The bacterium Streptococcus pneumoniae (S. pneumoniae), also called pneumococcus, causes IPD including bacteremia and meningitis, CAP and AOM.1 Pneumonia has been estimated to cause approximately 12.8% of all deaths in children aged 1–59 months worldwide.2 Over 90 serotypes of S. pneumoniae have been identified, and approximately 62% of IPD are caused by the 10 most common serotypes.3
The World Health Organization (WHO) recommends the inclusion of PCV in national childhood immunization programs worldwide.1 Two higher-valent safe and effective PCVs are available, PHiD-CV (Synflorix, GSK) and 13-valent PCV (PCV-13, Prevenar 13, Pfizer) formulations. The 2 vaccines differ in the number of pneumococcal serotypes included (10 serotypes in PHiD-CV and 13 in PCV-13), polysaccharide concentration and carrier protein. Eight of the serotypes in PHiD-CV are conjugated to a protein D from H. influenzae4; in PCV-13 all serotypes are conjugated to a CRM197 carrier (Corynebacterium diphtheria cross-reactive material 197).5 Brazil introduced PHiD-CV in its national immunization program (NIP) in 2010, reducing hospitalizations of children for pneumonia by 23.3%–28.7% in 3 of the 5 cities studied after introduction.6 A recent study analyzing childhood pneumonia mortality data in Brazil between 1980 and 2014 identified large reductions after the introduction of PHiD-CV vaccination, particularly in municipalities with extreme childhood poverty and poor maternal education.7
According to the Pan-American Health Organization, the International Vaccine Access Center, and the WHO there is, at present, no evidence of a difference between PHiD-CV and PCV-13 in their net impact on overall disease burden.8–10 Both higher-valent PCVs have a substantial impact against pneumonia, vaccine-type IPD and carriage.10 PCV-13 may have additional benefits in settings where a significant burden of disease is attributable to serotype 19A, according to the WHO Strategic Advisory Group of Experts.10 A recent study from the SIREVA II Laboratory Surveillance Network has shown a possible increase of 19A-related IPD in Brazil after PHiD-CV introduction.11 However, a case control study and an indirect cohort analysis have reported effectiveness of 71%–82% for PHiD-CV against serotype 19A.12,13
The objectives of this study were to estimate the impact of PHiD-CV vaccination on the burden of pneumococcal disease in infants and children <5 years of age in Brazil 8 years post vaccine introduction using prevaccination registry data, to explore the extent of residual IPD with particular reference to serotype 19A, and to examine the potential effect of a switch to PCV-13.
Materials and Methods
Overall Reduction of Pneumococcal Disease Burden Post-PHiD-CV Introduction
We estimated the health and cost burden of IPD and CAP in infants and children <5 years of age in Brazil. The number of cases of IPD (hospitalized cases of meningitis and bacteremia) and CAP before PHiD-CV introduction was estimated using epidemiologic data from the National Unified Health System (Sistema Único de Saúde),14–16 as published elsewhere.17 The number of all-cause AOM cases before vaccine introduction was obtained from a published study from Brazil.18
The effect of the PHiD-CV vaccination program was simulated using data on vaccine effect from published studies conducted in Brazil and the Americas.8,12,13,19–21 Based on these studies, vaccine effect was estimated by applying a reduction of 70% for IPD,12,19 26% for CAP8,19,20 and 40% for AOM21 to the estimated prevaccination disease burden. To explore the potential impact of variations in the vaccine effect, a sensitivity analysis was conducted using upper and lower 95% confidence intervals (CIs) based on the same studies.
The direct medical cost of IPD, CAP and all-cause AOM as well as the cost of the PHiD-CV vaccination program and the health outcomes included in the analysis (reduction of cases of IPD, CAP and all-cause AOM) were estimated as previously described.17 Costs were adjusted for inflation using the Consumer Price Index for Brazil.22 All costs were expressed in 2017 US$. The efficiency of PHiD-CV vaccination was analyzed using the cost per case avoided, calculated from the incremental cost of vaccination compared with no vaccination and the number of cases averted by vaccination compared with no vaccination. The analysis was conducted from the perspective of the unified health system as the healthcare payer and included direct costs only.
Residual IPD Burden and Potential Impact of Switching to PCV-13 Vaccine
The overall residual IPD burden in Brazil was calculated as the difference between the estimated prevaccination disease burden and the reduction in the disease burden from the vaccine effect, irrespective of serotypes.
