Effect of PCV Dosing Schedules on Prevention of Pneumonia
Effect of PCV Dosing Schedules on Prevention of Pneumonia
This analysis found strong evidence of PCV benefit against both clinical and radiologically confirmed pneumonia in the age group targeted for vaccination using 2+1, 3+0 and 3+1 schedules. Data from several RCTs, including trials in low-income settings, strongly support use of 3 primary dose schedules with or without a booster (ie, 3+0 or 3+1) for prevention of pneumonia. A large number of observational studies support use of either 3 primary doses, with or without a booster, or 2 primary doses plus 1 booster (2+1), which demonstrates the benefits of these schedules for pneumonia prevention in a routine immunization setting. Overall, half (21 of 42) of the studies in our review provided evidence for significant reductions in 1 or more disease endpoints. The evidence for 1 schedule over another and the impact of PCV in preventing pneumococcal pneumonia and empyema were less clear, given the small number of studies and their conflicting findings.
Immunization with PCV is critical to provide protection against pneumonia in the first year of life. However, quantifying the differences in benefit between 2-dose and 3-dose primary immunization schedules against pneumonia was difficult as only 2 studies directly compared different schedules within the same study. Pelton et al. directly compared 2 versus 3 primary doses in an observational study of an immature immunization program and found that 3 primary doses were superior to 2 doses in preventing hospitalizations for clinical pneumonia before a booster dose, but only early in the vaccination program (presumably before the indirect effect matured). The other study, conducted among Australian Indigenous infants, also found that 3 primary doses were superior to 2 doses, but under the condition of almost no effect from receipt of 3 primary doses compared with receipt of 0 doses in preventing clinical pneumonia and an increased risk with receipt of 2 primary doses. Study investigators speculated that replacement of vaccine serotypes with either nonvaccine serotypes or other respiratory pathogens carried in the nasopharynx may have increased clinical pneumonias among infants. The remaining studies evaluating a single schedule compared with no vaccination showed evidence of impact on pneumonia burden using 2+1, 3+0 or 3+1 schedules; there were no discernible differences in the magnitude of that impact according to a specific dosing schedule. Findings from individual studies were not comparable with each other as the measured impact was dependent on a variety of study methods, case definitions and populations, which, due to the heterogeneity of the data, we were unable to control for in analysis. Despite this limitation, our findings support the use of PCV in effectively reducing disease burden and complement a recent systematic review that evaluated the subset of PCV studies making direct schedule comparisons; because of limited or no data meeting inclusion criteria, that review was unable to assess clinical outcomes regarding pneumonia.
In addition to the heterogeneity of study designs evaluating different PCV schedules, the nonspecificity of pneumonia endpoints and myriad case definitions complicated the ability to adequately summarize and interpret findings regarding impact of PCV schedules on pneumonia. Studies using more narrow and specific endpoints and case definitions, such as World Health Organization (WHO)–standardized definitions, likely provide a more accurate picture of PCV impact on disease specifically caused by pneumococcus. Studies that use a more generic endpoint, such as clinical pneumonia, are more prone to include cases caused by pathogens other than pneumococcus and mask any true impact. A few studies have assessed the impact of specificity of disease endpoints by retrospectively applying more specific case definitions and re-evaluating PCV impact. In each case, a higher efficacy was measured with increased specificity for the disease endpoint. However, capturing cases with a more specific case definition is not always appropriate or feasible given limited resources (ie, access to laboratory or clinical diagnostics, population access to care, limited surveillance area) and confounding factors (ie, high burden of underlying conditions such as malaria or HIV) in many studies evaluating implementation in routine settings. We found evidence of this in our review of case definitions; the most rigorous and specific case definitions were more often used in the setting of controlled trials while observational studies were more likely to use nonspecific case definitions. Case definitions ranged in specificity and inclusion criteria with some studies using International Classification of Diseases, 9th edition (ICD-9) or International Classification of Diseases, 10th edition (ICD-10) administrative database codes or clinician diagnosis, while others used WHO-standardized definitions or laboratory confirmation. This lack of specificity and standardization within case definitions may explain some of the variability in findings and the inability to interpret reductions in certain disease endpoints. Nevertheless, our review found sufficient evidence of PCV impact against pneumonia outcomes: 12/20 (60%) studies found significant reductions in clinical pneumonia, 6/11 (55%) radiologically confirmed pneumonia and 7/16 (44%) pneumococcal pneumonia. It is essential for future studies to consider more pneumococcal-specific and standardized case definitions to accurately and consistently measure the impact of PCV against pneumonia.
