The broader impacts of otitis media and sequelae for informing economic evaluations of pneumococcal conjugate vaccines.

INTRODUCTION: Otitis media (OM) is a common childhood infection. Pneumococcal conjugate vaccines (PCVs) prevent OM episodes, thereby reducing short- and long-term clinical, economic, humanistic, and societal consequences. Most economic evaluations of PCVs focus on direct health gains and cost savings from prevented acute episodes but do not fully account for the broader societal impacts of OM prevention. AREAS COVERED: This review explores the broader burden of OM on children, caregivers, and society to better inform future economic evaluations of PCVs. EXPERT OPINION: OM causes a substantial burden to society through long-term sequelae, productivity losses, reduced quality of life for children and caregivers, and contribution to antimicrobial resistance from inappropriate antibiotic use. The effect of PCVs on acute OM has been recognized globally, yet the broader impact has not been consistently quantified, studied, or communicated. Economic evaluations of PCVs must evolve to include broader effects for patients, caregivers, and society from OM prevention. Future PCVs with broader coverage may further reduce OM incidence and antimicrobial resistance, but optimal uptake will depend on increasing the recognition and use of novel frameworks that include broader benefits. Communicating the full value of PCVs to decision makers may result in wider access and positive societal returns.

Public health impact of pneumococcal conjugate vaccination: a review of measurement challenges.

INTRODUCTION: Modeling analyses have attempted to quantify the global impact of pneumococcal conjugate vaccines (PCVs) on pneumococcal disease (PD), however these pediatric models face several challenges in obtaining comprehensive impact measurements. AREAS COVERED: We present several measurement challenges and discuss examples from recently published pediatric modeling evaluations. Challenges include estimating the number of infants fully or partially vaccinated with PCVs, inclusion of indirect effects of vaccination, accounting for various dosing schedules, capturing effect of PCVs on nonspecific, noninvasive PD, and inclusion of adult PCV use. EXPERT OPINION: The true impact of PCVs has been consistently underestimated in published analyses due to multiple measurement challenges. Nearly 100 million adults are estimated to have received PCV13 over the last decade globally, potentially preventing up to 662 thousand cases of PD. Approximately 4.1 million cases of invasive PD alone may have been averted through indirect protection. Estimates of PCV impact on noninvasive PD remain a challenge due to altered epidemiology. Program switches, incomplete vaccination, and private market uptake among children also confound PD impact estimates. Taken together, the number of averted PD cases from PCV use in the last ten years may be up to three times higher than estimated in previous studies.

Pneumococcal Conjugate Vaccine Impact on Serotype 3: A Review of Surveillance Data.

INTRODUCTION: Limited changes in serotype 3 invasive pneumococcal disease (IPD) incidence rates after a decade of 13-valent pneumococcal conjugate vaccine (PCV13) introduction into several national immunization programs (NIP) have raised questions about PCV13's effectiveness against this serotype. METHODS: We analyzed the impact of pediatric PCV programs on serotype 3 IPD with two approaches. First, we reviewed the publicly available surveillance data from countries identified in two recently published reviews to describe the population impact of pediatric PCV13 or PCV10 vaccination programs on serotype 3 IPD. We then compared the observed trends in PCV10 and PCV13 countries to a previously described dynamic transmission model that simulates the spread of pneumococcal carriage and development of IPD in a population over time. RESULTS: When serotype 3 disease rates are compared from countries that have introduced either a 10-valent (PCV10) vaccine that does not contain serotype 3 in its formulation or PCV13 in their pediatric NIP, over time, serotype 3 incidence rate trends are markedly different. Countries with a PCV10 NIP showed a substantial linear increase in serotype 3 pneumococcal disease among all age groups since the time of PCV10 introduction, whereas countries with a PCV13 NIP experienced a modest decline during the 3-4 years after vaccine introduction followed by an inflection upward in subsequent years. CONCLUSION: These data suggest that PCV13 provides a certain degree of direct and indirect protection against serotype 3 at the population level and direct adult vaccination with a serotype 3-containing vaccine is likely to provide substantial benefit in the context of a pediatric PCV NIP. Further research around serotype 3 transmission patterns and epidemiology is nonetheless warranted.

Streptococcus pneumoniae serotype distribution and antimicrobial nonsusceptibility trends among adults with pneumonia in the United States, 2009‒2017.