After PHiD-CV vaccination introduction in Brazil (2010), the prevalence of S. pneumoniae serotype 19A increased to an average of 21.1% (95% CI: 18.3%–24.1%) in the period 2012–2016.11 We used these data to estimate the number of residual IPD cases occurring in vaccinated individuals that were associated with serotype 19A. To explore the impact of variations in the prevalence of serotype 19A, we considered the upper and lower 95% CI for serotype 19A prevalence. In addition, to estimate the residual 19A IPD burden in vaccinated infants and children <5 years of age, the percentage of residual cases of IPD occurring in vaccinated individuals was estimated at 31.6%, based on data from a published study.13
The difference between the 2 vaccines in effectiveness against serotype 19A is unknown, so to simulate the effect of switching from PHiD-CV to PCV-13 we considered a range of scenarios for incremental vaccine effectiveness. Although PHiD-CV does not include serotype 19A, studies have reported vaccine effectiveness of 62%–82% against serotype 19A, reflecting cross-protection from serotype 19F.12,13,23 To explore the range of potential effects, we considered 3 scenarios for the incremental vaccine effectiveness for PCV-13 over PHiD-CV.12,13,23 The first scenario applied a 70% incremental reduction in serotype 19A IPD for PCV-13 compared with PHiD-CV, that is, the number of residual serotype 19A IPD cases with PCV-13 was 70% lower than with PHiD-CV. Two more realistic scenarios based on current evidence of cross-protection with PHiD-CV against serotype 19A (30% or 50% reduction in serotype 19A IPD for PCV-13 compared with PHiD-CV) were also analyzed. These vaccine effectiveness scenarios were applied to the residual burden of 19A-IPD cases in vaccinated individuals to estimate the potential number of IPD cases averted by using PCV-13 instead of PHiD-CV. Systematic reviews have shown no evidence for differences in the effects of the vaccines against pneumonia.8–10 We assumed that the vaccines would have an equal effect on CAP and, therefore, would not generate differences to be considered in the analysis. Potential differences in vaccine effect against all-cause AOM were not considered. We also assumed no difference between the vaccines for pneumococcal disease associated with serotype 3 and serotype 6A.
The direct medical cost savings resulting from this potential reduction in 19A-IPD cases were estimated using the same methods as previously described.17 The incremental cost of using PCV-13 in the vaccination program instead of PHiD-CV was estimated based on a vaccine price of US$12.85 per dose for PHiD-CV and US$14.50 per dose for PCV-13, obtained from the Pan-American Health Organization’s Revolving Fund 2019 prices.24 Vaccine delivery costs were assumed to be equal for both vaccines and were not included in the analysis.
The efficiency of a potential switch to PCV-13 to reduce the residual burden of serotype-19A-IPD was expressed as the incremental cost per IPD case avoided.
Overall Reduction of Pneumococcal Disease Burden Post-PHiD-CV Introduction
Figure 1A shows the estimated annual number of cases of IPD, CAP and all-cause AOM in infants and children <5 years of age in Brazil before and after the introduction of the PHiD-CV vaccination program. The estimated baseline economic burden of pneumococcal disease before PHiD-CV introduction and the annual remaining economic burden are shown for each outcome in Figure 1B.
Our results indicate that the PHiD-CV program averts more than 6000 IPD cases, more than 300,000 CAP cases and more than 600,000 all-cause AOM cases per year, and results in estimated cost savings of over US$84 million per year when all pneumococcal disease outcomes are considered (Table 1). Most of the cost savings are related to the reduction in CAP cases (Table 1).
The current annual cost of the PHiD-CV program is US$ 141,371,871. The incremental cost per case avoided for the current PHiD-CV vaccination program in Brazil, compared with prevaccination was US$22,232 for IPD, US$449 for CAP and US$211 for all-cause AOM.
Residual IPD Burden and Potential Impact of Switching to PCV-13 Vaccine
Figure 2 illustrates the annual burden of residual IPD cases in Brazil, calculated as previously described. The total number of residual IPD cases was estimated at 2725 per year in Brazil, comprising 451 cases of meningitis and 2275 cases of bacteremia. Published information for Brazil has indicated that 31.6% of residual cases occurred in vaccinated infants and children.13 Applying this value to our estimated number of residual IPD cases, corresponds to 861 residual IPD cases occurring in vaccinated infants and children per year (Figure 2).
After PHiD-CV vaccination introduction in Brazil (2010), the average prevalence of serotype 19A increased to 21.1% (95% CI: 18.3%–24.1%) between 2012–2016, in infants and children <5 years of age.11 Therefore, of the 861 residual IPD cases in vaccinated infants and children <5 years of age, we estimated that a mean of 181 cases (95% CI: 158–207) would be 19A-related IPD cases (Figure 2).