The studies included in this analysis represent a number of different settings and populations, which, while providing a breadth of data, also made it difficult to discern differences between schedules. Many data collected from settings of routine immunization focused on PCV7 and were from low disease burden, higher income countries, complicating the ability to extrapolate findings to other PCV products and to low- and middle-income countries, which often have higher rates of disease burden and more constrained resources. In addition, many populations in lower income countries have higher rates of underlying health conditions (eg, HIV or sickle cell disease) that can increase risk of developing pneumonia. We found only 6 studies that evaluated the impact of PCV in populations at higher risk for disease and magnitude of disease reduction varied greatly. Despite this limitation in geographical representation in settings of routine immunization, all RCTs evaluating 3+0 schedules were from low-income or lower-middle income countries and showed impact of PCV in these populations. As a greater number of countries have now introduced PCV into national immunization programs, ongoing studies in lower income settings and studies using various PCV products (PCV10 or PCV13) will contribute to additional evidence of impact.
Our review of the literature on impact of PCV dosing schedules found evidence of impact on varying pneumonia endpoints using 2+1, 3+0 and 3+1 schedules, although the preponderance of evidence informed 3+1 schedules, with fewer data available regarding 2+1 and 3+0 schedules. Our findings support recommendations by the Pan American Health Organization and WHO for using a 3-dose regimen, which can be given as either 3+0 or 2+1, and given a lack of evidence supporting 2+0 schedules, choosing a schedule that ensures high coverage with a third dose is essential. Furthermore, due to current data limitations and heterogeneity of the data, the optimal schedule in a given epidemiological setting for those 3 doses is dependent on a range of disease impact and programmatic considerations. As more countries make a decision to introduce PCV into national immunization programs, it will be essential for policy makers to consider programmatic and epidemiologic factors when making decisions regarding the ideal dosing schedule for their program. To ensure stakeholders are well-informed, more data are needed to evaluate PCV10 and PCV13 and the impact of these vaccines on pneumonia in developing countries. For all such studies, use of specific, standardized case definitions and evaluations that include direct schedule comparisons will greatly enhance the strength of evidence on which to formulate optimal dosing policies and achieve the greatest disease reductions for the doses administered.
Discussion
This analysis found strong evidence of PCV benefit against both clinical and radiologically confirmed pneumonia in the age group targeted for vaccination using 2+1, 3+0 and 3+1 schedules. Data from several RCTs, including trials in low-income settings, strongly support use of 3 primary dose schedules with or without a booster (ie, 3+0 or 3+1) for prevention of pneumonia. A large number of observational studies support use of either 3 primary doses, with or without a booster, or 2 primary doses plus 1 booster (2+1), which demonstrates the benefits of these schedules for pneumonia prevention in a routine immunization setting. Overall, half (21 of 42) of the studies in our review provided evidence for significant reductions in 1 or more disease endpoints. The evidence for 1 schedule over another and the impact of PCV in preventing pneumococcal pneumonia and empyema were less clear, given the small number of studies and their conflicting findings.
Immunization with PCV is critical to provide protection against pneumonia in the first year of life. However, quantifying the differences in benefit between 2-dose and 3-dose primary immunization schedules against pneumonia was difficult as only 2 studies directly compared different schedules within the same study. Pelton et al. directly compared 2 versus 3 primary doses in an observational study of an immature immunization program and found that 3 primary doses were superior to 2 doses in preventing hospitalizations for clinical pneumonia before a booster dose, but only early in the vaccination program (presumably before the indirect effect matured). The other study, conducted among Australian Indigenous infants, also found that 3 primary doses were superior to 2 doses, but under the condition of almost no effect from receipt of 3 primary doses compared with receipt of 0 doses in preventing clinical pneumonia and an increased risk with receipt of 2 primary doses. Study investigators speculated that replacement of vaccine serotypes with either nonvaccine serotypes or other respiratory pathogens carried in the nasopharynx may have increased clinical pneumonias among infants. The remaining studies evaluating a single schedule compared with no vaccination showed evidence of impact on pneumonia burden using 2+1, 3+0 or 3+1 schedules; there were no discernible differences in the magnitude of that impact according to a specific dosing schedule. Findings from individual studies were not comparable with each other as the measured impact was dependent on a variety of study methods, case definitions and populations, which, due to the heterogeneity of the data, we were unable to control for in analysis. Despite this limitation, our findings support the use of PCV in effectively reducing disease burden and complement a recent systematic review that evaluated the subset of PCV studies making direct schedule comparisons; because of limited or no data meeting inclusion criteria, that review was unable to assess clinical outcomes regarding pneumonia.
