is now increasingly recommended globally.

Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Hospitalization for Community-Acquired Pneumonia in Older US Adults: A Test-Negative Design

Our study demonstrated real-world, direct effectiveness of 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia following introduction into a routine immunization program among adults aged ≥65 years, many of whom had immunocompromising and chronic medical conditions.

Pneumococcal conjugate vaccine use in adults – Addressing an unmet medical need for non-bacteremic pneumococcal pneumonia

Streptococcus pneumoniae is a frequent cause of community acquired pneumonia (CAP), with the largest burden of disease attributed to non-bacteremic pneumonia. Due to the high persistent burden of disease, pneumococcal pneumonia, particularly non-bacteremic pneumococcal pneumonia, continues to be a major public health concern. There are currently two pneumococcal vaccines approved for use in adults in the United States (US) and other countries worldwide: a 23-valent pneumococcal simple polysaccharide vaccine (PPV23), and a 13-valent pneumococcal conjugate vaccine (PCV13). The capsular polysaccharides included in PPV23 induce antibodies primarily by a T-cell independent mechanism, thus the immune response is short lived and lacks the ability to elicit an anamnestic response. PCV13, on the other hand, has the bacterial polysaccharides covalently conjugated to an immunogenic carrier protein resulting in the formation of memory B lymphocytes, thus proving long-acting immunologic memory and an anamnestic response. Despite 30years of use, the question of PPV23 vaccine efficacy, particularly with respect to efficacy for non-bacteremic pneumonia, has been extensively debated and investigated; whereas PCV13 efficacy against vaccine-type pneumococcal CAP, both bacteremic and non-bacteremic, was confirmed in a large randomized controlled trial in older adults. PCV13 was approved under the US Food and Drug Administrations accelerated pathway, which allows for earlier approval of products that provide meaningful benefit over existing treatments - in this case, protection of adults from non-bacteremic pneumococcal pneumonia. Its use is now increasingly recommended globally. This article summarizes the history and use of PPV23 and PCV13 in adults and how vaccination of adults with PCV13 addresses an unmet medical need.

A public health evaluation of 13-valent pneumococcal conjugate vaccine impact on adult disease outcomes from a randomized clinical trial in the Netherlands

BACKGROUND We conducted a post-hoc analysis of a double blind, randomized, placebo-controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) among adults aged 65 years or older to assess public health impact. METHODS For all outcomes, we included all randomized subjects, using a modified intention-to-treat (mITT) approach to determine vaccine efficacy (VE), vaccine preventable disease incidence (VPDI) defined as control minus vaccinated group incidence, and numbers needed to vaccinate (NNV) (based on a five-year duration of protection). RESULTS Results are reported for, in order, clinical, adjudicated (clinical plus radiologic infiltrate determined by committee), pneumococcal, and vaccine-type pneumococcal (VT-Sp) community-acquired pneumonia; invasive pneumococcal disease (IPD) and VT-IPD. VEs (95% CI) for all hospital episodes were 8.1% (-0.6%, 16.1%), 6.7% (-4.1%, 16.3%), 22.2% (2.0%, 38.3%), 37.5% (14.3%, 54.5%), 49.3% (23.2%, 66.5%), and 75.8% (47.6%, 88.8%). VPDIs per 100,000 person-years of observation (PYOs) were 72, 37, 25, 25, 20, and 15 with NNVs of 277, 535, 816, 798, 1016, and 1342. For clinical CAP, PCV13 was associated with a reduction of 909 (-115, 2013) hospital days per 100,000 PYOs translating to a reduction over 5 years of one hospital day for every 22 people vaccinated. When comparing at-risk persons (defined by self-report of diabetes, chronic lung disease, or other underlying conditions) to not at-risk persons, VEs were similar or lower, but because baseline incidences were higher the VPDIs were approximately 2-10 times higher and NNVs 50-90% lower. CONCLUSION A public health analysis of pneumonia and IPD outcomes in a randomized controlled trial found substantial burden reduction following adult PCV13 immunization implemented in a setting with an ongoing infant PCV7-PCV10 program. VPDIs were higher among at-risk adults. FUNDING The original study and the current analysis were funded by Pfizer.