Some of these residual cases of 19A-related IPD could potentially be prevented by switching from PHiD-CV to PCV-13, if PCV-13 had higher effectiveness against serotype 19A than PHiD-CV. The difference between these 2 vaccines in effectiveness against serotype 19A is uncertain, so, to simulate the potential impact of such a vaccine switch, we considered a range of scenarios for incremental vaccine effectiveness. With incremental vaccine effectiveness of 70% (ie, a reduction of 70% more 19A-related IPD cases for PCV-13 compared with PHiD-CV), the potential mean annual reduction of IPD cases in infant and children <5 years of age would be 127 (95% CI: 110–145). With incremental vaccine effectiveness of 50%, the potential mean annual reduction of IPD cases would be 91 (95% CI: 79–104) and with incremental vaccine effectiveness of 30% the potential mean annual reduction of IPD cases would be 54 (95% CI: 47–62) in infants and children <5 years of age.
Replacing PHiD-CV with PCV-13 would result in an additional cost of US$ 18,152,808 per year. Figure 3 shows the estimated incremental cost per additional case of 19A-related IPD averted for each of the 3 scenarios on incremental vaccine effectiveness. In the scenario most favorable to PCV-13, with 70% incremental vaccine effectiveness compared with PHiD-CV, the incremental cost per case avoided ranged from US$125,192 to US$165,026 (Figure 3). In the more realistic scenarios with 30% or 50% incremental vaccine effectiveness, the incremental cost per case avoided would be higher, varying from US$174,546 to US$386,230 (Figure 3).
This study investigated the impact of the PHiD-CV vaccination program on the burden of pneumococcal disease in infants and children <5 years of age in Brazil, 8 years post-PHiD-CV vaccination. PHiD-CV vaccination was estimated to avert more than 6,000 IPD, 300,000 CAP and 600,000 all-cause AOM cases per year, with estimated savings in direct medical costs of over US$84 million per year when all pneumococcal disease outcomes were considered. Although IPD is the most severe outcome associated with pneumococcal disease and the vaccine contributes substantially to its reduction, IPD has a relatively low prevalence with a much smaller number of cases than CAP or all-cause AOM. As a result, IPD accounts for only a small proportion of the cost savings associated with the PHiD-CV vaccination program in Brazil, which has achieved most of its health and economic effects through the prevention of CAP (ambulatory and hospitalized cases) and all-cause AOM cases. This is consistent with reports from other countries; for example, in Finland, it was estimated that 95% of the reduction in disease episodes with PHiD-CV vaccination was related to mild upper respiratory disease, and that focusing only on severe invasive disease would grossly underestimate the health benefits of vaccination.25 Clinical trials of PHiD-CV have reported trends towards effectiveness against AOM related to non-typeable H. influenzae, although the studies were not powered to assess this outcome.26–28
Although the impact of the PHiD-CV vaccination program in Brazil is clearly substantial, there are still concerns over residual IPD, perhaps because the SIREVA II laboratory surveillance network11 is the only system regularly reporting information on IPD. Currently, the available interventions against pneumococcal disease cannot eliminate or eradicate all pneumococcal-related disease. Therefore, it is expected that some level of residual pneumococcal disease will remain, and the goal of the PCV in the NIP of Brazil is to control the burden of disease.
There is currently no evidence to determine whether there is a difference between the 2 vaccines in terms of their net impact on overall disease burden.8–10 Both vaccines have a substantial impact against IPD, CAP and all-cause AOM. According to the WHO Strategic Advisory Group of Experts, PCV-13 may have additional benefits in settings where serotype 19A disease is significant.10 To explore this issue, this study estimated the burden of residual 19A-related IPD in Brazil and the potential effect of switching from PHiD-CV to PCV-13. Although PHiD-CV does not contain serotype 19A, it has demonstrated effectiveness of 62%–82% against serotype 19A reflecting cross-protection from serotype 19F.12,13,23 The difference between the 2 higher-valent PCVs in vaccine effectiveness against serotype 19A is uncertain, and therefore, we used 3 scenarios to explore the range of potential effects of switching. The first scenario assumed that PCV-13 would reduce serotype 19A-related IPD cases by 70% more than PHiD-CV. This scenario would imply that the effect of PHiD-CV against serotype 19A was almost non-existent, which is not consistent with published studies.12,13,23 Two other scenarios used more realistic differences in incremental vaccine effectiveness (30% and 50%), based on subtracting the vaccine effectiveness for PHiD-CV from the vaccine effectiveness for PCV-13. Even using the most favorable scenario, switching to PCV-13 would avoid only a small proportion of the residual IPD cases because only a small number of residual cases of IPD are associated with 19A in vaccinated infants and children <5 years of age (estimated at 181 of the 2725 residual IPD cases per year). Using PCV-13 instead of PHiD-CV in the NIP would cost the government of Brazil over US$18 million per year in additional costs, or US$125,192 to US$386,230 per IPD case avoided. In contrast, the current PHiD-CV vaccination program is estimated to cost US$22,232 per IPD case avoided, compared with no vaccination. Our results indicate that there are too few residual cases of 19A-related IPD for switching to PCV-13 to be an efficient use of limited health resources for Brazil. Evaluating the impact of vaccines on overall disease is a more relevant approach for analyzing the public health benefits of PCVs than focusing narrowly on a single serotype.29 If additional healthcare budget is available, other interventions such as improving vaccine coverage or preventive interventions against other diseases may have potential to offer greater public health benefits than switching to PCV-13.