In addition to the heterogeneity of study designs evaluating different PCV schedules, the nonspecificity of pneumonia endpoints and myriad case definitions complicated the ability to adequately summarize and interpret findings regarding impact of PCV schedules on pneumonia. Studies using more narrow and specific endpoints and case definitions, such as World Health Organization (WHO)–standardized definitions, likely provide a more accurate picture of PCV impact on disease specifically caused by pneumococcus. Studies that use a more generic endpoint, such as clinical pneumonia, are more prone to include cases caused by pathogens other than pneumococcus and mask any true impact. A few studies have assessed the impact of specificity of disease endpoints by retrospectively applying more specific case definitions and re-evaluating PCV impact. In each case, a higher efficacy was measured with increased specificity for the disease endpoint. However, capturing cases with a more specific case definition is not always appropriate or feasible given limited resources (ie, access to laboratory or clinical diagnostics, population access to care, limited surveillance area) and confounding factors (ie, high burden of underlying conditions such as malaria or HIV) in many studies evaluating implementation in routine settings. We found evidence of this in our review of case definitions; the most rigorous and specific case definitions were more often used in the setting of controlled trials while observational studies were more likely to use nonspecific case definitions. Case definitions ranged in specificity and inclusion criteria with some studies using International Classification of Diseases, 9th edition (ICD-9) or International Classification of Diseases, 10th edition (ICD-10) administrative database codes or clinician diagnosis, while others used WHO-standardized definitions or laboratory confirmation. This lack of specificity and standardization within case definitions may explain some of the variability in findings and the inability to interpret reductions in certain disease endpoints. Nevertheless, our review found sufficient evidence of PCV impact against pneumonia outcomes: 12/20 (60%) studies found significant reductions in clinical pneumonia, 6/11 (55%) radiologically confirmed pneumonia and 7/16 (44%) pneumococcal pneumonia. It is essential for future studies to consider more pneumococcal-specific and standardized case definitions to accurately and consistently measure the impact of PCV against pneumonia.
The studies included in this analysis represent a number of different settings and populations, which, while providing a breadth of data, also made it difficult to discern differences between schedules. Many data collected from settings of routine immunization focused on PCV7 and were from low disease burden, higher income countries, complicating the ability to extrapolate findings to other PCV products and to low- and middle-income countries, which often have higher rates of disease burden and more constrained resources. In addition, many populations in lower income countries have higher rates of underlying health conditions (eg, HIV or sickle cell disease) that can increase risk of developing pneumonia. We found only 6 studies that evaluated the impact of PCV in populations at higher risk for disease and magnitude of disease reduction varied greatly. Despite this limitation in geographical representation in settings of routine immunization, all RCTs evaluating 3+0 schedules were from low-income or lower-middle income countries and showed impact of PCV in these populations. As a greater number of countries have now introduced PCV into national immunization programs, ongoing studies in lower income settings and studies using various PCV products (PCV10 or PCV13) will contribute to additional evidence of impact.
Our review of the literature on impact of PCV dosing schedules found evidence of impact on varying pneumonia endpoints using 2+1, 3+0 and 3+1 schedules, although the preponderance of evidence informed 3+1 schedules, with fewer data available regarding 2+1 and 3+0 schedules. Our findings support recommendations by the Pan American Health Organization and WHO for using a 3-dose regimen, which can be given as either 3+0 or 2+1, and given a lack of evidence supporting 2+0 schedules, choosing a schedule that ensures high coverage with a third dose is essential. Furthermore, due to current data limitations and heterogeneity of the data, the optimal schedule in a given epidemiological setting for those 3 doses is dependent on a range of disease impact and programmatic considerations. As more countries make a decision to introduce PCV into national immunization programs, it will be essential for policy makers to consider programmatic and epidemiologic factors when making decisions regarding the ideal dosing schedule for their program. To ensure stakeholders are well-informed, more data are needed to evaluate PCV10 and PCV13 and the impact of these vaccines on pneumonia in developing countries. For all such studies, use of specific, standardized case definitions and evaluations that include direct schedule comparisons will greatly enhance the strength of evidence on which to formulate optimal dosing policies and achieve the greatest disease reductions for the doses administered.
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