Pneumococcal Vaccination in Children: A Systematic Review and Meta-Analysis of Cost-Effectiveness Studies.

OBJECTIVES: Pneumococcal conjugate vaccines (PCVs) have significantly reduced disease burden caused by Streptococcus pneumoniae, a leading cause of childhood morbidity and mortality globally. This systematic review and meta-analysis aimed to assess the incremental net benefit (INB) of the 13-valent PCV (PCV13) and 10-valent PCV (PCV10) in children. METHODS: We performed a comprehensive search in several databases published before May 2022. Studies were included if they were cost-effectiveness or cost-utility analyses of PCV13 or PCV10 compared with no vaccination or with each other in children. Various monetary units were converted to purchasing power parity, adjusted to 2021 US dollars. The INBs were calculated and then pooled across studies stratified by country income level, perspective, and consideration of herd effects, using a random-effect model. RESULTS: Seventy studies were included. When herd effects were considered, PCV13 was cost-effective compared with PCV10 from the payer perspective in both high-income countries (HICs) (INB, $103.94; 95% confidence interval, $75.28-$132.60) and low- and middle-income countries (LMICs) (INB, $53.49; 95% confidence interval, $30.42-$76.55) with statistical significance. These findings were robust across a series of sensitivity analyses. PCV13 was cost-effective compared with no vaccination across perspectives and consideration of herd effects in both HICs and LMICs, whereas findings were less consistent for PCV10. CONCLUSION: PCVs were generally cost-effective compared with no vaccination in HICs and LMICs. Our study found that PCV13 was cost-effective compared with PCV10 when herd effects were considered from the payer perspective in both HICs and LMICs. The results are sensitive to the consideration of herd effects.

Cost-utility and cost-benefit analysis of pediatric PCV programs in Egypt.

New vaccine introductions (NVIs) raise issues of value for money (VfM) for self-financing middle-income countries like Egypt. We evaluate a pediatric pneumococcal conjugate vaccine (PCV) NVI in Egypt from health payer and societal perspectives, using cost-utility and cost-benefit analysis (CUA, CBA). We evaluate vaccinating 100 successive birth cohorts with the 13-valent PCV ("PCV13") and the 10-valent PCV ("PCV10") relative to no vaccination and each other. We quantify health effects with a disease incidence projection model and a multiple-cohort static disease model. Our CBA uses a health-augmented lifecycle model to generate willingness-to-pay for health gains from which we calculate rates of return (RoR). We obtain parameters from the published literature. We perform deterministic and probabilistic sensitivity analysis. Our base-case CUA finds incremental cost-effectiveness ratios (ICERs) for PCV13 and PCV10 relative to no program of $926 (95% confidence interval $512-$1,735) and $1,984 ($1,186-$3,805) per quality-adjusted life year (QALY), respectively; and for PCV13 relative to PCV10 of $174 ($88-$331) per QALY. Our base-case CBA finds RoRs to PCV13 and PCV10 relative to no program of 488% (188-993%) and 164% (33-336%), respectively, and to PCV13 relative to PCV10 of 3109% (1410-6602%). Both CUA and CBA find PCV13 to be good VfM relative to PCV10.

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.

A systematic literature review of economic evaluations of pneumococcal conjugate vaccines in east and southeast Asia (2006-2019).

INTRODUCTION: Pneumococcal infections can lead to serious invasive diseases such as meningitis, septicemia and pneumonia, as well as milder but more common illnesses such as sinusitis and otitis media. The World Health Organization (WHO) recommends the inclusion of pneumococcal conjugate vaccines (PCVs) in infant National Immunization Program (NIP) programs worldwide. Decision-makers in Asian countries planning to introduce PCVs in their respective NIP will need a comprehensive evidence of effectiveness of PCVs at the population level and economic evidence including cost-effectiveness. AREAS COVERED: A systematic literature review (from 1/1/2016 to 10/11/2019) of PCVs in East and Southeast Asia to understand (1) the contributing factors to cost-effectiveness results of PCVs and (2) whether gaps in evidence exist suggesting why the region may have yet to implement full NIPs. EXPERT OPINION: In East and Southeast Asia, vaccination with PCVs was found to significantly reduce the mortality and morbidity of pneumococcal diseases and was cost-effective compared to no vaccination. Study assumptions, specifically vaccine local acquisition, the inclusion or exclusion of indirect effects (serotype replacement and herd effect), cross-protection, and protection against nontypeable haemophilus influenzae and serotype 3, were the main drivers of cost-effectiveness.