Background In the United States, the 13-valent pneumococcal conjugate vaccine has been recommended for children since 2010 and for adults aged ≥65 years since 2014. We assessed S. pneumoniae antimicrobial nonsusceptibility among adults with suspected pneumonia from hospital settings. Methods Isolates were collected from 105 US sites between 2009 and 2017 in the SENTRY Antimicrobial Surveillance Program. Clinical and Laboratory Standards Institute methods were used for susceptibility testing. Serotypes were determined by cpsB sequence obtained by PCR or whole genome sequencing, plus multiplex PCR and/or Neufeld Quellung reactions as needed. Findings Of 7254 S. pneumoniae isolates analyzed, 63.6% and 36.4% were from patients aged 18‒64 and ≥65 years, respectively. Among all isolates, penicillin and ceftriaxone nonsusceptibility declined by 72.3% and 73.8%, respectively, with smaller changes observed for other antibiotics. Nonsusceptibility patterns were serotype-specific; for example, nonsusceptibility was relatively stable for serotype 19A but declined for 19F. Simultaneously, the percentage of serotype 19A isolates decreased from 17.4% to 3.9%, whereas for serotype 19F this percentage increased from 2.8% to 5.0%. The percentage of serotype 3 isolates that were nonsusceptible increased for select antibiotic classes, and the percentage of serotype 3 among all isolates increased minimally from 10.2% to 11.8%. Interpretation Overall pneumococcal nonsusceptibility patterns were influenced by distinct patterns within serotypes, indicating the likelihood of serotype-specific resistance mechanisms. Serotype 19A observations were consistent with vaccine-induced reductions in circulation with no change in the organism susceptibility, whereas the nonsusceptibility increases for serotypes 3 and 19F may indicate circulation of more antibiotic-resistant clones.

Health and Economic Impact of Routine Pediatric Pneumococcal Immunization Programs in Canada: A Retrospective Analysis.

OBJECTIVE: A model was developed to estimate the historical impact (including total societal health and economic benefit) of pneumococcal conjugate vaccine (PCV) programs in the overall Canadian population between 2005 and 2015, inclusively. METHODS: Historical incidence of invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM) were obtained from epidemiologic databases supplemented with published and unpublished data. Two scenarios were considered: (1) the observed historical incidence from 2005 to 2015 in the setting of PCV use; (2) a hypothetical scenario in which we estimated the number of disease cases assuming no PCV use. Disease cases averted as a result of PCV programs were calculated by subtracting the number of observed historical cases from the number of estimated cases expected in the absence of PCV use. RESULTS: PCV programs were estimated to have saved 6631 lives and averted 14,990 IPD cases, 735,700 pneumonia episodes, and 3,697,993 AOM episodes. Positive clinical outcomes resulted in total cost savings of CAD $1.76 billion over 11 years. Vaccination costs were offset by the direct medical cost savings from fewer cases of IPD, pneumonia, and AOM. CONCLUSIONS: Canadian PCV programs have provided significant health benefits and resulted in a substantial value for money. Net savings achieved over the reviewed period would have provided funding for $1.76 billion in other health care costs or public health initiatives. These findings highlight the importance of considering the total value of a vaccination program, rather than vaccine acquisition costs only, when assessing the value of immunization programs.

The impact of pneumococcal conjugate vaccines on serotype 19A nasopharyngeal carriage.

Introduction: By preventing nasopharyngeal carriage acquisition among vaccinated persons, and thus reducing transmission, pneumococcal conjugate vaccines (PCVs) provide protection against pneumococcal vaccine serotypes among unvaccinated individuals. This systematic review assessed PCVs containing serotype 19A or cross-reactive 19F for 19A carriage effects.Areas covered: Peer-reviewed literature was searched for manuscripts published between 1/1/2000 and 06/18/2018 assessing the impact of PCV on 19A carriage.Expert opinion: Fifty-five, 12, and 32 articles were identified for PCV7, PCV10, and PCV13, respectively. In two of four PCV7 randomized controlled trials (RCTs), 19A carriage was significantly higher in PCV7-vaccinated vs control subjects; in two of two PCV10 RCTs, there was no significant difference in 19A carriage and acquisition between PCV10-vaccinated (2 + 1 schedule) vs control subjects, apart from one timepoint (3 + 1 schedule); and one of one RCTs of PCV13 showed significant decreases in 19A carriage and acquisition in PCV13- vs PCV7-vaccinated (3 + 1 schedule) children. These findings were consistent with observational studies in which an increase or no change in 19A carriage was observed in 91% and 67% of PCV7 and PCV10 studies, respectively, whereas 87% of PCV13 studies documented a decrease. Countries in which serotype 19A transmission is substantial should consider the use of vaccines containing serotype 19A.