Review of vaccine effectiveness assumptions used in economic evaluations of infant pneumococcal conjugate vaccine

ABSTRACT Introduction: Pneumococcal conjugate vaccines (PCVs) have provided a significant clinical and economic impact globally. The majority of countries which have implemented an infant PCV program have observed a substantial reduction in the burden of invasive pneumococcal disease (IPD), pneumococcal pneumonia, and acute otitis media (AOM) due to vaccine serotypes. After 17 years of use, many countries have evaluated and re-evaluated the value of their vaccine program using cost-effectiveness analyses; however, many of these analyses do not reflect the current body of evidence. Areas covered: This literature review summarizes key assumptions used in cost-effectiveness analyses for PCVs and discusses whether these should be refined. Expert commentary: Many existing models continue to project cost-effectiveness of implementing a PCV program into a naïve population, despite sustained PCV use. Furthermore, many assumptions related to program effectiveness are based on evidence from controlled studies or extrapolated from vaccines that are no longer or were never used. Real world effectiveness data published from nearly 10 years of higher-valet vaccine use should be reflected in key assumptions that drive decision makers to choose one vaccine over another. As data continuously emerges, cost-effectiveness of programs should be evaluated in the context of the most current data.

Response to Mungall et al. letter to the editor on Streptococcus pneumoniae serotype 19A: worldwide epidemiology. Expert review of vaccines 2017;16(10):1007–27

We thank Mungall and colleagues for their interest in our manuscript that focused on serotype 19A. The letter addresses a diversity of issues beyond the original topic of our article. It also contains misinterpretation of the available literature. We address the most relevant: 1. ‘The cost-effectiveness results that Isturiz et al. allude to are also based on inaccurate assumptions around 19A efficacy for PHiD-CV as well as those around indirect protection and acute otitis media efficacy, and we refer the reader to a previous correction of these assumptions’ [1]. Reference [1] as cited by Mungall et al. was a letter to the editor in response to a cost-effectiveness publication by Wu and colleagues in 2016 [2]. This paper by Wu et al. was not referenced in our article. In addition, as data continuously emerge, cost-effectiveness of PCVs should be evaluated in the context of the most current data. We therefore refer the readers to a full and more recent review of the vaccine effectiveness (VE) assumptions used in economic evaluation of infant vaccination programs [3]. This review shows that the previous assumptions related to 19A effectiveness for PCV10 as well as those around indirect protection and ability to prevent acute otitis media are not consistent with the current body of evidence and may lead to spurious results in costeffectiveness evaluations published in recent years. 2. ‘PCV13 VE against serotype 3 has not been consistently demonstrated, with serotype-specific VE estimates reported by the majority of studies being not significantly different from zero.’ Our article focused on serotype 19A, andmade no reference to VE for serotype 3. However, in the interest of scientific accuracy, we think it essential to review the data. In summary, the above statement is inaccurate. The single primary reference cited by Mungall et al. is a study which was conducted in Catalonia, Spain [4]. Catalonia did not introduce PCV13 into the recommended program until January 2017. In this study, the reported statistical power for the VE estimate for serotype 3 invasive pneumococcal disease (IPD) in children for ≥1 dose was 23%. We conducted a systematic review of the literature and identified six published indirect cohort or case-control studies reporting the effectiveness of PCV13 against IPD associated with serotype 3 in children, using either at 2 + 1 or 3 + 1 regimen, including the study conducted in Spain [4–9]. When considering those studies with nonoverlapping datasets, all showed a positive VE estimate which ranged from 26% (2 + 1 regimen) to 80% (3 + 1 regimen). In addition, the Streptococcus pneumoniae Invasive Disease network (SpIDnet), which has been funded by the European Centre for Disease Prevention and Control (ECDC) since 2012 to perform active population-based surveillance of IPD in children across the European Union, has assessed PCV13 VE for serotype 3 [10,11]. In the largest indirect cohort analysis of PCV13 effectiveness reported to date, including data across nine sites in the EuropeanUnion, the PCV13 VE (adjusted for site, age, sex, underlying conditions, and year of notification) for serotype 3 IPD was 70% (95% confidence interval [CI]: 44–83) for at least one dose of PCV13 and 57% (95% CI: 5–81) for children who were fully vaccinated. The ECDC also recently reported the indirect effect of childhood PCV vaccination programs in the elderly across 13 sites in the European Union [12]. In sites with universal PCV10 vaccination, the incidence of serotype 3 IPD in adults aged ≥65 years increased in all sites (pooled increase of 58% in 2015 compared to 2010). In sites with universal PCV13 vaccination, the incidence of serotype 3 IPD in adults showed a pooled decrease of 11%. Scientific rigor requires that decisions about the utility of an intervention or the validity of a hypothesis not be based on the results of a single study, as results may vary from one study to the next and the dynamics of serotypes may vary per patient, season, calendar year, and geography. Rather, decisions on the utility of an intervention should be based on the totality of the evidence and such evidence demonstrates PCV13 provides direct protection for serotype 3. 3. ‘Surveillance data from countries using PHiD-CV indicate some variability in serotype 19A observations but does not suggest this is markedly different from what is seen with PCV13 use’. The above statement also is inaccurate and refuted by the totality of available evidence worldwide. In the aforementioned study by the ECDC, surveillance data from sites with universal PCV13 vaccination found that the incidence of serotype 19A IPD in adults aged ≥65 years declined in all sites (pooled decline of 40% in 2015). By contrast, in sites with universal PCV10 programs, serotype 19A increased in all sites (227% pooled increase in 2015). Finland, the Netherlands, Brazil, and Belgium all use PCV10 in their infant immunization programs. The most recent national population-based surveillance data from Finland, not included in the response by Mungall et al., found no net reduction in 19A IPD in the vaccine-eligible cohort following 6 years of PCV10 use [13]. Recent reports from the Netherlands

Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Disease Caused by Serotype 3 in Children: A Systematic Review and Meta-Analysis of Observational Studies

Abstract The 13-valent pneumococcal conjugate vaccine (PCV13) is the only licensed PCV with serotype 3 polysaccharide in its formulation. Postlicensure PCV13 effectiveness studies against serotype 3 invasive pneumococcal disease (IPD) in children have shown inconsistent results. We performed a systematic review and meta-analysis of observational studies to assess PCV13 vaccine effectiveness (VE) for serotype 3 IPD in children. We systematically searched PubMed, Embase, and the Cochrane library for studies published before 14 August 2017. We identified 4 published studies and 2 conference posters that provided PCV13 VE estimates stratified by serotype. The pooled PCV13 VE against serotype 3 IPD from the random-effects meta-analysis was 63.5% (95% confidence interval [CI], 37.3%–89.7%). A sensitivity analysis including conference posters gave a pooled VE estimate of 72.4% (95% CI, 56.7%–88.0%). The pooled data from case-control studies with similar methodologies and high quality support direct PCV13 protection against serotype 3 IPD in children.

Yearly Trends of Antimicrobial Non-susceptibility among Streptococcus pneumoniae Serotypes Causing Infections in Adult Patients in the United States (2009–2015)

Abstract Background The implementation of pneumococcal conjugate vaccination (PCV) in children with the 7-valent and 13-valent PCV in 2000 and 2010, respectively, has reduced the incidence of pneumococcal disease, nasopharyngeal carriage and changed the epidemiology of S. pneumoniae serotypes (STs). This study describes the yearly trends in antimicrobial non-susceptibility (NS) rates in pneumococci during 2009–2015. Methods 6,197 S. pneumoniae originated from patients (≥18 years old) seen/hospitalized in 105 US sites and recovered primarily (78.3%; 4,852/6,197) from lower respiratory tract specimens. Identification was performed by biochemical algorithms and/or PCR, and susceptibility (S) testing used broth microdilution. MIC interpretation applied CLSI criteria. The cpsB sequence was obtained by PCR or whole genome sequencing for STs determinations. Multiplex PCR and/or Quellung reactions were also performed, as needed. Results All isolates were highly S to levofloxacin (98.7–99.2%), vancomycin (100.0%), and linezolid (100.0%). PCV7 STs showed a reduction in the NS rates for penicillin G (PEN; from 30.3% in 2009 to 16.0% in 2015) and ceftriaxone (CRO; from 27.3% to 12.0%), as did PCV13 STs (from 34.5% to 16.0%% and from 27.5% to 8.6%, respectively). ST 19F showed stable S patterns over time and 19A remained the less S ST with high NS rates for PEN (49.0%–76.5%), CRO (24.5–64.8%), erythromycin (ERY; 76.9–90.8%), and clindamycin (CLI; 51.0–73.1%). These NS rates for 19A rose from 2009 to 2011–2012, decreasing in 2013–2016. NS rates for CLI and ERY against ST 3 increased to 19.6% and 23.9% in 2015, respectively. Non-vaccine STs showed stable NS rates for PEN, CRO, and CLI. However, an increasing trend for ERY NS (from 35.2% in 2009 to 45.0% in 2015) was noted, which was driven by increasing NS rates for 35B (from 42.3% in 2009 to 71.2% in 2015). Conclusion PCV13 ST exhibited decreasing trends for NS during the study period, except for ST 3, which showed stable S rates over time. Overall, implementation of PCV13 decreased considerably the NS rates in S. pneumoniae causing infections in the US adult population. Further surveillance will enhance understanding of future antimicrobial patterns in S pneumoniae in the context of adult pneumococcal vaccination programs. Disclosures R. E. Mendes, Pfizer, Inc.: Research Contractor, Research grant; H. L. Sings, Pfizer, Inc.: Employee, Salary; J. A. Suaya, Pfizer, Inc.: Employee, Salary; L. N. Woosley, Pfizer, Inc.: Research Contractor, Research grant; R. K. Flamm, Pfizer, Inc.: Research Contractor, Research grant; R. E. Isturiz, Pfizer, Inc.: Employee, Salary