Reply letter to "response to article by Johnna Perdrizet et al." by Gomez and colleagues.

This communication seeks to address the questions and criticisms issued by Gomez and colleagues in their letter on our original study "Cost-effectiveness analysis of replacing the 10-valent pneumococcal conjugate vaccine (PCV10) with the 13-valent pneumococcal conjugate vaccine (PCV13) in Brazil infants." Gomez and colleagues are concerned that the assumptions used in our model may have unintended negative impacts for Brazil decision-making and we intend to clarify any potential misinterpretation of our assessment.

Clinical and Economic Burden of Pneumococcal Disease Due to Serotypes Contained in Current and Investigational Pneumococcal Conjugate Vaccines in Children Under Five Years of Age.

INTRODUCTION: The widespread implementation of pneumococcal conjugate vaccines (PCVs) has significantly reduced the burden of pneumococcal disease around the world. Although licensed 10-valent (PCV10) and 13-valent (PCV13) vaccines have considerably reduced mortality and morbidity, a sizeable disease burden attributable to serotypes not contained in these PCVs remains. This study aimed to estimate the annual clinical and economic burden of pneumococcal disease attributable to licensed (PCV10 and PCV13) and investigational PCVs, notably 15-valent (PCV15) and 20-valent (PCV20) vaccines, in 13 countries in children under 5 years of age. METHODS: A decision-analytic model was created to aggregate total cases [inclusive of invasive pneumococcal disease (IPD), pneumonia, and otitis media (OM)], deaths, and direct costs in each country of interest [stratified by PCV10/PCV13 countries, depending on national immunization programs (NIPs)] over 1 year, using up to the three most recent years of available serotype coverage data. Data inputs were sourced from local databases, surveillance reports, and published literature. RESULTS: In 5 PCV10 NIPs (Austria, Finland, Netherlands, New Zealand, Sweden), most remaining PCV20-type disease was due to PCV13-unique serotypes (30-85%), followed by PCV20-unique (9-50%), PCV15-unique (4-15%), and PCV10-unique (2-14%) serotypes. In 8 PCV13 NIPs (Australia, Canada, France, Germany, Italy, South Korea, Spain, United Kingdom), most remaining PCV20-type disease was caused by PCV20-unique serotypes (16-69%), followed by PCV13-unique (11-54%), PCV15-unique (2-33%), and PCV10-unique serotypes (3-19%). Across all countries, PCV20 serotypes caused 3000 to 345,000 cases of disease and cost between $1.3 and $44.9 million USD annually with variability driven by population size, NIP status, and epidemiologic inputs. In aggregate, PCV20 serotypes caused 1,234,000 cases and $213.5 million in annual direct medical costs in children under 5 years of age. CONCLUSION: Despite the success of PCV10 and PCV13 in reducing pneumococcal disease, a substantial clinical and economic burden remains due to serotypes contained in investigational vaccines.

Estimating the Public Health and Economic Impact of Introducing the 13-Valent Pneumococcal Conjugate Vaccine or 10-Valent Pneumococcal Conjugate Vaccines into State Immunization Programs in India.