The impact of routine childhood immunization with higher-valent pneumococcal conjugate vaccines on antimicrobial-resistant pneumococcal diseases and carriage: a systematic literature review.

Introduction: The introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in childhood immunization programs reduced antimicrobial-resistant pneumococcal infections by vaccine serotypes. However, emerging antimicrobial-resistant non-vaccine serotypes, particularly serotype 19A, attenuated the overall effect. In 2010, higher-valent PCVs became available containing serotypes that are prone to become antimicrobial-resistant, like serotype 7F in PCV10 and PCV13, and serotype 19A in PCV13.Areas covered: This review evaluated literature published between June 1, 2008 and June 1, 2017 reporting on the effect of PCV10 or PCV13 implementation in routine infant immunization schedules on antimicrobial-resistant invasive pneumococcal disease (IPD), otitis media (OM), and nasopharyngeal carriage (NPC) in children and adults.Expert opinion: In countries with relatively high prior pneumococcal antimicrobial resistance (AMR), PCV13 childhood vaccination programs have reduced antimicrobial-resistant IPD, OM, and NPC in children and IPD in adults. The effectiveness of PCV13 against serotype 19A is likely an important contributing factor. Only few studies have documented the impact of PCV10 on AMR. Multiple factors may influence observed decreases in pneumococcal AMR including antimicrobial stewardship, case definition, time since PCV10/13 introduction, and pre-PCV10/13 AMR levels. This review emphasizes the importance of including impact on AMR when evaluating the full public health of pneumococcal vaccination programs.

Pneumococcal conjugate vaccine against serotype 3 pneumococcal pneumonia in adults: A systematic review and pooled analysis.

BACKGROUND: Serotype 3 pneumococcal disease has not substantially declined at the population level after the routine introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into pediatric immunization programs across the globe. This epidemiological finding has generated debate regarding the effectiveness of PCV13 against serotype 3 disease. Evaluating PCV13 effectiveness against serotype 3 is especially critical in adults, where serotype 3 makes up an important amount of remaining pneumococcal disease. METHODS: We performed a systematic review of the published literature to assess the direct effectiveness of PCV13 against serotype 3 community-acquired pneumonia (CAP) among adults. We then estimated overall vaccine effectiveness (VE) using a pooled analysis of the individual-level, raw data. RESULTS: Two published studies met inclusion criteria. One was a randomized controlled trial conducted in the Netherlands and published in 2014. The other was a recently-published case-control study conducted in Louisville, Kentucky that used a test-negative design (TND). We also identified a third TND study conducted in Argentina that was recently presented as a conference abstract but is not yet published. All three studies were conducted in adults aged ≥65 years. PCV13 VE against serotype 3 hospitalized CAP was 52.5% (95%CI: 6.2-75.9%) from the pooled analysis of individual-level data from all three studies. Results were similar if the unpublished estimate was excluded (serotype 3 VE = 53.6% [95%CI: 6.7-76.9%]). No heterogeneity was observed. CONCLUSIONS: Currently-available evidence, although limited to three studies, suggests that PCV13 provides direct protection against serotype 3 hospitalized CAP in adults aged ≥65 years.

A post-hoc analysis of serotype-specific vaccine efficacy of 13-valent pneumococcal conjugate vaccine against clinical community acquired pneumonia from a randomized clinical trial in the Netherlands.

BACKGROUND: Serotype-specific vaccine efficacy (VE) against adult community acquired pneumonia (CAP) remains poorly defined, yet such data are important for assessing the utility of adult pneumococcal conjugate vaccine (PCV) programs. METHODS: We evaluated the Community Acquired Pneumonia Immunization Trial in Adults to assess serotype-specific VE for CAP. This parallel-arm randomized clinical trial assessed 13-valent PCV (PCV13) VE among community dwelling persons aged ≥65 years in The Netherlands. In the original analysis, PCV13 VE against first episodes of vaccine-type (VT) chest radiology confirmed CAP was 45.6% (95% confidence interval [CI] 21.8-62.5%). Unlike the original analysis, we included any subject that met a clinical definition of CAP regardless of radiographic findings. VT-CAP was identified by culture (sterile or non-sterile) or serotype-specific urinary antigen detection (SSUAD) test. Only the five serotypes with at least 10 episodes in the control arm, based on the original analysis, were included for VE assessment. RESULTS: Of 272 clinical CAP visits with VT serotypes identified, 253 (93%) were identified by SSUAD including 210 (77%) by SSUAD alone. VE was determined for serotypes 1, 3, 6A, 7F, and 19A, with total first episodes of, respectively, 27, 36, 25, 38, and 48. VE (95%CI) for the five evaluated serotypes against first clinical CAP episodes were: serotype 1, 20.0% (-83.1% to 65.8%); serotype 3, 61.5% (17.6-83.4%); serotype 6A, 33.3% (-58.6% to 73.2%); serotype 7F, 73.3% (40.5-89.4%); and serotype 19A, 45.2% (-2.2% to 71.5%). DISCUSSION: Statistically significant VE was observed for serotypes 3 and 7F for clinical CAP among elderly community dwelling adults. The VE point estimates and CIs for serotypes 1, 6A, and 19A were lower but consistent with the overall VT-CAP VE of 45.6% previously reported. These findings may be relevant in models to accurately account for the potential impact of adult PCV13 immunization.