Distributions and Annual Changes of Streptococcus pneumoniae Serotypes Causing Infections in Adult Patients: Eight Years of US Surveillance (2009-2016)

Abstract Background A pneumococcal polysaccharide vaccine (PPSV23) has been available for use in adults ≥65 years old since 1983 with vaccination rates of ~65% in the past decade. A conjugate vaccine (PCV13) has been recommended for adults since 2014, and for children since 2010 (replaced PCV7 which was used since 2000). The serotype distribution of pneumococci causing infections in adult patients in the US was evaluated. Methods 6,491 S. pneumoniae isolates were collected from patients (≥18 years old) seen/hospitalized in 105 US centers and recovered primarily (77.8%; 5,052/6,491) from lower respiratory tract specimens. Identification was performed by biochemical algorithms and/or PCR. The cpsB sequence was obtained by PCR or next genome sequencing for serotype determination. Multiplex PCR and/or Quellung reaction were performed, as needed. Results 19F was the most prevalent PCV7 serotypes with annual rates of 1.6–3.1%, but no trends were observed for this serotype during the period. Overall, PCV13 serotype prevalence declined considerably from 38.6% in 2009 to 23.1% in 2016, but rates remained stable during 2013–2016 (21.5–24.6%). Serotype 19A (12.4%) and 3 (9.1%) were the most common PCV13 serotypes (2009–2016), followed by 7F (2.4%). Prevalence of 19A and 7F declined from 17.5% to 7.1% and from 4.6% to 0.7%, respectively, while the prevalence of serotype 3 remained stable. The proportion of non-vaccine serotypes increased, as did PPSV23 (non-PCV13). Among non-vaccine serotypes, 35B (8.1%), 23A (6.2%), and 6C/6D (5.8%) were the most common, followed by 23B (4.8%) and 15A/15F (4.8%). Prevalence of serotype 35B (from 3.9% to 12.6%) and 23B (from 3.7% to 7.8%) increased considerably during the study period. Serotypes 23A and 15A/15F remained stable throughout; however, serotype 6C/6D decreased from 7.6% to 3.4%. Conclusion Prevalence of serotype 19F remained low and stable during the study period. PCV13 serotypes declined considerably, but serotypes 19A and 3 remained elevated. The consistent increase of non-vaccine serotypes, especially 35B, may be a reason for concern since it exhibits decreased susceptibility to β-lactams. Continued surveillance is needed to constantly assess the dynamic changes of serotypes affecting the adult US population. Disclosures R. E. Mendes, Pfizer, Inc.: Research Contractor, Research grant; H. L. Sings, Pfizer, Inc.: Employee, Salary; B. Hilton, Pfizer, Inc.: Employee, Salary; T. P. Doyle, Pfizer, Inc.: Research Contractor, Research grant; L. N. Woosley, Pfizer, Inc.: Research Contractor, Research grant; R. K. Flamm, Pfizer, Inc.: Research Contractor, Research grant; R. E. Isturiz, Pfizer, Inc.: Employee, Salary