INTRODUCTION: Although the pneumococcal conjugate vaccine (PCV) has been introduced into select state immunization programs (SIPs) in India, many children remain unvaccinated. Recently, India's Advisory Committee on Vaccines & Immunization Practices recommended PCV on the pediatric immunization schedule nationally. This study estimates the public health and economic impact of introducing either Pfizer's 13-valent PCV (PCV13-PFE), GlaxoSmithKline's 10-valent PCV (PCV10-GSK), or Serum Institute of India's 10-valent PCV (PCV10-SII) into every pediatric SIP. METHODS: A model was developed to predict the disease cases, deaths, and costs associated with implementing PCV13-PFE, PCV10-GSK, or PCV10-SII in SIPs compared to no vaccination program across a 5-year period (2021-2025). State and national-level uptake rate and clinical and economic input parameters were collected from published literature. Disease outcomes included invasive pneumococcal disease, inpatient and outpatient pneumonia, and otitis media. Costs were estimated as vaccine-related costs and direct medical costs incurred to the healthcare system. Results were reported by individual state and aggregated nationally. RESULTS: Estimated over 5 years, implementing PCV13-PFE in SIPs could avert 12.1 million cases and save 626,512 lives among children under 5 years old compared to no vaccination. This corresponds to net national cost savings of over $1.0 billion. Both lower-valent PCVs are estimated to provide less economic savings than PCV13-PFE inclusive of vaccine-related costs. Compared with PCV13-PFE, implementing PCV10-GSK or PCV10-SII nationally is estimated to have a smaller public health impact, with PCV10-GSK averting 8.4 million cases (436,577 deaths) and PCV10-SII preventing 10.3 million cases (531,545 deaths) in India compared to no vaccination, respectively. CONCLUSION: Implementation of PCV13-PFE throughout India is estimated to provide greater public health and economic benefits than PCV10-GSK or PCV10-SII SIPs. Our analysis highlights the substantial disease cases, deaths, and health system cost savings that may be realized from implementing PCV programs throughout India.

Retrospective Impact Analysis and Cost-Effectiveness of the Pneumococcal Conjugate Vaccine Infant Program in Australia.

Australia introduced the 7-valent pneumococcal conjugate vaccine (7vPCV) on the universal infant National Immunisation Program (NIP) in 2005 and replaced it with the 13-valent pneumococcal conjugate vaccine (13vPCV) in 2011, both under a 3 + 0 schedule. The objective of this analysis was to quantify the clinical and economic impact of the universal infant PCV program in Australia from its introduction. A decision-analytic model was developed to estimate the historical impact of pneumococcal conjugate vaccine (PCV) programs in Australia from a direct health care perspective. Historical incidence of invasive pneumococcal disease (IPD), pneumonia, and otitis media (OM) were obtained from available Australian epidemiologic databases supplemented with published data. Costs were from Medicare Benefits Schedule in 2018 Australian dollars and utility weights from published sources. Historical observed changes in disease for the universal PCV NIP era (2005-2017) were compared against a "no-vaccine" scenario. The expected incidence for the no-vaccine scenario in years 2005-2017 was calculated using pre-universal PCV NIP era (2001-2004) data. Averted cases, deaths, incremental costs, and quality-adjusted life years (QALYs) were obtained by subtracting the vaccine scenario totals from the no-vaccine scenario totals. From the inclusion in the universal infant NIP, 7vPCV and 13vPCV are estimated to have prevented 1,770,024 cases of pneumococcal disease (IPD = 16,392; OM = 1,575,491; pneumonia = 102,059) and 1195 associated deaths. Over this period, there was a total 24,335 QALYs gained. Costs for the universal infant NIP were offset by $733 million direct costs saved, resulting in an incremental cost-effectiveness ratio of $3347 per QALY gained. PCVs have provided substantial public health and economic value from sustained use in Australia. Results are conservative, since long-term pneumococcal disease consequences and broader socioeconomic benefits were not considered. Maintaining 13vPCV on the Australian infant NIP under the newly implemented 2 + 1 schedule will likely provide more return on investment and sustained reductions in pneumococcal disease.

Cost-effectiveness analysis of replacing the 10-valent pneumococcal conjugate vaccine (PCV10) with the 13-valent pneumococcal conjugate vaccine (PCV13) in Brazil infants.