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.

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.

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.

Clinical and Economic Impact of a Potential Switch from 13-Valent to 10-Valent Pneumococcal Conjugate Infant Vaccination in Canada.

INTRODUCTION: Pneumococcal conjugate vaccines (PCVs) have been available in Canada since 2001, with 13-valent PCV (PCV13) added to the infant routine immunization program throughout all Canadian provinces by 2011. The use of PCVs has dramatically reduced the burden of pneumococcal disease in Canada. As a result, decision-makers may consider switching from a more costly, higher-valent vaccine to a lower-cost, lower-valent vaccine in an attempt to allocate funds for other vaccine programs. We assessed the health and economic impact of switching the infant vaccination program from PCV13 to 10-valent PCV (PCV10) in the context of the Canadian health care system. METHODS: We performed a review of Canadian databases supplemented with published and unpublished data to obtain the historical incidence of pneumococcal disease and direct and indirect medical costs. Observed invasive pneumococcal disease (IPD) trends from surveillance data were used as a basis to forecast the future number of cases of IPD, pneumococcal pneumonia, and acute otitis media given a PCV13- or PCV10-based program. Costs and outcomes over 10 years were then estimated and presented in 2017 Canadian dollars discounted at 3% per year. RESULTS: Switching from PCV13 to PCV10 would result in an additional 762,531 cases of pneumococcal disease over 10 years. Although PCV13 has a higher acquisition cost, switching to PCV10 would increase overall costs by over $500 million. Forecasted overall disease incidence was estimated substantially higher with PCV10 than with PCV13 primarily because of the potential reemergence of serotypes 3 and 19A. PCV13 was also cost saving compared with PCV10, even within a 5-year time horizon. Probabilistic sensitivity analysis showed that a PCV13-based program remained cost saving in all simulations. CONCLUSION: Although switching to a PCV10-based infant vaccination program in Canada might result in lower acquisition costs, it would also result in higher public health cost and burden because of serotype reemergence. FUNDING: Pfizer Inc.

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

Background: Following universal recommendation for use of 13-valent pneumococcal conjugate vaccine (PCV13) in US adults aged ≥65 years in September 2014, we conducted the first real-world evaluation of PCV13 vaccine effectiveness (VE) against hospitalized vaccine-type community-acquired pneumonia (CAP) in this population. Methods: Using a test-negative design, we identified cases and controls from a population-based surveillance study of adults in Louisville, Kentucky, who were hospitalized with CAP. We analyzed a subset of CAP patients enrolled 1 April 2015 through 30 April 2016 who were aged ≥65 years and consented to have their pneumococcal vaccination history confirmed by health insurance records. Cases were defined as hospitalized CAP patients with PCV13 serotypes identified via culture or serotype-specific urinary antigen detection assay. Remaining CAP patients served as test-negative controls. Results: Of 2034 CAP hospitalizations, we identified PCV13 serotypes in 68 (3.3%) participants (ie, cases), of whom 6 of 68 (8.8%) had a positive blood culture. Cases were less likely to be immunocompromised (29.4% vs 46.4%, P = .02) and overweight or obese (41.2% vs 58.6%, P = .01) compared to controls, but were otherwise similar. Cases were less likely to have received PCV13 than controls (3/68 [4.4%] vs 285/1966 [14.5%]; unadjusted VE, 72.8% [95% confidence interval, 12.8%-91.5%]). No confounding was observed during adjustment for patient characteristics, including immunocompromised status, body mass index, and history of influenza and pneumococcal polysaccharide vaccination (adjusted VE range, 71.1%-73.3%). Conclusions: Our study is the first to demonstrate real-world effectiveness of PCV13 against vaccine-type CAP in adults aged ≥65 years following introduction into a national immunization program.

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

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.

Streptococcus pneumoniae serotype 19A: worldwide epidemiology.

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.