A strength of the present analysis is that it assesses the importance of serotype 19A IPD cases in the context of overall pneumococcal disease in the whole Brazilian population. The SIREVA II laboratory surveillance network11 has reported increases in the prevalence of serotype 19A since the introduction of PHiD-CV vaccination. Our analysis considers serotype 19A IPD from the broad perspective of controlling overall pneumococcal disease, instead of a narrow focus on pneumococcal serotypes, and evaluates the value of switching vaccines in this context. The analysis also has some limitations. We extrapolated data from published studies conducted in specific geographic areas and populations to the national population. Brazil is a large country with diverse geography and socioeconomic conditions, and such extrapolation is subject to uncertainties. We explored the potential impact of uncertainty by conducting a sensitivity analysis using the 95% CI values for serotype 19A prevalence and vaccine effect and by using 3 different estimates for the incremental effectiveness of PCV-13 over PHiD-CV against serotype 19A.
Less than one-third of residual IPD cases are estimated to occur in vaccinated infants and children <5 years of age. Most IPD cases occur in unvaccinated infants and children, indicating that improving vaccine coverage offers a greater opportunity than vaccine switching to reduce residual IPD cases in Brazil. In 2018, average coverage across the country was 83.15% with booster dose coverage of 73.45%.30 The lower coverage for the booster dose indicates that a large number of infants and children are not fully protected against pneumococcal disease, and this condition might even be worse in certain specific municipalities with below-average vaccine coverage. A recent study of childhood pneumonia mortality in Brazil reported that more substantial reductions occurred in less privileged municipalities after PHiD-CV introduction, suggesting that the benefits of vaccination may be particularly apparent in low-income areas.7
Healthcare resources saved due to the reduction of cases as a result of the vaccination program could be invested in other public health problems that have the potential to provide substantial health benefits in Brazil. These could include yellow fever vaccine,31 measles vaccine32 (Brazil is currently facing an outbreak of both diseases), interventions against syphilis (which is now epidemic in Brazil)33 and the campaign to control the Aedes aegypti mosquito (an important action to mitigate cases of Dengue, Chikungunya and Zika in Brazil).34 These interventions could provide opportunities for investment of health funds that may yield greater health benefits to the Brazilian population than switching PCVs. The results of the present analysis show that although IPD is the most severe manifestation of pneumococcal disease, its low prevalence means that it comprises a smaller part of the disease burden than CAP or all-cause AOM. Our findings underscore the importance of considering the total burden of pneumococcal disease, including but not limited to IPD.
The PHiD-CV vaccination program in Brazil has resulted in important reductions in pneumococcal disease and substantial cost savings, mainly attributed to reductions in CAP and all-cause AOM cases. Residual 19A-IPD cases reported are limited, and substituting PCV-13 for PHiD-CV would not be an efficient use of healthcare resources due to the higher costs of PCV-13 introduction. Increasing vaccine coverage or investment in other health interventions could offer more efficient ways of improving the health of the Brazilian population (Figure, Supplemental Digital Content 1, http://links.lww.com/INF/D592).
The authors would like to thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination. Pierre-Paul Prevot coordinated publication development and editorial support. Carole Nadin (Fleetwith Ltd, on behalf of GSK) provided medical writing assistance. Synflorix is a trademark of the GSK group of companies. Prevenar 13 is a trademark of Pfizer Inc. All authors participated in the design or implementation or analysis, and interpretation of the study. All authors had full access to the data and participated in the development of the manuscript, revised it critically for important intellectual content, approved the final version before submission, and agreed to be accountable for all aspects of the work.
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