Brazil currently has a 10-valent pneumococcal conjugate vaccine (PCV10) pediatric national immunization program (NIP). However, in recent years, there has been significant progressive increases in pneumococcal disease attributed to serotypes 3, 6A, and 19A, which are covered by the 13-valent PCV (PCV13). We sought to evaluate the cost-effectiveness and budget impact of switching from PCV10 to PCV13 for Brazilian infants from a payer perspective. A decision-analytic model was adapted to evaluate the clinical and economic outcomes of continuing PCV10 or switching to PCV13. The analysis estimated future costs ($BRL), quality-adjusted life-years (QALYs), and health outcomes for PCV10 and PCV13 over 5 y. Input parameters were from published sources. Future serotype dynamics were predicted using Brazilian and global historical trends. Over 5 y, PCV13 could prevent 12,342 bacteremia, 15,330 meningitis, 170,191 hospitalized pneumonia, and 25,872 otitis media cases, avert 13,709 pneumococcal disease deaths, gain 20,317 QALYs, and save 172 million direct costs compared with PCV10. The use of PCV13 in the Brazilian NIP could reduce pneumococcal disease, improve population health, and save substantial health-care costs. Results are reliable even when considering uncertainty for possible serotype dynamics with different underlying assumptions.

Cost-effectiveness of a national immunization program with the 13-valent pneumococcal conjugate vaccine compared with the 10-valent pneumococcal conjugate vaccine in South Korea.

INTRODUCTION: Globally, pneumococcal disease represents a significant burden. South Korea implemented the 7-valent pneumococcal conjugate vaccine (PCV7) in 2003, replaced with the 10-valent (PCV10) and 13-valent (PCV13) vaccine in 2010. In 2014, both vaccines were introduced in the national immunization program (NIP) for infants with 3 primary doses and one booster dose We performed a cost-effectiveness evaluation to elucidate which vaccine may be expected to provide greater impact if included in a NIP. METHODOLOGY: Using an established model, we estimated the impact of introducing either PCV13 or PCV10 into the South Korean NIP in 2015. Vaccine impact was based on historic observed impact of PCV13 from 2010 to 2015 in Korea given high uptake of PCV13, and PCV10 impact was estimated based on experiences in countries using PCV10. Incidence and costs for all ages and including invasive pneumococcal disease, pneumonia, and acute otitis media were derived from the literature and Health Insurance Review and Assessment database. RESULTS: In the base-case, over 5-years PCV13 was estimated to avert 550,000 more cases of pneumococcal disease compared to PCV10, driven by broader serotype coverage and less replacement due to serotypes 3 and 19A. This translated to a cost-savings of $47.4 million USD despite PCV13's higher cost. Sensitivity analysis found incremental cost-effectiveness ratios (ICERs) ranged from cost-saving to $7,300 USD per quality-adjusted life year (QALY). CONCLUSION: A NIP using PCV13 was estimated to have a more substantial public health impact and be cost-saving compared to a program with PCV10 due to broader serotype coverage.

Estimating the Impact of Switching from a Lower to Higher Valent Pneumococcal Conjugate Vaccine in Colombia, Finland, and The Netherlands: A Cost-Effectiveness Analysis.

INTRODUCTION: Widespread use of ten-valent (Synflorix™, GSK) or 13-valent (Prevenar 13™; Pfizer) conjugate vaccination programs has effectively reduced invasive pneumococcal disease (IPD) globally. However, IPD caused by serotypes not contained within the respective vaccines continues to increase, notably serotypes 3, 6A, and 19A in countries using lower-valent vaccines. Our objective was to estimate the clinical and economic benefit of replacing PCV10 with PCV13 in Colombia, Finland, and The Netherlands. METHODS: Country-specific databases, supplemented with published and unpublished data, informed the historical incidence of pneumococcal disease as well as direct and indirect medical costs. A decision-analytic forecasting model was applied, and both costs and outcomes were discounted. The observed invasive pneumococcal disease (IPD) trends from each country were used to forecast the future number of IPD cases given a PCV13 or PCV10 program. RESULTS: Over a 5-year time horizon, a switch to a PCV13 program was estimated to reduce overall IPD among 0-2 year olds by an incremental - 37.6% in Colombia, - 32.9% in Finland, and - 26% in The Netherlands, respectively, over PCV10. Adults > 65 years experienced a comparable incremental decrease in overall IPD in Colombia (- 32.2%), Finland (- 15%), and The Netherlands (- 3.7%). Serotypes 3, 6A, and 19A drove the incremental decrease in disease for PCV13 over PCV10 in both age groups. A PCV13 program was dominant in Colombia and Finland and cost-effective in The Netherlands at 1 × GDP per capita (€34,054/QALY). CONCLUSION: In Colombia, Finland, and The Netherlands, countries with diverse epidemiologic and population distributions, switching from a PCV10 to PCV13 program would significantly reduce the burden of IPD in all three countries in as few as 5 years.

Comment on Gomez et. al. "Response to article by Wasserman et. al. (2018) 'Modelling the sustained use of the 13-valent pneumococcal conjugate vaccine compared to switching to the 10-valent vaccine in Mexico'".

In a recent Letter, Gomez et. al. provided a critique of our original analysis estimating the clinical and economic impact of switching from the 13-valent (PCV13) to the 10-valent (PCV10) pneumococcal conjugate vaccine in Mexico. This comment addresses Gomez et. al.'s comments with additional information and clarifies potential misinterpretations.

Cost-Effectiveness of the Pneumococcal Conjugate Vaccine (10- or 13-Valent) Versus No Vaccination for a National Immunization Program in Tunisia or Algeria.

INTRODUCTION: To evaluate the expected impact of the Algeria national immunization program (NIP) and potential impact for a Tunisia NIP, this study assessed the public health and economic value of vaccination, through a cost-effectiveness analysis, for a PCV13 or PCV10 NIP, compared with no vaccination. METHODS: A decision-analytic model was programmed in Microsoft Excel™ and adapted to evaluate the clinical and economic outcomes of PCV vaccination. Assuming a steady state, the model estimated invasive pneumococcal disease (IPD; bacteremia and meningitis), all-cause pneumonia (inpatient and outpatient), and all-cause otitis media cases as well as the associated costs from a payer perspective. The base case scenario assumed direct effects for both PCVs and indirect effects (against IPD) for PCV13 only. RESULTS: In Algeria, compared with no vaccination program, PCV13 would save 2177 lives and avoid nearly 349,000 cases of IPD, pneumonia, and AOM at a highly cost-effective value of $308 per QALY. In Tunisia, PCV13 would save 308 lives and avoid 1305 cases of IPD, 4833 cases of pneumonia, and 54,957 cases of AOM at a highly cost-effective value of $848 per QALY. PCV10 prevented 1224 deaths and 270,483 cases of disease in Algeria and prevented 172 deaths and 56,610 cases in Tunisia. PCV10 was cost-effective in both Algeria at $731/QALY and in Tunisia at $1366/QALY. CONCLUSION: The ongoing NIP in Algeria is projected to reduce the impact and economic toll of pneumococcal disease in Algeria. If an NIP were also introduced in Tunisia, a commensurate impact would be expected. PCV NIPs are highly cost-effective, highly impactful public health interventions. FUNDING: Pfizer.

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.

Modeling Possible Inclusion of Pneumococcal Conjugate Vaccine into the National Immunization Program for Infants in India.

BACKGROUND: India is home to up to 28 million infants born annually, and yet to a large extent these children do not benefit from the protection provided by a pneumococcal conjugate vaccine (PCV) immunization program. The Government of India, with support from Gavi, The Vaccine Alliance (in short, Gavi), has committed to a pilot implementation of PCV. There are few public health impact evaluations available for India, and equally limited epidemiologic data. OBJECTIVES: To estimate the potential impact of an infant pneumococcal vaccination program in India. METHODS: Using a well-established pneumococcal disease impact model parameterized with local data to the extent possible, we calculated the potential impact of introducing an infant PCV program in India. The model considered direct vaccine protection by PCV10 or PCV13, focusing on children younger than 5 years, while varying vaccine uptake according to the implementation method (i.e., state-level programs [Gavi funding] or a government-supported national immunization program [NIP]). RESULTS: With state-level PCV13 programs comprising 25% uptake across the country, approximately 1.9 million cases of pneumococcal disease and approximately 77,000 deaths could be prevented annually. An NIP with PCV13 could prevent approximately 7.6 million cases of pneumococcal disease and approximately 0.3 million pneumococcal deaths annually, compared with no vaccination, considering 100% vaccine uptake. These results are likely to have underestimated the additional potential benefits of herd effects in unvaccinated children and adults. CONCLUSIONS: Incorporation of PCV into an Indian vaccination program for infants is predicted to have a substantially positive health impact. Gavi funding of state-level programs is an important step toward achieving the full benefits of an NIP in India.

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.